Pressure-controlled ventilation-volume guaranteed (PCV-VG) for postoperative pulmonary complications: a protocol for a systematic review with meta-analysis and trial sequential analysis

More than 300 million major surgical procedures are performed worldwide yearly. Above 30% of patients undergoing surgery with mechanical ventilation may experience postoperative pulmonary complications (PPCs). PPCs are the main cause of perioperative morbidity and mortality and it can be decreased by optimizing the mechanical ventilation. Pressure-controlled ventilation-volume guaranteed (PCV-VG) is a new ventilation mode, which combines the advantages of volume-controlled ventilation and pressure-controlled ventilation, might reduce PPCs. The ecacy of PCV-VG for PPCs has not yet been systematically reviewed. Hence, we will conduct a systematic review to evaluate the ecacy of PCV-VG for PPCs. The aim of this protocol is to investigate the benets of PCV-VG versus conventional ventilation mode for PPCs. saturation; PaCO 2 PEtCO 2 pressure dioxide; FiO 2 : fraction of inspiration O 2 ; V D : Dead space volume ; V T : Tidal volume; P peak : Peak inspiratory pressure; P mean : mean inspiratory pressure; P plateau : plateau inspiratory pressure; C dyn : pulmonary dynamic compliance; MAP: Mean arterial pressure; HR: Heart rate; CVP: Central venous pressure; PRISMA-P: Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol; RCTs: Randomized controlled trials; CIs: Condence intervals; MDs: Mean differences; SMD: Standardized MDs; RR: Risk ratio; EPCO: European Perioperative Clinical Outcome; TSA: Trial Sequential Analysis; RIS: Required information size.

mortality rate after major surgery of patients developing PPCs was 14-30%, higher than the rate (ranges from 0.2-3%) of those without a PPCs [6]. Considering more than 300 million surgical procedures are performed worldwide per year, decreasing the incidence of PPCs could reduce the global morbidity and mortality, improve the quality of medical care and decrease the health system costs [1,7].
Mechanical ventilation during general anesthesia has the potential risk to cause ventilator-associated lung injury (VALI) and therefore, lead to PPCs [8]. According to an international expert panel-based consensus, prevention of PPCs is an important therapeutic and economic goal, which may in part be accomplished by the optimization of mechanical ventilation [9,10].
Volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) are the most common mechanical ventilation mode during anesthesia. In VCV mode, ventilator delivers a target volume with a constant ow, the preset tidal volume and minute ventilation can be guaranteed during ventilation.
However, this ow pattern may lead to higher peak inspiratory pressure (PIP) in response to reduced compliance or increased resistance. High inspiratory pressure can lead to shear stress injury, barotrauma and volutrauma to the alveoli, increasing the incidence of micro atelectasis and causing imbalanced distribution of pulmonary gases and in ammatory mediator release, which are the characteristic of ventilator-associated lung injury [11][12][13][14].
Compared with VCV, PCV provides tidal volume at a preset pressure with decelerating ow, and the tidal volume can be changed depending on lung compliance. 15 This ow pattern can produce lower airway pressure, maintain the uniform distribution of pulmonary gas, improve oxygenation and reduce the incidence of barotrauma [16,17]. However, PCV has the limitation of variable tidal volume and minute ventilation according to the respiratory system compliance and resistance. So, there is always a risk of hypoventilation or hyperventilation, especially during transition from the supine to the trendelenburg position, or during pneumoperitoneum with carbon dioxide (CO 2 ) [18,19].
Therefore, we present this systematic review protocol designed to quantitatively investigate the e cacy of PCV-VG for intraoperative mechanical ventilation, especially to investigate the in uence of PCV-VG on PPCs.

Methods/design Study registration
This systematic review has been registered with PROSPERO (registration number: CRD 42020207555). This protocol was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines. The review will be conducted in accordance with the PRISMA guidelines [37,38]. The study is expected to begin searching in May 2021 and end in November 2021.

