Effects of preoperative and postoperative carbohydrate loading on gastrointestinal function and stress-induced inflammation after radical prostatectomy

Background: Early postoperative oral clear liquid diet has been shown to enhance postoperative recovery. However, the standard strategy for this diet has not been established. The authors’ aim was to investigate the combined effect of preoperative and early postoperative carbohydrate loading on postoperative stress and gastrointestinal function of patients by standardizing the starting time, type, volume, and concentration of carbohydrate drinks. Materials and methods: Fifty-three patients undergoing radical prostatectomy were randomly assigned to two groups. Both groups received a carbohydrate loading of 400 ml (12.5%) overnight and 2 h before surgery. The intervention group (n=29) started a 400 ml (12.5%) carbohydrate loading 6 h after surgery and consumed it within 24 h, while the control group (n=32) drank water. The primary outcomes–postoperative fasting blood glucose, fasting insulin, C-reactive protein (CRP), interleukin-6 levels, and gastrointestinal function–were recorded. Secondary outcomes included subjective comfort assessment, the first postoperative intake of semi-fluid food time, and drainage volume. Results: Compared with the control group, the intervention group had lower CRP levels on postoperative day 1 (POD1)/POD2 and less drainage volume on POD1. The intervention group also experienced shorter times to the first postoperative flatus and the first consumption of semi-fluid foods; their 72-h postoperative protein intake was higher than that of the control group. Conclusion: The results suggest that combined preoperative and postoperative carbohydrate loading can alleviate stress-induced inflammation and promote the recovery of postoperative gastrointestinal function.


Introduction
Patients residing in hospitals often experience stress due to their illnesses, particularly those undergoing surgery [1] .The postoperative stress response, triggered by surgical procedures, can elevate fasting plasma glucose (FPG) levels, induce insulin resistance (IR), and lead to stress-induced inflammatory reactions and postoperative ileus (POI) [2][3][4] .Recovery from POI, characterized by the ability to tolerate a solid diet and the presence of flatus or bowel motion [5] , is a primary discharge criterion following various surgical procedures [5,6] .Stress reactions not only diminish patients' subjective comfort but also increase complication rates, prolong the length of stay (LOS), and increases healthcare costs [7] .To expedite post-surgical recovery, the widespread introduction of enhanced recovery after surgery (ERAS), which includes multimodal interventions, has been implemented [8] .Karimian et al. [7] and Lillemoe et al. [9] suggest that minimally invasive surgery and preoperative carbohydrate loading can help maintain insulin sensitivity.Nevertheless, the clinical issue of

HIGHLIGHTS
• All patients in the research were managed with strict enhanced recovery after surgery protocol.• The timing, volume, type, and concentration of clear liquids administered postoperatively are standardized.• The levels of stress-induced inflammation are decreased, and the recovery of postoperative gastrointestinal function is improved.
poor gastrointestinal motility recovery persists.POI delays the resumption of oral nutrition intake, which is essential for wound healing and immune function, and is associated with an ~15% increase (about $8182) in hospital costs [10] .For example, after radical prostatectomy (RP), 34.2% of patients with an LOS greater than 2 days were hospitalized for gastrointestinal reasons, 38.0% of all 30-day readmissions were due to gastrointestinal issues, and 20.0% of all 30-day mortalities were related to gastrointestinal causes [11] .Reduced oral intake has been identified as a contributing factor to POI [12] .Moreover, elevated stressinduced inflammation levels may exacerbate POI [13] .Both interleukin-6 (IL-6) and C-reactive protein (CRP) are commonly used to assess the presence and severity of low-grade inflammation, as they are universally recognized inflammatory biomarkers [14] .A high IL-6 level on the first postoperative day is associated with a threefold increased risk of postoperative complications and a longer hospital stay [15] .After minimally invasive surgery, patients with complications exhibit a 1.4-fold increase in CRP levels at 24 h postoperatively and a 1.6-fold increase at 72 h postoperatively compared to those without complications [16] .Preoperative carbohydrate loading is a crucial strategy to mitigate surgical stress [17] , and the literature on its initiation timing and volume is well-established [18][19][20] .However, studies on early postoperative clear liquids are comparatively sparse.While previous research has verified that early postoperative clear fluids can facilitate gastrointestinal function recovery [21,22] , these studies have not provided explicit recommendations regarding the initiation timing, type, and concentration of postoperative oral clear liquids.Moreover, the role of postoperative oral clear liquids in alleviating stress-induced inflammation remains uncertain.This study aimed to standardize the start time, type, and concentration of postoperative clear liquids in prostate cancer (PCa) patients undergoing laparoscopic radical prostatectomy (LRP) and roboticassisted radical prostatectomy (RARP) to assess the restoration of stress-induced gastrointestinal motility and inflammation.
PCa is the second most frequent cancer globally and the fifth leading cause of cancer death among men [23] .Currently, the primary surgical methods for PCa are LRP and RARP [24] .Compared with open procedures, minimally invasive surgeries offer benefits such as less intraoperative bleeding, fewer operative adverse events, and earlier hospital discharge [25] .However, even with minimally invasive approaches, the increased intra-abdominal pressure associated with pneumoperitoneum significantly impairs splanchnic perfusion, elevates oxidative stress in the body, and compromises the gastrointestinal barrier [26] .Patients often exhibit varying degrees of postoperative stress and clinical symptoms, including increased FPG, bloating, and nausea.In our clinical practice, we observed that administering early oral clear fluids rich in carbohydrates (such as porridge soup made with rice or millet) 6 h postoperatively can enhance subjective comfort in PCa patients and expedite the time to postoperative flatus.
Therefore, this randomized controlled trial (RCT) aimed to evaluate the impact of a combined preoperative and early postoperative oral dose of 400 ml of 12.5% carbohydrates on postoperative stress and the recovery of gastrointestinal function.

