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

doi:10.21203/rs.2.477/v4

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Study protocol

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

https://doi.org/10.21203/rs.2.477/v4

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published 01 Nov, 2019

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Background: Postoperative pulmonary complications (PPCs) is the most common perioperative complication following surgical site infection (SSI), which prolongs the hospital stay and increases health care cost. Lung-protective ventilation strategy is considered better practice in abdominal surgery to prevent PPCs. However, the role of inspiratory oxygen fraction (FiO₂) in the strategy remains disputable. Previous trials have focused on reducing SSI by increasing inhaled oxygen concentration but higher FiO₂ (80%) was found to be associated with a greater incidence of atelectasis and mortality in recent researches. The trial aims at evaluating the effect of different FiO₂ added to lung-protective ventilation strategy on the incidence of PPCs during general anesthesia for abdominal surgery. Methods: 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 hours. The patients will be randomly assigned to (1) a low FiO₂ (30% FiO₂) group and (2) a high FiO₂ (80% FiO₂) group in 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: PROVIO trial assesses the effect of low versus high FiO₂ added to lung-protective ventilation strategy on PPCs for abdominal surgery patients and the results will provide practical approaches to intraoperative oxygen management. Trial registration number: Registered at www.ChiCTR.org.cn on 13 February 2018 with identifier no. ChiCTR18 00014901. Keywords: Postoperative pulmonary complications, Lung-protective ventilation, Fraction of inspired oxygen, Abdominal surgery.

General Medicine

Postoperative pulmonary complications

Lung-protective ventilation

Fraction of inspired oxygen

Abdominal surgery.

About 2.0% to 5.6% of more than 234 million patients undergoing the surgery developed 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) [1-6]. PPCs, especially respiratory failure, add to morbidity and mortality risk in hospitalized patients [1, 4, 5]. Moreover, PPCs prolong the hospital stay and increase medical expense and resources utilization [2, 5]. 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, local inflammatory response and circulation disorder [7, 8]. Thus, decreased lung volumes, ventilator-induced 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 to surgery and intensive care unit (ICU) population [10-13]. The decreases of PPCs, mortality and health care costs have been observed in the protective ventilated population. On the basis of the robust evidence available, a combination of low V_T(6 to 8 ml per kilogram of predicted body weight) [11, 14], a level of PEEP at 5-8 cmH₂O [15] and repeated recruitment maneuvers [16] are now widely adopted.

Setting FiO₂ intraoperatively is a significant task of anesthetists, but has not based on evidence-based guidelines. Obtaining comprehensive knowledge about hyperoxia caused by high FiO₂ has been stressed by clinicians over the past few decades, including its potential deleterious effects on lung. Even mildly elevated FIO₂ levels have been reported to exacerbate lung injury with up-regulating proinflammatory cytokines and inducing neutrophil infiltration in the alveolar spaces [17-19].

Even if there’s no significant difference in pulse oximetry and oxygenation index for several time-points with 30% or 80% FiO₂ 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. Recent systematic review revealed that the trials of this decade about the effects of FiO₂ on SSI have been inconclusive, and we should also focus on clinically relevant pulmonary side-effects and other adverse events [22-25]. In addtion, exposure to oxygen is related to adverse effects in critically ill patients [26, 27]. The proper level of FiO₂ in lung-protective ventilation strategy to protect against PPCs and improve clinical outcomes has not been addressed in the perioperative period.

The relationship between FiO₂ and PPCs in surgical patients is mainly affected by hyperoxia-induced respiratory mechanism change. Higher FiO₂ seems to be associated with pulmonary complications and adverse clinical outcomes, but the existing evidence is insufficient to warrant its effect to promote PPCs [28-30]. We hypothesize that a low level of FiO₂(30%) compared with high FiO₂ (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 FiO₂ in lung-protective ventilation strategy in an abdominal surgical population of patients on PPCs, extra-pulmonary 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 Consolidated Standards of Reporting Trials (CONSORT) diagram is presented in Figure 1.

Figure 1. CONSORT diagram of the PROVIO trial.

Study population

The inclusion criteria of the study are: American Society of Anesthesiologists (ASA) physical status I to III patients aged 18 years or older, scheduled for elective abdominal surgery with an expected duration of at least 2 hours and planned to be extubated in the operating room. Laparotomy and laparoscopy surgery will not be restricted. Patients are ineligible if they are suffered pneumothorax, acute lung injury or acute respiratory distress syndrome within the last three months. Other exclusion criteria are: 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/m².

