Intraoperative ventilation strategies to prevent postoperative pulmonary complications: a network meta-analysis of randomised controlled trials

British Journal of Anaesthesia, xxx (xxx): xxx (xxxx) doi: 10.1016/j.bja.2019.10.024 Advance Access Publication Date: xxx Clinical Investigation

CLINICAL INVESTIGATION

Intraoperative ventilation strategies to prevent postoperative pulmonary complications: a network meta-analysis of randomised controlled trials Qi-Wen Deng1,y, Wen-Cheng Tan2,y, Bing-Cheng Zhao3,y, Shi-Hong Wen1, Jian-Tong Shen1 and Miao Xu1,* 1

Department of Anaesthesiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China, 2Department of

Endoscopy, Sun Yat-sen University Cancer Center, Guangzhou, China and 3Department of Anaesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China *Corresponding author. E-mail: [email protected] y

These authors contributed equally to this work.

Abstract Background: The debate on lung-protective ventilation strategies for surgical patients is ongoing. Evidence suggests that the use of low tidal volume VT improves clinical outcomes. However, the optimal levels of PEEP and recruitment manoeuvre (RM) strategies incorporated into low VT ventilation remain unclear. Methods: Several electronic databases were searched to identify RCTs that focused on comparison between low VT strategy and conventional mechanical ventilation (CMV), or between two different low VT strategies in surgical patients. The primary outcome was postoperative pulmonary complications (PPCs). The secondary outcomes were atelectasis, pneumonia, acute respiratory distress syndrome, and short-term mortality. Bayesian network meta-analyses were performed using WinBUGS. The odds ratios (ORs) and corresponding 95% credible intervals (CrIs) were estimated. Results: Compared with CMV, low VT ventilation with moderate-to-high PEEP reduced the risk of PPCs (moderate PEEP [5e8 cm H2O]: OR 0.50 [95% CrI: 0.28, 0.89]; moderate PEEPþRMs: 0.39 [0.19, 0.78]; and high PEEP [9 cm H2O]þRMs: 0.34 [0.14, 0.79]). Low VT ventilation with moderate-to-high PEEP and RMs also specifically reduced the risk of atelectasis compared with CMV (moderate PEEPþRMs: OR 0.36 [95% CrI: 0.16, 0.87]; and high PEEPþRMs: 0.41 [0.15, 0.97]), whilst low VT ventilation with moderate PEEP was superior to CMV in reducing the risk of pneumonia (OR 0.46 [95% CrI: 0.15, 0.94]). Conclusions: The combination of low VT ventilation and moderate-to-high PEEP (5 cm H2O) seems to confer lung protection in surgical patients undergoing general anaesthesia. Clinical trial registration: PROSPERO (CRD42019144561) Keywords: mechanical ventilation; positive end-expiratory pressure; pulmonary complications; recruitment manoeuvre; surgery; tidal volume; ventilation

Editor’s key points  The authors used a network meta-analytical method to allow comparison and ranking of intraoperative ventilation strategies.

 Of the ventilation strategies examined, tidal volume 8 ml kg1 with PEEP 5 cm H2O was found to be associated with a reduced risk of postoperative pulmonary complications.  High-quality clinical investigations are needed to clarify the optimal levels of PEEP and to identify the best recruitment strategies.

Received: 29 August 2019 Accepted: 31 October 2019 © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved. For Permissions, please email: [email protected]

