Effect of glucose-insulin-potassium on lactate levels at the end of surgery in patients undergoing cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy: study protocol for a randomized controlled trial

Abstract

Introduction

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has been established as an effective treatment for peritoneal cancer (PC). However, this kind of combination therapy is associated with a high lactate level. Moreover, studies have suggested that the rate of complications early after surgery directly increased with elevated lactate levels. Glucose-insulin-potassium (GIP), a potent cardioprotective intervention, has been demonstrated to adjust blood glucose (BG) levels and reduce lactate levels. However, the insulin-glucose ratio should be adjusted according to the surgery performed. Here, we aimed to evaluate the advantages of using modified GIP during CRS/HIPEC to reduce the lactate level at the end of surgery and further reduce the incidence of early postoperative complications.

Methods and analysis

The modified GIP versus conventional management during surgery study is a single-center, randomized, single-blinded outcome assessment clinical trial of 80 patients with PC who are between 18 and 64 years old and undergoing CRS/HIPEC. Participants will be randomly allocated to receive modified GIP or conventional treatment (1:1). The primary outcome will be the plasma lactate level at the end of surgery. The secondary outcomes will include the highest levels and fluctuation ranges of lactate and BG during surgery, extubation time, APACHE-II score 24 h after surgery, postoperative defecation and exhaust time, postoperative lactate clearance time, postoperative liver and kidney function, incidence of complications within 7 days after surgery, length of intensive care unit stay (LIS), length of hospital stay (LHS), and total cost of hospitalization.

Ethics and dissemination

The trial protocol was approved by the Scientific Research Ethics Committee of Beijing Shijitan Hospital Affiliated with Capital Medical University, approval number sjtky11-1x-2022(118). The results will be published in international peer-reviewed journals.

Trial registration

ChiCTR2200057258. Registered on March 5, 2022.

Strengths and limitations of this study

►Applied the GIP to CRS/HIPEC, to explore its function on glucose and lactate levels.

►Recording lactate level and the lactate clearance time during and early after CRS/HIPEC.

►This is a single-center trial, which may limit the generalization of conclusions; consequently, multi-center clinical studies with a larger sample size will be required.

►Patients with diabetes or plasma glucose control which is not ideal before surgery will be excluded during this study.

Background

Peritoneal cancer (PC) refers to a class of malignant tumors occurring and (or) developing on the peritoneum, including primary and secondary; the former is a typical representative of primary peritoneal carcinoma and malignant peritoneal mesothelioma; the latter is a typical representative of the peritoneal metastasis cancer formed by various tumors [1]. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), which was developed in the last decade as a therapeutic option, has been suggested to have a unique efficacy in the prevention and treatment of peritoneal implant metastasis in abdominal malignant tumors such as gastric cancer, colorectal cancer, ovarian cancer, peritoneal pseudomyxoma, and intraperitoneal malignancy [2–6]. For HIPEC, the perfusion solution, temperature, time, circulating flow rate, and other parameters are set as follows: (1) the perfusion solution is a mixture of normal saline and chemotherapy drugs, the general dosage of normal saline is 3000 to 5000 ml, the amount of perfusion fluid is based on the principle of abdominal filling and smooth circulation, chemotherapeutic drugs select sensitive drugs based on the primary tumor, and dose refers to intravenous chemotherapy dose; (2) the treatment temperature is set to 43 °C; (3) the treatment time ranges from 60 to 90 min, select treatment times according on different drugs, most of the drugs were at 60 min, and at multiple HIPECs, each interval was 24 h; (4) the circulating flow rate is generally 300 ~ 600 ml/min [7]. Otherwise, the diluted solution of oxaliplatin and domestic carboplatin with normal saline will cause unstable efficacy. The perfusion solution of these two drugs requires 5% glucose solution, which can increase blood sugar during surgery, and should be used for corresponding treatment, especially for patients with diabetes [7]. Compared with systemic chemotherapy alone, the median survival can be improved to 16–24 months, with a 5-year survival rate of 30–45% [8, 9]. Consistently, the results of an open, nonrandomized study of 50 patients demonstrated that the 1-, 3-, and 5-year post-surgery survival rates were 89%, 69%, and 69%, respectively [10]. Therefore, the number of patients receiving CRS/HIPEC has increased recently [11]. However, there is still a high incidence of complications that challenge perioperative period management because of high-temperature chemotherapy drugs, advanced tumors, long operation time (an average of 8–10 h), and significant fluid and blood loss [12–14]. A comprehensive review of the reported results from over 20 CRS/HIPEC centers since 2003 shows complication morbidity rates of 0–50% and mortality rates fluctuating between 0 and 6% [15]. The length of hospital stay (LHS) ranges from 8 to 22 days [16].

