Objectives of the study:
This trial aimed to compare the effects of low tidal volumes combined with standard PEEP (6-8 cmH2O) to those of low PEEP (≤ 2 cm H2O) in patients at risk for complications undergoing robot-assisted laparoscopic radical resection for bladder cancer or prostate cancer during general anesthesia in terms of: (1) PPCs, (2) mCPIS score, postoperative extrapulmonary complications, changes in chest X-ray findings and oxygenation; (3) intraoperative complications including hypoxemia, hypotension and massive transfusion; and (4) postoperative surgical complications, intensive care unit (ICU) lengths of stay, hospital lengths of stay and thirty-day mortality.
Study design: This is an unfunded, parallel-group, double-blinded, prospective, randomized controlled clinical trial was registered at http://www.chictr.org.cn (ChiCTR1800019867) and was conducted at the Department of Anesthesiology and Intensive Care of Zhejiang Provincial People's Hospital. The first patient will be randomized in January 2019. This trail protocol is conducted according to the Consolidated Standards of Reporting Trials (CONSORT) guidelines (Figure 1). The SPIRIT 2013 Checklist is given in Additional file 1.
Blinding, data collection, randomization and recordkeeping
Selection of the participants
Researchers will be trained prior to investigation. Study data including patient clinical characteristics, intraoperative respiratory parameters, postoperative outcomes, and laboratory test will be collected onto case report forms (CRF) (Additional file 2).
An independent researcher will randomize the participants into the study group (standard group PEEP) and control group (low PEEP group) in a ratio of 1:1. The random sequence will be computer-generated and participants will be allocated in numerical order with sealed opaque envelopes. The attending anesthesiologist performs anesthesia strictly according to the research protocol and is also responsible for data during the preoperative, intraoperative and PACU period. The chief surgeon performs the postoperative laboratory testing. An independent researcher will be involved in postoperative follow-up and data collection. Statistical analysis will be performed by a statistician who does not participate in the data collection. Patients, research staff, surgeons, intensive care physicians and the statistician will be unaware of the group allocation. Some preoperative characteristics and laboratory results will automatically derived from a computer data base.
The original data (CRF and relevant records) will be maintained for 10 years and then destroyed according to hospital standards.
Selection of the participants
Patients scheduled for elective robot-assisted laparoscopic radical resection for bladder cancer or prostate cancer under general anesthesia will be screened and recruited during preoperative assessment. Patients meeting inclusion criteria will be required to provide their written informed consent. The participant can withdraw from the trial at any time.
Inclusion criteria are patients older than 18 y, American Society of Anesthesiologists (ASA) physical status I - III, body mass index (BMI) between 18-35 kg/m2.
Exclusion criteria are emergency surgery or history of previous lung surgery, history of mechanical ventilation within the 2 weeks before recruitment, non–invasive ventilation or oxygen therapy at home, acute respiratory failure (pneumonia, acute lung injury or acute respiratory distress syndrome), history of chronic obstructive pulmonary disease (COPD), persistent hemodynamic instability or severe cardiac disease (New York Heart Association class III or IV, or persistent ventricular tachyarrhythmia’s, or acute coronary syndrome), sepsis or septic shock, need renal replacement therapy (CRRT), progressive neuromuscular illness, pregnancy, participation in another study or refusal to participate.
Time course of the study
Medical history, ASA physical status, BMI, 12-lead ECG, laboratory results, chest X-ray or computed tomography (CT) scan, ARISCAT score (the Assess Respiratory Risk in Surgical Patients in Catalonia study, the Additional file 3) and nutritional risk screening (NRS 2002 tool), the results of echocardiography and spirometry (in cases of history of coronary artery disease or smoking) will be recorded.
A central venous catheter and an arterial cannula will be placed before induction of anesthesia. Peripheral oxygen saturation (SpO2), arterial blood pressure, heart rate (HR), ECG, end-tidal carbon dioxide tension (EtCO2) and bispectral index (BIS) will be monitored continuously. Pneumoperitoneum (PnP), tidal volume, PEEP, airway pressures including peak pressure and plateau pressure, airway resistance (Raw), Vds/Vt, core temperature, and arterial blood gas analysis data will be recorded.
