2.1 Ethics and Registration
This study will strictly adhere to the tenets of the Helsinki Declaration and the Belmont Report. We fully respect the autonomy of the participants and aim to maximize the benefits for them while minimizing any potential harm. The research protocol has been reviewed and approved by the Medical Thesis Committee of Henan Provincial Chest Hospital & Chest Hospital of Zhengzhou University on April 29, 2023. We have also registered the study on the Chinese Clinical Trial Registry (https://www.chictr.org.cn/) on June 27, 2023 (registration number: ChiCTR2300072869). The study will be conducted at Henan Provincial Chest Hospital and Zhengzhou University Affiliated Chest Hospital. We will strictly follow the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines [17], which can be found on their official website at https://www.spirit-statement.org.
The study protocol and procedures described in this article have been approved by the Institutional Review Board (IRB) of Henan Provincial Chest Hospital & Chest Hospital of Zhengzhou University. All participants will provide written informed consent before participating in the study. The study is conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. Participants will be recruited from Henan Provincial Chest Hospital & Chest Hospital of Zhengzhou University and be eligible if they meet the inclusion criteria and exclusion criteria. Overall, this study will be conducted with the utmost respect for ethical principles and the well-being and confidentiality of the participants.
2.2 Trial Design
The study is designed to be a single center, prospective, randomized, double-blind, controlled trial. Participants will be randomly assigned to two different treatment groups: one group will receive the control drug (normal saline), and the other group will receive the test drug (paracetamol and mannitol injection). To maintain the double-blind design, neither the researchers nor the participants will be aware of the assigned study group. This will reduce the impact of subjective bias and ensure objectivity of the results. In addition, this trial is temporarily a single-center trial since no agreement has been reached with other research centers, and we will include at least three research branch centers in the later period to provide more convincing research evidence.
2.3 Trial Status
This study is currently ongoing. Study execution period: July 1, 2023, to October 1, 2024. Recruiting period: August 1, 2023, to May 1, 2024. The flow chart of the trial is shown in Fig. 1.
2.4 Eligibility Criteria
The eligibility criteria were determined by a research participant independent of the study based on patients' admission. Patients enrolled in this study or their authorized representatives are required to sign an informed consent form prior to the start of the study. The template for the informed consent form can be found in the supplementary materials.
2.5 Inclusion Criteria
Patients will be included possibly in this trial if they 1) are aged between 18 and 64 years; 2) are diagnosed to be lung cancer either preoperatively or through rapid frozen pathological examination during the operation, and need to undergoing thoracoscopic lung cancer surgery, including lobectomy, wedge resection, or lobectomy; 3) are with American Society of Anesthesiologists (ASA) physical status I–III; 4) are able to understand the purpose of the study and will agree to participate in the study and sign informed consent.
2.6 Exclusion Criteria
Patients will be excluded from this trial if they 1) only receive conservative treatment without surgery during hospitalization; 2) have mental illness or cognitive impairment and are unable to cooperate with the study requirements; 3) are diagnosed as severe coagulation dysfunction; 4) suffer from serious infectious diseases; 5) are dependent on drug abuse or long-term use of psychotropic drugs; 6) get long-term use of steroids or hormone drugs; 7) have Gilbert syndrome; 8) are accompanied by inadequate hepatic glutathione reserve due to chronic malnutrition, anorexia, overeating, or cachexia; 9) suffer from glucose-6-phosphatase dehydrogenase deficiency, which may lead to hemolytic anemia; 10) are allergic to acetaminophen, mannitol or other anesthetic drugs.
2.7 Elimination Criteria
Patients will be eliminated in this trial if 1) they or their families actively request to withdraw from the study during the study period; 2) temporary thoracotomy occurs during the operation; 3) there are severe heart, brain, liver, and kidney dysfunction after the operation; 4) there are no postoperative recovery, automatic discharge, or perioperative death; 5) they or their families cannot be contacted for three or more times during the follow-up period.