Materials and methods
The research was registered at https://www.chictr.org.cn/with the unique identifying number ChiCTR2200065539.This research paper is reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT-10) guidelines [27] .

Study design
This single-centre, two-group, observer-blinded RCT was conducted from August 2022 to October 2023 in a hospital setting.Non-diabetic PCa patients aged 55-90, scheduled for elective LRP and RARP, and who provided written informed consent were eligible for enrolment.The exclusion criteria included diabetes, a BMI greater than or equal to 35 kg/m 2 , an inability to perform scale evaluations, and a history of total gastric resection.

Sample size estimation
Based on a preliminary survey, the time to first flatus after surgery was 28.53 8.94 hours in the intervention group.We hypothesized that postoperative carbohydrate loading could reduce this time interval by 12 h, a notion supported by a pilot trial involving 22 individuals in the control group and 19 in the intervention group.To achieve 90% power while accounting for a 20% dropout rate, we aimed to enrol 58 patients, with 29 in each group.We conducted the sample size calculation using https://clincalc.com/Stats/SampleSize.aspx, following the methodology of Gómez, F et al. [28] .

Ethical approval
The study protocol received approval from the Second Hospital of Dalian Medical University Ethics Committee, with the ethical approval number 2022/092.

Randomization and blinding
Random numbers were generated using SPSS 25.0 (IBM Corp.) at a 1:1 ratio.These numbers were then sealed in sequentially numbered, opaque envelopes until an investigator allocated groups and managed preoperative routines for the enroled patients.A separate investigator administered the postoperative intervention according to the assigned group allocations.Surgeons treated the patients, who were subsequently followed up by an independent observer.To maintain blinding, drinks were prepared in identically shaped and appearing bottles.However, the distinct tastes of carbohydrates and water meant that patients were not blinded.Additionally, patients were placed in different wards or at different times to prevent communication among them.All other researchers and surgeons remained blinded throughout the study.

Perioperative intervention
All patients abstained from solid food starting at 22:00 the night before surgery, although clear liquids were permitted.They were allowed a 400 ml drink with 12.5% carbohydrate (osmotic pressure 290 mmol/l; providing 213 kJ of energy, 12.5 g of carbohydrate, 50 mg of sodium, 66.7 mg of potassium, 63 mg of phosphorus, and 65 mg of chlorine per 100 ml) both overnight and 2-3 h prior to the surgery.
All patients began an oral clear liquid diet 6 hours after surgery.Those in the intervention group with a surgery end time before 4 pm on the day of surgery received a 200 ml 12.5% carbohydrate drink 6 h post-surgery and completed it before the early morning of POD1.The first postoperative fasting blood sample was collected in the early morning of POD1.After consuming an additional 200 ml of the 12.5% carbohydrate drink on POD1, the second fasting blood sample was collected in the early morning of POD3.Patients with a surgery end time after 4 pm faced challenges initiating an oral clear liquid diet on the day of surgery.These patients started a 400 ml 12.5% carbohydrate drink on the morning of POD1 and finished it that day.Their first and second postoperative fasting blood samples were collected in the early mornings of POD2 and POD4, respectively.The control group followed the same management procedures as the intervention group, except they received water instead of carbohydrate drinks post-surgery (Fig. 1).Discharge criteria included the ability to consume semi-fluid or soft food orally, manage pain with or without oral analgesics, walk unassisted, and present no further risk of complications [29] .

