A randomized clinical trial and a prospective registry with two parallel groups will be conducted at general surgery department of the Second Affiliated Hospital of Anhui Medical University in China. The aim of this study is to compare the effect of two hepatectomy methods for hepatolithiasis by assessing factors related to mortality and morbidity, including postoperative length of hospital stay, biliary leakage[19], post-hepatectomy hemorrhage[20], post-hepatectomy liver failure[21], incisional hernias, residual stone rate, and recurrence of calculus[22].
Sample size
The sample size calculation is based on the primary endpoint: the LOS. According to published data, an assumed a 1.3-day reduction in LOS is the appropriate basis for the calculation, assuming 4.5 days in the LLH group and 5.8 days in the OLH group[23]. This calculation yields a total of 40 patients in each group, which assures 90% power at a two-sided level of significance of 5% (NCSS and PASS 11 (NCSS Statistical Software, Kaysville, UT, USA)). Assuming an expected withdrawal rate of 10% during the trial, 8 additional patients will be included and randomized; therefore, the total sample size required is n = 88 patients. Figure 1.
Eligibility criteria
Inclusion criteria
Patients who meet the following criteria will be included in the study:
1. Patients suitable for undergoing both laparoscopic left hepatectomy and open left hepatectomy of the liver
2. Patients who be able to understand the nature of the study and what will be required of them
3. Men and nonpregnant, nonlactating women between the ages of 18 and 80
4. Patients with ASA I-II-III.
Exclusion criteria
Patients who meet any of the following criteria will be excluded from the study:
1. Inability to provide informed consent
2. Patients associated with a tumor or who require bilioenteric anastomosis or left caudate lobectomy
3. Immunodeficiency disease, such as HIV
4. Previous upper abdominal surgery (except for laparoscopic and open cholecystectomy).
Withdrawal
Patients can withdraw from the trial at any time at their own request or at the request of their legal representative. Patients may be removed if, in the researchers’ opinion, continuing the trial may be detrimental to the patient’s health, if left hepatectomy is not performed due to a technical inability, or for other reasons. Every withdrawal will be recorded in the clinical report forms (CRFs) and in the patient’s medical case records. All examinations scheduled for the final trial day will be performed on all patients and documented. All dates will be analyzed according to the intention-to-treat (ITT) principle[24].
Ethics, study registration, and consent
The study has been approved by the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University (identifier: KY20190809). The trial protocol has also been registered in the protocol registration system at ClinicalTrials.gov (identifier: NCT03958825). Patients willing to participate in this trial will receive both verbal and written information at the time of recruitment in the outpatient clinic of the Second Affiliated Hospital of Anhui Medical University. All participants of the study will be provided a participant information sheet and informed consent form entailing sufficient information. The participants will sign the general consent for the further use of personal data and biologic material. The investigators affirm and uphold the principle of the participant’s right to privacy and that they shall comply with applicable privacy laws and/or the corresponding section of the study specific consent. The study procedure, benefits, risks, and data management will be clarified in detail during the preoperative conversation. All trial data will be saved and stored on a server during the trial, and patients will be asked to agree to future analysis.
Trial interventions
The procedures of LLH
The LLH operative procedures will be completed by the same surgical team in each group led by two experienced board-certified surgeons. LLH and left lateral segmentectomy will be performed with the patient in the French position, with two experienced surgeons at each side (bilateral two chief surgeons) and a video laparoscope operator between the legs, which is different from the classic laparoscopic technique. Laparoscopic operations will be performed using 5 trocars. Common bile duct exploration (CBDE) will be performed in all patients with suspected stones in a dilated common bile duct (> 10 mm) using a choledochoscope, followed by T-tube placement if postoperative cholangiography is required[12]. Figure 3.
The procedures of OLH
OLH will be performed under general anesthesia with the patient in the supine position. An inverted L-shaped incision will be performed. The left hepatic artery and left portal vein will be individually dissected, ligated, and divided. Then, the left bile duct and left hepatic vein will be ligated, divided, and closed after hepatic parenchymal resection. The CBDE will be the same as the LLH.
Primary and secondary endpoints
Primary endpoint
The LOS is designated as the primary outcome of this trial. Only the researchers and surgical surgeons will know the true operation. A blinded ward doctor will decide whether the patient should be discharged.