Due to the special operative procedure and the patient’s condition, we found an abnormal increase in lactate levels during and early after surgery. It should be clarified that lactate itself is non-toxic, and it is not the increase in lactate itself that causes death in critically ill patients, but a signal of metabolic abnormalities in critically ill patients. The serum lactate concentration is an important indicator in clinical treatment that reflects the degree of ischemia and hypoxia in tissues and organs [17], and lactate is produced by most tissues in the human body. Under normal conditions, lactate is quickly cleared by the liver and kidneys. Pyruvate is oxidized to acetyl-CoA via pyruvate dehydrogenase and enters the Krebs cycle. Therefore, lactate production is avoided [12]. However, under anaerobic conditions, pyruvate dehydrogenase activity is inhibited, and lactate is the final product of glycolysis, becoming a substrate for gluconeogenesis in the Cori cycle. Therefore, lactate production is increased under hypoperfusion or stress conditions, causing an increase in glycolysis [18–20]. According to Spiliotis et al., postoperative lactacidemia is an independent predictor of morbidity and mortality for patients undergoing CRS and HIPEC [21]. Marta et al. also observed that a lactate level of 2.5 mmol/L early after CRS/HIPEC marks the threshold for an increased risk of complications among patients in intensive care units (ICUs) [22]. In a study focused on patients undergoing major abdominal surgery, those with elevated lactate levels had a significantly higher complication rate [23]. Therefore, studies have employed lactate levels as a measure of tissue hypoperfusion and used lactate clearance as a resuscitation guide [24].

Laboratory studies have shown glucose-insulin-potassium (GIP) to be a potent cardioprotective intervention; GIP could also adjust blood glucose (BG), reduce the level of lactate, and decrease the incidence rates of prolonged ICU stay and extended ventilator support [25]. Sustained GIP infusion during ischemia could enhance glycolysis and increase the production of glycolytic ATP, so total cellular ATP can be maintained at a safe level. As the oxidation of glucose as a substrate is more efficient than fatty acids, GIP improves oxygen use efficiency during ischemia by stimulating glucose metabolism [26–29]. Furthermore, the insulin in GIP stimulates intracellular signaling pathways that promote cell survival and inhibit adverse events related to apoptosis [30]. However, most studies on GIP have been limited to the field of cardiac surgery, and studies have shown different effects across different surgeries [31]. Studies of patients undergoing coronary artery bypass graft surgery have shown that GIP tends to decrease atrial fibrillation (AF), ventricular fibrillation (VF), and mortality. Additionally, among patients undergoing cardiac-related surgery, it can also significantly decrease LIS, although it is ineffective in terms of reducing stroke, infections, and renal disorders and does not have a beneficial influence on the length of ventilation time or LHS [32–34]. However, GIP therapy in patients undergoing percutaneous coronary intervention might be associated with more complications (hypoglycemia, hyperglycemia, hyperkalemia, and phlebitis) than protective effects [35, 36]. Here, we will focus on the effect of intravenously infused GIP during surgery on the regulation of lactate levels to further explore the potential value of GIP in CRS/HIPEC surgery based on its advanced application in cardiac surgery. In this study, modified GIP will be applied, in which the ratio of insulin to glucose is 1:2.5, while in most conventional GIPs, the ratio is located in the range of 1:4 to 1:6.