Indicators collection
Baseline data consisted of variables that could affect outcomes.The Gleason score was classified according to Parker et al. [30] .Tumour stage was defined as the pathological stage and classified according to the NCCN Guidelines Version 4.2022 Prostate Cancer [31] .Subjective comfort was evaluated using the visual analogue scale (VAS), ranging from 0 to 10, with 0 indicating no discomfort and 10 indicating the most severe discomfort.
Pre-albumin and haemoglobin levels were measured upon admission and on POD1 , while albumin was measured on admission, POD1, and POD3.CRP, IL-6, FPG, and fasting insulin (FIns) were measured two hours before surgery, as well as on POD1/POD2 and POD3/POD4.The times of first flatus and  first semi-fluid food intake after surgery were recorded.Protein and calorie intake at lunch on POD3/POD4 were observed.LOS, postoperative LOS, complications, hospitalization costs, drainage volume, and duration were also recorded.The use of lactulose, glycerol enema, and artificial anus dilatation after surgery was recorded.Subjective comfort was evaluated using VAS at 4 pm on the day before the scheduled surgery and 24 hours postsurgery.According to Ali Abdelhamid et al. [32] , VAS measures the severity of hunger, abdominal distension, nausea, and thirst.Tewari et al. [33] and Sugi et al. [34] .noted that postoperative complications, such as ileus, anastomotic leakage, deep vein thrombosis, and wound infections, were counted.
The primary outcomes included were IR relative indicators (HOMA-IR, HOMA-β, HOMA-%S), stress-induced inflammation, the time to first flatus, and energy and protein intake at lunch on POD3/POD4.Secondary outcomes encompassed the VAS, time to first postoperative semi-fluid food intake, use of promotility agents, postoperative nutritional biochemical markers (albumin, pre-albumin, and haemoglobin), LOS, postoperative LOS, drainage volume from POD1-3, and postoperative complications.

Statistical methods
The Statistical Package for SPSS 25.0 (IBM Corp.) was used for the analyses.Statistical significance was set at two-sided P values less than 0.05.Credible intervals for the parameters were calculated at 95%.For normally distributed data, differences between groups were tested using a two-tailed Student's t-test or ANOVA, while the Wilcoxon test was applied to data with non-normal distributions.Categorical data analysis was conducted using Fisher's exact test or the χ 2 test.

Results
A total of 61 of the 67 patients were enroled, including 29 patients in the intervention group and 32 in the control group (Fig. 2).

Patient characteristics
Baseline characteristics of the two groups are presented (Table 1).No significant differences were found in the baseline data between the two groups, with the exception of 6 m walking speed (P > 0.05, Table 1).All patients were diagnosed with adenocarcinoma.

Insulin resistance
The study's results regarding FPG, Flns, and IR-related indicators (HOMA-IR, HOMA-β, and HOMA-%S) are presented in Table 2.No significant differences were observed in the levels of Flns, HOMA-IR, and HOMA-%S between the two groups at pre 2 h, POD 1 / POD 2 and POD 3 / POD 4 (P > 0.05, Table 2).
Postoperative IR was evident in both groups.FPG levels at pre 2 h and POD 3/POD 4 were lower in the control group than in the intervention group (P < 0.05, Table 2).No significant differences were detected in 2 h the numerical variation of FPG, Flns, and IRrelated indicators between the two groups when compared with pre 2 h (P > 0.05, Table 2).

Stress-induced inflammation levels
CRP levels peaked on POD 3, while IL-6 levels peaked on POD 1.At Pre 2 h, there were no significant differences in stress-induced inflammation levels (CRP, IL-6) between the two groups.
Intervention group exhibited lower CRP levels than the control group on POD 1 and POD 2 (P < 0.05, Table 3).IL-6 levels did not differ significantly between the groups on POD 1 and POD 2 (P > 0.05, Table 3).No significant differences were observed between the groups on POD 3 and POD 4 (P > 0.05, Table 3).The numerical variations in CRP and IL-6 from pre 2h did not show significant differences in either group (P > 0.05, Table 3).

