Protective ventilation with high versus low positive end-expiratory pressure during one-lung ventilation for thoracic surgery (PROTHOR): study protocol for a randomized controlled trial

T Kiss, J Wittenstein, C Becker, K Birr, G Cinnella, E Cohen, M R El Tahan, L F Falcão, C Gregoretti, M Granell, T Hachenberg, M W Hollmann, R Jankovic, W Karzai, J Krassler, T Loop, M J Licker, N Marczin, G H Mills, M T Murrell, V Neskovic, Z Nisnevitch-Savarese, P Pelosi, R Rossaint, M J Schultz, A Serpa Neto, P Severgnini, L Szegedi, T Vegh, G Voyagis, J Zhong, M Gama de Abreu, M Senturk, PROTHOR investigators, Research Workgroup PROtective VEntilation Network (PROVEnet) of the European Society of Anaesthesiology (ESA), Vojislava Neskovic, Nevena Radovic, Goran Rondovic, Dusica Stamenkovic, Rade Vukovic, Snjezana Zeba, Rolf Rossaint, Mark Coburn, Ana Kowark, Sebastian Ziemann, Julia van Waesberghe, Wolfgang Bauer, Lotte Terwindt, Kostas Kostopanagiotou, Andreas Kostroglou, Katerina Kyttari, Tatiana Sidiropoulou, María-José Jiménez Andújar, Manuel López-Baamonde, Ricard Navarro Ripoll, Lorena Rivera Vallejo, Matthew Henry, Anita Jegarl, Matthew Murrell, Patrick O'Hara, Michele Steinkamp, Jens Kraßler, Susanne Schäfer, Charlotte Becker, Katja Birr, Thomas Bluth, Marcelo Gama de Abreu, Sara Hattenhauer, Thomas Kiss, Martin Scharffenberg, Robert Teichmann, Jakob Wittenstein, Costanza Vitali, Savino Spadaro, Carlo Alberto Volta, Riccardo Ragazzi, Karim Mariano, Lucia Mirabella, Giuseppina Mollica, Luigi Montrano, Torsten Loop, Axel Semmelmann, Steffen Wirth, Changhong Miao, Jing Zhong, Hu Lv, Hui Wang, Xue Zhang, Yue Zhang, Paolo Pelosi, Laura Corsi, Nicolò Partroniti, Maura Mandelli, Giulia Bonatti, Francesca Simonassi, Angelo Gratarola, Juan José Rodriguez Ruiz, Tania Socorro, Maria Christofaki, Vasileia Nyktari, Alexandra Papaioannou, Nüzhet Mert Şentürk, Emre Bingul, Mukadder Orhan Sungur, Zerrin Sungur, Manuel Heidegger, Vera Dossow, Wiebke Jerichow, Tobias Kammerer, Julia Richter, Barbara Schuba, Eike Speck, Anna-Lisa Stierle, Jan Bruthans, Jan Matek, Pavel Michálek, Loes Didden, Jan Hofland, Marieke Kuut, Jo Mourisse, Sonsoles Aragon, Rafael Esturi, Encarna Miñana, Fernando Sanchez, Elaine Sfikas, Athanasios Kapezanos, Konstantinos Papamichail, Levon Toufektzian, Gregorios Voyagis, Manuel Granell Gil, Asunción Vergara Sánchez, José De Andres, Javier Morales Sarabia, Ana Broseta Lleó, Javier Hernández Laforet, Mercedes Murcia Anaya, Denis Pereira Matalobos, Pilar Aguirre Puig, Jasna Špiček Macan, Vjekoslav Karadza, Nevenka Kolaric, Lea Andjelković, Mojca Drnovšek Globokar, Kristina Gorjup, Ana Mavko, Dejan Pirc, Cadar Genoveva, Raluca Istrate, Radu Stoica, Dan Corneci, Narcis Valentin Tanase, Jankovic Radmilo, Vladan Cvetanovic, Vesna Dinic, Tijana Grbesa, Katarina Jovic, Aleksandar Nikolic, Milena Stojanovic, Ines Veselinovic, Anita Vukovic, Frank Wappler, Jerome Michel Defosse, Stefanie Wehmeier, Thomas Ermert, Carola Wempe, Manuel Wenk, Daniela Iolanda Ion, Cristian Ionescu, Thomas Schilling, Tamar Macharadze, Pei-Ching