On the basis of the existing literature and the characteristics of CRS/HIPEC, our working hypothesis is that compared with traditional formulas, intravenous infusion of modified GIP during surgery could effectively reduce the lactate acid levels at the end of the surgery, decrease the incidence of complications after surgery, enhance recovery after surgery, and avoid increasing the incidence of adverse reactions.

Method

Trial design

The trial will be conducted at Beijing Shijitan Hospital, Capital Medical University, in Beijing, China, where approximately two CRS/HIPEC procedures are performed per day, and there is a specialized ward for providing systematic postoperative management, which makes it easy to follow up after surgery. The study started recruiting patients in April 2023 and will continue for 6 months. This study is an investigator-initiated, parallel-group, single-blinded, comparative randomized clinical trial in which patients being hospitalized for CRS/HIPEC surgery are allocated in a 1:1 ratio to a modified GIP group (GIP) or a conventional group (CV). The trial design is summarized in Fig. 1. We report the study protocol according to the Standard Protocol Items: Recommendations for Interventional Trials statement [37].

Fig. 1.

Study flow diagram of GIP versus CV trial. BG, blood glucose; LIS, length of intensive care unit stay; LHS, length of hospital stay

Objectives

The purpose of this study was to verify whether modified GIP could reduce the lactate acid levels of patients undergoing CRS/HIPEC at the end of the surgery (before extubation), which may decrease the rate of associated complications during the immediate postoperative period in the ICU.

Participants

Inclusion criteria

Patients who meet all of the following criteria are eligible for inclusion:

1. Age ranging from 18 to 64 years old.

2. American Society of Anesthesiologists grades I to III.

3. Peritoneal metastasis cancer formed by various tumors.

4. CRS/HIPEC will be performed under general anesthesia.

5. Written consent to participate in the study.

Exclusion criteria

The exclusion criteria are as follows:

1. Established diagnosis of primary peritoneal carcinoma

2. History of cardiac surgery

3. Abnormal coagulation function before surgery

4. Patients with elevated preoperative lactate levels

5. Uncontrolled systemic infections

6. Diabetes

7. Hemoglobin (HGB) < 9 g/dL

8. Abnormal coagulation function

9. Hepatic or renal failure

10. Pregnancy or lactation

11. Patient refusal to sign the informed consent form

12. Patient participation in another clinical treatment study

13. Hypertensive patients

Randomization and blinding

An independent statistician will perform randomization using a computer random number list generated by Stata software version 15.1. All qualified participants will be randomly divided into two groups: GIP and CV. An investigator who is not exposed to any of the participants will give each of them a random number (1 or 2) to divide the two groups at a ratio of 1:1. The numbers will be saved in envelopes. Before surgery, the envelope will be opened to obtain the group information after the informed consent form is signed. Neither the patients nor the medical staff will be aware of the randomization arm. To guarantee the safety of patients and the reliability of the study, this experiment is a single-blind study, and the anesthesiologist assisting in the operation is aware of the relevant interventions and treatment. After surgery, another investigator who has no knowledge of the group information will collect the perioperative data.