Inclusion criteria
Type of studies We will include randomized controlled trials (RCTs) that evaluated the PCV-VG, dualcontrolled ventilation or PRVC ventilation for intraoperative mechanical ventilation in adults (aged 18 years old or over). Only studies published in English or Chinese will be included. No time limits will be applied to the searches.
Types of participants Adult Participants (18 years of age or older) undergoing operations requiring intraoperative mechanical ventilation will be included. Intraoperative mechanical ventilation with PCV-VG, PRVC or dual-controlled ventilation will be included. There will be no limits on study participants in terms of gender, ethnicity and types of surgery.
Types of interventions In the intervention group, participants had to have received intraoperative mechanical ventilation with PCV-VG, PRVC or dual-controlled ventilation.
Types of comparators The comparator group will be the participants received intraoperative mechanical ventilation with conventional mechanical ventilation modes (Such as VCV or PCV) Type of outcome measurements Primary outcomes The primary outcome will be the incidence of PPCs, expressed as risk ratio (RR). PPCs being de ned as the composite of any of respiratory infection, respiratory failure, pleural effusion, atelectasis, or pneumothorax, as de ned in the de nition of postoperative respiratory complications from European Perioperative Clinical Outcome (EPCO) consensus statement and the recent consensus de nitions [39,40].
Secondary outcome The secondary outcomes will be: 2. Intraoperative respiratory parameters: peak inspiratory pressure (P peak ), mean inspiratory pressure (P mean ), plateau inspiratory pressure (P plateau ), pulmonary dynamic compliance (C dyn ).

Exclusion criteria
Studies with the following situations will be excluded: (a) participants undergoing emergency surgery; (b) participants with respiratory complications before surgery; (c) studies with insu cient data or without an effective classi cation; duplicated data or data that cannot be extracted; (d) crossover trials, cluster-RCTs, quasi-RCTs, uncontrolled trial, animal study, review, comment, case report, case series, non-clinical study.
Databases and search strategy The following electronic databases will be searched from inception: English database including-PubMed, Web of Science, Cochrane Library, Ovid MEDLINE and Embase; Chinese database including-China National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature, Wanfang database and VIP Database. These electronic databases will be searched from inception to May 2021. In addition, we will scrutinize the list of references, relevant conference literature, dissertations and trial registry database (WHO International Clinical Trials Registry Platform and Clinical Trials.gov) to overcome the publication bias due to identify additional studies.
The search strategy for PubMed (as an example) is shown in table 1. The following search terms will be used singly or as combinations (MeSH terms and free words): pressure-controlled volume guaranteed, PCV-VG, dual controlled ventilation, pressure regulated volume controlled, PRVC, intraoperative and randomized controlled trial. The search terms will be translated into Chinese for study identi cation in Chinese databases. Prior to nal publication, we will perform a new search in the databases to check if any studies were published during the elaboration of the systematic review. The preliminary search strategy of other electronic databases is given in (online supplementary additional le 1). Two authors (JQZ and LD) will independently perform study selection based on pre-designed eligibility criteria. All searched records will be imported into citation management system (Endnote X9), and we will lter and remove all duplicates. First, all studies will be identi ed by screening titles/abstracts, and irrelevant records will be eliminated. Then, the full text of potential studies will be obtained and checked against all pre-designed inclusion criteria. If divergences occur, a third author will help determine and solve them to reach a nal decision about whether the trial meets the eligibility criteria through discussion or consensus meeting.
Two reviewers (JQZ and LD) will be required to screen the retrieved studies independently. We will import the searched records into citation management system (Endnote X9), lter and remove all duplicates. Brie y, they will exclude studies not matching the inclusion criteria by reading title and abstracts. Then they will read the full text of each study to select those meeting the inclusion criteria. Any disagreements will be resolved through discussion with a third reviewer (JW). A fourth reviewer (LZ) will check all procedures before approving the data extraction. The entire study selection process is shown in the ow diagram ( gure 1).

