Intravenous Lidocaine on Chronic Pain in Patients Undergoing Hepatectomy

Study Overview
=================
Brief Summary
-----------------
This study is a further observation and follow-up of the patients enrolled in the registration number NCT04295330 to further evaluate the effect of long-term infusion of lidocaine on postoperative chronic pain, long-term quality of life and survival rate in patients undergoing liver cancer surgery.

Detailed Description
-----------------
This study is a further observation and follow-up of the patients enrolled in the registration number NCT04295330 to further evaluate the effect of long-term infusion of lidocaine on postoperative chronic pain, long-term quality of life and survival rate in patients undergoing liver cancer surgery. 272 patients with primary liver cancer who meet the inclusion criteria are included. According to the random number, the patients are divided into lidocaine group and conventional analgesia group.In the lidocaine group, a bolus injection of lidocaine 1.5 mg/kg, given as an infusion over 10 minutes, followed by a continuous infusion of lidocaine at 1.5 mg/kg per hour for the whole surgical procedure and will be discontinued at the end of surgery. Postoperative pain management during the first 72 postoperative hours will involve the use of a PCIA device, which will contain lidocaine , sufentanil , granisetron diluted to 200 mL in 0.9 % normal saline. In the placebo group, the same volume of normal saline instead of lidocaine will be administered. Blood samples will be drawn immediately after the bolus infusion of lidocaine, at the end of surgery, and 24 hours after surgery to measure plasma lidocaine concentrations. Blood samples will also be collected at 24 hours after surgery for subsequent measurement of inflammatory factors. Numeric rating scale(NRS) is used to evaluate pain at rest and light activities at postoperative 24, 48, 72 hours. The recovery time of postoperative gastrointestinal function, length of hospital stay, and the incidence of lidocaine toxicity within postoperative 72 hours will be recorded. Follow-up after discharge includes chronic pain and accessible survival at postoperative 3 months, 6 months,1 year, 3 year and 5 year, relapse-free survival and overall survival at postoperative 6 months, 1 year, 3 years and 5 years after surgery.

Official Title
-----------------
Effect of Prolonging Intravenous Lidocaine on Chronic Pain and Long-term Quality of Life in Patients Undergoing Hepatectomy

Conditions
-----------------
Postoperative Chronic Pain

Intervention / Treatment
-----------------
* Drug: Lidocaine Hydrochloride, Injectable
* Drug: 0.9% normal saline


