Trial design
This is a prospective, randomized controlled, single-blind, single-center clinical
trial (Fig. 1). This study protocol is conceived based on the Standard Protocol Items:
Recommendation for Interventional Trials (SPIRIT). The SPIRIT figure (Fig. 2) summaries
the items of enrollment, intervention and follow-up. The detailed SPIRIT checklist
is also provided [see Additional file 1].
Study objective
We aim to identify the effects of different volume of pleural lavage fluid on perioperative
outcomes and long-term survival of NSCLC patients following VATS lobectomy and MLND.
Study location
This study will be conducted in NSCLC patients undergoing VATS lobectomy and MLND in the Department of Thoracic Surgery, West China Hospital, Sichuan University.
Recruitment
Patients eligible for the trial must comply with all of the inclusion criteria and
do not meet with any exclusion criteria before randomization.
Inclusion criteria
Patients who, at the start of the treatment, meet all the following criteria, are
eligible for the study: (i) patients aged between 18 and 75 years; (ii) patients undergoing
planned VATS lobectomy and MLND; (iii) ASA risk class of I-II; (iv) essential materials
were complete such as clinical staging of lung cancer and medication; (v) confirmed
with NSCLC through pathological examination after surgery; (vi) willing to participant
after reading and signing an informed consent form.
Exclusion criteria
Patients who, at the start of treatment, meet any of the following criteria are not
eligible for the study: (i) last smoked <2 weeks prior to surgery for current smokers;
(ii) preoperative hydrothorax of patients was predominant; (iii) patients were pregnant
or breastfeeding women (females aged 18 to 55 should receive pregnancy test); (iv)
patients with preoperative severe mental illness; (v) patients with preoperative gastrointestinal
or blood system disease; (vi) patients underwent cardiac ischemia; (vii) patients
received preoperative radiotherapy or neoadjuvant chemotherapy; (viii) intraoperative
accidents happened to the patients, such as hemorrhage (>500ml), conversion to open
surgery, and cardiac arrest; (ix) patients with severe postoperative bleeding or persistent
air leakage, which require reoperations.
Randomization and blinding
We will perform the randomization to assign candidates into 2 groups based on computer-generated
random numbers shortly prior to the surgery. The random numbers will be printed and
placed in consecutively numbered and separate sealed opaque envelopes, which will
be only opened once a patient is deemed eligible. When receiving a patient who meets
the inclusion criteria, the principal doctors will assign the newly participant to
a group and inform the treatment group. The research assistant should receive the
notification timely and assign patients to their study group strictly as required.
The study is double blind. The participants and investigators are blinded to the allocation
of the participants, while the project manager is unblinded. If unexpected emergency
circumstances happen, the allocation will be disclosed to the investigators. If unblinding
happens, the participant will withdraw from this study and a detailed explanation
will be recorded.
Sample size
This is the first study focusing on the effect of different volume of pleural lavage
on the clinical outcomes following VATS lobectomy and MLND, and no reference could
be available to estimate sample size. With respect to our experience, a total of 400
candidates will be recruited in this study, with each group consists of 200 candidates.
Intervention
A total of 400 NSCLC patients aged 18-75 years, who will undergo VATS lobectomy and
MLND will be recruited in our study according to inclusion and exclusion criteria.
All the patients will be divided into 2 groups:
Group A (experimental group): 500 ml pleural lavage fluid
Before closing the chest wall, we will perform careful hemostasis and then flush the
thoracic cavity with 500 ml 0.9% sodium chloride injection at 38-40 ℃. A 28F catheter
will be indwelled to drainage.
Group B (experimental group): 3000 ml pleural lavage fluid
We will use 3000ml 0.9% sodium chloride injection at 38-40 ℃ to flush the thoracic
cavity in this group. Other procedures are the same with group A.
Study dropouts
All the recruited participants have the right to quit this study at any time for any
reason based on the ethical consideration, without any negative effect on their further
therapy. Meanwhile, all the researchers have the right to terminate the enrollment
of any patients at any time with reasonable circumstance. All the changes and reasons
will be recorded immediately in the Case reported form (CRF). If dropout rate is higher
than 10%, we will apply multiple imputation to avoid pitfalls involved with listwise
deletion of cases. Intention-to-treatment (ITT) principle will be applied to analyze
the data.
Data management
All the data recorded in CRF will be checked twice by two independent investigators.
A data management safety committee (DMSC) is needed, which is comprised of 3 independent
investigators. They will supervise the study protocol adherence and confirm that the
CRF is correctly completed and consistent with the original data. All the data can
only be acquired by the study investigators who have signed the confidential disclosure
agreement and only identical data will be published. The adherence to the study protocol,
data collection, statistical analysis and publication issue as well as related safe
issues will be strictly monitored by the Institutional Ethic Committee of West China
Hospital, Sichuan University.
Statistics analysis
The main content of the analysis is effectiveness analysis and safety analysis. The
analysis of all continuous variable will be presented as mean, standard deviation
(SD), median, quartile spacing, maximum and minimum values. The analysis of all dichotomous
variable will be presented as rate, constituent ratio and hazard ratio. We will use
the t-test and χ2 test, analysis of variance, univariate and multivariate logistic regression analysis
to describe our data. The factors (p<0.15) in univariate analysis will be analyzed
in multivariate analysis. All the data will be checked twice by two independent investigators.
We will perform subgroup analysis to identify potential significant factors based
on age, surgery time, tumor location and so on. Demographics and clinical characteristic
of the subjects are summarized as mean ± SD for continuous variables and number (%)
for categorical variables. The difference between groups will be considered statistically
significant if P<0.05. All data will be analyzed using SPSS (software version 25.0,
Chicago, IL).
Study organization
Data collection and test
Collecting blood sample of patients to check leukocytes, neutrophils and inflammatory
factors.
Complications
Some postoperative complications, such as bleeding, incision site pain, postoperative
air leak, prolonged air leak, atelectasis, will be treated according to clinical guidelines
and recorded in our CRF.
Primary and secondary outcomes
Primary outcomes:
The plasma levels of leukocytes, neutrophils, inflammatory factors, and the incidence
of fever after operation were observed 1 to 3 days after operation.
Secondary outcomes:
Volumes of thoracic drainage and total drainage on 1 to 3 days after operation; drainage
time; postoperative hospitalization; perioperative complications (incision infection,
pain, atelectasis, hemorrhage, etc.); the incidence of pleural effusion requiring
thoracic puncture or drainage within 30 days after surgery.
Protocol amendments
The current protocol is version 1.0 (25 September 2018). Any amendments in the protocol during the trial which will affect
the process of study, the benefit and risk of participants will require a formal amendments
agreement of Ethic Committee.