PROtective Ventilation with a low versus high Inspiratory Oxygen fraction (PROVIO) and its effects on postoperative pulmonary complications: protocol for a randomized controlled trial

Background Postoperative pulmonary complications (PPCs) are the most common perioperative complications following surgical site infection (SSI). They prolong the hospital stay and increase health care costs. A lung-protective ventilation strategy is considered better practice in abdominal surgery to prevent PPCs. However, the role of the inspiratory oxygen fraction (FiO2) in the strategy remains disputed. Previous trials have focused on reducing SSI by increasing the inhaled oxygen concentration but higher FiO2 (80%) was found to be associated with a greater incidence of atelectasis and mortality in recent research. The trial aims at evaluating the effect of different FiO2 added to the lung-protective ventilation strategy on the incidence of PPCs during general anesthesia for abdominal surgery. Methods and design PROtective Ventilation with a low versus high Inspiratory Oxygen fraction trial (PROVIO) is a single-center, prospective, randomized controlled trial planning to recruit 252 patients undergoing abdominal surgery lasting for at least 2 h. The patients will be randomly assigned to (1) a low-FiO2 (30% FiO2) group and (2) a high-FiO2 (80% FiO2) group in the lung-protective ventilation strategy. The primary outcome of the study is the occurrence of PPCs within the postoperative 7 days. Secondary outcomes include the severity grade of PPCs, the occurrence of postoperative extrapulmonary complications and all-cause mortality within the postoperative 7 and 30 days. Discussion The PROVIO trial assesses the effect of low versus high FiO2 added to a lung-protective ventilation strategy on PPCs for abdominal surgery patients and the results should provide practical approaches to intraoperative oxygen management. Trial registration www.ChiCTR.org.cn, identifier: ChiCTR18 00014901. Registered on 13 February 2018. Electronic supplementary material The online version of this article (10.1186/s13063-019-3668-x) contains supplementary material, which is available to authorized users.


Background
About 2.0 to 5.6% of more than 234 million patients undergoing surgery develop postoperative pulmonary complications (PPCs), especially after general and vascular surgeries (approximately 40%), which makes PPCs the most common perioperative complications following surgical site infection (SSI) [1][2][3][4][5][6]. PPCs, especially respiratory failure, add to the morbidity and mortality risk in hospitalized patients [1,4,5]. Moreover, PPCs prolong hospital stay and increase medical expense and resource utilization [2,5]. A reduction of PPCs is a very important evaluation index of medical quality management. A possible explanation for increasing morbidity in patients who develop PPCs is that mechanical ventilation under general anesthesia results in gas-exchange impairment, a local inflammatory response and circulatory disorder [7,8]. Thus, decreased lung volumes, ventilatorinduced lung injury and atelectasis are strongly associated with the incidence of PPCs [9].
Prior studies noted that so-called lung-protective ventilation, referring to low-tidal-volume (V T ), appropriate positive end-expiratory pressure (PEEP) level and recruitment maneuvers, seems to be the optimum option for the surgical and intensive care unit (ICU) populations [10][11][12][13]. The decrease in PPCs, mortality and health care costs have been observed in the protectiveventilated population. On the basis of the robust evidence available, a combination of low V T (6-8 ml/kg of predicted body weight) [11,14], a level of PEEP at 5-8 cmH 2 O [15] and repeated recruitment maneuvers [16] are now widely adopted.
Setting the inspiratory oxygen fraction (FiO 2 ) intraoperatively is a significant task of anesthetists, but has not been based on evidence-based guidelines. Obtaining comprehensive knowledge about hyperoxia caused by high FiO 2 has been stressed as important by clinicians over the past few decades, including its potentially deleterious effects on lung. Even mildly elevated FiO 2 levels have been reported to exacerbate lung injury by upregulating pro-inflammatory cytokines and inducing neutrophil infiltration in the alveolar spaces [17][18][19].
Even if there is no significant difference in pulse oximetry and the oxygenation index for several time-points with 30 or 80% FiO 2 intraoperatively, hyperoxia and substantial oxygen exposure are common in clinical practice [20,21]. Questions have been raised about the use of oxygen in ventilated patients undergoing elective surgery. A recent systematic review revealed that the trials of this decade about the effects of FiO 2 on SSI have been inconclusive, and we should also focus on clinically relevant pulmonary side-effects and other adverse events (AEs) [22][23][24][25]. In addition, exposure to oxygen is related to adverse effects in critically ill patients [26,27]. The ideal FiO 2 level in the lung-protective ventilation strategy to protect against PPCs and improve clinical outcomes has not been addressed in the perioperative period.
The relationship between FiO 2 and PPCs in surgical patients is mainly affected by a hyperoxia-induced change in the respiratory mechanism. Higher FiO 2 seems to be associated with pulmonary complications and adverse clinical outcomes, but the existing evidence is insufficient to warrant its effect to promote PPCs [28][29][30]. We hypothesize that a low level of FiO 2 (30%) compared with high FiO 2 (80%) could decrease the incidence of PPCs in patients undergoing abdominal surgery when lung-protective ventilation strategy is administered.