Anesthesia management

The anesthesia regimen will be consistent between the two groups. After the patient enters the operating room, venous access will be established, and midazolam will be administered (0.05 mg/kg intravenously) to the patients. Then, standard monitoring (pulse oximetry, ECG, and noninvasive and invasive arterial blood pressure monitoring) will be established. The first arterial blood gas analysis will be performed. Urbason 80 mg and ondansetron 4 mg will be given before induction. Sufentanil 0.3 μg/kg, propofol 2.5 mg/kg, and rocuronium 0.6 mg/kg will be adopted for general anesthesia induction. Ventilator parameter settings will be as follows: SpO2 50% oxygen, VT 8 ml/kg, RR 14 times/min, PEEP 6 mmH₂O. Anesthesia will be maintained with inhalation of sevoflurane and intravenous (IV) remifentanil, propofol, and rocuronium. The depth of anesthesia throughout and maintaining a BIS value of 40–60 will be monitored. Extubation will be performed after confirming that the patient’s eyes are open and that he or she exhibits adequate spontaneous breathing and purposeful movement. All patients involved will be given a postoperative pain constant speed pump administering sufentanil 0.3 μg/kg, dexmedetomidine 200 μg, and physiological saline 250 ml. Goal-directed resuscitation strategy during surgery will be similar for both groups through monitoring stroke volume variability (SVV); make sure the fluid and resuscitation management of these patients is no different.

HIPEC

The perfusion solution, temperature, time, circulating flow rate, and other parameters are set as follows: (1) the perfusion solution is a mixture of normal saline and chemotherapy drugs, the general dosage of normal saline is 3000 to 5000 ml, the amount of perfusion fluid is based on the principle of abdominal filling and smooth circulation, chemotherapeutic drugs select sensitive drugs based on the primary tumor, dose refers to intravenous chemotherapy dose; (2) the treatment temperature is set to 43 °C; (3) the treatment time ranges from 60 to 90 min, select treatment times according on different drugs, most of the drugs were at 60 min, and at multiple HIPECs, each interval was 24 h; (4) the circulating flow rate is generally 300 ~ 600 ml/min.

Pharmacy

In this study, the intervention drug involved will be glucose-insulin-potassium chloride, and insulin will be stored in a refrigerator (2–8 °C) before infusion. Modified GIP consists of 20% glucose (200 g/L), 80 U/L regular insulin (Novo Nordisk A/S, Bagsvaerd, Denmark), and 80 mmol/L KCl. The ratio of insulin to glucose is 1:2.5 in this formula (while in most traditional GIPs, it is 1:4 to 1:6) [25].

Intervention

For all patients in the intervention group, modified GIP will be continuously injected intravenously at a rate of 0.1 ml/kg/h. Arterial blood gas will be monitored every 2 h during the operation to adjust the pump speed according to the patient’s BG level and be maintained in the range of 80–180 mg/dL, which was recommended by the American Diabetes Association Standards for perioperative care [38]. Plasma glucose below this range can reduce the pump speed by 0.02 ml/kg/h; if glucose is above 180 mg/dL, the pump speed by volume will be increased by 0.02 ml/kg/h. For patients with hyperkalemia, KCl-free solution will be administered. All patients in the control group will receive intraoperative anesthesia as usual, and no special treatment will be given.

Safety consideration

During the operation, the anesthesiologist will know the dose and formula of the relevant experimental intervention and will be able to handle various events to ensure the safety of patients. The standards for terminating and stopping clinical trials include patients with severe intraoperative cardiovascular events (cardiac arrest, ventricular fibrillation, pulmonary embolism, etc.) and allergies.

Outcomes

Table 1 provides an overview of the outcomes and intervention or assessment time points.

Table 1.

Study visits of the GIP vs CV trial

	Enrolment	Allocation	O.R							ICU
Time point		0 d	T0	T1	T2	T3		T4	Leaving	T5	T6	T7	T8	T9	T10	Discharged
Enrolment
Eligibility screen	X
Informed consent	X
Allocation		X
Interventions
GIP			X	X	X	X	X
CV
Assessments
Demographic data		X
Baseline variables		X
BG		X	X	X	X	X	X			X	X	X	X	X
Lactate level		X	X	X	X	X	X			X	X	X	X	X
Operating duration (min)									X
HIPEC duration (min)									X
Extubation time (min)									X
The lowest BG									X							X
The highest BG									X							X
The highest lactate									X							X
Visceral resections									X
Total norepinephrine dosage (ug/kg)									X							X
Blood loss									X							X
Complications															X
Clavien–Dindo															X
Lactate clearance time (hour)																X
LIS
LHS																X
Total cost of the hospitalization																X