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The detrimental effects of mechanical ventilation on surgical patients undergoing general anaesthesia cause ventilationinduced lung injury, and therefore, postoperative pulmonary complications (PPCs). The incidence of PPCs, a compositae outcome of minor and major pulmonary complications, ranges from 11% to 33% amongst the surgical population.1,2 PPCs have been shown to have a negative impact on postoperative recovery by increasing morbidity, prolongation of hospital stay (including ICU), and early mortality.3 Although protective ventilation with low tidal volumes VT (4e8 ml kg1 predicted body weight [PBW]), moderate level of PEEP, and recruitment manoeuvres (RMs) have been recommended in ICU patients with acute respiratory distress syndrome (ARDS),4 the optimal intraoperative ventilation strategies for surgical patients without severe lung injury remain unknown. Decades of research attempted to determine the most beneficial ventilation strategies by assessing VT, PEEP, and RM. However, these studies yielded mixed conclusions. For VT, there was an agreement that low rather than high VT ventilation was associated with improved pulmonary function. However, various levels of PEEP or RM strategies were incorporated into these low VT ventilation strategies. It is difficult to identify what levels of PEEP and RM strategies confer lung protection apart from low VT. Although two large-scale, multicentre RCTs showed that the combination of high level of PEEP (12 cm H2O) and RMs did not protect surgical patients from PPCs compared with low levels of PEEP (4 or 2 cm H2O),5,6 these studies did not evaluate moderate levels of PEEP between the two extreme values. In addition, other small RCTs using different levels of PEEP could not provide sufficient evidence because of the small sample size. Furthermore, the main endpoints within the majority of these studies were pulmonary function tests but not clinical outcomes. It is inappropriate to draw conclusions on the beneficial effects of these ventilation strategies, for improved pulmonary function is not necessarily associated with reduced PPCs or mortality. Consequently, the optimal intraoperative ventilation strategies in surgical patients are still lacking. Conventional mechanical ventilation (CMV) with high VT (>8 ml kg1 PBW) and little or no PEEP (5 cm H2O) without RMs is still suggested during general anaesthesia.2,7 Taking into consideration the ventilation strategies involving the use of different levels of VT, PEEP, and RMs, the aim of the present study was to complete a network metaanalysis (NMA) to clarify the following question: is there any statistically significant difference between low VT ventilation strategies and CMV, or between two particular low VT strategies in terms of PPCs or short-term mortality?

Methods This study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension statement for reporting network meta-analyses.8

Literature search Two authors (QWD and WCT) independently searched PubMed, Cochrane Library, EMBASE, and ClinicalTrials.gov for eligible studies published from inception to October 2019. No language restriction was applied. The keywords used in our search of the PubMed database were ((ventilation OR ventilatory) OR (tidal volume) OR (positive end-expiratory pressure OR positive end expiratory pressure OR PEEP) OR (recruitment manoeuvre)) AND (surgery OR surgical OR operation OR

operative). The bibliographies of previous reviews and metaanalyses were screened for additional relevant studies.

Criteria used for selection of published studies Two authors (QWD and WCT) independently assessed the study eligibility based on reading the study titles, abstracts, and full texts. Two other authors (BCZ and MX) arrived at a consensus when a disagreement occurred. Studies were included in the NMA if they met the following criteria: (i) The study subjects were surgical patients aged 18 yr or older, who underwent mechanical ventilation for general anaesthesia. Studies involving cardiopulmonary bypass or extracorporeal membrane oxygenation were excluded. Patients receiving laryngeal mask airway or noninvasive ventilation during general anaesthesia were also excluded. (ii) Interventions were defined as intraoperative ventilation strategies based on low VT (8 ml kg1 PBW). They were divided into several groups according to the levels of PEEP (low [4 cm H2O], moderate [5e8 cm H2O], and high [9 cm H2O]) and RMs (with or without RMs). The control group was defined as CMV high VT (9 ml kg1 PBW) and low PEEP (5 cm H2O), with or without RMs. (iii) The RCTs reported a comparison between a particular low VT ventilation strategy and CMV, or between two different low VT ventilation strategies. (iv) We included only studies with the primary outcome of PPC, a compositae outcome of minor and major pulmonary complications during follow-up, as defined in the original studies. The secondary outcomes included atelectasis, pneumonia, ARDS, and short-term mortality. The latter included in-hospital and 30 day mortality. Available data on other pulmonary complications (pneumothorax, pleural effusion, pulmonary oedema, and pulmonary embolism) were also collected. Studies not reporting these clinical outcomes were excluded.

Data extraction Two authors (SHW and JTS) extracted the data from the original studies into a predesigned form. The following variables were collected: first author, year of publication, study design, type of surgery, patient information (age, ASA class, BMI, and sample size), intervention information (levels of VT, PEEP, and RMs during general anaesthesia, and postoperative ventilation strategies), and outcome measures (PPCs, atelectasis, pneumonia, ARDS, pneumothorax, pleural effusion, pulmonary oedema, pulmonary embolism, and short-term mortality).

Quality assessment The Cochrane Collaboration tool focussing on selection bias, performance bias, detection bias, attrition bias, and reporting bias was applied to assess the risk of bias.