Nutritional indicators
The albumin and pre-albumin levels did not differ significantly between the two groups at admission, or on POD 1 and POD 3 (P > 0.05, Table 4).

Gastrointestinal function
The intervention group experienced shorter times to first postoperative flatus and to first postoperative semi-fluid food intake than the control group.Additionally, the intervention group 's protein intake at 72 h postoperatively was greater than that of the control group (P < 0.05, Table 5).However, there were no significant differences in energy intake at 72 h postoperatively between the two groups.Six patients in the control group and three in the intervention group required a glycerine enema; two patients in the control group and one in the intervention group received lactulose; and one patient from each group underwent artificial anal dilatation (P > 0.05, Table 5).

Other indicators
The postoperative 24-h VAS scores, which include measures of starvation, abdominal distention, nausea, and thirst, showed no significant differences between the control and intervention groups, with incidences of 6.2%, 21.9%, 9.4%, and 9.4% in the control group and 6.9%, 37.9%, 3.4%, and 3.4% in the intervention group, respectively (P > 0.05, Table 6).The total scores were 48 for the control group and 33 for the intervention group.There were no instances of intraoperative reflux aspiration in the study.The drainage volume in the intervention group on POD1 was lower than that in the control group (P < 0.05, Table 7).
There were no significant differences in the number of complications, LOS, LOS after surgery, or postoperative costs between the two groups (P > 0.05, Tables 7 and 8).

