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Adaptive Support Ventilation versus Conventional Ventilation during Hypoxemic Respiratory Failure: A Meta-analysis of Randomized Controlled Trials

Background The purpose of the study is to examine whether the adaptive support ventilation (ASV) mode compared with conventional ventilation reduces the duration of mechanical ventilation (MV) in patients with acute respiratory failure. Methods We searched PubMed, the Cochrane Library Central Register of Controlled Trials, EMBASE and Web of Science databases from inception through July 27, 2019. We considered all the randomized controlled studies (RCTs) that examined the efficacy of ASV in comparison with conventional ventilation in mechanically ventilated adults. The primary outcomes were (1) the length of MV, (2) weaning duration and (3) length of stay (LOS) in ICU. Results We included three RCTs for the analysis enrolling a total of 374 patients. Patients treated with ASV had a lower weaning duration than patients treated with conventional ventilation (MD -28.98 [95% CI -42.42, -15.54, p˂0.0001]). Then, 28-day mortality was not different between the two groups (OR 0.95 [95%CI 0.6, 1.52, p=0.83; I2=0%, p=0.96]). The incidence of ventilator-associated pneumonia and sedation level was not included into the quantitative analysis. Conclusions The study showed that a lower number of duration of MV and a shorter number of weaning duration in acute hypoxemic respiratory failure patients treated with ASV than conventional ventilation. Acute hypoxemic respiratory failure is disorder of the ASV VCV COPD chronic obstructive pulmonary disease, ARDS acute respiratory distress syndrome Pressure, P-ACV Assist/Control Ventilation, MV mechanical ventilation, fR respiratory rate, FIO 2 fraction of inspired oxygen, VE Minute ventilation, IBW Ideal body weight, PBW predicted body weight, PEEP positive end expiratory pressure, Pinsp inspiratory pressure on ASV, Pplat plateau pressure, Vt tidal volume. ICU intensive care unit, Delta SOFA delta sequential organ failure assessment score, MinVol% minute ventilation, PBW predicted body weight, ETS expiratory trigger sensitivity

