Protective intraoperative ventilation with higher versus lower levels of positive end-expiratory pressure in obese patients (PROBESE): study protocol for a randomized controlled trial

Background Postoperative pulmonary complications (PPCs) increase the morbidity and mortality of surgery in obese patients. High levels of positive end-expiratory pressure (PEEP) with lung recruitment maneuvers may improve intraoperative respiratory function, but they can also compromise hemodynamics, and the effects on PPCs are uncertain. We hypothesized that intraoperative mechanical ventilation using high PEEP with periodic recruitment maneuvers, as compared with low PEEP without recruitment maneuvers, prevents PPCs in obese patients. Methods/design The PRotective Ventilation with Higher versus Lower PEEP during General Anesthesia for Surgery in OBESE Patients (PROBESE) study is a multicenter, two-arm, international randomized controlled trial. In total, 2013 obese patients with body mass index ≥35 kg/m2 scheduled for at least 2 h of surgery under general anesthesia and at intermediate to high risk for PPCs will be included. Patients are ventilated intraoperatively with a low tidal volume of 7 ml/kg (predicted body weight) and randomly assigned to PEEP of 12 cmH2O with lung recruitment maneuvers (high PEEP) or PEEP of 4 cmH2O without recruitment maneuvers (low PEEP). The occurrence of PPCs will be recorded as collapsed composite of single adverse pulmonary events and represents the primary endpoint. Discussion To our knowledge, the PROBESE trial is the first multicenter, international randomized controlled trial to compare the effects of two different levels of intraoperative PEEP during protective low tidal volume ventilation on PPCs in obese patients. The results of the PROBESE trial will support anesthesiologists in their decision to choose a certain PEEP level during general anesthesia for surgery in obese patients in an attempt to prevent PPCs. Trial registration ClinicalTrials.gov identifier: NCT02148692. Registered on 23 May 2014; last updated 7 June 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-1929-0) contains supplementary material, which is available to authorized users.


Rationale
Postoperative respiratory failure, particularly after surgery under general anesthesia, adds to the morbidity and mortality of surgical patients. Anesthesiologists inconsistently use positive end-expiratory pressure (PEEP) and recruitment maneuvers in the hope that this may improve oxygenation and protect against postoperative pulmonary complications (PPCs), especially in obese patients. While it is uncertain whether a strategy that uses higher levels of PEEP with recruitment maneuvers truly prevents PPCs in these patients, use of higher levels of PEEP with recruitment maneuvers could compromise intra-operative hemodynamics.

Objectives
To compare a ventilation strategy using higher levels of PEEP with recruitment maneuvers with one using lower levels of PEEP without recruitment maneuvers in obese patients at an intermediate-to-high risk for PPCs.

Hypotheses
An intra-operative ventilation strategy using higher levels of PEEP and recruitment maneuvers, as compared to ventilation with lower levels of PEEP without recruitment maneuvers, prevents PPCs in obese patients at an intermediate-to-high risk for PPC.

Study design
International multicenter randomized controlled trial.

Study population
Obese patients with BMI ≥ 35 kg/m 2 at intermediate-to-high risk for PPCs scheduled for surgery under general anesthesia.

Main study parameters/endpoints
The primary endpoint is the proportion of patients with PPCs. Secondary endpoints include intra-operative complications, need for postoperative ventilatory support (invasive and/or non-invasive ventilation), need for unexpected ICU admission or ICU readmission, the number of hospital-free days and 90-day survival/mortality.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness
In the intra-operative period, patients will not experience discomfort from either strategy because of general anesthesia. However, systemic hypotension could occur in the higher PEEP group, which would be treated with intravascular volume therapy and/or vasoactive drugs. If the hypothesis proves to be true, patients in the higher PEEP group could benefit from a lower incidence of PPCs. Blood samples will be collected via an existing intravenous catheter or via direct vein puncture, but always in combination with blood sampling for routine care; the amount of additional blood samples can be considered minimal.

Postoperative pulmonary complications
Postoperative pulmonary complications, especially postoperative respiratory failure, add to the morbidity and mortality of surgical patients 1,2 . An ARISCAT score ≥ 26 is associated with an intermediate-to-high risk of postoperative pulmonary complications (PPCs), independent of BMI 3 .

Ventilator-associated lung injury
Even though mechanical ventilation is a life-saving strategy in patients with respiratory failure and frequently necessary during general anesthesia, both experimental 4-6 and clinical [7][8][9] studies show that mechanical ventilation has the potential to aggravate or even initiate lung injury (so-called ventilator-associated lung injury, VALI). Repetitive collapse/reopening of lung units (atelectrauma) and overdistension of lung units (volutrauma) are possible mechanisms underlying VALI [10][11][12] . While positive end-expiratory pressure (PEEP) can minimize atelectrauma, lower tidal volumes are thought to reduce volutrauma. One metaanalysis showed that use of lower tidal volumes is associated with a better outcome for patients with uninjured lungs 13 . This study included both surgery patients who underwent mechanical ventilation for general anesthesia as well as critically ill patients who required longer mechanical ventilation. Notably, a more recent meta-analysis showed a decrease in lung injury development, pulmonary infection and atelectasis in patients receiving intraoperative mechanical ventilation with both lower tidal volumes and higher levels of PEEP 14 .

