PROtective Ventilation With FLOW-Controlled Ventilation to Improve Postoperative Pulmonary Outcome After THORACic Surgery - an International Multicenter Pilot Randomized Clinical Trial
PROtective Ventilation With FLOW-Controlled Ventilation to Improve Postoperative Pulmonary Outcome After THORACic Surgery - an International Multicenter Pilot Randomized Clinical Trial
In an international multicenter randomized clinical pilot trial, intraoperative flow-controlled ventilation (FCV) will be compared with volume-controlled ventilation (VCV) in patients scheduled for (open, video- or robot-assisted) thoracic surgery with one-lung ventilation (OLV). This pilot trial is designed to test the feasibility and safety of FCV during all phases of intraoperative ventilation, and in particular during OLV, and to inform the design of a future trial testing the efficacy of FCV with regard to postoperative outcomes, including postoperative pulmonary complications (PPC).
The ventilation modes are conducted with CE-marked medical devices (anesthesia ventilators or medical ventilators), however these medical devices themselves are not under investigation. All CE-marked standard medical devices from varied manufacturers in use at the participating study centers will be used in full accordance with their instructions for use. FCV has shown safety and feasibility in various surgical settings, including thoracic surgery with OLV, however its feasibility in a multicenter trial has not been investigated yet.
The PROFLOW-THORACic pilot trial is an international multicenter randomized clinical pilot trial designed to evaluate the feasibility and safety of flow-controlled ventilation (FCV) during thoracic surgery requiring one-lung ventilation (OLV). The study specifically investigates whether FCV can be consistently and safely applied during all phases of intraoperative ventilation, particularly during OLV, across multiple international centers, and whether the study protocol itself is feasible for a future large-scale randomized clinical trial evaluating postoperative pulmonary outcomes. The trial further aims to generate exploratory clinical data regarding postoperative pulmonary complications (PPCs) and to provide the methodological foundation for a definitive efficacy trial. The study protocol was developed by the Department of Anaesthesiology, Rescue- and Pain Medicine at HOCH Health Ostschweiz, Cantonal Hospital St. Gallen, Switzerland, in collaboration with several international thoracic anesthesia centers.
Postoperative pulmonary complications remain among the most important causes of perioperative morbidity and mortality following thoracic surgery. Patients undergoing open, video-assisted, or robot-assisted thoracic procedures are particularly susceptible to pulmonary injury because of the physiologic challenges associated with OLV. During OLV, only one lung is ventilated while the contralateral lung is intentionally collapsed to facilitate surgical exposure. This results in reduced functional lung volume, impaired respiratory mechanics, ventilation-perfusion mismatch, increased airway pressures, and heterogeneous ventilation distribution. Despite advances in perioperative care and the implementation of lung-protective ventilation strategies using lower tidal volumes and moderate levels of PEEP, PPCs remain frequent after thoracic surgery and are associated with prolonged hospitalization, increased ICU admission, and higher mortality. Conventional ventilation strategies during OLV often require elevated inspired oxygen concentrations, recruitment maneuvers, and adjustments of airway pressures to maintain adequate oxygenation, potentially contributing to ventilator-induced lung injury, atelectasis, hemodynamic instability, and cyclic alveolar collapse.
Flow-controlled ventilation represents a novel ventilation mode that fundamentally differs from conventional pressure- or volume-controlled ventilation. FCV delivers constant inspiratory and expiratory flow throughout the entire respiratory cycle, resulting in linear changes in airway pressure and volume. In contrast to conventional ventilation modes, expiration during FCV is actively controlled rather than passive. Experimental and early clinical studies suggest that FCV may improve lung recruitment, optimize ventilation homogeneity, reduce cyclic alveolar collapse, and improve gas exchange. Preclinical studies demonstrated reductions in inflammatory lung injury and improved respiratory mechanics, while small clinical studies in obese patients and thoracic surgery patients reported improved oxygenation and carbon dioxide elimination compared with conventional ventilation. However, current evidence remains limited to small physiologic studies and single-center experiences. Therefore, before conducting a larger efficacy trial evaluating the impact of FCV on patient-centered postoperative outcomes, the feasibility and safety of implementing FCV in a multicenter thoracic surgery setting must first be established.
The PROFLOW-THORACic pilot trial is designed as a prospective, randomized, controlled pilot study involving multiple international centers in Switzerland, Austria, Germany, France, and the Netherlands. A total of 140 patients undergoing elective thoracic surgery requiring OLV will be enrolled. Patients will be randomized in a 1:1 ratio to either receive FCV or conventional volume-controlled ventilation (VCV). Randomization will be stratified by center using a block randomization process. The study follows a single-blinded design in which patients remain blinded to group allocation, while anesthesiologists cannot be blinded because different ventilators are required for the two ventilation strategies.
Eligible participants are adult patients aged 18 years or older who are scheduled for elective open, video-assisted, or robot-assisted thoracic surgery requiring OLV using a double-lumen tube and who are able to provide written informed consent. Major exclusion criteria include severe pulmonary disease such as COPD GOLD stage III or IV, severe emphysema, pulmonary fibrosis, pulmonary hypertension, previous lung surgery, planned postoperative mechanical ventilation, severe cardiac disease, intracranial pathology, bilateral thoracic procedures, pregnancy, and pre-existing severe respiratory failure or hypercapnia. The study specifically excludes patients with conditions that could substantially increase perioperative respiratory risk or interfere with interpretation of pulmonary outcomes.