T0, entering the operating room; T1(T1-1 to T1-n), the performance of CRS (every 2 h); T2, before HIPEC; T3, after HIPEC; T4, at the end of surgery; T5, 24 h after surgery; T6, 48 h after surgery; T7, 96 h after surgery; T8, 7 days after surgery; T9, 14 days after surgery; T10, 30 days after surgery; LIS length of intensive care unit stay, LHS length of hospital stay, BG blood glucose, HIPEC hyperthermic intraperitoneal chemotherapy

Primary outcome

The primary outcome is that the average level of lactate levels at the end of the surgery will be lower than 2.5 mmol/L. The time point at the end of the surgery refers to immediately after the end of the procedure and before tracheal extubation.

Secondary outcomes

• ➢ The highest levels and fluctuation ranges of lactate and BG during surgery

• ➢ Extubation time

• ➢ APACHE-II score 24 h after surgery [39]

• ➢ Postoperative defecation and exhaust time

• ➢ Postoperative lactate clearance time. Arterial lactate levels will be drawn at 12-h intervals after surgery for 4 days until the patient reaches and maintains a serum lactate level of less than 2.5 mmol/L on two repeated measurements, and the time will be recorded [19, 22]

• ➢ Postoperative liver and kidney function

• ➢ The incidence of complications within 30 days after surgery

• ➢ LIS and LHS

• ➢ The total cost of hospitalization

Data collection and management

All the study-related data of recruited patients will be recorded in an electronic storage system. The data of each patient will be entered into the EpiData database using a dual data entry system and will not be disclosed to other researchers until the study is completed. An inspector will regularly check and revise these records to ensure data quality. Clinical information will include age, sex, body mass index (BMI), blood pressure, plasma glucose, glycated hemoglobin (HbA1c) level, renal function, liver function, presence of ascites, current tumor (primary or relapsed), carcinomatosis index, HGB, and albumin level, which will be extracted from the Information Center. Data on lactic acid levels will be obtained using arterial blood samples. Postsurgical complications in the ICU will be recorded according to failure-to-rescue analysis [40] (Table 2) and their severity stratified according to the Clavien–Dindo classification [41]. If several complications occur in the same patient, the complication with the greatest degree of severity will be considered the priority.

Table 2.

Complications used in traditional failure-to-rescue analysis

Cardiac	Arrhythmias, arrest, infarction, congestive heart failure
Respiratory	Pneumonia, Pneumothorax, Bronchospasm, Respiratory compromise, Aspiration pneumonia
Circulatory	Hypotension, Shock, Hypovolemia
Neurologic	Stroke, Transient ischemic attack, Seizure, Psychosis, Coma
Vascular	Deep vein thrombosis, Pulmonary embolus, Arterial clot, Phlebitis
General	Internal organ damage, Return to surgery
Infection	Deep wound infection, Sepsis, Gangrene, Amputation
Others	Gastrointestinal bleeding, Blood loss, Peritonitis; Intestinal obstruction, Renal dysfunction, Hepatitis, Pancreatitis, Decubitus ul- cers, Orthopedic complication, Compartment syndromes

Before the start of the study, uniform standard operating procedures will be developed, and effective training will be provided to researchers, doctors, and nurses in each center. During the patient’s hospitalization, the investigator will follow up with the participants and provide diagnosis and treatment recommendations to improve patient compliance.

Nonidentifiable data of the study will be collected on the electronic case report form (eCRF) using a unique patient identification number for reporting. Only the study site will have access to the information to maintain participant confidentiality. After the completion of the anonymous eCRF, the researcher shall confirm the authenticity and validity of all data and give a reasonable explanation for any missing data. All essential documents will be kept in a secure commercial vault for a minimum of 10 years after completion of the trial.

