Highlights
The PROTHOR trial found that higher PEEP (10 cm H2O) combined with recruitment manoeuvres during one-lung ventilation did not significantly reduce the incidence of postoperative pulmonary complications compared to a lower PEEP (5 cm H2O) strategy. While the high PEEP group experienced fewer intraoperative hypoxaemia rescue manoeuvres, this benefit was offset by a significantly higher rate of intraoperative hemodynamic complications, including hypotension and new-onset arrhythmias. The findings suggest that a standardized high PEEP strategy is not warranted for thoracic surgery patients with a BMI under 35 kg/m2, emphasizing the need for individualized hemodynamic and respiratory management.
Background: The Challenge of One-Lung Ventilation
Thoracic surgery presents a unique physiological challenge for anesthesiologists: the requirement for one-lung ventilation (OLV). During OLV, the non-dependent lung is intentionally collapsed to provide a quiet surgical field, while the dependent lung must handle the entire minute ventilation and cardiac output. This setup inherently predisposes patients to several pathological processes, including atelectasis in the dependent lung, ventilation-perfusion (V/Q) mismatch, and potential barotrauma or volutrauma.
For years, the cornerstone of intraoperative lung protection has been the use of low tidal volumes. However, the optimal level of positive end-expiratory pressure (PEEP) and the utility of periodic lung recruitment manoeuvres (RM) have remained subjects of intense debate. Proponents of high PEEP and RM argue that opening the lung and keeping it open prevents atelectasis and reduces inflammatory lung injury. Conversely, skeptics suggest that excessive PEEP may cause overdistension of healthy alveoli, impede venous return, and increase right ventricular afterload, leading to hemodynamic instability without necessarily improving postoperative outcomes. The PROTHOR trial was designed to provide a definitive, large-scale investigation into these competing strategies.
Study Design and Methodology
The PROTHOR trial was a multicentre, international, randomised, controlled, phase 3 trial conducted across 74 sites in 28 countries. It enrolled 2,200 adult patients with a BMI less than 35 kg/m2 undergoing open thoracic or video-assisted thoracoscopic surgery (VATS). A key inclusion criterion was the requirement for OLV using a double-lumen tube for a planned duration of more than 60 minutes.
Patients were randomly assigned in a 1:1 ratio to one of two groups:
The High PEEP Group
This group received a PEEP of 10 cm H2O during OLV, supplemented by periodic lung recruitment manoeuvres. The goal was active lung expansion to prevent atelectasis.
The Low PEEP Group
This group received a PEEP of 5 cm H2O without routine recruitment manoeuvres. This strategy essentially allowed for permissive atelectasis unless clinical hypoxaemia mandated intervention.
All patients in both groups received lung-protective tidal volumes: 5 mL/kg of predicted body weight (PBW) during OLV and 7 mL/kg PBW during two-lung ventilation. The primary endpoint was a composite of postoperative pulmonary complications (PPCs) within the first five postoperative days, including ARDS, pneumonia, pleural effusion, atelectasis, and prolonged air leak.
Key Findings: No Superiority for High PEEP
The results of the PROTHOR trial challenge the traditional advocacy for aggressive lung recruitment during thoracic surgery.
Primary Outcome: Postoperative Pulmonary Complications
In the modified intention-to-treat analysis, the primary composite outcome of PPCs occurred in 53.6% (555 of 1,036) of patients in the high PEEP group and 56.4% (592 of 1,049) of patients in the low PEEP group. The absolute risk difference was -2.68 percentage points, which did not reach statistical significance (p=0.155). This suggests that the more aggressive lung expansion strategy did not provide a meaningful clinical advantage in preventing postoperative respiratory issues.
Safety and Hemodynamic Consequences
While the primary outcomes were similar, the safety profiles of the two strategies differed significantly. Intraoperative complications were substantially more frequent in the high PEEP group (49.8% vs. 31.3%). Specific hemodynamic issues were more prevalent with high PEEP: hypotension occurred in 37.3% of the high PEEP group compared to only 14.3% in the low PEEP group, and new arrhythmias were observed in 9.9% of the high PEEP group versus 3.9% in the low PEEP group. These findings underscore the significant cardiovascular strain imposed by higher intrathoracic pressures and recruitment manoeuvres.
Intraoperative Oxygenation
There was one area where the high PEEP strategy showed a statistical advantage: the need for hypoxaemia rescue manoeuvres. Only 3.3% of patients in the high PEEP group required rescue manoeuvres for low oxygen levels, compared to 8.8% in the low PEEP group. This indicates that while 10 cm H2O of PEEP and recruitment manoeuvres do improve intraoperative oxygenation, this physiological benefit does not translate into better postoperative outcomes.
Expert Commentary and Clinical Implications
The PROTHOR trial provides high-level evidence that a fixed strategy of high PEEP and recruitment manoeuvres is not a universal solution for thoracic surgery. For clinicians, these results suggest several critical takeaways.
Individualized vs. Standardized PEEP
The trial highlights the danger of standardized protocols that do not account for individual patient physiology. While 10 cm H2O might be appropriate for some, for many it leads to unnecessary hemodynamic instability. The study authors suggest that the choice between lung expansion and permissive atelectasis should be dynamic, taking into account real-time gas exchange and hemodynamic status.
The Open Lung Paradox
The concept of the open lung is attractive in theory, but the PROTHOR data suggests that for non-obese patients, the closed parts of the lung might be less harmful than the cardiovascular consequences of the pressure required to open them. The lack of difference in extrapulmonary complications further suggests that the systemic inflammatory response was not significantly modulated by the PEEP strategy.
Limitations and Generalizability
It is important to note that the trial excluded patients with a BMI of 35 kg/m2 or higher. In obese patients, the chest wall compliance is lower, and the pressure required to overcome atelectasis is generally higher. Therefore, the findings of PROTHOR may not be generalizable to the morbidly obese population. Additionally, the study used a fixed PEEP of 10 cm H2O; it remains unknown whether PEEP titrated to individual lung compliance would yield different results.
Conclusion
The PROTHOR trial represents a milestone in thoracic anesthesia research. By demonstrating that a high PEEP and recruitment manoeuvre strategy does not reduce PPCs and significantly increases the risk of hypotension and arrhythmias, it shifts the focus away from aggressive recruitment toward more balanced, individualized care. For the majority of non-obese patients undergoing thoracic surgery, a lower PEEP of 5 cm H2O appears to be safe and is associated with greater hemodynamic stability.
Funding and Registration
The PROTHOR trial was funded by the Clinical Trials Network of the European Society of Anaesthesiology and Intensive Care (ESAIC), the University Hospital Carl Gustav Carus (Dresden, Germany), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brazil), and the Association of Anaesthetists of GB and Ireland. The trial is registered at ClinicalTrials.gov (NCT02963025).
Reference：
PROtective VEntilation Network (PROVE Network) for the Clinical Trial Network of the European Society of Anaesthesiology and Intensive Care. Effects of intraoperative higher versus lower positive end-expiratory pressure during one-lung ventilation for thoracic surgery on postoperative pulmonary complications (PROTHOR): a multicentre, international, randomised, controlled, phase 3 trial. Lancet Respir Med. 2026 Jan;14(1):17-28. doi: 10.1016/S2213-2600(25)00330-3.