Statistical analysis We performed Bayesian network meta-analyses to compare the effects of a particular low VT ventilation strategy with CMV, or two different low VT ventilation strategies with each other on PPCs, atelectasis, pneumonia, ARDS, and short-term mortality. The odds ratios (ORs) and corresponding 95%

Ventilation strategies and pulmonary complications

credible intervals (CrIs) were estimated. We also estimated the number of patients needed to treat (NNT) and the probability that each ventilation strategy was the most efficacious (Pbest), and calculated the surface under the cumulative ranking curve (SUCRA). Bayesian network meta-analyses were performed using WinBUGS 1.4.3 (MRC Biostatistics Unit, Cambridge, UK). Furthermore, we calculated the direct estimate for each pair of treatment with the ManteleHaenszel method of the conventional pairwise meta-analysis. The ORs and corresponding 95% confidence intervals were estimated. Conventional pairwise meta-analyses were performed using Review Manager 5.3.3 (Cochrane Collaboration, Nordic Cochrane Centre, Copenhagen, Denmark). For other pulmonary complications with insufficient data to perform NMA, we performed a conventional pairwise metaanalysis to compare the effects of a particular low VT ventilation strategy with CMV on them. Finally, we conducted two sensitivity analyses on studies that enrolled patients with BMI <35 kg m2 or those scheduled for noncardiac surgery. To further clarify the impact of thoracic surgery (requiring one-lung ventilation) on the result, we also performed a subgroup analysis on studies of noncardiac surgery according to the type of surgery (thoracic and noncardiac, non-thoracic surgery).

Results Study selection and characteristics The initial search identified 72 375 citations. After screening the titles and abstracts, 94 studies were selected for full-text review. Of these, 34 studies proved eligible for inclusion in the study.5,6,9e40 The process used for study selection is illustrated in Supplementary Fig. S1. The 34 selected studies enrolled 5273 patients who were randomly assigned to receive either CMV or one of the following low VT ventilation strategies: (low VT [8 ml kg1 PBW]þlow PEEP [4 cm H2O], low VT [8 ml kg1 PBW]þlow PEEP [4 cm H2O]þRMs, low VT [8 ml kg1 PBW]þmoderate PEEP [5e8 cm H2O], low VT [8 ml kg1

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PBW]þmoderate PEEP [5e8 cm H2O]þRMs, and low VT [8 ml kg1 PBW]þhigh PEEP [9 cm H2O]þRMs) (Fig. 1). Of the studies that involved low VT (8 ml kg1 PBW)þhigh PEEP (9 cm H2O) without RMs, one study23 reported on PPCs, whereas two20,21 analysed short-term mortality. Unfortunately, the low event rates or even zero events in one or both arms of the studies resulted in invalidation of the network models. Therefore, this particular combination of intervention does not appear as one of the ventilation strategies of interest. The main characteristics of the selected studies are summarised in Table 1.

Quality assessment The details of risk-of-bias assessment for each included study are summarised in Supplementary Fig. S2. All 34 studies reported clear randomisation, whereas 18 reported allocation. No blinding methods were used in three studies for participants and seven studies for outcome assessors. Incomplete outcome data were identified in one publication and selective reporting in two studies.

Meta-analysis Postoperative pulmonary complications Of the total, 28 RCTs that included 4820 patients reported on PPCs. The NMA results showed that low VT and moderate-tohigh PEEP, with or without RMs, reduced the risk of PPCs compared with CMV (low VTþmoderate PEEP: OR 0.50 [95% CrI: 0.28, 0.89]; low VTþmoderate PEEPþRMs: 0.39 [0.19, 0.78]; and low VTþhigh PEEPþRMs: 0.34 [0.14, 0.79]). However, low VT and low PEEP were not associated with a reduced risk of PPCs compared with CMV (low VTþlow PEEP: OR 0.44 [95% CrI: 0.20, 1.10]; and low VTþlow PEEPþRMs: 0.58 [0.08, 4.39]). The results of NMA were consistent with those of conventional pairwise comparison. Amongst low VT ventilation strategies with CrIs excluding 1.0, the ranking probabilities and SUCRA statistic showed that low VTþhigh PEEPþRMs ranked first, followed by low VTþmoderate PEEPþRMs and low VTþmoderate PEEP. The NNT for these to reduce one case of PPC were 9.8, 10.6, 13.7, respectively (Fig. 2). There was no difference amongst low VT ventilation strategies with respect to PPCs (Fig. 3).