Conclusions The study showed that a lower number of duration of MV and a shorter number of weaning duration in acute hypoxemic respiratory failure patients treated with ASV than conventional ventilation. Keywords: pulmonary infection; critically ill patients; adaptive support ventilation; hypoxemic respiratory failure Background Acute hypoxemic respiratory failure is a severe disorder of the respiratory system to maintain oxygenation or eliminate carbon dioxide (CO2), leading to a series of metabolic disorders and physiological dysfunction. Mechanical ventilation (MV) serve as a lifesaving therapy is widely employed in intensive care units (ICU) for treating clinical symptoms related to critically illness. [1,2] Employment of mechanical ventilation in patients could help effectively to replace, control and change spontaneous breathing, reduce or eliminate respiratory muscle oxygen consumption, increasing ventilation and improving ventilation [3], removing the residual mucous in airway. [4] The choice of ventilation mode is such a very important issue in ICU that clinicians capable to choose the ventilation mode and adapt the ventilator controls according to the patient's respiratory mechanics.
3 Background Acute hypoxemic respiratory failure is a severe disorder of the respiratory system to maintain oxygenation or eliminate carbon dioxide (CO 2 ), leading to a series of metabolic disorders and physiological dysfunction. Mechanical ventilation (MV) serve as a lifesaving therapy is widely employed in intensive care units (ICU) for treating clinical symptoms related to critically illness. [1,2] Employment of mechanical ventilation in patients could help effectively to replace, control and change spontaneous breathing, reduce or eliminate respiratory muscle oxygen consumption, increasing ventilation and improving ventilation [3], removing the residual mucous in airway. [4] The choice of ventilation mode is such a very important issue in ICU that clinicians capable to choose the ventilation mode and adapt the ventilator controls according to the patient's respiratory mechanics.
Adaptive support ventilation (ASV) is a closed-loop mode, as a newer protective ventilation mode, which can act both as pressure-control synchronized intermittent mandatory ventilation or pressure support ventilation. The first clinical application was described in the literature in 1994 by Laubscher and colleagues [5,6] that characterized with assist-control, pressure-targeted, time-cycled mode of ventilation. It is considered to be the first available ventilator system that uses an "optimal" targeting schema [7]. When using ASV, the preset parameters are far less than other modes. It includes three parameters: (1) minute ventilation percentage (MinVol%). When the preset MinVol% is 100%, the minute ventilation provided by the ventilator is 0.1 l/kg (adult) and 0.2 l/kg (child); (2) airway pressure alarm high limit; (3) patient ideal weight. Theoretically, this optimal ventilator work may ensure adequate MinVol% with least possible airway pressure [8] which, in turn, reducing the risk of ventilator-associated lung injury. The majority of benefits regarding the ASV used in weaning postoperative patients with shortening weaning time, reducing the need for arterial blood gas (ABG) analyses, and fewer number of manual ventilator setting changes [9][10][11]. In a clinical study of ASV compared with synchronized intermittent mandatory ventilation (SIMV) of chronic obstructive pulmonary disease (COPD) patients showed that PaO 2 , pH, and SaO 2 values were remarkably increased, peak airway pressure (PIP) value was significantly decreased, showed that lowing pressure of ASV could reduce the occurrence of ventilator-associated lung injury (VALI), and improve the respiratory function and ventilation volume and decrease the burden of respiratory muscles and improve clinical outcomes [12]. In experiments related to respiratory mechanics showed that decreased inspiratory load and improved patient-ventilator interactions benefit from the central respiratory drive and sternocleidomastoid activity were obviously decrease [13]. A physiological study of respiratory failure, ASV was found superior in hemodynamics, ventilatory and gas exchange parameters [14].
ASV was well known as safety, comfort, and liberation, which can minimize the work of breathing and improve the outcomes in hypoxemic respiratory failure (HRA), and have largely fallen under this "lessis-more" mechanical ventilation strategy, then commonly used in invasive mechanical ventilation.
However, Agarwal et al [15]showed that acute respiratory distress syndrome (ARDS) patients with ASV and volume-cycled ventilation (VCV) have no significant difference in duration of MV, intensive care unit and hospital stay, the mortality and the number of arterial blood gas also have no statistically significant between the two group, when respiratory system compliance failure or mechanical-ventilator asynchrony may amplify VALI. [16] Whether the ASV mode have a positive impact on passive ventilation patients compared to conventional ventilation strategies remains unclear. Herein, the aim of this meta-analysis is to assess the outcomes of duration of MV, ICU length of stay, successfully extubated rate, the mortality day of 28 and weaning duration in ASV versus conventional ventilation in critically ill adults with hypoxemic respiratory failure.

Methods
A meta-analysis of RCTs was conducted to compare the length of MV, ICU length of stay (LOS), and weaning period in ASV outcomes of acute respiratory failure. All the data of the study were included from published RCTs, we complied with the PRISM (Preferred Reporting Items for Systematic Reviews and Meta-analyses) [17]statement for reporting this study.

Data sources and search strategy
We performed an electronic databases search of PubMed, Cochrane Central Register of Controlled Trials, EMBASE and Web of Science database from their inception to July 27, 2019 for eligible studies, we combined the terms 'adaptive support ventilation ,' 'closed-loop control ventilation,' 'ASV,' 'anoxemia,' 'hypoxemia,' 'hypoxemic respiratory failure,' 'oxygen deficiency' 'COPD,' 'chronic obstructive pulmonary disease', 'ARF,' and 'acute respiratory failure' were used. The searches were limited to English publications as well as RCTs. Results were then filtered for adult human ' s studies.
Furthermore, we also trying to contact the authors to get the original studies to obtain additional information.

Eligibility criteria
We included randomized controlled trials (RCTs) that examined the efficacy of ASV mode in comparison with conventional ventilation in adults (aged≥18 years, who were diagnosed with acute hypoxemic respiratory failure (PaO2/FiO2˂300mmHg). All these patients were hospitalized in ICU in respiratory department. All patients had been found to have respiratory failure, which required mechanical ventilation. We excluded observational studies, case series and case reports, studies published in abstracts, literature reviews, editorials, as well as randomized control group studies that applied ASV mode no clinical prognostic related results.