Discussion
This research, following a single-centre, two-group, observerblinded RCT, found that combining preoperative and postoperative carbohydrate loading contributes to improved outcomes.The timing, volume, type, and concentration of clear liquids administered postoperatively were standardized in this study.Compared with the control group, the intervention group exhibited lower postoperative CRP levels and enhanced recovery of gastrointestinal function.
In the past, patients commonly fasted for several days postsurgery until flatus [35] , while current guidelines for perioperative care in elective rectal/pelvic surgery recommend an oral ad-libitum diet 4 h after surgery [36] .The European Society of Parenteral and Enteral Nutrition surgical guidelines now advise that most postoperative patients should consume clear liquids within hours after surgery [37] .Extensive research has shown that early oral feeding post-operation can improve gastrointestinal function in patients who have undergone colorectal surgery, without adverse effects [38][39][40][41][42] .Yet, the type, volume, and concentration of oral fluids have not been fully standardized.Previous studies provided 500 ml or 30 ml/h of oral "restricted fluid" or "liquid diet" on POD 1 for colonic surgery patients without specifying the type and concentration [21,22,43] .A randomized controlled trial examined the effects of 450 ml of oral coffee after hysterectomy and bilateral salpingectomy 6 h into POI recovery [44] .These interventions all supported gastrointestinal function recovery.Therefore, our study standardized fluid type, volume, concentration, and initiation time to investigate their potential benefits in promoting gastrointestinal function recovery.The intervention group showed a reduced time to first flatus and time to first semi-fluid food consumption, as well as an increase in 72-h postoperative protein intake, aligning with the results of similar literature mentioned above.Thus, combining pre-and postoperative carbohydrate loading aids in POI recovery.However, the underlying mechanism remains unclear.Post-surgery stressinduced inflammation increases macrophage expression within gastrointestinal endothelial cells, inhibiting gastrointestinal peristalsis [13] .Consequently, reducing stress-induced inflammation may expedite the recovery of gastrointestinal function.
The stress-induced inflammatory response is triggered by tissue damage from surgery [45] .Key cytokines involved in this inflammation include IL-1b, IL-17, tumour necrosis factor alpha (TNF-a), and IL-6.These cytokines recruit neutrophils and monocytes, further amplifying the inflammatory response.IL-6 also stimulates CRP and other acute phase protein production in the liver [14] .A  high IL-6 level on the first postoperative day is associated with a threefold increased risk of postoperative complications and a longer LOS [15] .CRP may serve as a useful biomarker for diagnosing postoperative infection [46] .In our study, CRP levels at POD1/POD2 were lower in the intervention group than in the control group.Research on the impact of postoperative standardized clear fluids on stress-induced inflammation is scarce.Thus, we compared our findings with other similar studies.Zhang et al. [20] demonstrated that preoperative carbohydrate loading could reduce postoperative stress reactions compared to a fasting group.Sun et al. [47] explored the effects of early oral fluids (EOF) on patients undergoing minimally invasive esophagectomy and found that this approach could decrease stress-induced inflammation levels.However, the EOF strategy lacked standardization.We precisely defined the volume, type, and concentration of postoperative clear liquids.Our results indicated that combining preoperative and postoperative carbohydrate loading could mitigate stress-induced inflammation levels.There was no statistical difference in the volume of fluids consumed during the first postoperative fasting blood collections between the two groups.This suggests that the lower CRP levels in the intervention group at POD 1/POD 2 were due to carbohydrate loading rather than fluid volume.
Although CRP levels on POD 1/POD 2 were reduced in the intervention group, CRP and IL-6 remained higher than normal in both groups, indicating that inflammatory factors may inhibit insulin signalling [48,49] .Concurrently, postoperative carbohydrate loading could exacerbate stress hyperglycaemia, while gastrointestinal issues such as abdominal and pelvic abdominal distension have long been a concern for clinicians.Thus, safety, subjective comfort, and the timing of postoperative carbohydrate loading should be prioritized.Tools such as HOMA-β, which assesses pancreatic beta cell function, HOMA-%S, which assesses insulin sensitivity, and HOMA-IR, which assesses the degree of IR, are instrumental in evaluating IR.HOMA-%β values <100 indicate a deficiency in insulin secretion; a HOMA-%S of 100% is considered normal; and a HOMA-IR greater than 1 indicates IR [50,51] .However, β-cell function cannot be interpreted without a measure of insulin sensitivity; thus, HOMA-%S should always accompany HOMA-β [51] .In our study, postoperative FPG, Flns, HOMA-IR, HOMA-β, and HOMA-%S showed no significant differences between the two groups.Although FPG was higher in the intervention group than in the control group on POD3/POD4, it remained within the normal range.Both groups exhibited similar levels of Flns, HOMA-IR, HOMA-% β, and HOMA-%S, suggesting that postoperative oral carbohydrate administration is safe for glucose metabolism.Additionally, we found that other indicators also support the safety of combining preoperative and postoperative carbohydrate loading for recovery after surgery.
The number of instances of hunger, abdominal distention, nausea, thirst, and the total score were not statistically different in the postoperative VAS.The intervention group had four more patients with abdominal distention than the control group, and their total score was three points higher.Lu et al. [52] observed that patients undergoing radical total gastrectomy and given a clear liquid diet on   POD 1 had a slightly higher rate of abdominal distension, though the difference was not statistically significant.Our study confirms this finding.Previously, it was commonly feared that consuming a high-glucose drink early in the postoperative period would lead to abdominal distension.However, current data do not support the notion that this type of feeding causes widespread abdominal distension.This may be attributed to our provision of a multi-carbohydrate drink containing maltodextrin, glucose, and fructose.Multi-carbohydrate intake, as opposed to single carbohydrate consumption, results in fewer carbohydrates remaining in the intestine, potentially reducing osmotic shifts and malabsorption [53] .Studies assessing gastrointestinal discomfort during exercise have corroborated this [54] .This could partially explain the lack of significant abdominal distension in the intervention group.Except for abdominal distension, all other VAS indicators appeared to trend more favourably in the intervention group.Furthermore, we observed no differences in postoperative complications, LOS, or hospitalization costs between the two groups.Therefore, the intervention method is deemed safe and feasible.The strengths of this study lie in: (1) a strict recruitment protocol and ERAS process management; (2) standardization of the carbohydrate drink; (3) provision of ideas for clinical practice in future research related to postoperative carbohydrate loading.The limitations of this study are: (1) its single-centre trial nature; (2) the inability to conduct double-blind clinical trials, as it was impossible to blind patients to their assigned group; (3) and the measurement of relatively few laboratory indicators.The study requires further improvement.Future research should consider increasing the number of gastrointestinal surgery patients, incorporating nutritional and stress-induced inflammation indicators, employing a randomized multicenter double-blind design, and including a larger sample size.

Conclusion
In conclusion, combining preoperative and postoperative carbohydrate loading exhibits an excellent safety profile in minimally invasive surgery.This intervention can alleviate stress-induced inflammation postoperatively and enhance the recovery of gastrointestinal function.

Table 3
Stress-induced inflammation levels in the two groups (M (range)).

Table 4
Nutritional indicators in the two groups (mean ± SD/M (range)).

Table 5
Gastrointestinal function in the two groups.
M, median; VAS, visual analogue scale.P < 0.05 indicates the statistical difference.

Table 7
Drainage volume and complications.

Table 8
LOS and hospitalization cost [Mean ± SD / M (range)]., length of stay; M, median.P < 0.05 indicates the statistical difference. LOS