Atelectasis Of the 34 RCTs, 22 of 4497 patients reported on atelectasis. The NMA results showed that low VT and moderate-to-high PEEP with RMs were associated with a reduced risk of atelectasis compared with CMV (low VTþmoderate PEEPþRMs: OR 0.36 [95% CrI: 0.16, 0.87]; and low VTþhigh PEEPþRMs: 0.41 [0.15, 0.97]). Other low VT ventilation strategies did not reduce the risk of atelectasis. The NNT for low VTþmoderate PEEPþRMs and low VTþhigh PEEPþRMs strategies to reduce atelectasis were 14.7 and 16.2, respectively (Fig. 2). There was no difference amongst low VT ventilation strategies in terms of atelectasis (Fig. 3).

Pneumonia Fig 1. Network plot of intraoperative ventilation strategies assessed in RCTs. CMV, conventional mechanical ventilation; HPEEP, high PEEP; LPEEP, low PEEP; LVT, low tidal volume ventilation; MPEEP, moderate PEEP; RM, recruitment manoeuvre.

Pneumonia was reported in 16 RCTs of 4406 patients. The NMA results showed that low VT and moderate PEEP without RMs were superior to CMV in reducing the risk of pneumonia (OR 0.46 [95% CrI: 0.15, 0.94]). The result was in line with that of a conventional pairwise comparison. The NNT necessary to reduce one case of pneumonia was 40.8 (Fig. 2). There was no

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Table 1 Main characteristics of the included studies. ASA class, ASA physical status classification system; N, without recruitment manoeuvre; NR, not reported; RM, recruitment manoeuvre; VT, tidal volume; Y, with recruitment manoeuvre. Study

Cardiac surgery Bolzan and colleagues9 (2016) 10

Shim and colleagues

(2009)

Thoracic surgery Ahn and colleagues11 (2012) Kim and colleagues12 (2019)

Lin and colleagues13 (2008)

Type of surgery

Age (yr)

ASA class

BMI (kg m¡2)

Sample size

VT (ml kg¡1)

PEEP (cm H2O)

RM

Off-pump coronary artery bypass Off-pump coronary artery bypass

NR

NR

NR

NR

NR

NR

30 31 25 25

6 8 7e8 7e8

10 0 5 5

Y N Y N

NR

1e2

NR

20e80

1e2

NR

25 25 20 20 20 20 20

6 10 6e8 6e8 10 5e6 10

5 0 5 5 0 3e5 0

N N Y N N N N

168 167 16 16 26 26 50 50 45 45 45 45

5 10 5 10 5 9 6 10 <8 <8 >8 >8

5e8 0 5 0 5 0 5 0 5 0 5 0

N N N N N N N N N N N N

Video-assisted thoracic surgery Video-assisted thoracic surgery Esophagectomy Oesophagectomy for oesophageal cancer Thoracic surgery

41e65

NR

NR

18e90

NR

NR

Thoracic surgery

18e90

NR

NR

Oesophagectomy for oesophageal cancer Thoracic surgery

>18

NR

NR

NR

1e2

NR

Oesophagectomy for oesophageal cancer

60e75

1e2

NR

Neurological surgery Cai and colleagues19 (2007)

Neurological surgery

20e50

1e2

<25

8 8

6 10

0 0

N N

Abdominal surgery Choi and colleagues20 (2006)

Major abdominal surgery

NR

NR

NR

Emergency laparotomy

NR

NR

NR

Major abdominal surgery

>40

NR

<35

Laparotomic aortic aneurismectomy Pancreatoduodenal surgery

46e84

2e4

NR

45e60

NR

NR

Laparoscopic hepatobiliary surgery Open abdominal surgery

18e70

1e2

NR

>60

NR

<35

Noncardiac, non-neurological surgery Open abdominal surgery

>18

NR

>35

>18

NR

<40

Open abdominal surgery

>18

NR

<40

Upper abdominal surgery

>50

2

NR

Laparoscopic bariatric surgery

18e65

2e3

>40

Open abdominal surgery

>65

NR

<35

Laparoscopic bariatric surgery

25e65

2e3

>40

21 19 30 30 200 200 20 25 20 20 20 19 21 20 22 989 987 445 449 28 27 50 51 11 11 12 20 20 10 10