Data extraction and bias assessment
The retrieved results were combined and removed duplicated records. Two investigators (Xiaoli Liu and Wei Zhang) independently abstracted titles and abstracts and screed the full-text of the reports from our search. Details of the adaptive support ventilation mode used and relevant outcomes were recorded. When data about an outcome of the study were missing, the authors were contacted to clarify abstracted data and obtain patient-relevant data to ensure accuracy in the review. All disagreements at any step of the process were resolved by discussion or by the opinion of a third investigator (Zongan Liang) if necessary.
The same investigators also independently assessed the risk of bias using Cochrane risk bias tool [18] (http://ims.cochrane.org/revman). Two investigators (Xiaoli Liu and Wei Zhang) subjectively reviewed all studies and assigned a value of 'high,' 'low,' or 'unclear' in the following: (1) selection bias (was there randomization sequence? Was allocation concealment satisfactory?) (2) performance bias (was there adopted uniform and standardized treatment plan?) (was there blinding participants, personnel, and outcome assessment?) (3) measurement bias (was there adopt standardized measurement methods?) (4) attrition bias (were incomplete outcome data Fully evaluated and processed?) (5) reporting bias (was there selective outcome reporting?) (6) other biases (was the study avoid other problems that could put it at a high risk of bias?).

Collection and Analysis of Data
The RCTs included in this study, duration of mechanical ventilation, ICU LOS and weaning period in acute respiratory failure applied in ASV was the primary outcome. We abstracted and collected data, including the first author, published year, participants' baseline characteristics, the type of patients, PaO2/FiO2 at baseline (mmHg), MV before randomization (h), ASV initial setting, intervention, and outcome.

Outcomes
Our Primary outcomes were: (1) duration of mechanical ventilation, defined as the time from intubation until last successful extubation; (2) ICU length of stay; (3) weaning duration, defined as the time from randomization to spontaneous breathing with or without a tracheotomy; the secondary outcomes included (1) 28-day mortality; (2) weaning success rates.

Statistical analysis
We used RevMan version 5.3 software for all data and statistical analyses. For dichotomous outcomes were calculated using the Mantel-Haenszel (MH) method and were expressed with odds ratios (OR), for continuous outcomes, using random-effects model and were calculated by weighted mean difference (WMD) and presented the results with associated 95% confidence intervals (CIs) for the included studies reported continuous outcomes in medians and interquartile ranges, we estimated the means and standard deviations (SD) using a method proposed by Wan et al. [19] Heterogeneity was assessed with the I 2 statistic and defined as greater than 50% being considered substantial, [20] the random-effects model was used for all analyses. Potential publication bias was not assessed because of the number of included studies of less than 10. [18] A p value of less than 0.05 was considered statistically significant.

Study identification and selection
Using the outlined search strategy, we identified 742 citations. Fig 1 shows the study search strategy according to PRISMA guidelines [17]. After removal of duplicates, a total of 653 citations were screed of titles and abstracts, and assessed the full text of twenty articles. Of these, we considered three RCTs [15,21,22], 374 patients,186 ventilated with ASV and 188 with conventional ventilation mode) met criteria for inclusion (Fig.1). Table 1  MinVol % 100% (0.1/kg PBW( predicted body weight)), positive end expiratory pressure (PEEP) 3-5cmH20, FiO2≤40% and use this data to set tidal volume (VT) and respiratory frequency (fR).

Secondary outcomes
Two studies [21,22] did not show any differences in weaning successful rate (OR 1.36 [95% CI 0.87, 2.12, p=0.18; I 2 =0%, p=0.64]) (Fig 2-4). Then, 28-day mortality was not different between the two groups (OR 0.95 [95%CI 0.6, 1.52, p=0.83; I 2 =0%, p=0.96]) (Fig 2-5). This may be an inaccurate results for the small scale of literature pooled.  [22], two of the studies [15,22] described an explicit generation process of a random sequence and the methods that were applied to allocation concealment. As the studies included were less than ten, a publication bias analysis was not performed. All of the studies were estimated to have a low risk of bias.