Crystalloid (12-15ml/kg/h) was infused to maintain hemodynamic stability and central venous pressure 5-12 cm H2O. Blood loss and vasodilation was supplemented by colloidal fluid.
Routine anesthesia was induced with intravenous dexmedetomidine(1 ug/kg) or midazolam (0.05-0.075mg/kg), cisatracurium (2 mg/kg), propofol (2-3 mg/kg) and fentanyl (1-3 μ/kg) for tracheal intubation. Anesthesia was maintained with propofol, sevoflurane and remifentanil infusion to maintain the BIS 40-50 until skin suturing was completed. Cisatracurium (1.0-1.5 mg/kg) is administered every hour and is adjusted according to the anesthesiologist’s decision.
Ropivacaine is administrated as local anesthetic before and at the end of operation respectively. Fentanyl (1-3 μg/kg) and flurbiprofenaxetil 50 mg are required before remifentanil is stopped.
Patients will be transferred to the post anesthesia care unit (PACU) after surgery regardless of whether they are still intubated.
Postoperative pain management will be suggested to achieve a visual analogue scale (VAS) pain score of < 3/10 using a patient-controlled intravenous analgesia pump including fentanyl (0.3-0.5 μg/kg), flurbiprofenaxetil (100 mg) and palonosetron hydrochloride (0.25 mg) palazidine.
The ICU physician and surgeon will independently monitor clinical progress and all endpoints by daily physical examinations. Appropriate prophylactic antibiotics and antithrombotic treatments will be administered as required during the postoperative period. Chest X-ray or CT scanning will be performed when clinically indicated. Arterial blood gas analysis will be performed on POD 1 and POD 3 and other laboratory tests will performed on POD 1, POD 3, POD 5 and POD 7. The examinations will be repeated and microbiology tests will be performed when the development of pulmonary complications are suspected.
Study arms and intraoperative ventilation protocol
Patients will be randomly assigned to with the low PEEP ventilation group (PEEP ≤ 2 cm H2O) or the standard PEEP group (PEEP = 6-8 cm H2O) using a volume-controlled ventilation strategy (Datex Ohmeda S/5 Avance; GE Healthcare, Helsinki, Finland) with a tidal volume of 8 ml/kg ideal body weight (IBW), an inspired oxygen fraction (FiO2) of 0.50 and inspiratory to expiratory ratio of 1:2. Respiratory rate should be adjusted to maintain ETCO2 between 35 and 45 mmHg) and plateau pressure should be no more than 30 cmH2O. IBW is calculated with formulas as follows : 45.5 + 0.91 x (centimeters of height -152.4) for females and 50 + 0.91 x (centimeters of height - 152.4) for males. Recruitment maneuvers (RMs)  will be performed immediately after tracheal intubation and every time ventilator is interrupted until the end of surgery in each group. The compliance of the respiratory system will be calculated with the formulas of VT/ (plateau pressure of the respiratory system - PEEP).
Recruitment maneuvers will be performed as follows:
(1). Pressure support ventilation (PSV) mode
(2). Positive end-expiratory pressure (PEEP) set to 30 cm of water
(3). Inspiratory gas flow set to the highest value
(4). Duration of the maneuver = 30 sec
A rescue therapy will be applied in case of desaturation (defined as a peripheral SpO2 of less than 92%), consisting of increased FiO2 to 100% in each group and increasing PEEP in the low PEEP group (Additional file 4).
Primary outcome measure
The primary endpoint was PPCs including new atelectasis or infiltrates on a chest X-ray or CT scanning, respiratory failure defined as the need for noninvasive or invasive ventilation or partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) < 300 within 7 days after surgery .
Secondary outcome measures
Secondary outcome variables were any pulmonary complications and extrapulmonary complications as follows (Additional file 5):
1. Intraoperative complications: pneumothorax confirmed by chest X-ray and any other complications.
2. Postoperative pulmonary complications (PPCs) within 30 days after surgery. Those PPCs are scored according to a grading scale ranging from 0 to 4  (grade 0 representing no PPCs and grades 1 to 4 representing gradually worse forms of PPCs) within 7 and 30 days after surgery (Table 1).