Study design
The PROVIO trial is a single-center, prospective, randomized controlled and two-arm study and is conducted in accordance with the Declaration of Helsinki. The trial will be conducted in West China Hospital of Sichuan University, China. We aim to assess the effect of FiO 2 in a lung-protective ventilation strategy, in an abdominal surgical population of patients, on PPCs, extrapulmonary complications (e.g., SSI, sepsis, etc.), hospital stay and mortality.
The protocol follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement. The SPIRIT checklist can be found inAdditional file 1. The diagram of the Consolidated Standards of Reporting Trials (CONSORT), which are also followed, is presented in Fig. 1.

Study population
The inclusion criteria of the study are: American Society of Anesthesiologists (ASA) physical status I-III patients aged 18 years or older, scheduled for elective abdominal surgery with an expected duration of at least 2 h and planned to be extubated in the operating room. Laparotomy and laparoscopy surgery will not be restricted. Patients are ineligible if they have suffered from pneumothorax, acute lung injury or acute respiratory distress syndrome within the last 3 months. Other exclusion criteria are: a diagnosis of heart failure (New York Heart Association classes; NYHA IV), chronic renal failure (glomerular filtration rate < 30 ml/min), serious hepatic diseases (e.g., hepatic failure), scheduled for reoperation or postoperative mechanical circulatory support, known pregnancy, participation in another interventional study, and with a body mass index (BMI) of > 30 kg/m 2 .

Randomization, blinding and bias minimization
Patients will be recruited from West China Hospital of Sichuan University. Consecutive male or female patients aged 18 years or older who will undergo abdominal surgery under general anesthesia are screened for study eligibility. Randomization will be performed using a computer-generated randomization list (SPSS 22.0) with an allocation rate of 1:1. The allocation is concealed in an opaque envelope and will be sent to the attending anesthetist by a blinded investigator.
Given the characteristics of the study, the attending anesthetist must know the intervention. Researchers, including the investigator in the operating room, the data collector and the data analyzer, will all be blinded to the randomization arm. All the surgeons, nurses and anesthetists in the post-anesthesia care unit (PACU) will not know the allocation. Postoperative visits and outcome assessment will be performed by a blinded investigator. Emergency unblinding is permissible if hypoxemia occurs (defined as pulse oxygen saturation (SpO 2 ) < 92% or partial pressure of oxygen in arterial blood (PaO 2 ) < 60 mmHg).