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 under general anesthesia who will undergo abdominal surgery 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 an investigator without knowing it.

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 post-anesthesia care unit (PACU) do 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 SpO₂ < 92% or PaO₂ < 60 mmHg).

Standard procedures

The risk of PPCs will be assessed with the Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT) risk score [31] before the randomization (Table 1). An investigator assesses the individual risk of PPCs with the seven predictors of ARISCAT risk score (age, preoperative pulse oxygen saturation (SpO₂), respiratory infection in the last month, preoperative anemia, duration of surgery, and emergency procedure). The ARISCAT score will help to analyze the effect of FiO₂ to intermediate-high risk patients who get a score of more than 26. All patients receiving assessment will be included and randomized.

All randomized participants will receive the standard care and monitoring including five leads electrocardiogram, SpO₂, blood pressure (invasive or noninvasive) and end-tidal carbon dioxide (E_TCO₂). The attending anesthetist responsible for the patient can choose the bispectral index (BIS), muscle relaxant monitoring and cardiac output monitoring according to clinical routines.

There will be no limitation to anesthetic regimen and individualized health care will be performed intraoperatively. Use of antiemetics and muscle relaxant antagonist (mainly neostigmine) will be recorded in case report form (CRF).

Table 1. Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT) risk score in the logistic regression model

Intraoperative ventilatory management

Pre-oxygenation will be prescribed for 5 minutes at 100% FiO₂ with a mask. In accordance with the allocation, the participants will be randomized to receive low (30%) or high (80%) FiO₂ throughout the whole period of intraoperative mechanical ventilation after tracheal intubation. FiO₂ implement through adjusting the air-O₂ ratio when total gas flow remains 2 L/min. FiO₂ in our protocol refers to the actual fraction of inspired oxygen presented in the anesthesia machine panel. Table 2 shows the ventilation settings.

Intraoperative ventilation in all participants will be performed via lung-protective ventilation strategy. A recruitment maneuver with peak airway pressure (P_aw) 30 cmH₂O for 30s will be performed after intubation instantly, every 60 min after intubation and before extubation. Other settings are shown in table 2. Ventilatory parameters, including tidal volume, minute volume (MV), P_aw, plateau pressure (P_plat), fresh gas flow, PEEP and FiO₂, will be monitored.

After extubation, patients will be sent to the PACU or ward where they will be oxygenated with 2L/min, pure oxygen via a nasal tube in 24 hours. At the same time, they will receive standard monitoring.

Table 2: Intraoperative ventilation settings for the PROVIO trial

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.

Table 3: Standard state target

Rescue strategies for intraoperative hypoxemia

Around 30% FiO₂ has been proved to be safe in mechanically ventilated patients and rarely causes hypoxemia [21]. We designed a rescue strategy for patients in whom SpO₂ measured by pulse oximetry fell to less than 92% or PaO₂ less than 60 mmHg for more than one minute.

Checking if there exists endotracheal tube displacement, airway secretion blocking, bronchospasm, pneumothorax, and hemodynamic change. After excluding the underlying causes, a rescue recruitment maneuver with P_aw 30 cmH₂O for 30s will be implemented [12, 16, 32]. If failed, FiO₂ and ventilation settings are permitted to alter until acquiring the satisfied oxygenation (SpO₂≥ 92% or PaO₂≥ 60 mmHg).

Outcome measurements

The primary outcome is the occurrence of pulmonary complications within the first 7 days postoperatively. Definition of PPCs follows the ARISCAT study (respiratory infection, respiratory failure, bronchospasm, atelectasis, pleural effusion, pneumothorax, or aspiration pneumonitis.) [4].

The secondary outcomes include the occurrence of PPCs in the postoperative 30 days; SSI, postoperative nausea and vomiting (PONV) in the postoperative 7 days; the severity grade of pulmonary complications in the postoperative 7 and 30 days (Table 4); and death rate in the postoperative 7 and 30 days.

Pulmonary complications will be scored with a grade scale ranging from 0 to 5 adapted from Kroenke et al, Hulzebos et al, Fernandez-Bustamante et al and Canet et al [4, 5, 33, 34]. Grade 0 in scale represents no PPCs, grades 1 to 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].