2.8 Randomization and Blinding
This study is a randomized controlled trial, strictly implementing random allocation and blinding. Random numbers were used to group patients. The specific steps are as follows: ① Use a computer to generate random numbers in advance, and then put them into sequentially numbered, sealed, opaque envelopes, which are managed by designated personnel. ② Number the patients who meet the inclusion criteria according to the order of enrollment. ③ Match the random numbers with the patient numbers to obtain the grouping results. ④ Hand over the randomized grouping results to an anesthesia nurse, who prepares either acetaminophen mannitol injection or normal saline. The appearance, packaging, and labeling of these two drugs are identical. The syringes are only labeled as "test drugs" to ensure that the patients, anesthesiologists, and outcome assessors are unaware of the grouping. The anesthesiologist administers the drugs in sequential order. The random coding table for the clinical trial is called a blind bottom, which is kept at the Clinical Trial Center of Henan Provincial Chest Hospital & Chest Hospital of Zhengzhou University.
All anesthesiologists, anesthesia nurses, beneficiaries, and data collection and analysis personnel will be blinded to the grouping throughout this trial. The follow-up of acute and chronic postoperative pain will be completed by an anesthesiologist blinded to patient grouping. Emergency unblinding will be implemented and overseen by the Data Monitoring Committee.
2.9 Anesthesia Management
All patients will receive standardized anesthesia protocols. After entering the operating room, routine monitoring of blood pressure (BP), electrocardiogram (ECG), and oxygen saturation (SpO2) will be performed. A venous access will be established and invasive arterial blood pressure monitoring will be established. Intravenous inhalation anesthesia will be administered. For anesthesia induction, midazolam 0.04 mg/kg, etomidate 0.3 mg/kg, sufentanil 0.4 µg/kg, and rocuronium 0.8 mg/kg will be intravenously (i.v.) administered. Visualization-guided double-lumen endotracheal intubation will be performed, followed by mechanical ventilation. After successful tracheal intubation, right internal jugular vein cannulation will be performed under ultrasound guidance. Bispectral index (BIS) will be continuously monitored during the surgery to maintain a range of 40–60. Inhalation of 1% sevoflurane, continuous infusion of propofol (4–8 mg·kg− 1·h− 1), remifentanil (0.05–0.2 µg·kg− 1·min− 1), and rocuronium (0.3–0.6 mg·kg− 1·h− 1) will be administered. Appropriate tidal volume, respiratory rate, positive end-expiratory pressure (PEEP), and fraction of inspired oxygen (FiO2) will be adjusted. Balanced crystalloid fluid will be continuously infused at a rate of 3 ml·kg− 1·h− 1, maintaining urine output > 0.5 ml·kg− 1·h− 1. Rocuronium will be discontinued 30 min before the end of surgery, and sugammadex will be used for neuromuscular blockade reversal. The double-lumen endotracheal tube will be removed. A patient-controlled intravenous analgesia (PCIA) pump will be connected to the intravenous access, and the patient will be transferred to the post-anesthesia care unit (PACU). The surgical procedure will be thoracoscopic radical resection of lung cancer. The operations will be performed by the same group of surgeons.
2.10 Study Interventions
Patients in the test group will be i.v. administered with 500 mg paracetamol and mannitol injection 15 min before the end of operation, and will be i.v. administered with 500 mg paracetamol and mannitol injection on postoperative days 1 and 2, respectively. Patients in the control group will be i.v. administered 50 mL normal saline at the same time points (Table 1).
2.11 Primary Outcome
We will communicate with patients on preoperative day 1 and guide the use of PCIA pumps. The numerical rating scale (NRS) will be used to evaluate the degree of pain [18]. NRS is a commonly used pain scoring tool to assess the degree of pain in patients. NRS is scored on a scale of 0 to 10, where 0 indicates no pain and 10 indicates the most severe pain. Patients will be asked to select a number to describe their current level of pain. Usually, 0 indicates no pain, 1–3 indicates mild pain, 4–6 indicates moderate pain, 7–9 indicates severe pain, and 10 indicates the most severe pain.