Standard procedures
The risk of PPCs will be assessed using the Assess Respiratory Risk in Surgical Patients in Catalonia (ARIS-CAT) risk score [31] before randomization (Table 1). An investigator assesses the individual risk of PPCs with the seven predictors of the ARISCAT risk score (age, SpO 2 , respiratory infection in the last month, preoperative anemia, duration of surgery, and whether an emergency procedure). The ARISCAT score will help to analyze the effect of FiO 2 to intermediate-high-risk patients who obtain a score of more than 26. All patients receiving an assessment will be included and randomized.
All randomized participants will receive standard care and monitoring including a five-lead electrocardiogram, SpO 2 , blood pressure (invasive or noninvasive) and endtidal carbon dioxide (E T CO 2 ). The attending anesthetist responsible for the patient can choose the bispectral index (BIS), muscle-relaxant monitoring and cardiacoutput monitoring techniques according to clinical routines.
There will be no restriction to the anesthetic regimen and individualized health care will be performed intraoperatively. Use of antiemetics and muscle-relaxant antagonists (mainly neostigmine) will be recorded in the case report form (CRF).

Intraoperative ventilatory management
Pre-oxygenation will be prescribed for 5 min at 100% FiO 2 using a mask. In accordance with the group allocation, the participants will be randomized to receive a low (30%) or a high (80%) FiO 2 throughout the whole period of intraoperative mechanical ventilation after tracheal intubation. The FiO 2 level is implemented through adjusting the air-oxygen ratio when the total gas flow remains at 2 L/min. The FiO 2 in our protocol refers to the actual fraction of inspired oxygen presented in the display panel on the anesthesthetic machine. Table 2 shows the ventilation settings. Intraoperative ventilation in all participants will be performed via the lung-protective ventilation strategy. A recruitment maneuver with peak airway pressure (P aw ) of 30 cmH 2 O for 30 s will be performed instantly after intubation, every 60 min after intubation and before extubation. Other settings are shown in Table 2. Ventilatory parameters, including tidal volume (V T ), minute volume (MV), airway pressure (P aw ), plateau pressure (P plat ), fresh gas flow, PEEP and FiO 2 , will be monitored.
After extubation, patients will be sent to the PACU or the ward where they will be oxygenated with 2 L/min, pure oxygen via a nasal tube over 24 h. At the same time, they will receive standard monitoring.

Intraoperative care
After induction, standard intraoperative care will be applied in both groups to reach a target of standard state (Table 3). Vasoactive drugs can be used in patients with unstable hemodynamics as appropriate.

Rescue strategies for intraoperative hypoxemia
Around 30% FiO 2 has been proved to be safe in mechanically ventilated patients and rarely causes hypoxemia [21]. We designed a rescue strategy for patients in whom SpO 2 , measured by pulse oximetry, fell to less than 92% or PaO 2 to less than 60 mmHg for more than 1 min.
Endotracheal-tube displacement, airway-secretion blockage, bronchospasm, pneumothorax, and hemodynamic change would all be checked for. After excluding these as underlying causes, a rescue recruitment maneuver with P aw 30 cmH 2 O for 30 s will be implemented [12,16,32]. If this were to fail, FiO 2 and ventilation settings would be altered until acquiring the required oxygenation (SpO 2 ≥ 92% or PaO 2 ≥ 60 mmHg).

Outcome measurements
The primary outcome is the occurrence of pulmonary complications within the first 7 days postoperatively.  The definition of PPCs follows the ARISCAT study (respiratory infection, respiratory failure, bronchospasm, atelectasis, pleural effusion, pneumothorax or aspiration pneumonitis.) [4].  [4,5,33,34]. Grade 0 in the scale represents no PPCs, grades 1-4 represent increasing severity levels of pulmonary complications, and grade 5 represents death before discharge. SSI will be defined with the criteria from the Centers for Disease Control and Prevention (CDC) [35].
Tertiary outcomes in the first 7 and 30 days postoperatively are as follows: Acute kidney injury: defined according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria [38] 6. Anastomotic fistula 7. Reintubation 8. Unplanned admission to the ICU 9. Hospital length of stay postoperatively