Table 4. The grade of pulmonary complications

Tertiary outcomes in the first 7 and 30 days postoperatively are as follows:

Sepsis: the infection-centric systemic response which needs to meet two or more criteria of the Systemic Inflammatory Response Syndrome (SIRS) [36].
Septic shock: defined as a composite of sepsis-induced response, perfusion abnormalities, and hypotension despite adequate fluid resuscitation [36].
Myocardial ischemia [37].
Heart failure [37].
Urinary system infection [37].
Acute kidney injury: defined according to the KDIGO criteria [38].
Anastomosis fistula.
Reintubation.
Unplanned admission to ICU.
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 day 1, 2, 3, 5, 7 or at discharge by interview. On postoperative day 30, participants will be visited by phone (Figure 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 (COPD, atelectasis, asthma respiratory infection within the last three months, use of ventilatory support), routine laboratory tests (hemoglobin, white blood cell count, platelet count, neutrophil count) and medical history.

Figure 2. Standard Protocol Items: Recommendation for Interventional Trials (SPIRIT) schedule of enrollment, interventions and assessments

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 from measurable fluid intake during anesthesia), drugs during anesthesia (e.g., anesthetics and antiemetics), adjustment of ventilatory parameters or FiO₂, hypoxemia event, the need for rescue strategy, number of emergency recruitment maneuvers, and unplanned admission to ICU.

Postoperative visits will be conducted daily and clinical data required to assess PPCs 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.

Data and Safety Monitoring Board (DSMB) composed of five independent individuals is set to supervise the overall conduct of the study (the screening, recruitment and adherence to the protocol). 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 visited completely. DSMB has access to patient allocation, but the results of 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 best interests of participants. Both situations will be recorded in CRF and discussed.

Any adverse events and treatments will be sent to DSMB and discussed if the participant should drop out according to this.

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% FiO₂ after abdominal surgery (sample size: 100). And assuming a round 50% rate of PPCs in the high (80%) FiO₂ 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% dropout. We will conduct a sample size reassessment after recruiting half of patients for safety consideration.

All statistics will be analyzed by SPSS 22.0 statistical software (IBM Corporation, USA) through the intention-to-treat principle, which covers all randomized patients receiving surgery. Participants with adjusted FiO₂ are still treated as low FiO₂ population when analyzed. In a descriptive analysis of 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. Student t-test will be used for continuous normally distributed variables and the Mann-Whitney U test will be used for continuous non-normally distributed data. The primary and secondary outcomes will be compared using the χ² test or Fisher’s exact test, while multiple logistic-regression analysis used to identify hazards. A 2-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 completes, the investigators can get the data.

The optimal intraoperative FiO₂ is more highly debated. Many physicians consider excessive oxygen supplement a salutary pattern which is now widely applied in the routine practice of simplicity and easy availability [39]. Despite the controversy, the majority of published randomized trials comparing 30% and 80% FiO₂ mainly in SSI and PONV show that intraoperative high FiO₂ decreases the risk of both [40-42]. Furthermore, new 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% FiO₂ intraoperatively [43]. What remains controversial is whether the intraoperative use of an elevated FiO₂ is essential to all intubated patients without hypoxemia, although 30% and 80% FiO₂ provide similar oxygenation [21]. A multicenter observational trial collecting the ventilator data 1h after induction showed that most patients (83%) in Japan were exposed to potentially preventable hyperoxia, especially in one-lung ventilation 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 FiO₂ were raised [44-46][34]. Endothelial activation may initiate progressive hyperoxic lung injury when hyperoxic ventilated at 70% FiO₂persistently [19]. In addition, excessive oxygen can lead to pulmonary endothelial cells damage through mitochondrial fragmentation [47]. This can be explained by the formation of reactive oxygen species (ROS) and pro-inflammatory 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 FiO₂ to keep SpO₂≥95% weaken oxygen toxicity by less ROS production [48]. However, there is contradictory view on high FiO₂’s detrimental effect on endothelial dysfunction in healthy volunteers solely [49]. Another interpretation is that high FiO₂ may change pulmonary gas exchange in surgical patients. Ventilation with high FiO₂(80%-100%) increases intrapulmonary shunt [50] and impairs gas exchange [51]. In addition, resorption atelectasis results from a phenomenon which nitrogen is displaced by O₂ that can diffuse more rapidly into the blood. Resorption atelectasis can also promote pulmonary shunt and cause hypoxemia [52]. Ventilation for induction of anesthesia with 100% FiO₂ leads to significantly larger atelectasis areas than with 60% FiO₂ [53]. Atelectasis area tends towards being 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 the damage of lung tissue [54]. The synergetic action of above factors increases the risk of lung injury and pulmonary complications.

