This study is designed as a prospective randomized, multicenter, investigator-initiated study, of interventional type performed at 3 high volume Italian Thoracic Surgery Units: Thoracic Surgery Unit of Padua University Hospital, Thoracic Surgery Unit of Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico - University of Milan and Thoracic Surgery Unit of Vito Fazzi Hospital, Lecce.
This protocol is reported in line with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines using the SPIRIT Figure (Figure 1), trial flow chart (Fig. 2) and Checklist (Additional file 1).
It will enroll 382 patients undergoing pulmonary lobectomy through a standard uniportal, biportal or triportal VATS approach, either for benign or malignant disease.
Potential participants will be identified and recruited into the trial by surgeons who work in the abovementioned Thoracic Surgery Units.
Patients will be enrolled if they meet the inclusion criteria specified afterwards and sign the informed consent form (ICF).
Inclusion criteria:
- Able and willing to read, understand and provide written informed consent
- Patients undergoing VATS lobectomy
- Age 18 – 80 years
- Gender: both
- Estimated life expectancy of at least 6 months.
- Tumour considered potentially resectable by R0 surgery
- Adequate respiratory function for surgery.
- Must have signed and dated an ICF, before performance of any study-specific procedures or tests. Subjects must be fully informed about their illness and the investigational nature of the study protocol.
Exclusion criteria:
- Patients requiring ICU care with mechanical ventilation
- Patients needing reintervention during postoperative care
- Patients requiring a thoracotomy
- Tumour considered potentially resectable by incomplete surgical resection with microscopic residual disease (R1) or gross residual disease (R2).
- Evidence of extra-thoracic disease.
- Major thoracic surgical procedure before enrolment.
- Any other significant co-morbid condition that, in opinion of the investigator, would impair study participation or cooperation.
Screening
Subjects are screened prior to the surgery. The following activities and/or assessments will be performed during screening:
- Obtain written ICF by subject or subject’s legal representative.
- Collect subject’s medical history.
- Record concomitant medications.
- Perform physical examination.
- Record vital signs, height, and weight.
- Collect blood sample for haematology, coagulation tests, blood chemistry, renal and liver function tests, and measurement of electrolytes (obtain within 30 days prior to the surgery).
- Record 12-lead electrocardiogram (ECG).
- Record spirometry, hemogasanalysis, bronchoscopy.
- Perform baseline CT scan, PET-CT and chest X-ray.
- Perform anaesthesiological evaluation.
Device Description
The Drentech™ Palm EVO device is a portable vacuum unit connected to a compatible collection system.
The collection system is a standard disposable drainage unit that will be connected to a chest drain, with a water seal valve.
The Unit is capable of generating suction that can be adjusted independent of central vacuum and/or energy sources. The Unit can be powered and/or the batteries recharged using the power supply provided.
The mobile unit is equipped with a display to show the following information:
- Indication of the “instantaneous” air leakage corresponding to the last minute of operation. - Mean air leakage value of the patient in the last hour of measurement.
- Indication of the hours of device operation, calculated starting from the moment of activation.
- History of the air leakages and minimum and maximum intrapleural pressures relating to the last 99 hours of operation and available in numerical and graphic form.
- Measurement and storage of the minimum and maximum intrapleural pressure values of the patient relating to the last minute of operation.
- Real-time measurement of the minimum and maximum intrapleural pressure values for each respiratory act of the patient.
The Unit can transfer data to a USB storage device in order to view and/or store them on a PC. The USB storage device can be connected to the dedicated port on the Unit using the adapter provided, and the data can be viewed with standard spreadsheet programs or the RedaxPlot software provided.
Randomization
A person not involved with either enrollment, assessments nor training of participants will generate the allocation sequence. Individual randomization, stratified for Centres and with blocking to reduce variability, will be performed with a 1:1 allocation to the intervention and control groups. The assignment to one of the two devices will be performed using closed envelopes containing notes reading either “T” for traditional water seal system or “D” for digital system. The randomization will be done in the surgical theater at the end of thoracoscopic lobectomy by one of the surgeons by opening the envelope assigned to the patient. Due to the nature of the intervention neither participants nor investigators will be masked during the intervention.
Intervention
The day of surgery, after induction of anaesthesia a double lumen endotracheal tube is used for the selective ventilation of the lungs. During the procedure patients are monitored by ECG, arterial line, pulse oximeter and urine output. Patients are placed in a lateral decubitus and undergo a VATS lobectomy associated with lymphadenectomy. During surgery patient receives fluid and eventually blood replacement, maintaining adequate blood pressure and urine volume. After VATS lobectomy, the presence of an air leak is tested by a water submersion test under standard airway pressure of 25 cm H2O and the air leaks measured by a volumetric system. In case of significant air leaks (i.e. more than 100 ml/min) application of sutures are allowed., whereas no buttressing material, no sealants nor pleural tents are permitted. At the end of the procedure, a single apical 28Ch chest tube is placed.