Data collection and follow-up
The study will be conducted in the operating room and visits are restricted during the screening, hospitalization and follow-up periods. The primary and secondary outcomes will be measured on postoperative days 1, 2, 3, 5 and 7 or at discharge by interview. On postoperative day 30, participants will be contacted by phone (Fig. 2). Demographic and baseline data will be collected preoperatively, which include age, sex, weight, BMI, ASA physical status, ARISCAT risk score, smoking status, pulmonary status (chronic pbstructive pulmonary disease (COPD), atelectasis, asthma respiratory infection within the last 3 months, use of ventilatory support), routine laboratory tests (hemoglobin, white blood cell count, platelet count, neutrophil count) and medical history.
Both intraoperative surgery-and anesthesia-associated data will be recorded, including type of surgery, surgical incision or approach, duration of surgery and ventilation, blood loss, transfusion of blood products, fluid balance (calculated by subtracting the measurable fluid losses  We only classified as grade 2 if two or more items in grade 2 were present PaCO 2 partial pressure of arterial carbon dioxide, SpO 2 pulse oxygen saturation from measurable fluid intake during anesthesia), drugs during anesthesia (e.g., anesthetics and antiemetics), adjustment of ventilatory parameters or FiO 2 , hypoxemia events, the need for rescue strategy, number of emergency recruitment maneuvers, and unplanned admission to the ICU. Postoperative visits will be conducted daily and clinical data required to assess PPC grade include body temperature, lung auscultation, symptoms (e.g., cough, expectoration and dyspnea), chest-imaging manifestations, and laboratory tests. Surgical incision assessment, PONV and other outcomes will also be measured and collected daily according to the evaluation criterion mentioned above.
The Data and Safety Monitoring Board (DSMB) composed of five independent individuals is set up to supervise the overall conduct of the study (the screening, recruitment and adherence to the protocol). The DSMB is responsible for checking and ensuring the completeness and validity of data recording. The interim analysis will be conducted when the first 120 participants are recruited and have been visited to completion. The DSMB has access to patient allocation, but the results of the interim analysis will be treated as strictly confidential.

Study drop-out
Participants have the right to withdraw from the study at any time without any consequences for further treatment. Investigators have the right to terminate the study at any time in consideration of the best interests of the participants. Both situations will be recorded in the CRF and discussed.
Any AEs and treatment side-effects will be sent to the DSMB which will discussed whether the participant should drop out accordingly.

Statistical considerations
The sample size required was estimated based on the investigative data in our medical center. The pilot study showed that PPCs (respiratory infection, respiratory failure, bronchospasm, atelectasis, pleural effusion, pneumothorax or aspiration pneumonitis) occurred in 50.4% patients received 80% FiO 2 after abdominal surgery (sample size: 100). And assuming a round 50% rate of PPCs in the high-FiO 2 (80%) group, we calculated that a total sample size of 252 patients (126 in each group) will have 80% power to detect a relative risk reduction of 35% in PPCs between groups, at a two-sided alpha level of 0.05 and 5% drop-out. We will conduct a sample size reassessment after recruiting half of the patients for safety consideration.
All statistics will be analyzed by SPSS 22.0 statistical software (IBM Corporation, Chicago, IL, USA) through the intention-to-treat principle, which covers all randomized patients receiving surgery. Participants with adjusted FiO 2 values are still treated as the low-FiO 2 population when analyzed. In a descriptive analysis of the population, mean and standard deviation (SD) will be used for normally distributed variables, medians and interquartile ranges used for non-normally distributed variables and percentages used for categorical variables. Stratified description will be used as appropriate.
There will be a baseline comparison of age, gender, BMI, type of surgery, surgical approach, duration of surgery and ARISCAT score between groups and logistic regression analysis will be performed if an imbalance between groups exists. The Student's t test will be used for continuous, normally distributed variables and the Mann-Whitney U test will be used for continuous, nonnormally distributed data. The primary and secondary outcomes will be compared using the χ 2 test or Fisher's exact test, while multiple logistic-regression analysis will be used to identify hazards. A two-sided P value < 0.05 is considered statistically significant.
A custom-made folder is made to store the participants' data, which consists of documents and forms. Only blinded researchers have access to the folder. Only when the study is complete will the investigators obtain the data.