Indeed, supplemental oxygen results in hyperoxia, as reported an independent risk factor for ventilator-associated pneumonia in an observational study [55]. Liberal oxygen use is considered detrimental in mechanically ventilated patients in the aspect of lung function [56] 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% FiO₂ [57]; nevertheless, the former suffers higher long-term mortality (23.3% vs. 18.3%) [58]. And an observational trial has suggested a dose-dependent manner in FiO₂ and 30 days mortality. The incidence of PPCs has declined by half in low FiO₂ group with a median of 31% (range 16%-34%) [30].

Yet, no direct evidence revealed the relationship of FiO₂ in lung-protective ventilation and PPCs, and existing data reported postoperative pulmonary function is better protected with a relative low FiO₂ intraoperatively [59]. A systematic review showed that the included trials only focused on postoperative atelectasis, rather than all forms of PPCs [60]. Despite PROXI trial demonstrated that PPCs did not differ after inhalation of 80% vs 30% oxygen, the results are worth discussing. Emergency surgery population were not excluded in PROXI trial, which is an independent risk factor of pulmonary complications [4]. Intubation time is also a key element of causing pneumonia and atelectasis. Moreover, complication measures of PROXI lacked a standard and comprehensive judgment, which only assessed the three types of PPCs (atelectasis, pneumonia and respiratory failure) according to CDC criteria. And above all, the ventilation strategy to patients is not specified, which plays a key role in the incidence of pulmonary complications. The iPROVE-O₂ trial is an ongoing randomized controlled trial (clinicaltrials.gov identifier：NCT02776046) comparing the efficacy of 80% and 30% FiO₂ with individualized open-lung ventilatory strategy in reducing the incidence of SSI [61]. The major differences compared to PROVIO trial are: the appearance of pulmonary complications as one of secondary outcome; individualized open-lung ventilation as ventilatory mode that is a combination of 8 ml/kg V_T, recruitment maneuver and the optimal individualized PEEP. Recruitment maneuver will be performed by a PEEP-titration trial [62]. Undoubtedly, individualized open-lung ventilation strategy is more complex to implement clinically, when comparing to lung-protective ventilation [62].

Limitations of our study must be mentioned. Firstly, we conducted a pilot study to acquire the incidence of PPCs in our medical center referring to the sample size calculation. Hope our results will provide the possible direction and reference to subsequent researches of FiO₂. Secondly, the study excludes the patients scheduled for some types of surgery because of the duration of 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 intraoperative lung-protective ventilation strategy, previous studies failed to identify the certain relationship between FiO₂ and PPCs. We insist that lung-protective ventilation in both groups will reduce bias about the ventilation-associated impact and enhance lung protection. Conclusively, PROVIO trial is the first clinical trial focusing on the effect of FiO₂ added to lung-protective ventilation on PPCs. The results of the trial will support anesthetists in routine oxygen management during general anesthesia in an attempt to prevent PPCs.

Trial status

The trial is ongoing from February 2018, and expected to complete in May 2019. The protocol version is 3.0 (issue date: 25 December 2018)

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

AE: Adverse Event; ARISCAT: Assess Respiratory Risk in Surgical Patients in Catalonia; ASA: American Society of Anesthesiologists; BIS: the bispectral index; BMI: body mass index; CDC: the Centers for Disease Control and Prevention; CONSORT: The Consolidated Standards of Reporting Trials; COPD: chronic obstructive pulmonary disease; CRF: case report form; DSMB: Data and Safety Monitoring Board; ETCO2: end-tidal carbon dioxide; FiO2: inspiratory oxygen fraction; Hb: hemoglobin; HR: Heart rate; KDIGO: Kidney Disease: Improving Global Outcomes; MAP: Mean arterial pressure; MV: minute volume; NYHA: New York Heart Association classes; ICU: Intensive Care Unit; I: E: Inspiratory to Expiratory ratio; P plat: plateau pressure; PACU: post-anesthesia care unit; PEEP: positive end-expiratory pressure; PONV: postoperative nausea and vomiting; PPCs: Postoperative pulmonary complications; PROVIO: PROtective Ventilation with a low versus high Inspiratory Oxygen fraction trial; ROS: reactive oxygen species; SD: standard deviation; SIRS: the Systemic Inflammatory Response Syndrome; SPIRIT: the Standard Protocol Items: Recommendations for Interventional Trials; SpO2: pulse oxygen saturation; SSI: surgical site infection; VT: tidal volume.