Sample size calculation

The Pass 11.0 software package was used for sample size evaluation. According to previous reports and our previous analysis of 30 cases, the plasma lactate level of the conventional management group was 4.2 ± 1.5 mmol/L at the end of surgery, while that was 2.5 ± 1.0 mmol/L when using modified GIP. Superiority test was used with a difference power of 1, α = 0.05, β = 0.2. Each group needs 36 patients, controlling for 10% follow-up rate; a total of 80 patients need to be involved in this study.

Statistical analysis

As long as the participants are enrolled, even if they have only gone through a partial trial procedure, they will still be included in the statistical analysis in accordance with the intention-to-treat analysis principle. Moreover, the per-protocol analysis will be used as a sensitivity analysis. We expect very few patients to be lost to follow-up during the hospital stay. As a result, missing data will be minimized when analyzing primary outcomes. If statistical methods are needed to interpret missing data for secondary outcomes, multiple imputation will be used. No interim analysis has been designed for this study.

Data analyses will be performed by the statistical software SPSS V.25.0. The Kolmogorov–Smirnov test will be used to test the normality of the distribution of continuous variables. If data values are normally distributed, they will be presented as the mean ± SD and will be compared using an independent t test. Categorical variables are presented using relative frequencies and percentages and compared using the χ ² test or Fisher’s exact test. If data values are not normally distributed, they will be presented as the median and IQR and compared using a nonparametric test. P < 0.05 will be considered indicative of statistical significance.

An adjustment for confounding effects will be performed with logistic regression using the multivariate propensity score method. Possible confounding factors will be considered, including the Charlson age score, presence of ascites, current tumor (primary or relapsed), carcinomatosis index, HGB, albumin [42], number of visceral resections, blood loss, and norepinephrine dosage [22].

Ethics and consent

The trial protocol was approved by the scientific research ethics committee of Beijing Shijitan Hospital Affiliated with Capital Medical University, approval number sjtky11-1x-2022(118). Informed consent will be provided prior to administration of any trial intervention. Participants will also be asked to provide consent for future data linkage studies. All patients have the right to refuse participation and withdraw from the trial at any time for any reason and without prejudice of further treatment.

Patient and public involvement

Patients and/or the public were not involved in the design or conduct, reporting, or dissemination plans of this research.

Discussion

Peritoneal carcinomatosis remains one of the greatest challenges in cancer treatment. Since the 1980s, the use of CRS/HIPEC has increased with significant survival gains in these patients. However, the performance has been hampered by a lack of prospective clinical trials. Therefore, formal education on the technical aspects of this performance has not been standardized thus far [16]. Our study is a single-center, randomized clinical trial with a blinded outcome assessment that aims to assess whether the application of GIP is better than conventional management in patients undergoing CRS/HIPEC. If it can be proven that compared with the conventional group, the GIP group exhibits a lower lactate level at the end of surgery, a more stable perioperative BG, quicker lactate clearance after surgery, a lower incidence of complications, and no increase in the incidence of adverse events, then the modified GIP can be safely infused intravenously during surgery to control the lactate level and achieve a better prognosis.

However, the ratio of insulin to glucose in previous GIP formulas was usually between 1:6 and 1:4, which often led to significant elevation of blood glucose [43–45]. Studies have shown that an insulin-glucose ratio of 1:3 did not further elevate blood glucose in patients undergoing cardiac surgery [25]. A retrospective observational study found that the unified GIP regimen was more effective than the previously used diverse version of the GIP regimen in terms of glycemic control [24]. Therefore, in the pre-experiment, we used a 1:3 insulin-glucose ratio and found that blood sugar and lactate still increased during the surgical progress. Therefore, we adjusted the ratio to 1:2.5 and found that blood sugar could be controlled in the recommended range just by controlling the infusion speed. This phenomenon can be explained by the characteristics of the surgery. Achieving complete cytoreduction often involves major abdominal surgery: peritoneal stripping, multivisceral resections (often including the omentum, large and small bowel, stomach, spleen, gallbladder, uterus and ovaries, pancreas, ureters, bladder), and the creation of temporary or permanent stomas [2]. Surgery of this magnitude, combined with heated chemotherapy, puts the patient in a highly stressed state so that the blood glucose levels are often beyond the normal range. Moreover, studies have shown that not only the macrocirculation but also the microcirculation is affected during the HIPEC period, which has an impact on metabolism [46].