3. Postoperative pulmonary complications will also be analyzed separately (Table 1).
(1) Pneumonia is defined according to Centers for Disease Control (CDC) criteria ;
(2) Purulent sputum;
(3) Postoperative hypoxemia and severe hypoxemia ;
(4) Suspected pulmonary infection is described in a previous study ;
(5) Pulmonary infiltrate is defined according to consensus guidelines: Chest X–ray demonstrating monolateral or bilateral infiltrate.
(6) Atelectasis, pleural effusion or pneumothorax are identified by chest X-ray.
(7) The modified clinical pulmonary infection score (mCPIS) is calculated as previously described  (Table 2).
(8) Suspected pulmonary complications ;
(9) Requirement for postoperative ventilation (respiratory failure that requires noninvasive and/or invasive ventilation) for at any time after surgery according to standard criteria and clinical practice guidelines .
4. Postoperative extrapulmonary complications within 30 days after surgery:
(1) Systemic inflammatory response syndrome (SIRS) criteria ;
(2) Sepsis and severe sepsis ;
(3) Septic shock ;
(4) Other extrapulmonary infection including surgical site infection (SSI)  and intraabdominal abscess;
(5) Need for postoperative blood transfusion.
(6) Postoperative surgical complications: anastomotic leakage and need for surgical reintervention, defined according to consensus criteria .
(7) Unexpected intensive care unit (ICU) admission or readmission.
(8) ICU length of stay and hospital length of stay.
(9) Hospital free-days at follow-up day 30.
(10) In-hospital mortality and thirty-day mortality (all-cause mortality 30 days after randomization).
From postoperative day 7 (POD 7 to POD 30, follow-up)
Secondary endpoints and any mortality will also be evaluated during the follow-up period. The CONSORT flowchart of the trial is shown in Figure 2.
Data monitoring and Handling of implausible values or missing values: A clinical investigator will identify implausible values. Missing continuous variables should be less than 10% and will be replaced by median. Missing values will be replaced by the mean of all plausible data (both groups) of the respective endpoint. Data monitoring is managed by an independent investigator who is not involved in the study. The progress of the study will be evaluated and the completeness and accuracy of the data (Informed Consent Forms, source data, CRF and outcome variables) will be verified.
Normally distributed variables will be expressed as the mean ± standard deviation (SD) and will be compared with the Student’s t-test. Categorical variables will be compared using the chi-square test or the Fisher’s exact test. Non-normal continuous variables will be expressed as median (interquartile range (IQR)) and evaluated with the Mann-Whitney U-test. Intention-to-treat (ITT) analyses are performed to compare the composite outcome measure at 7 days in the two groups by the chi-squared test (or Fisher’s exact test as appropriate) and multiple logistic regression analysis adjusting will be performed to identify various risk factors (for the primary outcome and the pulmonary complications at postoperative Day 30). Adjusted analyses were performed with the use of robust Poisson generalized-linear-model regression for continuous outcomes and are presented as relative risks with 95% confidence intervals. P <0.05 will be considered statistically significant and all reported p values will be 2-sided. Interim analysis of safety will be conducted after enrolment of the first 200 patients. All analyses will be conducted using the SPSS Version 18.0 (SPSS, Chicago, IL, USA) software.
Sample size calculation
The incidence rate of postoperative pulmonary complications was 39% in the low PEEP group . Two tailed chi-squared test was performed and we estimated that 188 patients were required to provide 90% power to detect a 50% relative difference between the two groups (39% to 20%), with a type I error probability of 0.05. Assuming that follow-up lost rate was 10 %, and then a total of 208 cases are needed. Analysis was computed using G-Power (version 3.1; Informer Technologies, Inc.).
Adverse events and interruption of the trial:
All patients will be continuously monitored during the study including daily visits during in-hospital and daily phone-call visits during the out of hospital follow-up period (until POD 30). All serious adverse, unexpected or possibly related events will be recorded in the CRF and will be reported to the data monitoring and safety committee (DMSC). DMSC will recommend that the study must be stopped unless there is evidence that patient will safety (a between-group difference in serious adverse events or in 30- day mortality is found).