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 from all patients in written form who meet all the inclusion criteria and none of the exclusion criteria before arrival to 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.

Confidentiality

The personal information of patients will be confidential at all periods of trial. Data will be handled according to China law and archived for at least 5 years. Meanwhile, the database will be anonymized and kept for 5 years. Then, data will be destroyed according to the hospital standards concerning destruction of confidential information.

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

Consent for publication: Not applicable.

Author Contributions: XFL, XYY, and HY (Hai Yu) provided substantial contributions to study conception and design. XFL and HY (Hai Yu) drafted protocol and edited manuscript. DJ, HY (Hong Yu), YLJ, JLJ, LLH anticipated in study design. All the authors read and approved the final manuscript.

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

Competing interests: None declared.

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Table 1. Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT) risk score in the logistic regression model

βCoefficient

Score *

Age (years)

≤50

51-80

> 80

Preoperative SpO2 (%)

≥96

91-95

≤90

Respiratory infection in the last month

Yes

Preoperative anemia (Hb ≤10 g/dl)

Yes

Surgical incision

Peripheral

Upper abdominal

Intrathoracic

Duration of surgery (h)

≤2

2–3

Emergency procedure

Yes

0.331

1.619

0.802

2.375

1.698

1.105

1.480

2.431

1.593

2.268

0.768

*A risk score ≥26 predicts an intermediate to high risk for postoperative pulmonary complications after abdominal surgery. The simplified risk score was the sum of each logistic regression coefficient multiplied by 10, after rounding off its value.

Hb = hemoglobin.

Table 2: Intraoperative ventilation settings for the PROVIO trial

	Low FiO2 group	High FiO2 group
FiO2	0.30	0.80
VT	8 ml/kg	8 ml/kg
PEEP	6-8 cmH2O	6-8 cmH2O
I: E	1:2	1:2
RR	Adjusted according to ETCO2 (35-45 mmHg)	Adjusted according to ETCO2 (35-45 mmHg)
P max	30 cmH2O	30 cmH2O

Table 3: Standard state target

	Parameter	Value
Hemodynamics	Mean arterial pressure (MAP)	70 mmHg < MAP < 100 mmHg
Hemodynamics	Heart rate (HR)	50/min < HR < 100/min
Oxygenation	SpO2	≥92%

Table 4. The grade of pulmonary complications

Postoperative pulmonary complications grade
Grade 1	-Cough, dry -Microatelectasis: abnormal lung findings and temperature > 37.5°C without other documented cause; normal chest radiograph -Dyspnea, not due to other documented cause
Grade 2*	-Cough, productive, not due to other documented cause -Bronchospasm: new wheezing or preexistent wheezing resulting in a change in therapy -Hypoxemia: SpO2 < 90 at room air -Atelectasis: gross radiological confirmation (concordance of 2 independent experts) plus either temperature > 37.5°C or abnormal lung findings -Hypercarbia (PaCO2 > 50mmHg), requiring treatment.
Grade 3	-Pleural effusion, resulting in thoracentesis -Pneumonia: radiological evidence (concordance of 2 independent experts) plus clinical symptoms (two of the following: leucocytosis or leucopenia, abnormal temperature, purulent secretions), plus either a pathological organism (by Gram stain or culture), or a required change in antibiotics -Pneumothorax -Noninvasive ventilation, strictly applied to those with all of the following: a) SpO2 ≤ 92% under supplemental oxygen; b) need of supplemental oxygen > 5L/min; and respiratory rate ≥ 30 bpm -Reintubation postoperative or intubation, period of ventilator dependence does not exceed 48 hours
Grade 4	-Ventilatory failure: postoperative ventilator dependence exceeding 48 hours, or reintubation with subsequent period of ventilator dependence exceeding 48 hours
Grade 5	-Death

*We only classified as grade 2 if two or more items in the grade 2 were present.

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

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