Li, Yi-Ting Chang, Alberto Noto, Placido Calì, Giovanni Desalvo, Raffaele Deluca, Nicola Giofre, T Kiss, J Wittenstein, C Becker, K Birr, G Cinnella, E Cohen, M R El Tahan, L F Falcão, C Gregoretti, M Granell, T Hachenberg, M W Hollmann, R Jankovic, W Karzai, J Krassler, T Loop, M J Licker, N Marczin, G H Mills, M T Murrell, V Neskovic, Z Nisnevitch-Savarese, P Pelosi, R Rossaint, M J Schultz, A Serpa Neto, P Severgnini, L Szegedi, T Vegh, G Voyagis, J Zhong, M Gama de Abreu, M Senturk, PROTHOR investigators, Research Workgroup PROtective VEntilation Network (PROVEnet) of the European Society of Anaesthesiology (ESA), Vojislava Neskovic, Nevena Radovic, Goran Rondovic, Dusica Stamenkovic, Rade Vukovic, Snjezana Zeba, Rolf Rossaint, Mark Coburn, Ana Kowark, Sebastian Ziemann, Julia van Waesberghe, Wolfgang Bauer, Lotte Terwindt, Kostas Kostopanagiotou, Andreas Kostroglou, Katerina Kyttari, Tatiana Sidiropoulou, María-José Jiménez Andújar, Manuel López-Baamonde, Ricard Navarro Ripoll, Lorena Rivera Vallejo, Matthew Henry, Anita Jegarl, Matthew Murrell, Patrick O'Hara, Michele Steinkamp, Jens Kraßler, Susanne Schäfer, Charlotte Becker, Katja Birr, Thomas Bluth, Marcelo Gama de Abreu, Sara Hattenhauer, Thomas Kiss, Martin Scharffenberg, Robert Teichmann, Jakob Wittenstein, Costanza Vitali, Savino Spadaro, Carlo Alberto Volta, Riccardo Ragazzi, Karim Mariano, Lucia Mirabella, Giuseppina Mollica, Luigi Montrano, Torsten Loop, Axel Semmelmann, Steffen Wirth, Changhong Miao, Jing Zhong, Hu Lv, Hui Wang, Xue Zhang, Yue Zhang, Paolo Pelosi, Laura Corsi, Nicolò Partroniti, Maura Mandelli, Giulia Bonatti, Francesca Simonassi, Angelo Gratarola, Juan José Rodriguez Ruiz, Tania Socorro, Maria Christofaki, Vasileia Nyktari, Alexandra Papaioannou, Nüzhet Mert Şentürk, Emre Bingul, Mukadder Orhan Sungur, Zerrin Sungur, Manuel Heidegger, Vera Dossow, Wiebke Jerichow, Tobias Kammerer, Julia Richter, Barbara Schuba, Eike Speck, Anna-Lisa Stierle, Jan Bruthans, Jan Matek, Pavel Michálek, Loes Didden, Jan Hofland, Marieke Kuut, Jo Mourisse, Sonsoles Aragon, Rafael Esturi, Encarna Miñana, Fernando Sanchez, Elaine Sfikas, Athanasios Kapezanos, Konstantinos Papamichail, Levon Toufektzian, Gregorios Voyagis, Manuel Granell Gil, Asunción Vergara Sánchez, José De Andres, Javier Morales Sarabia, Ana Broseta Lleó, Javier Hernández Laforet, Mercedes Murcia Anaya, Denis Pereira Matalobos, Pilar Aguirre Puig, Jasna Špiček Macan, Vjekoslav Karadza, Nevenka Kolaric, Lea Andjelković, Mojca Drnovšek Globokar, Kristina Gorjup, Ana Mavko, Dejan Pirc, Cadar Genoveva, Raluca Istrate, Radu Stoica, Dan Corneci, Narcis Valentin Tanase, Jankovic Radmilo, Vladan Cvetanovic, Vesna Dinic, Tijana Grbesa, Katarina Jovic, Aleksandar Nikolic, Milena Stojanovic, Ines Veselinovic, Anita Vukovic, Frank Wappler, Jerome Michel Defosse, Stefanie Wehmeier, Thomas Ermert, Carola Wempe, Manuel Wenk, Daniela Iolanda Ion, Cristian Ionescu, Thomas Schilling, Tamar Macharadze, Pei-Ching Li, Yi-Ting Chang, Alberto Noto, Placido Calì, Giovanni Desalvo, Raffaele Deluca, Nicola Giofre