Discussion
The optimal intraoperative FiO 2 remains highly debated. Many physicians consider excessive oxygen supplement a salutary practice which is now widely applied in routine practice due to its simplicity and ease of availability [39]. Despite the controversy, the majority of published randomized trials comparing 30 and 80% FiO 2 , mainly in SSI and PONV, show that intraoperative high FiO 2 decreases the risk of both [40][41][42]. Furthermore, new World Health Organization (WHO) recommendations on intraoperative and postoperative measures for SSI prevention in 2016 suggest that patients undergoing general anesthesia with endotracheal intubation for surgical procedures should receive 80% FiO 2 intraoperatively [43]. What remains controversial is whether the intraoperative use of an elevated FiO 2 is essential to all intubated patients without hypoxemia, although both 30 and 80% FiO 2 provide similar oxygenation [21]. A multicenter observational trial collecting the ventilator data 1 h after induction showed that most ventilated patients (83%) in Japan were exposed to potentially preventable hyperoxia, especially in one-lung ventilation patients and the elderly [20].
The "benefit" of this pervasive liberal oxygen management has recently been questioned. Concerns on potential detrimental effects, such as impairing lung-capillary endothelial function and facilitating oxidative stress due to the use of high FiO 2 , were raised [44][45][46]. Endothelial activation may initiate progressive hyperoxic lung injury when persistently ventilated under hyperoxic conditions at 70% FiO 2 [19]. In addition, excessive oxygen can lead to pulmonary endothelial-cell damage through mitochondrial fragmentation [47]. This can be explained by the formation of reactive oxygen species (ROS) and proinflammatory cytokines in endothelial cells which were found in an animal study [19,46]. Romagnoli et al. demonstrated that protective ventilation with the lowest level of FiO 2 to keep the SpO 2 ≥ 95% reduces oxygen toxicity by generating less ROS production [45]. However, there is a contradictory view on the detrimental effects of high FiO 2 on endothelial function in healthy volunteers [48]. Another interpretation is that high FiO 2 may change pulmonary-gas exchange in surgical patients. Ventilation with high FiO 2 (80-100%) increases the intrapulmonary shunt [49] and impairs gas exchange [50]. In addition, resorption atelectasis results from a phenomenon in which nitrogen is displaced by oxygen which can diffuse more rapidly into the blood. Resorption atelectasis can also promote pulmonary shunting and cause hypoxemia [51]. Ventilation for induction of anesthesia with 100% FiO 2 leads to significantly larger atelectatic areas than with 60% FiO 2 [52]. Atelectatic areas tend towards having a low ventilation/perfusion ratio. Hyperoxia is also an important factor contributing to the apoptosis of alveolar epithelial cells and lowers the level of surfactant proteins that indicate damage of the lung tissue [53]. The synergetic action of the above factors increases the risk of lung injury and pulmonary complications.
Indeed, supplemental oxygen results in hyperoxia, and is reported as an independent risk factor for ventilatorassociated pneumonia in one observational study [54]. Liberal oxygen use is considered detrimental in mechanically ventilated patients in the aspect of lung function [55] and clinical outcomes [27]. The PROXI trial demonstrated that the incidence of PPCs, PONV and SSI after abdominal surgery were not significantly different in patients receiving 80 or 30% FiO 2 [56]; nevertheless, the former suffers higher long-term mortality (23.3 vs 18.3%) [57]. Also one observational trial has suggested a dose-dependent manner in FiO 2 and 30-day mortality. The incidence of PPCs has declined by half in the low-FiO 2 group with a median of 31% (range 16-34%) [30].
Yet, no direct evidence has revealed the relationship between FiO 2 in lung-protective ventilation and PPCs, and existing data reported that postoperative pulmonary function is better protected with a relative low FiO 2 intraoperatively [58]. One systematic review showed that the included trials only focused on postoperative atelectasis, rather than on all forms of PPC [59]. Despite the PROXI trial demonstrating that PPCs did not differ after inhalation of 80 vs 30% oxygen, the results are worth discussing. The emergency surgery population was not excluded in the PROXI trial, emergency surgery being an independent risk factor for pulmonary complications [4]. Intubation time is also a key element for causing pneumonia and atelectasis. Moreover, the complication measures of PROXI lacked a standard and comprehensive judgment evaluation, which only assessed the three types of PPC (atelectasis, pneumonia and respiratory failure) according to the CDC criteria. And, above all, the ventilation strategy for patients is not specified, which plays a key role in the incidence of pulmonary complications. The iPROVE-O 2 trial is an ongoing randomized controlled trial (ClinicalTrials.gov identifier: NCT02776046) comparing the efficacy of 80 and 30% FiO 2 using an individualized, open-lung ventilatory strategy in reducing the incidence of SSI [60]. The major differences compared to the PROVIO trial are: the appearance of pulmonary complications as one of the secondary outcomes; individualized, open-lung ventilation as the ventilatory mode which is a combination of 8 ml/kg V T , recruitment maneuver and the optimal individualized PEEP. The recruitment maneuver will be performed by a PEEP-titration trial [61]. Undoubtedly, the individualized, open-lung ventilation strategy is more complex to implement clinically when compared to lung-protective ventilation [61].
The limitations of our study must be mentioned. Firstly, we conducted a pilot study to determine the incidence of PPCs in our medical center with reference to the sample size calculation. We hope that our results will provide the possible direction and reference for subsequent research into FiO 2 . Secondly, the study excludes the patients scheduled for some types of surgery because of the duration of the surgery. Thirdly, the oxygenation index and arterial oxygen pressure that may reflect the actual oxygenation state will not be measured during the perioperative period.
In the absence of an intraoperative lung-protective ventilation strategy, previous studies failed to identify a certain relationship between FiO 2 and PPCs. We insist that lung-protective ventilation in both groups will reduce bias regarding ventilation-associated impact, and enhance lung protection. Conclusively, the PROVIO trial is the first clinical trial focusing on the effects of FiO 2 added to lung-protective ventilation on PPCs. The results of the trial should support anesthetists in routine oxygen management during general anesthesia in an attempt to prevent PPCs.