The primary outcome of this study is the incidence of CPTP at 3 months after surgery. We will recruit individuals who meet the diagnostic criteria for chronic postsurgical pain (CPSP) based on the International Association for the Study of Pain (IASP) (ICD-11) standards [4]. CPSP is defined as pain that persists or increases in intensity for more than 3 months following surgery or tissue injury (including any trauma such as burns). The pain may not be limited to the original surgical or injury site but may radiate to the entire area innervated by the nerves that supply that region (e.g., deep somatic or visceral tissues). When diagnosing CPSP, other potential causes of pain, such as acute or chronic infections, malignant tumors, or pre-existing chronic pain conditions must be ruled out. CPSP is typically neuropathic in nature, but even if the neuropathic mechanism plays a significant role in the pathogenesis, the diagnosis should be CPSP rather than neuropathic pain. The etiology of CPSP should be identified, and if the cause cannot be determined, the diagnosis should be chronic primary pain.
2.12 Secondary Outcomes
The secondary outcomes mainly include the dosage of propofol and remifentanil used; NRS pain scores at PACU entry, 30 min after PACU entry, and 12 h, 24 h, and 48 h after surgery; PCIA pressing times at 24 h and 48 h after surgery; the occurrence of postoperative nausea and vomiting, and other adverse reactions including headache, insomnia, itching, respiratory depression, excessive sedation, urinary retention, allergic reactions, liver injury and kidney injury; postoperative anal exsufflation time and postoperative ambulation time; length of hospital stay; surgeon satisfaction and patient satisfaction; and the incidence of CPTP at 6 and 12 months after surgery.
In the context of postoperative follow-up, the NRS pain scores can be used during telephone interviews conducted at 3, 6, and 12 months after the surgery. The main focus of these interviews is to assess if the patient is experiencing any pain at the surgical site (NRS score: > 0).
Additionally, the impact of the pain on the patient’s quality of daily life is evaluated, categorizing it as having no impact, mild impact, moderate impact, or severe impact [19]. The level of intervention required to manage the pain is also assessed, using a grading system. This grading system includes:
- Grade A: No intervention required;
- Grade B: Rest or reduction in activity;
- Grade C: Self-administered medication;
- Grade D: Seeking medical help from a healthcare professional.
These assessments help in monitoring the patient's recovery progress and determining the appropriate management strategies for postoperative pain.
2.13 Data Collection
The data collection mainly will include the following aspects:
1) Patient recruitment and screening: Researchers will recruit patients who meet specific criteria. The recruitment process will involve screening the patients' medical records and matching them with the research objectives.
2) Follow-up and data collection: At selected time points, researchers will conduct telephonic follow-ups with the patients and collect data by using standardized questionnaires and assessment tools. These tools may include pain rating scales, quality of life questionnaires, and adverse events-reporting forms.
3) Clinical data recording: Researchers will record patients' basic information, including age, sex, disease characteristics, and surgical details. Additionally, they will document detailed information about the treatment regimens, medication dosages, and frequency of use that the patients receive.
4) Data analysis: The collected data will undergo statistical analysis to evaluate differences and correlations. Researchers will use appropriate statistical methods, such as t test and analysis of variance.
5) Data collection will utilize Case Record Forms (CRFs). Data management will involve the use of an Electronic Data Capture (EDC) system. All raw data will be publicly available on the Chinese Clinical Trial Registry website at https://www.chictr.org.cn/.
2.14 Safety Monitoring
Patients’ safety will be closely monitored throughout the study. Adverse events and side effects will be assessed and recorded using a standardized evaluation tool. These events and side effects may include drug allergies, abnormal liver function, and renal dysfunction. Any adverse events or side effects will be promptly reported to the study team and appropriate measures will be taken to ensure patients’ safety.
An independent safety monitoring committee will be established to oversee and evaluate patient safety throughout the study. This committee will review all adverse events and side effects reported and provide recommendations for any necessary adjustments to the study protocol.
All patients participating in the study will provide informed consent. The study protocol has been approved by the ethics review committee. Any changes to the study protocol will be submitted for further ethical review and approval.