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age: 18-80 years old American Society of Anesthesiologists(ASA) Ⅰ～III BMI≤30 Primary single hepatocellular carcinoma resection was proposed for patients undergoing laparotomy (median incision, right subcostal incision/inverted L-shaped incision) Exclusion Criteria: Primary liver cancer with malignant tumors of other organs (such as lung, kidney, intestine, etc.). Primary hepatocellular carcinoma with portal vein or inferior vena cava and other large vascular thrombus. Long-term opioid use, alcohol or drug abuse or any of the drugs (lidocaine, etc.) used in this study were contraindicated and allergic for patients. Patients with severe hepatic and renal dysfunction (total bilirubin >1.46mg/dl, glomerular filtration rate <30ml/min /1.73㎡ or end-stage renal disease). Severe heart disease (severe heart block (including sinoatrial, atrioventricular, and intraventricular block); Severe heart failure (ejection fraction <20%); Sinus bradycardia; Patients with Adams-Stokes syndrome, preexcitation syndrome, etc Patients with a history of uncontrolled seizures or acute porphyria. Long-term use of cimetidine and β-blockers (lidocaine metabolism is inhibited through the liver, resulting in increased blood concentration of the drug, which can lead to adverse cardiac and nervous system reactions). Patients treated with drugs that are contraindicated with lidocaine (phenobarbital, thiopental, sodium nitroprusside, mannitol, amphotericin B, ampicillin, mesonotal, sulfadiazine sodium); Patients who are using enoxacin, lomefloxacin, norfloxacin, and prulifloxacin. Patients with a history of gastrointestinal bleeding or perforation after nsaids;Patients with active gastrointestinal ulcers/bleeding or who have had recurrent ulcers/bleeding in the past. Patients who had taken other experimental drugs or were participating or participating in other clinical trials within 3 months of enrollment. Failure to cooperate with the study for any reason or the researcher considers it inappropriate to be included in the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The experimental group received lidocaine and the control group received the same amount of saline.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lidocaine group<br>General anesthesia is induced in the lidocaine group with intravenous lidocaine 1.5mg/kg for ten minutes, followed by continuous injection of lidocaine 1.5mg/kg.h. At the end of the operation, the patient controlled intravenous analgesia with lidocaine is used, and the dose of lidocaine is 30mg/kg(no more than 2000mg at most). | Drug: Lidocaine Hydrochloride, Injectable<br>* In the lidocaine group, at the end of the induction of general anesthesia, a bolus injection of lidocaine 1.5 mg/kg, calculated using the patient's ideal body weight and given as an infusion over 10 minutes, followed by a continuous infusion of lidocaine at 1.5 mg/kg per hour for the whole surgical procedure and will be discontinued at the end of surgery. Postoperative pain management during the first 72 postoperative hours will involve the use of a PCIA device, which will contain lidocaine 30mg/kg, sufentanil 2 μg/kg, granisetron 12 mg diluted to 200 mL in 0.9 % normal saline.<br>* Other names: lidocaine group;|
| Placebo Comparator: Conventional analgesia group<br>The lidocaine is replaced by identical volumes and rates of 0.9% saline. At the end of the operation, the patient controlled intravenous analgesia without lidocaine is used. | Drug: 0.9% normal saline<br>* In the placebo group, the same volume of normal saline will be administered during anesthesia. The postoperative PCIA device will contain sufentanil 2 μg/kg, granisetron 12 mg diluted to 200 mL in 0.9% normal saline solution with a total volume of 200 ml.<br>* Other names: placebo group;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of chronic pain at 3 months postoperatively | Chronic pain is deﬁned as pain that lasts or recurs for longer than 3 months . For CPSP, it mainly refers to the pain that persists past normal healing time.Pain scoring is performed at 3 months using the Digital Evaluation Scale (NRS), with 11 digits ranging from 0 to 10 indicating the degree of pain, 0 indicating no pain, and 10 indicating severe pain. Subjects choose a number to indicate the degree of pain based on their personal pain experience. | 3 months postoperatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of chronic pain at 6 months , 1 year, 3 year and 5year postoperatively | Chronic pain is deﬁned as pain that lasts or recurs for longer than 3 months. For CPSP, it mainly refers to the pain that persists past normal healing time.Pain scoring is performed at 6 months postoperatively using the Digital Evaluation Scale (NRS), with 11 digits ranging from 0 to 10 indicating the degree of pain, 0 indicating no pain, and 10 indicating severe pain. Subjects choose a number to indicate the degree of pain based on their personal pain experience. | 6 months, 1 year and 3 year postoperatively | 
| The levels of inflammatory factors at 24 hours after surgery | Peripheral blood NK cells, TNF-α, CXCL10, CX3CL1, cytokines IL-6, IL-8, C3a, C5a, P(CD62P)-selectin, NETosis-specific indicators (MPO and Histone H3), three tumor progressions and metastasis-related markers (VEGF-A, MMP-3, MMP-9,MMP-2) are measured 24 hours after operation. | 24 hours postoperatively | 
| The incidence of moderate to severe pain at 24, 48 and 72 hours after surgery at rest and during movement; | The pain is evaluated using numerical rating scale（NRS). NRS scores range from 0 to 10 points, with 0 points representing no pain, 1-3 points representing mild pain, 4-6 points representing moderate pain, 7-9 points representing severe pain and 10 points | At 3 days after surgery | 
| The cumulative morphine consumption at 24, 48 and 72 hours postoperatively | Intraoperative and postoperative opioid use is reported as morphine milligram equivalents, calculated using the Practical Pain Management calculator | At the end of the surgery，24，48 and 72 hours after surgery | 
| The incidence of a composite of postoperative pulmonary complications during | defined as positive if any component developed before discharge after surgery; These complications included respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, or aspiration pneumonitis loading dose, immediately after the end of surgery, and at the first 24 hours after surgery | during the period from the end of surgery to discharge | 
| Length of hospital stay | determined by the number of days from admittance to discharge | during the period from the end of surgery to discharge | 
| Plasma lidocaine concentration immediately after loading，after surgery and 24-hours postoperatively | Plasma lidocaine concentration is an important indicator for evaluating the safety of the drug during use. | Immediately after bolus, after surgery and 24-hour postoperatively | 
| The incidence of lidocaine toxicity within 72 hours after operation | Lidocaine toxicity mainly includes neurological manifestations such as dizziness, tinnitus, convulsions, cardiac manifestations such as bradycardia, new severe atrioventricular block and so on. | within 72 hours after operation | 
| Overall survival | Overall survival is defined as the time between the date od surgery and the date of death | 6 months, 1 year, 3 years, 5 years postoperatively | 
| Recurrence-free survival | Postoperative re-examination is based on the diagnosis of enhanced CT, MRI, ultrasound or blood examination to determine whether the patient has recurrence and metastasis. Recurrence-free time refers to the time from surgery to tumor recurrence based on the above CT, MRI, etc. | 6 months, 1 year, 3 years, 5 years postoperatively | 
| accessible survival | Patient self-assessment is carried out by using the World Health Organization(WHO) Disability Scale, with a minimum score of 12 points and a maximum score of 60 points. The lower the score, the higher the quality of life | 3 months, 6 months, 1 year, 3 years, 5 years postoperatively | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
lidocaine