In terms of the time points, a study on patients undergoing CRS/HIPEC highlighted that an increase of 1 mmol/L in the average lactate value on days 3 and 4 increases the risk of a minor complication by 1.9, the risk of a major complication by 10.9, and the risk of mortality by 32.1% [47]. Marta et al. also demonstrated that the risk of developing complications almost tripled when lactate levels were > 2.5 mmol/L at ICU admission [22]. Furthermore, it has been hypothesized that several incidents during anesthesia [48] result in lactate elevation. This analysis would be strengthened by incorporating earlier time points (including intraoperative time points) of lactic acid measurement. Thus, the selection of our study time points included intraoperative (the performance of CRS, before HIPEC, after HIPEC, at the end of surgery) and continuous monitoring of lactate levels to the fourth day after surgery. The lactate level immediately before extubation at the end of the surgery was chosen as the primary outcome to highlight the value of intraoperative intervention.

According to a previous study, not only the increase in lactate levels but also the time until normalization of the levels was associated with postoperative morbidity and mortality of patients in the surgical intensive care unit [19, 49]. Therefore, in our study, we will test lactate levels every 12 h after surgery for 4 days until the patient reaches and maintains a serum lactate level of less than 2.5 mmol/L (this finding is from the CUSUM graphs, a study showing that a lactic acid level of 2.5 mmol/L marks the threshold for an increased risk of complications) on two repeated measurements, and the time will be recorded as the lactate clearance time.

With respect to the limitations of this study, one was its observational design. The data were from a small series and a single center during the immediate postoperative period in the ICU, thus making generalization impossible, although they supported the findings of similar studies. To control for the baseline levels, our data did not include patients with diabetes or patients with elevated preoperative lactic acid levels, and such patients are also of high research value. Furthermore, this trial did not include long-term postoperative follow-up or tumor survival rates. These limitations will be addressed in our next study, and we will focus on the study of perioperative nutritional metabolism to provide a scientific research basis for the perioperative metabolic management of cancer patients.

Trial status

The protocol version number is V1.0, and the protocol version date is November 10, 2022. The recruitment began in June 2023 and will be completed approximately in December 2023.

Composition, roles, and responsibilities for overseeing the study

The coordination center (CC) will comprise the principal investigator (PI), two anesthesiologists, one surgeon, one nurse, and an independent statistician. The responsibilities of the CC are coordinating and overseeing each stage of the trial including the recruitment, preoperative evaluation, perioperative intervention, postoperative follow-up visit, and analysis process to ensure study completion. The trial steering committee (TSC) will include the PI, two anesthesiologists, and a statistician. TSC will be responsible for training all the researchers involved in the trial and overseeing the review and approval of publications and presentations. An independent data monitoring committee (DMC) including two statisticians and a clinician will be formed to independently review the data security and accuracy of participants on a monthly basis.

Auditing

An external independent physician who will not be involved in the study will provide monitoring, including verifying the progress of the study and all observational data. The DMC will be responsible for monitoring the data, and the coordination center (CC) will audit the data every month. We do not have any interim analysis plan because the intervention risk in this study is low, and it is a short-term trial. An external independent physician who will not be involved in the study will provide monitoring, including verifying the progress of the study and all observational data. The DMC will be responsible for monitoring the data, and the coordination center (CC) will audit the data every month. We do not have any interim analysis plan because the intervention risk in this study is low, and it is a short-term trial. An external independent physician who will not be involved in the study will provide monitoring, including verifying the progress of the study and all observational data. The DMC will be responsible for monitoring the data, and the coordination center (CC) will audit the data every month. We do not have any interim analysis plan because the intervention risk in this study is low, and it is a short-term trial.