Discussion
This study was the first meta-analysis investigating the clinical effects of ASV on critically ill adult patients affected by acute HRA. Our results demonstrated that ASV as a ventilation mode has a positive improvement effect on shortening mechanical ventilation time and expedited weaning.
Therefore, for patients with acute respiratory failure may lead to the reduction of complications and costs, ASV could be a viable alternative to MV.
ARF could result in a series of physiological functions and metabolic disorders in the body. The onset of illness develops rapidly, which required emergency treatment, or admitted to the intensive care unit (ICU). MV is the main treatment for ARF, which can alleviate the patient's conditions. Researches on clinical ASV have been approaching more than 20 years, while this technique can facilitate many scenes. Currently, ASV as a mode of MV has become one of the hot spots of severe rescue treatment, applying in the acute and weaning phases of ventilation. The computerized control system is used to comprehensively monitor the patient's immediate conditions, and the breathing parameters are automatically set according to the patient's ventilation needs and respiratory capacity. And adjustment, which in turning converts complete supports ventilation into partial support ventilation.
ASV also replaces other ventilation modes designed solely for a specific phase of MV, during the initiation, maintenance or weaning from MV. [24] It cannot only provide the most benefit in resource limited environments [25,26] saving cost and according to change the delivered pattern (VT and fR) based on the underlying condition, but minimize the incidence of VALI, [27][28][29] successfully fast weaning and reduce the risk of reintubated. [30,31] Studies have indicated a reduces in respiratory load and establish a state of hyperventilation to provide a safe and efficient ventilation mode for patients [32].
At the same time, it is also able to guide the patient to prepare for the weaning, and assist and retain the patient's spontaneous breathing function on the basis of ensuring the patient's basic oxygen supply requirements. [33] However, these studies did not provide adequate data or sufficient clinical evidence to support the beneficial effects of ASV ventilator mode on these relevant findings.
Our results suggested that the ventilation mode of ASV shortened ICU LOS in three studies [15,21,22]. This results indicates that ASV can have a clinical effect on HRF patients, our meta-analysis also found that patients treated with ASV had a statistically significant higher value of weaning duration than patients on conventional ventilation, the difference was clinically significant (MD -28.98; 95%CI -42.42, -15.54, p˂0.0001). This result shows that the ASV mode is a good alternative to the ventilator weaning phase, consistent with the literature report. [26] The mechanisms of ASV responsible for its beneficial effects that differ from other mode of ventilation have yet to be elucidated. Several factors may be responsible for the beneficial effects seen in the patients undergoing ASV ventilation aside from conventional ventilation.
There are several theoretical advantages of ASV. Extubation readiness was recognized earlier with ASV, [26] since ASV can help recognize extubation readiness with fewer manipulations. [34] Additionally, the airway pressure is always in a safe range, through a lung protection strategy, and solves the relevant mechanical complications such as apnea, volutrauma, barotrauma and/or dead space ventilation. [35] Finally, the patient is always in the best breathing state, may also decrease inspiratory load, improve patient-ventilator interaction, [36] and decrease the need to adjust ventilator settings, [37] avoiding the rapid breathing or suffocation.
Several limitation are identified in our study. Firstly, included trials significantly varied in terms of disease, intervention protocol, duration, patient population, and study quality, which limit the

Conclusions
In the study we found that ASV effectively improves the rate of successful extubation in patients with ARF compared with conventional therapy.

Ethics approval and consent to participate
This is a meta-analysis article, so the ethics approval and consent to participate could not be required.

Consent for publication
All authors have read and approved the manuscript version, and agree to submit for consideration for publication in the journal.

Availability of data and material
The data and material are available in this paper.

Competing interests
There are no ethical/legal conflicts involved in the article.     icmje-coi-form (1).pdf