6 12 6 10 6e8 10e12 8 8 6 10 6 10 7 7 9 7 7 8 8 7 9 6 12 8 8 8 6 10 8 8

10 0 10 0 6e8 0 5 0 4 4 5 0 8 8 0 12 4 12 2 10 0 5 5 8 0 0 12 0 12 4

N N N N Y N N N N N N Y Y N N Y N Y N Y N N N Y Y N Y N Y N

Caesarean section

>18

NR

18e44

Laparoscopic radical prostatectomy

60e80

1e2

<31

41 40 26 25

6 8 6e8 6e8

8 0 5 5

Y N Y N

Marret and colleagues14 (2018) Maslow and colleagues15 (2013) Michelet and colleagues16 (2006) Yang and colleagues17 (2011) Zhang and colleagues18 (2018)

Chugh and colleagues

21

(2012)

Futier and colleagues22 (2013) 23

Giustiniano and colleagues (2009) Kuzkov and colleagues24 (2016) Park and colleagues25 (2016) Pi and colleagues26 (2015)

Bluth and colleagues5 (2019) Hemmes and colleagues6 (2014) Severgnini and colleagues27 (2013) Treschan and colleagues28 (2012) Wei and colleagues29 (2018)

Weingarten and colleagues30 (2010) Whalen and colleagues31 (2006) Pelvic surgery Aretha and colleagues32 (2017) Choi and colleagues33 (2017)

Continued

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Table 1 Continued Study

Chun and colleagues34 (2019) Ryu and colleagues

35

(2017)

Spinazzola and colleagues36 (2019) Orthopaedic surgery Fernandez-Bustamante and colleagues37 (2014) Ge and colleagues38 (2013) Memtsoudis and colleagues39 (2012) Soh and colleagues40 (2018)

Type of surgery

Age (yr)

ASA class

BMI (kg m¡2)

Sample size

VT (ml kg¡1)

PEEP (cm H2O)

RM

Robotic gynaecological surgery Laparoscopic gynaecological surgery Laparoscopic gynaecological surgery

20e60

1e2

<35

19e65

1e2

NR

>18

1e2

>40

20 20 30 30 20 20

6 6 7e9 7e9 6 10

8 4 0 0 8e10 5

N N Y N Y N

Knee replacement surgery

<70

1e3

<35

Lumbar spinal surgery

70e85

2e3

NR

Lumbar spinal surgery

NR

1e2

NR

Lumbar spinal surgery

NR

NR

<35

14 14 30 30 13 13 39 39

6 10 6 10e12 6 12 6 10

5 5 10 0 8 0 6 0

N N Y N N N Y N

ASA class: American Society of Anesthesiologists Physical Status; BMI: body mass index; N: without recruitment manoeuvre; NR: not reported; PEEP: positive end-expiratory pressure; RM: recruitment manoeuvre; VT: tidal volume; Y: with recruitment manoeuvre.

difference amongst low VT ventilation strategies in terms of pneumonia (Fig. 3).

Acute respiratory distress syndrome ARDS was analysed in 11 RCTs of 4006 patients. The NMA results showed no difference amongst low VT ventilation strategies and CMV, or between two particular low VT ventilation strategies (Figs 2 and 3). The conventional pairwise comparison also showed no difference amongst them.

Short-term mortality Short-term mortality was analysed in 12 RCTs of 4088 patients. The results of NMA and conventional pairwise comparison showed no difference between low VT ventilation strategies and CMV, or between two particular low VT ventilation strategies (Figs 2 and 3).

Other pulmonary complications The conventional pairwise comparison showed that none of the low VT ventilation strategies had any effect on the risk of other pulmonary complications, such as pneumothorax, pleural effusion, pulmonary oedema, and pulmonary embolism (Fig. 4).

Sensitivity analysis and subgroup analysis The results on PPCs did not change after sensitivity analyses, including patients with BMI <35 kg m2 (low VTþmoderate PEEP: OR 0.50 [95% CrI: 0.25, 0.99]; low VTþmoderate PEEPþRMs: 0.36 [0.14, 0.92]; and low VTþhigh PEEPþRMs: 0.28 [0.09, 0.79]) or scheduled for noncardiac surgery (low VTþmoderate PEEP: OR 0.49 [95% CrI: 0.26, 0.87]; low VTþmoderate PEEPþRMs: 0.41 (0.20, 0.88); and low VTþhigh PEEPþRMs: 0.34 [0.14, 0.80]). The subgroup analysis showed a non-significant trend for a reduced risk of PPCs with low VT and moderate PEEP in thoracic surgery, and the superiority of low VT and moderate-to-high PEEP with RMs to CMV in noncardiac, nonthoracic surgery (low VTþmoderate PEEPþRMs: OR 0.43 [95% CrI: 0.19, 0.99]; and low VTþhigh PEEPþRMs: 0.31 [0.12, 0.81]) (Fig. 5; Supplementary Fig. S3).