Secondary endpoints
The secondary outcomes are biliary leak[19], hemorrhage[20], post-hepatectomy liver failure[21], wound infection, intra-abdominal fluid collection or abscess, relaparotomy, mortality, long-term abdominal wall hernias, hospital costs, residual stone rate and recurrence of calculus[22]. Existent ISGLS definitions will be used to ensure the comparability and generalizability of the results. Postoperative complications will be graded based on severity according to the Clavien-Dindo definition[25]. Table 1 and Table 2.
Table 1
Definition of the endpoints
Endpoints
|
Definition and assessment of outcomes
|
postoperative length of hospital stay
|
Time from the day of the operation until discharge (days)
|
Operative time
|
Time from the beginning to end of the operation
|
Mortality
|
Death due to any cause until 90 days after the operation and the reason
|
Morbidity
|
Postoperative complications will be recorded until 90 days after the operation. The severity of complications will be graded according to the Clavien-Dindo classification[ 25]
|
Blood loss
|
Total blood loss during the operation
|
Intraoperative blood transfusion
|
Massive hemorrhage with a hemoglobin level < 7 g/dl or Hct < 22
|
postoperative length of hospital stay
|
Time from the day of the operation until discharge (days)
|
Post-hepatectomy hemorrhage
|
Evidence of blood loss from drains and/or nasogastric tube based on ultrasonography, as defined by ISGPS (grade A, B or C) [ 20]
|
Biliary leak
|
Bilirubin concentration in the drain fluid at least three times the serum bilirubin concentration, as defined by ISGLS (grade A, B or C)[19]
|
Post-hepatectomy liver failure
|
The impaired ability of the liver to maintain its synthetic, excretory, and detoxifying functions, which are characterized by an increased international normalized ratio and concomitant hyperbilirubinemia (according to the normal
limits of the local laboratory) on or after postoperative day 5, as defined by ISGLS (grade A, B or C)[21]
|
Intraabdominal fluid collection
|
Collection of fluid measuring ≥ 3 cm associated with clinical or laboratory abnormalities
|
Pneumonia
|
Presence of a new infiltrate on the chest X-ray as well as the following: body temperature༞38℃, abnormal elevation of WBC, or positive sputum, and requiring antibiotic treatment
|
Wound infection
|
Surgical site infection associated with laparotomy that develops during the initial hospital stay
|
Abdominal rupture
|
Dehiscence of abnormal closure with the need for resuture of the laparotomy during the initial hospital stay
|
Total hospitalization expenses
|
Hospital costs from admission to discharge ($)
|
Recurrence of calculus
|
Calculi in the intrahepatic duct within 3 months after hepatectomy are
defined as residual stones[22]
|
Table 2
Severity grade according to the Clavien-Dindo definition[25]
Grade
|
Definition
|
Ⅰ
|
Any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic, and radiological intervention.
|
Ⅱ
|
Requiring pharmacological treatment with drugs other than those allowed for grade Ⅰ complications
|
Ⅲ
|
Requiring surgical, endoscopic or radiological intervention
|
Ⅲa
|
Intervention not under general anesthesia
|
Ⅲb
|
Intervention under general anesthesia
|
Ⅳ
|
Lifer-threatening complication. Requiring intensive care unit management
|
Ⅳa
|
Single-organ dysfunction
|
Ⅳb
|
Multiorgan dysfunction
|
Ⅴ
|
Death of patient
|
Table 3
Schedule of enrollment, interventions, and assessments
Screening
|
|
before surgery
|
surgery
|
POD1
|
POD2
|
POD3
|
Discharge
|
POD30
|
6 months
Postop
|
12 months
Postop
|
24 months
Postop
|
Selection criteria and informed consent
|
X
|
|
|
|
|
|
|
|
|
|
Medical history Demographics
|
X
|
|
|
|
|
|
|
|
|
|
Physical examination
|
X
|
|
|
|
|
|
|
|
|
|
Laboratory texts
|
X
|
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
Trial intervention
|
|
X
|
|
|
|
|
|
|
|
|
Intraoperative outcomes
|
|
X
|
|
|
|
|
|
|
|
|
Postoperative outcomes
|
|
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
X
|
POD postoperative day, postop postoperatively,
|
Type of trial
The trial is a prospective randomized interventional single-center study comparing two parallel groups with a prospective registry to determine whether patients underwent LLS by laparoscopic surgery rather than open surgery with an enhanced recovery program. The types of interventions by patients, nurses, and ward doctors (not the surgeons performing the operations) before postoperative day (POD) 3 will be blinded. However, patients who are randomized to receive open or laparoscopic liver resection are at risk, as explained earlier. In addition, there is another potential source of bias when randomly selecting patients with strong treatment preferences. When patients are not informed about their treatment allocation (POD 3), they may be resentful and feel demoralized if they do not receive their preferred treatment. Thus, their compliance may be poor. By contrast, patients receiving their preferred treatment may have above-average compliance. Thus, to capitalize on centers both with and without preference for laparoscopic liver surgery and to acquire an uninterrupted prospective series of patients, all nonrandomized patients undergoing LLS will be approached to participate in the prospective registry. Registration of these patients is imperative to guarantee a consecutive series of patients and also because the absence of such a series may restrict the generalization of the results, as randomized participants may not, in fact, be representative[26]. The combination of an RCT and a prospective registry will improve the overall power and strengthen the external validity and generalizability of the study results[15, 27, 28].