Trial status
The

Acknowledgements
We thank the patients for participating in the trial dissemination. We also thank the authors of the primary studies and our colleagues supporting the study.

Confidentiality
The personal information of the patients will be confidential at all periods of the trial. Data will be handled according to Chinese law and archived for at least 5 years. Meanwhile, the database will be anonymized and kept for 5 years. Then, the data will be destroyed according to the hospital standards concerning the destruction of confidential information.
Authors' contributions X-FL, X-YY and HaiY provided substantial contributions to the study conception and design. X-FL and HaiY drafted the protocol and edited the manuscript. DJ, HongY, Y-LJ, J-LJ and L-LH participated in the study design. All the authors read and approved the final manuscript.

Funding
This research received a funding grant from the 1·3·5 project for disciplines of excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University (project number: 2018HXFH052). The 1·3·5 project will in no way intervene in any aspect of the trial, including its design, data collection, analysis or presentation.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate
The study has been approved by The Ethical Committee of the West China Hospital of Sichuan University (2018 approval No. 8) and informed consent will be obtained from all study patients before participating. Our trial was registered at http://www.chictr.org.cn (ChiCTR1800014901). We will obtain informed consent in written form from all patients who meet all the inclusion criteria and none of the exclusion criteria before arrival in the operating room. The results of the PROVIO trial will be published in peer-reviewed journals focused on perioperative medicine and presented at national and international conferences.

Consent for publication
Not applicable.