Data extraction and management
Two reviewers (JQZ and XQD) will extract data from the included studies independently following a previously designed standard data acquisition excel form. The form will include the basic information (e.g., rst author, title, journal, country, year of publication, and sample size), patient characteristics (e.g., age, sex, body mass index, eligibility criteria, surgical type and surgical position), study design and quality (e.g., random sequence generation, allocation concealment and blinding methods), detail information of interventions and controls [e.g., conventional ventilation mode (PCV-VG, VCV or PCV) , ventilation mode (One lung ventilation, two lung ventilation), intra-abdominal pressure during pneumoperitoneum, target value of tidal volume, inspiratory to expiratory ratio (I/E), respiratory rate (RR), FiO 2 , positive endexpiratory pressure (PEEP), target value of PETCO 2 ], outcome measures, con icts of interest, and any other relevant information. Third reviewer (GC) will double-check the data to ensure consistency.
If necessary, we will extract numerical data from graphs using Adobe Photoshop as described by Sevda Gheibi [41]. If data are missing or incomplete in any study, we will contact with the authors to obtain the original data. In case it is impossible to obtain the data, to ensure the statistical power and avoid bias, the last observation carried forward imputation method will be used to assume a missing value and then an intent-to-treat analysis and sensitivity analysis will be performed to assess whether that the results are consistent.
For continuous outcome data, the mean differences (MDs) or the standardised mean difference (SMDs) with 95% con dence intervals (CIs) will be used for analysis. For dichotomous data, the RR with 95% CIs will be used for analysis.

Assessment of risk of bias
The risk of bias in the included studies will be determined by two reviewers (JW and LZ) independently using the Cochrane Collaboration tool [42]. The Cochrane Collaboration's tool covers six aspects, random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias. The risk will be divided into three levels (low risk, unclear and high risk) in accordance with the item in the checklist. If any disagreements, the risk assignment will be settled through arbitration of a third reviewer (GC).

Quality of evidence
The modi ed Jadad scale will be applied to assess the quality of literatures [43,44]. The overall quality of included studies will be conducted in eight Items: randomization (with score 0-2), allocation concealment (with score 0-2), blinding (with score 0-2), withdrawals and dropouts (with score 0-1) adverse effects (with score 0-1), and statistical analysis (with score 0-1) ( Table 2). Scale scores for each study could range from 0 to 8 points, with higher scores indicating better quality. Studies with a score less than 4 are de ned as low-quality, while 4-8 are considered as high-quality. test. if the p≥0.1, and if Ι 2 ≤50%, the xed-effects model will be used. if the p<0.1 or the Ι 2 >50%, the random-effects models will be applied. When the heterogeneity is statistically signi cant, we will conduct a subgroup analysis to investigate the possible sources of heterogeneity according to the patient characteristics and the classi cation of surgery. If the Ι 2 >75%, a meta-analysis will not be performed and a narrative, qualitative summary will be provided.

Subgroup analysis
If data are available, subgroup analysis will be performed to assess the heterogeneity according to the conventional mechanical ventilation mode and types of surgery. To explore signi cant heterogeneity, if a su cient number of trials are available, we will conduct the following prespeci ed subgroup analyses separately (hypothesised direction of effect in parentheses): (a) Type of conventional mechanical ventilation mode (PCV-VG is more effective in surgery as compared with PCV or VCV mode). (b) Type of surgery (PCV-VG is more effective in thoracic surgery with one-lung ventilation or laparoscopic gynecologic surgery with carbon dioxide pneumoperitoneum as compared with conventional mechanical ventilation modes).