2.15 Pain Management
The patients in both groups will be administered 5 mg i.v. oxycodone 15 min before the end of surgery and receive PCIA immediately after surgery. The analgesic pump formula will consist of sufentanil 2.5 µg/kg and tropisetron 10 mg, which will be diluted to 100 mL with normal saline. The analgesic pump parameters will be as follows: background dose 2 µg/h, single dose 2 µg/time, lockout time 15 min. When the patients' pain NRS ≥ 4 points, the patient will be instructed to press the intravenous analgesia pump as a remedial analgesic measure.
2.16 Sample Size Calculation
The sample size estimation in this study is based on the incidence of chronic post-surgical pain (CPSP) in patients undergoing lung cancer surgery as the primary efficacy evaluation indicator. This study is designed as a randomized controlled trial, with the experimental group receiving intravenous injection of paracetamol and mannitol injection, and the control group receiving normal saline. The primary evaluation indicator is the incidence of CPTP at 3 months postoperatively. According to the literature, the incidence of CPTP ranges from 25–57% [3]. Therefore, it is assumed that the incidence of CPTP in the control group at 3 months postoperatively is 50%. Fortier et al. [7] suggested that a 30% reduction in the incidence of CPTP after thoracic surgery is clinically significant. Hence, the incidence of CPSP in the experimental group is set at 35%. With a bilateral α of 0.05 and a power (1-β) of 0.8, the sample size ratio between the experimental and control groups is 1:1. Referring to the method proposed by Chow et al. [20] and using the R language for calculation, the sample size of both the study group and the control group is estimated to be 167 cases. Considering a 15% loss to follow-up rate, a minimum of 197 cases in both groups are required. Therefore, a total of 394 cases will be included in the study.
2.17 Statistical Analysis
SPSS 19.0 statistical software (IBM Corporation, Armonk, NY, USA) will be used for all statistical analysis. The data analysis will cover the following aspects:
1) Descriptive statistical analysis: We will conduct descriptive statistical analysis of the basic characteristics of the study population, including age, sex, and weight. For continuous variables, we will report the mean and standard deviation; for categorical variables, we will report frequency and percentage. First, normality will be tested by the Shapiro–Wilk test. If the measurement data conform to normal distribution, it will be presented as mean ± standard deviation (± s); otherwise, it will be presented as median (M) and interquartile range (IQR).
2) Baseline comparison: We will use the t-test or the Mann–Whitney U test (depending on the normality of the data) to compare the continuous variables at the baseline between the two groups. For categorical variables, we will use the chi-square test or Fisher 's exact test to compare intergroup differences.
3) Main outcome measures: We will use NRS to evaluate the efficacy of paracetamol and mannitol injection for pain after chronic thoracotomy. We will use repeated measures analysis of variance (ANOVA) to compare the pain scores of the two groups at different time points. If significant differences are found, we will perform further comparisons.
4) Secondary efficacy evaluation: We will also evaluate the secondary efficacy of paracetamol and mannitol injection on pain after chronic thoracotomy, including analgesic use and quality of life. For continuous variables, we will use the t-test or the Mann–Whitney U test for comparison; for categorical variables, we will use the chi-squared test or Fisher 's exact test for comparison.
5) Safety evaluation: We will evaluate the safety of paracetamol and mannitol injections, including the incidence of adverse events and complications. We will use the chi-squared test or Fisher’s exact test to compare the differences between the two groups.
6) Subgroup analysis: If required, we will perform a pre-specified subgroup analysis to evaluate the efficacy of paracetamol and mannitol injections in different subgroups.
7) Missing data processing: We will use appropriate methods to deal with missing data, such as multiple imputation or sensitivity analysis.
8) Intent-to-treat (ITT) analysis: An ITT analysis will be carried out to reduce the impact of bias and make the results more reliable. The ITT analysis will include all randomized participants, regardless of whether they received the assigned treatment or completed the study protocol.
Statistical significance: We will use the two-tailed P value for statistical significance testing. P < 0.05 will be considered to indicate statistically significant differences.