All patients receive standard perioperative anesthesia care according to institutional practice. General anesthesia is induced and maintained using total intravenous anesthesia, and quantitative neuromuscular monitoring is mandatory. Double-lumen tube placement is confirmed according to local standards. Routine perioperative monitoring includes electrocardiography, invasive blood pressure monitoring, pulse oximetry, capnography, and respiratory mechanics monitoring.
Patients randomized to the intervention group receive FCV using the EVONE ventilator system. During FCV, ventilation parameters are individualized based on dynamic respiratory compliance. Ventilation starts with a PEEP of 5 cmH2O and a peak inspiratory pressure of 15 cmH2O. PEEP and peak inspiratory pressure are subsequently titrated stepwise to identify the combination associated with highest tidal volume and best dynamic compliance. Inspiratory-to-expiratory ratio is set at 1:1, and inspiratory flow is adjusted to maintain normocapnia with target end-tidal CO2 values between 4.5 and 5.8 kPa. FiO2 is adjusted to maintain peripheral oxygen saturation above 92%. Recruitment maneuvers are not routinely performed during FCV. Rescue crossover to conventional ventilation is allowed in cases of technical malfunction or clinically relevant respiratory compromise that cannot be corrected by adjusting FCV parameters.
Patients randomized to the control group receive conventional lung-protective VCV using standard anesthesia ventilators routinely used at participating centers. Tidal volume is set at 7-9 ml/kg predicted body weight during two-lung ventilation and 5-6 ml/kg predicted body weight during OLV. Respiratory rate is adjusted to maintain normocapnia, inspiratory-to-expiratory ratio is maintained between 1:1 and 1:2, and ventilation is initiated with a PEEP of 5 cmH2O. Additional ventilatory adjustments are left to the discretion of the attending anesthesiologist according to institutional practice. The control strategy was intentionally designed pragmatically to reflect current standard perioperative care and because the pilot study focuses primarily on feasibility rather than efficacy comparisons.
The primary outcome of the pilot study is a composite feasibility endpoint evaluating adherence to the assigned ventilation strategy and protocol implementation. This includes correct application of predefined ventilator settings, successful compliance-guided titration during FCV, correct implementation of VCV settings, adherence to FiO2 targets and respiratory monitoring requirements, and documentation of protocol deviations. In addition, surgeons assess the influence of ventilation on overall surgical conditions, visibility within the surgical field, and motion artifacts caused by mechanical ventilation using a seven-point Likert scale ranging from "very poor" to "excellent." A predefined traffic-light system is used to determine progression toward a larger trial. Protocol adherence above 80% is considered acceptable for progression, adherence between 40% and 80% suggests that modifications are required before proceeding, and adherence below 40% would indicate that the trial should not progress further in its current form.
Secondary outcomes focus on safety and protocol feasibility. Safety assessments include hourly measurements of arterial oxygenation and carbon dioxide levels, continuous pulse oximetry and capnography, ventilator parameters such as tidal volume, respiratory rate, driving pressure, compliance, and mechanical power, as well as hemodynamic variables including hypotension, vasopressor requirements, and arrhythmias. Respiratory complications such as severe atelectasis and pneumothorax are documented. Protocol feasibility assessments include recruitment and randomization feasibility, completeness of electronic case report form documentation, and adherence to study procedures across participating centers.
Exploratory clinical outcomes include the incidence of PPCs during the first seven postoperative days or until discharge. PPCs are assessed using standardized definitions and include atelectasis, pneumonia, respiratory failure, pleural effusion, pulmonary embolism, pneumothorax, ARDS, aspiration pneumonitis, reintubation, bronchospasm, empyema, unplanned postoperative ventilation, bronchoscopy, and surgical re-intervention related to pulmonary complications. These exploratory outcomes are intended to provide estimates for future sample size calculations and to identify clinically relevant endpoints for the definitive trial.
The planned sample size of 140 patients was selected based on feasibility considerations rather than statistical power for clinical outcomes. The sample size corresponds to approximately ten patients per treatment arm at each participating center and is considered sufficient to evaluate multicenter protocol adherence, safety, and variability of exploratory outcomes. Statistical analyses will primarily be descriptive and exploratory, following the intention-to-treat principle. Results will be summarized using descriptive statistics, proportions, mean differences, and confidence intervals. A comprehensive statistical analysis plan will be finalized before closure of the study database.
The study will be conducted in accordance with the Declaration of Helsinki, ICH-GCP guidelines, Swiss Human Research Act requirements, and country-specific regulatory standards. The study is classified as a low-risk interventional clinical trial because all ventilators are CE-certified and used within their approved indications. Written informed consent is obtained from all participants prior to enrollment. Adverse events and serious adverse events are continuously monitored and documented throughout the study. Particular attention is paid to severe hypoxemia, hypercapnia, hemodynamic instability, rescue ventilation requirements, and respiratory complications.
The PROFLOW-THORACic pilot trial is expected to provide essential multicenter feasibility and safety data regarding the perioperative use of FCV during thoracic surgery with OLV. The study will identify operational challenges, provide estimates for protocol adherence and variability of physiologic outcomes, and generate exploratory clinical outcome data that will guide the development of a future large-scale randomized controlled trial investigating whether FCV can reduce postoperative pulmonary complications after thoracic surgery.
Inclusion Criteria:
Exclusion Criteria:
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