Postoperative pulmonary complications and mechanical ventilation
Mechanical ventilation is frequently required in patients undergoing surgery. Our group has shown that an intraoperative ventilation strategy with lower tidal volume and positive endexpiratory pressure (PEEP) may improve postoperative lung function 15

Mechanical ventilation in obese patients
According to Pelosi and Gregoretti 19 , body mass is an important determinant of respiratory function before and during anesthesia not only in morbidly, but also in moderately obese patients. The impairment can manifest as (a) reduced lung volume with increased atelectasis and/or small airway closure; (b) derangements in respiratory system, lung and chest wall

Hypothesis
We hypothesize that an intra-operative ventilation strategy using higher levels of PEEP and centers to participate in the trial. Surgical patients in these centers will be screened daily.
Demographic data on screened patients, regardless of enrollment criteria match, will be recorded (registry). We will randomize 2013 patients admitted to the participating centers and expect each participating center to randomize at least 24 patients who meet all inclusion criteria.

Other study parameters
 Systemic levels of markers of (pulmonary) inflammation  Systemic levels of markers of lung injury  Systemic levels of markers of distal organ injury

Study procedures
Surgical patients in participating centers will be considered eligible if they fulfill the entry criteria. Eligible patients will be screened, their demographic data recorded (registry: age, gender, type of surgery), and those without exclusion criteria will be randomized. In total, 748 patients will be included.

Patient Consent
All patients or legal guardians must provide written informed consent according to local regulations before inclusion in the study.

Randomization procedure
Randomization will be performed using a dedicated website and will be balanced per center.
Randomization must take into account the risk of developing pulmonary complications (ARISCAT, see APPENDIX i.) to assure a balance for both intermediate and high-risk subgroups.

Randomization arms
Central randomization with the use of a permutated-block randomization list (block length 6) will be used. Before surgery patients will be randomly assigned 1:1 to mechanical ventilation with PEEP of 4 cmH 2 O without recruitment maneuvers (the "lower PEEP level") or mechanical ventilation with PEEP of 12 cmH 2 O with the use of recruitment maneuvers (the "higher PEEP level"). If desaturation, defined as SpO 2 ≤ 92% for > 1 min, occurs, rescue is At each site at least two investigators will be involved: one who will be aware of the allocated intervention and collect intra-operative data; the other who will remain blinded to the intraoperative interventions and evaluate the outcomes, scoring postoperative pulmonary and extrapulmonary complications.

Mechanical ventilation
Mechanical ventilation will be administered through the anesthesia ventilators in use in each individual center participating in the study. Patients will undergo volume-controlled mechanical ventilation with the lowest possible oxygen fraction (but at least 0.4) to maintain an oxygen saturation of 93% or higher, an inspiratory to expiratory ratio (I:E) of 1:2 and a respiratory rate adjusted to normocapnia (end-tidal carbon dioxide partial pressure between 35 and 45 mmHg). It is left to the discretion of the attending anesthesiologist to use a higher fraction of inspired oxygen.
Tidal volume will be set to 7 ml/kg Ideal Body Weight (IBW

Recruitment maneuver
The recruitment maneuver, as part of the protective strategy, will be performed directly after induction of anesthesia, after any disconnection from the mechanical ventilator, every one hour during surgery, and before end of surgery, in a hemodynamically stable situation as 8.

Protocol deviation
Anesthesiologists may deviate from the ventilation protocol at any time if concerns about the patient's safety arise, or upon the surgeon's request.
If one of the following complications occurs and is unresponsive to specific conventional therapy, PEEP may be modified according to the anesthesiologist's judgment:  Systolic arterial pressure lower than 90 mmHg for more than three minutes and unresponsive to fluids and/or vasoactive drugs In case of desaturation (SpO 2 ≤ 92%) of a patient in the higher PEEP level group, it is crucial to exclude hemodynamic impairment as a possible cause. Also, airway problems, auto-PEEP, and ventilator malfunction must be ruled out as possible causes.
Provided those factors are excluded, a rescue strategy is allowed according to the following table: Step* FIO 2 PEEP   To perform postoperative pain management in order to achieve a VAS pain score below 3. Regional or neuraxial analgesia should be used whenever indicated

Pre-operative variables
Pre-operative variables will be collected at the pre-anesthetic visit or before induction of general anesthesia:

Induction variables
During anesthesia induction, patient's position and use of CPAP or NPPV will be documented.

Intra-operative variables
During the intra-operative period, the following variables will be recorded (variables are to be measured after induction, hourly and immediately before and after recruitment maneuvers):  Duration of anesthesia procedure; from tracheal intubation to extubation or exit from operation room (in case patient remains on mechanical ventilation); minutes  Other event, specify:

Post-operative variables
The patients will be assessed daily between the first and the fifth day after surgery as well as on the last day before discharge from hospital. Clinical data and the presence of pulmonary and extra-pulmonary postoperative complications will be scored, the date of development of any complication documented (for definitions, see APPENDIX iii.).
The documentation will adhere to the timetable in APPENDIX iv.