Discussion Our network meta-analysis shows that the combination of low VT and moderate-to-high PEEP (5 cm H2O), with or without recruitment manoeuvres, was superior to conventional mechanical ventilation in reducing the risk of PPCs. Particularly, compared with CMV, low VT ventilation with moderate-tohigh PEEP and RMs was associated with a reduced risk of atelectasis, whereas low VT ventilation with moderate PEEP was associated with a reduced risk of pneumonia. However, there were no differences amongst these ventilation strategies with respect to other pulmonary complications and shortterm mortality. Low VT is likely the most important component of lungprotective ventilation. However, it seems that not all ventilation strategies based on low VT confer lung protection. Our study showed that only low VT ventilation with PEEP more than 4 cm H2O was associated with a reduced risk of pulmonary complications, which supported the recently published international expert-panel-based consensus recommendations on lung-protective ventilation for surgical patients.41 The potential explanations of these results include less pulmonary atelectasis, and better pulmonary compliance and oxygenation induced by moderate-to-high PEEP.42e46 However, although the lower limit of optimal level of PEEP may be 5 cm H2O, the upper limit remains unclear. Two large-scale multicentre RCTs showed no additional benefit in patients who received low VT ventilation with 12 cm H2O PEEP compared with PEEP below 4 cm H2O.5,6 These results suggest that PEEP as high as 12 cm H2O is unnecessary for surgical patients without severe lung injury. The optimal PEEP could keep more lung units open for gas change, and therefore, improve regional ventilation/perfusion mismatching. However, PEEP as high as 12 cm H2O may induce repetitive lung over-distension and release of inflammation cytokines,47,48 which promotes ventilation-induced lung injury and counteracts the beneficial effects of the strategy. An important element of any ventilation strategy is driving pressure, which is calculated as plateau pressure minus PEEP. Although we did not assess the effects of driving pressure directly in the study, the association between low VT ventilation and moderate-to-high PEEP and improved clinical

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Fig 2. Results of the Bayesian network meta-analysis for comparison between low tidal volume ventilation strategies and conventional mechanical ventilation on the incidence of postoperative pulmonary complications, atelectasis, pneumonia, acute respiratory distress syndrome, and short-term mortality. ARDS, acute respiratory distress syndrome; CI, confidence interval; CMV, conventional mechanical ventilation; CrI, credible interval; HPEEP, high PEEP; LMV, low tidal volume mechanical ventilation; LPEEP, low PEEP; LVT, low tidal volume ventilation; MPEEP, moderate PEEP; NMA, network meta-analysis; NNT, number of patients needed to treat; OR, odds ratio; Pbest, probability of being best; PPCs, postoperative pulmonary complications; RM, recruitment manoeuvre; SUCRA, surface under cumulating ranking curve. *Credible interval or confidence interval excluding 1.0.

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Fig 3. Results of the Bayesian network meta-analysis for comparison amongst different low tidal volume ventilation strategies on postoperative pulmonary complications, atelectasis, pneumonia, acute respiratory distress syndrome, and short-term mortality. ARDS, acute respiratory distress syndrome; CI, confidence interval; CMV, conventional mechanical ventilation; CrI, credible interval; HPEEP, high PEEP; LPEEP, low PEEP; LVT, low tidal volume ventilation; MPEEP, moderate PEEP; NMA, network meta-analysis; OR, odds ratio; PPCs, postoperative pulmonary complications; RM, recruitment manoeuvre.

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Fig 4. Results of the conventional pairwise meta-analyses for comparison between low tidal volume ventilation strategies and conventional mechanical ventilation on other pulmonary complications. CI, confidence interval; CMV, conventional mechanical ventilation; LMV, low tidal volume mechanical ventilation.