Patients are then randomized 1:1 to receive 2 different types of chest drainage management: digital, connected to Drentech™ Palm Evo system, or traditional, connected to the water-seal drain system already in use in each center. After surgery patients are transferred to the ward.
Patients with digital chest drainage system are managed by setting the pump to –20 cmH2O after the patient is extubated and until the morning of the first postoperative day (POD) and then turning off the suction (0 cmH2O). Patients with traditional devices are connected to wall suction (-20 cmH2O) until POD 1 and are subsequently disconnected from suction.
The following activities and/or assessments will be performed after surgery:
- Daily assessment of the cardio-pulmonary parameters (blood pressure, cardiac frequency, oxygen saturation) all along the hospitalization.
- Complete blood count, liver and renal functional tests the first day after surgery and then depending on the clinical condition of the patient or medical judgement.
- Chest X-ray immediately after the return to the ward and afterwards depending on clinical condition of the patient or medical judgement. After drains are removed, another chest X-ray is performed before discharge.
Postoperative treatments include respiratory rehabilitation and mobilization, antithrombotic and antibiotic prophylaxis. Pain will be controlled by means of analgesic drugs according to each Center’s analgesic protocol based on its routine practice (intravenous, epidural, intercostal blocks, or mixed regimens).
Chest tube is removed when chest X-rays show a complete lung expansion and there is no detectable air leak on traditional devices. For digital devices, absence of air leak is defined as a recorded airflow lower than 20 mL/min, with suction set at 0 cmH2O, for at least 8 hours and without significant spikes of air leak on the graph. Daily fluid drainage threshold for drain removal is based on each Center’s routine practice (generally 300 ml). During morning and evening rounds, the presence of an air leak and pleural effusion volume are checked for both type of drain system. In particular, the Drentech™ Palm Evo is equipped both with the standard traditional “water seal” system and with the digital electronic device: for the evaluation of correspondence between subjective clinical observation of air leaks and objective digital results, at each visit round the presence of air leak will be checked by two Clinicians by observation of bubbles in the chamber with the digital screen switched off in order to be blinded regarding the digital features. Then, the electronic screen is switched on and the data are recorded. For the purpose of clinical management, in this group of patients the Clinician responsible of the ward, will consider only the features of the digital device.
In case of a “pleural space” effect is suspected on the basis of features of digital system a provocative clamping maneuver will be performed and a control chest X-ray at 24 hours will be done for confirmation in order to decide for chest drain removal. Air leak duration is calculated, as usual, from the day of operation until the day an air leak is no longer detectable. Duration of air leaks for more than 7 days are considered prolonged air leaks and are managed according to each center’s routine (e.g. discharge with a portable chest drainage system or reoperation). Moreover, in these cases, the air leak duration will be measured and data will be collected until the eighth POD.
Follow-up
Post-operative follow-up will consist of a scheduled visit with chest X-rays about 30 days after discharge.
Study termination and drop out
The patient has the right to terminate the research and evaluation at any time point, without sacrificing further medical treatment. There is no replacement of patients who withdraw from the study or who interrupt him prematurely. In the data collection form it will be given the reason for discontinuation of the study.
Statistical analysis
It will be performed periodical checking of the input data in order to verify the completeness and consistency of the database.
Checks on the consistency and plausibility of the reported data will be still carried out prior to data analysis.
The study is powered based on its primary end points: the duration of chest tube placement and the length of stay. Sample size was calculated to detect a difference in duration of chest tube placement and/or hospital stay after thoracoscopic lobectomy of at least 1 day and based on previously published data (standard deviation= 3) [5]. A sample size of 382 patients (191 patients per group) was determined based on a 90% statistical power, with a significance level of 0.05, and allowing for dropouts.
Risks and benefits for the patient
The patient's participation to the study will not involve additional risks other than those required in normal clinical and surgical practice for pulmonary lobectomy. The complications occurring after operation until discharge, or within 30 days post-operation in discharged patients, are considered post-operative complications; death during the same period is defined as peri-operative death. Postoperative complications are described according to the Common Terminology Criteria for Adverse Events 4.1 published (CTCAE version 4.1) by National Cancer Institute of the US, reported, classified, and recorded into case report form (CRF).
Data collection and management
The CRF of the study will be paper-based. Data will be collected at the time of the patient enrolment in the study, during hospitalization and at 1 month after discharge.
All data collected will be recorded in a computer database (Microsoft Excel) with a protection of password. A sequential identification number will be attributed to each patient registered in the study. This number will identify the patient and must be included on all case report forms.
The database will be kept at the Thoracic Surgery Unit of Padua University Hospital. The data will be collected during the pre-operative assessment, during surgery, in the post-operative days during the daily evaluation of patients (in two visit rounds, in the morning and in the afternoon) and at 1 month after discharge from the hospital.