Harms

The anesthesia schemes of the patients enrolled in this project have been clinically verified for a long time and will be completed by experienced doctors. If a patient’s health condition is harmed as a result of participating in the study, necessary medical measures will be taken in a timely manner for treatment, and compensation and treatment will be provided in accordance with current national laws. If there are serious adverse events related to the study agent, they will be reported to PI and recorded in the study database. Then, the blinded method will be broken if necessary.

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees)

Any deviations from the protocol will be recorded and reported to the corresponding regulatory organization. The PI will revise the protocol according to the record and update the new version on the clinical trial registration website. The revised protocol amendments have been sent to the investigators.

Ancillary and post-trial care

The interventions or follow-ups of this study will be completed during the patient’s hospitalization. There is no specific ancillary or post-trial care.

Consent to participate

Before surgery, when the patients meet the eligibility criteria, the researcher will explain the study plan and all potential risks to the participants and their authorized surrogates. Then, the participants will be required to sign an informed consent before enrollment. Throughout the research process, participants would be free to withdraw their consent or discontinue participation at any time without any restrictions. The reasons and corresponding circumstances will be recorded in the case report form (CRF). Participants will be asked if their data can be used in a specific research project after they have signed the informed consent form. This trial will not involve the collection of biological specimens for storage.

The relevant private information of the involved patients, such as name, home address, and contact phone number, will be kept confidential. The information paper will be locked in a safety box and the electronic information will be stored in an encrypted electronic database with restricted access by the principal investigator (PI) who will sign the confidential disclosure agreement. Data and information will not be printed or transmitted to any auxiliary media and will record the date and time when team members accessed the database. Each patient will be assigned a unique study identifier that will only appear on the data and documents during evaluation or statistical analysis. In addition, all original records, such as informed consent and CRF, will be destroyed according to hospital standards.

Publication plan

Scientific presentations and reports corresponding to the study will be written under the responsibility of the coordinating investigator of the study with the agreement of the principal investigators and the methodologist. Based on the proportion of contribution to the study, the participating researchers and clinicians as well as biostatisticians and related researchers will be the coauthors of the ensuing report and publication. Rules on publication will follow international recommendations [50].

Authors’ contributions

YH and TG contributed equally to this work and should be considered co-first authors. YH contributed to the drafting of the protocol and this manuscript. TG and YH contributed to the conception and design of the research protocol, assisted by LP. TG, LG, and SW provided critical input pertaining to the design of the trial interventions and procedures. PL designed the statistical analysis plan; QZ designed the health economics analysis. All authors critically revised and modified the protocol and the article.

Roles and responsibilities

The principal investigator and research physician have contributed the following: designing and conducting of the trial, preparation of the protocol and revisions, and publication of study reports.

Provenance and peer review

Not commissioned; externally peer-reviewed.

Open access

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Data sharing plan

Study-specific data, which is non-identifiable, will be collected on the electronic case report form (eCRF) and eCollect system (EDC). After the completion of the anonymous CRF table, the researcher shall confirm the authenticity and validity of all data, give a reasonable explanation for any missing data, or choose to exclude the test scheme. Data integrity is assured by strictly controlled procedures, including secure data transfer procedures. All essential documents will be archived in eCollect system for a minimum of 5 years after completion of the trial.

Funding

No foundation.

Availability of data and materials

The cases completed in the experiment will be stored in the security database of the Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University. The study protocol is available on ClinicalTrials.gov (identifer: ChiCTR2200057258), and the research results, analyzed data sets, etc., can be made available upon reasonable request from the corresponding author.

Declarations

Consent for publication

Obtained.

Competing interests

The authors declare that they have no competing interests.