Randomization
The randomization sequence is performed with sealed opaque envelopes. Upon completion of the screening assessment, participants who satisfy all the inclusion criteria and none of the exclusion criteria will be randomly assigned to the intervention and control groups in a 1:1 allocation ratio. Randomisation assignment will be computer generated using the ‘randomize’ library of SPSS22.0 (SPSS, Chicago, USA), with a complete randomising method based on permutations that guarantees balanced groups. A research nurse who will not participate in patient care will perform the randomization. Study group allocation will depend on the contents of sealed opaque envelopes generated in the above-described manner, and envelopes will be opened before operation.
Blinding
The patients and outcome observers will be blinded before POD 3 with respect to the trial intervention. Blinding of the surgeons and people involved in the operation is not feasible due to the nature of the interventions.
Participating surgeons
The surgical experience of surgeons can affect complication rates, which might bias the results. To prevent surgeon bias, surgeons should meet the following criteria: (1) have performed more than 200 open hepatectomies, (2) have performed more than 100 laparoscopic hepatectomies, and (3) be a qualified surgeon according to the China College of Laparoscopic Hepatectomy. LLH will be performed by two surgeons (Hui Hou and CL Wu), and OLH will be performed by three surgeons (Hui Hou, XP Geng and QR Xiong).
Data management and quality assurance
Data is collected prospectively for all patients including history, physical examination, laboratory data, pathologic examination, perioperative clinical information, and complications. Data is collected via datasheets on paper and kept securely. Study subjects will complete the examinations at inclusion, 1 weeks after surgery, and3, 6, 12, and 24months postoperatively. Follow-up will be followed up to 24 months postoperatively (Table 1). All handling cases are managed by subject identification code or anonymized registration number. The correspondence table of the anonymizing code and names and the consent form containing the names are kept strictly in the separate lockable document storage. All required parameters are collected in an SPSS data file (SPSS version 25, IBM statistics, Chicago, IL, USA).
ERAS-Program
All patients will participate in the ERAS liver program with a standardized peri-operative management. For the daily guidelines on the pre- and postoperative care of patients undergoing liver resection, see Fig. 2.
Follow-up
Follow-up is conducted at 1 month postoperatively and then 3, 6, 12, and 24 months postoperatively by telephone or as outpatients with liver function test and abdominal ultrasonography for 2 years or until death. CT or MRCP is performed in cases of suspected stone recurrence or cholangitis.
Statistical analysis
The two-sided null hypothesis for the primary endpoint states that both study interventions will lead to a similar time to the LOS; the alternative hypothesis is that one intervention will perform better than the other. The null hypothesis will be tested by analyzing the covariance while adjusting for age and the type of liver resection. A binary logistic regression will be applied to compare the time to functional recovery between groups after adjusting for other factors. Background characteristics and surgical outcome measures will be compared using chi-squared or Fisher’s exact tests for categorical data and two-tailed t-tests or nonparametric Mann-Whitney U tests for continuous variables. Categorical data will be presented as frequencies and group percentages, and continuous variables will be expressed as means and standard deviations. The homogeneity of the two groups will be described by comparison of the demographic data and baseline values. All analyses will be performed on an ITT basis [17]. For the ITT analyses, the data will be processed for all trial patients in their randomized groups. A P-value < 0.05 will be considered statistically significant. All statistical calculations will be performed using SPSS22.0 (SPSS version 25, IBM statistics, Chicago, IL, USA).