Blood and urine samples
Before, at the end of, and five days after surgery, blood samples (2 x 5 ml in EDTA, citrate and heparin) and urine samples will be collected and stored at -80°C for measurement of:

Descriptive statistics
Patient characteristics will be compared and described by appropriate statistics.

Analysis
The  For the primary efficacy analysis rates of postoperative pulmonary complications will be compared between the two intervention groups and the odds ratio relative risks with corresponding 95% confidence levels interval will be calculated using logistic regression analysis.
With regard to the remaining parameters: Normally distributed variables will be expressed by their mean and standard deviation; non-normally distributed variables will be expressed by their medians and interquartile ranges. Categorical variables will be expressed as n (%).
Student's t-test will be used to test groups of continuous normally distributed variables.
Conversely, if continuous data is non-normally distributed, the Mann-Whitney-U test will be used. Categorical variables will be compared with the Chi-square test, Fisher's exact tests or, where appropriate, as relative risks. Time dependent data will be analyzed using a proportional hazard model adjusted for possible imbalances of patients' baseline characteristics.
Data analyses will follow an a priori documented statistical analysis plan which will be finalized before the end of data collection. By definition, only the analysis of the primary outcome is confirmatory, all other analyses are exploratory. The analysis strategy follows the intention-to-treat principle. The analysis will be undertaken blinded by a statistical expert.
Statistical significance is considered to be at a p-value of 0.05. Where appropriate, statistical uncertainty will be expressed by 95% confidence levels.
The analysis will be performed with SPSS.

Data Safety Management Board (DSMB)
The DSMB will be composed of five individuals, one of whom will be the chairperson.  The DSMB will first convene after the first 100 patients  Subsequently, the DSMB will attend videoconferences every six months  All adverse events will be reported to the DSMB for review. All serious events will be reported within 24 hours after being received by the coordinating center. Non-serious events will be reported within one week of reception by the coordinating center

Cumulated Ambulation Score (CAS)
The patient is assessed on the following functions: . Transfer from supine-to-sitting-to-supine . Transfer from sitting-to-standing-to-sitting (from armchair) . Walking (with appropriate walking aid) Each function is scored as follows: . Able to perform function independently -2 . Only able to perform function with assistance from one or two people -1 . Unable to perform function despite assistance from two people -0 The CAS is calculated as the sum of values on a given day.   APPENDIX v.

Definitions
An adverse event (AE) is generally defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding) syndrome or disease which either occurs during the study, having been absent at baseline, or if present at baseline, appears to worsen. Adverse events are to be recorded regardless of their relationship to the study intervention. With respect to intensity, adverse events are classified as follows: • Mild some awareness of symptoms, but easily tolerated; • Moderate symptoms causing enough discomfort to interfere with usual activity; • Severe incapacitating event causing inability to work or to perform usual activity.
A Serious Adverse Event (SAE) is defined as any experience that suggests a significant hazard or side effect with respect to participants participating in a clinical study. This includes any experience which: • is fatal or life threatening, • is permanently disabling, i.e. incapacitating or interfering with the ability to resume normal life patterns, • requires hospitalisation or prolongation of hospitalisation, • requires other medically important circumstance (requires medical treatment to avoid one of the above mentioned conditions).
A special form of the SAE is the Suspected Unexpected Serious Adverse Reaction (SUSAR).
Adverse events possibly occurring during this study include but are not limited to unexpected death, inadvertent extubation, development of hemodynamic compromise during a recruitment maneuver or PEEP adjustment, sudden hypoxemia, hypercarbia or a pneumothorax during changes in ventilator setting in either the control or treatment group

Documentation of AEs and SAEs
All adverse events that occur between start of randomized intervention and 90-days follow information about relationship to study intervention, overall intensity and outcome of the adverse event.

Reporting of Adverse Events
Reporting responsibilities of the local coordinator Any AE occurring after start of randomized study intervention will be reported. The participant will be followed until remission of the symptoms. When reporting an AE/SAE, a clinical narrative on each AE/SAE should be added, which gives the clinical context of the event and allows the DSMB to carefully review the AE/SAEs.
AEs are reported via electronic CRF within one week of reception by the coordinating center.
SAEs as well as all related or possibly related events and all unexpected events are reported via electronic CRF within 24 hours after being received by the coordinating center. In case of a SUSAR (suspected unexpected serious adverse reaction) as well as death of study patients the SAE manager has to be informed additionally by email.

Management of AE/SAE
SAE manager: Ary Serpa Neto, MD, MSc, Amsterdam, The Netherlands The SAE manager collects and judges the reports within predefined time frames. All related or possibly related events and all unexpected events are forwarded to the DSMB for further review. The DSMB members assess forwarded events and review all SAE and AE from all centers every 6 months or sooner if requested by them. If the DSMB rates an event to be related to the study therapy, the DSMB should inform the principle investigator.
In case of a SUSAR (suspected unexpected serious adverse reaction) as well as death of study patients the ethics committee of Dresden University will be informed within 7 days.
Additionally a summary of all SAE will be provided twice per year.