Trial Sequential Analysis
Trial Sequential Analysis (TSA) will be conducted to control the risks of type I errors and type II errors [45][46][47]. The required information size (RIS: the number of participants needed in a meta-analysis to detect or reject a certain intervention effect) and the cumulative Z-curve's breach of relevant trial sequential to monitor boundaries will be calculated for all outcomes [48][49]. For continuous outcomes, we will use the observed SD, a mean difference of the observed SD/2, an alpha of 2.5% and a beta of 10% for outcomes in the TSA [50]. For dichotomous outcomes, we will use the proportion of participants with an outcome in the control group, a relative risk reduction of 20%, and an alpha of 2.5% and a beta of 10% in the TSA [51]. TSA will be performed using the TSA program version 0.9.5.10 Beta (http://www.ctu.dk/tsa) [52].

Sensitivity analysis
If possible, sensitivity analysis will be used to evaluate how uncertain assumptions of data and usage affect the robustness of the combined results. We will exclude low quality studies, re-analyse the included studies, and assess whether there are signi cant differences between the combined effects. If necessary, we will remove the included studies one by one from the pooled analyses.

Assessment of reporting biases
The potential publication bias will be statistically analysed using funnel plots analysis and Egger's regression test when more than 10 studies are involved for an outcome [53]. In the presence of plot asymmetry for a given analysis (e.g., publication bias), trim-and-ll method will be used to determine the impact of removing smaller studies on the overall estimate and provide adjusted results [54]. Reporting biases will be performed by Stata/MP 16.0 (Stata Corp, College Station, TX, USA).

Discussion
Mechanical ventilation has the potential risk to cause PPCs, which are the main cause of overall perioperative morbidity and mortality in patients. Optimization of mechanical ventilation could reduce PPCs, reduce global morbidity and mortality, improve the quality of medical care and decrease hospital costs. PCV-VG is a new mode introduced recently in the eld of anesthesiology. It combines the advantages of VCV and PCV, which might improve arterial oxygenation, reduce in ammatory factors and ALI. However, whether PCV-VG could reduce the postoperative pulmonary complications remains uncertain.
This review might be the most comprehensive review about PCV-VG for PPCs. We will summarize the current evidence and providing valuable information for trial design in the future. Our systematic review and meta-analysis will examine the effect of PCV-VG compared with conventional mechanical ventilation modes on PPCs. This will help clinical practitioners in decision-making when choosing optimal intraoperative mechanical ventilation mode and support the development of clinical practice guidelines in the future.

Strengths And Limitations
This systematic review protocol follows the preferred reporting items for systematic review and metaanalysis protocols guidelines conducting a rigorous risk of bias assessment. We will use the modi ed Jadad Scale to assess the quality of evidence. TSA will be used to assess the optimal sample size for the outcomes and control the risk of random errors. Publication bias will be assessed by Funnel plots and Egger's regression test. Subgroup analysis will be performed to assess the heterogeneity according to the conventional mechanical ventilation mode and types of surgery.
There are also limitations to our analysis. First, studies with different mechanical ventilation time, different value of preset tidal volume and different value of preset pressure will be included, resulting in potential heterogeneity. Second, the sample size in each study may be small. Third, number of studies with eligible data for subgroup analyses may be limited. Fourth, another limitation may be the current lack of high-level evidence, such as well-designed randomized controlled trials with double-blind.

Declarations
Ethics approval and consent to participate Ethical approval is not applicable as this is a systematic review protocol; we will not involve the human population directly.

Consent for publication
Not applicable as the manuscript does not contain data from any person.

Availability of data and materials
The data acquisition for this systematic review has not yet started. We plan to conduct the search in mid-May. Subsequently, dataset generated through this systematic review can be requested from the corresponding author.

Competing interests
The authors declare no competing interests. Authors' contributions JQZ and LD conceived the idea for this systematic review. All authors (JQZ, LD, JW, LZ, XQD, GC) developed the methodology for the systematic review. The manuscript was drafted by JQZ, LD, and revised by all authors. XQD and GC will screen potential studies, perform duplicate independent data abstraction. JQZ and LZ will undertake risk of bias assessment and assess the evidence quality. JQZ and LD will conduct the data synthesis. All authors contributed to the research and agreed to be responsible for all aspects of the work. GC is the guarantor of the review.

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