Abstract

Background: Postoperative pulmonary complications (PPC) may result in longer duration of in-hospital stay and even mortality. Both thoracic surgery and intraoperative mechanical ventilation settings add considerably to the risk of PPC. It is unclear if one-lung ventilation (OLV) for thoracic surgery with a strategy of intraoperative high positive end-expiratory pressure (PEEP) and recruitment maneuvers (RM) reduces PPC, compared to low PEEP without RM.

Methods: PROTHOR is an international, multicenter, randomized, controlled, assessor-blinded, two-arm trial initiated by investigators of the PROtective VEntilation NETwork. In total, 2378 patients will be randomly assigned to one of two different intraoperative mechanical ventilation strategies. Investigators screen patients aged 18 years or older, scheduled for open thoracic or video-assisted thoracoscopic surgery under general anesthesia requiring OLV, with a maximal body mass index of 35 kg/m2, and a planned duration of surgery of more than 60 min. Further, the expected duration of OLV shall be longer than two-lung ventilation, and lung separation is planned with a double lumen tube. Patients will be randomly assigned to PEEP of 10 cmH2O with lung RM, or PEEP of 5 cmH2O without RM. During two-lung ventilation tidal volume is set at 7 mL/kg predicted body weight and, during OLV, it will be decreased to 5 mL/kg. The occurrence of PPC will be recorded as a collapsed composite of single adverse pulmonary events and represents the primary endpoint.

Discussion: PROTHOR is the first randomized controlled trial in patients undergoing thoracic surgery with OLV that is adequately powered to compare the effects of intraoperative high PEEP with RM versus low PEEP without RM on PPC. The results of the PROTHOR trial will support anesthesiologists in their decision to set intraoperative PEEP during protective ventilation for OLV in thoracic surgery.

Trial registration: The trial was registered in clinicaltrials.gov ( NCT02963025 ) on 15 November 2016.

Keywords: Mechanical ventilation; one-lung ventilation; positive end-expiratory pressure; postoperative pulmonary complication; recruitment maneuver; thoracic surgery.

Conflict of interest statement

Authors’ information

Not applicable.

Ethics approval and consent to participate

The Istanbul University, Medical Faculty, Ethical Committee of clinical research approved the study on 08.04.2016 (File number 2016/483, study protocol version 1.9). Additionally, the institutional review board at the University Hospital Dresden, Technische Universität Dresden, Dresden, Germany, approved the study on 23.09.2016 (reference no. EK 392092016, study protocol version 1.9). The respective review boards of participating sites also approved the study. PROTHOR is designed in accordance to the principles of the Declaration of Helsinki. Written informed consent was obtained from every enrolled patient upon request by the local institutional review board.

Consent for publication

Not applicable.

Competing interests

MRET received free airway device samples from Ambu in April 2014 and from Airtraq in March 2015 for use in another three published studies. He has no direct financial or other interests in Ambu or Airtraq (in the context of this and his studies).

All other authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
CONSORT Diagram for the PROTHOR trial. OLV one-lung ventilation, PEEP positive end-expiratory airway pressure
Fig. 2
Fig. 2
Standardized lung recruitment maneuver in the high PEEP group. Ppeak peak airway pressure, Pplat plateau airway pressure, PEEP positive end-expiratory airway pressure, VT tidal volume normalized for predicted body weight, RR respiratory rate, I:E ratio between inspiratory and expiratory time
Fig. 3
Fig. 3
Schedule of enrolment, interventions, and assessments. POD postoperative day, PEEP positive end-expiratory airway pressure, RM (lung) recruitment maneuver, SpO2 peripheral oxygen saturation
Fig. 4
Fig. 4
Effect size (Z) according to enrollment of patients in the PROTHOR trial (including dropouts). Values of Z were obtained from an adaptive sequential design (see text) with stopping criteria for harm, futility, and efficacy of the intervention

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