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Fig 5. Bayesian network meta-analysis of sensitivity analysis and subgroup analysis for comparison between low tidal volume ventilation strategies and conventional mechanical ventilation in terms of postoperative pulmonary complications. CMV, conventional mechanical ventilation; CI, confidence interval; CrI, credible interval; HPEEP, high PEEP; LMV, low tidal volume mechanical ventilation; LPEEP, low PEEP; LVT, low tidal volume ventilation; MPEEP, moderate PEEP; NMA, network meta-analysis; NNT, number of patients needed to treat; OR, odds ratio; Pbest, probability of being best; RM, recruitment manoeuvre; SUCRA, surface under cumulating ranking curve. *Credible interval or confidence interval excluding 1.0. **Subgroup analysis of thoracic and noncardiac, non-thoracic surgery was conducted on RCTs of noncardiac surgery.

outcome inferred that low driving pressure might benefit surgical patients. The finding is in line with that of a recent meta-analysis of individual patient data,49 which showed the

association between increased driving pressure and more pulmonary complications. Atelectasis reduces lung compliance, and increases pulmonary vascular resistance and intrapulmonary shunting,

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leading to the development of PPCs. In this study, the combination of low VT, moderate-to-high PEEP, and RMs was superior to CMV in reducing the risk of atelectasis. Moderate-tohigh levels of PEEP can maintain end-expiratory lung volume, improve compliance, and therefore prevent atelectasis. In addition, this effect could be promoted by RMs, which usually overcomes the opening pressure of the alveoli. However, the use of PEEP at less than 5 cm H2O was neither associated with a reduced risk of atelectasis nor PPCs. A large cohort study even showed that low VT with minimal PEEP was associated with an increased risk of 30 day mortality.50 These results suggest that the so-called intraoperative permissive atelectasis induced by low PEEP, the collapsed lung region of which is thought to be protected against ventilation-induced lung injury,47 is not beneficial but even harmful for the surgical population. Our study demonstrated that the combination of low VT ventilation and moderate PEEP reduced the risk of pneumonia. The application of high VT induces volutrauma, which damages alveolar, vascular endothelial, and epithelial cells, and extracellular matrix. This can trigger an inflammation response and promote the translocation of bacteria. Several RCTs have suggested that lung-protective ventilation strategies attenuated the release of local and systemic inflammatory mediators.16,51,52 Furthermore, animal studies showed that low VT ventilation with moderate-to-high PEEP attenuated bacterial growth and translocation in a piglet model of experimental pneumonia.53e55 We conclude that the combination of low VT ventilation and PEEP 5 cm H2O seems to protect the lungs from infection. We did not find any beneficial effect for any low VT ventilation strategies on ARDS in surgical patients compared with CMV. However, a previous individual patient data metaanalysis did find a significant difference between protective ventilation and conventional ventilation in terms of ARDS.56 The difference may stem from different methodologies used in the two studies. When compared with CMV, they defined protective ventilation as the combination strategy of VT <8 ml kg1 PBW and PEEP >5 cm H2O, and pooled them together, whereas we divided protective ventilation into subgroups according to the levels of PEEP and RM. Another reason may be related to the different sample size included. They included 15 RCTs of 2127 patients, whereas we included 34 RCTs of 5273 individuals. Cardiac and thoracic surgeries may have a considerable impact on the results. Patients scheduled for cardiac surgery usually have pulmonary dysfunction secondary to the underlying cardiac disease. Moreover, despite avoiding cardiopulmonary bypass, the off-pump surgical procedures still promote the development of atelectasis. On the other hand, patients scheduled for thoracic surgery have intrinsic lung disease and require one-lung ventilation. Furthermore, the ventilation interventions were usually performed during onelung but not two-lung ventilation. Restricting our analysis to noncardiac surgery did not alter the result. However, when further stratification of noncardiac surgery into thoracic and noncardiac, non-thoracic surgery was performed, we found out that it was low VT ventilation with moderate-to-high PEEP with RMs, but not without RM, that reduced the risk of PPCs in noncardiac, non-thoracic surgery. The potential reason might be the large proportion of patients in this subgroup who underwent abdominal or pelvic surgery, especially laparoscopic surgery. Pneumoperitoneum during surgery causes increased intrathoracic pressure, and decreased lung compliance and

functional residual capacity.57 RM followed by subsequent moderate-to-high PEEP is more effective than PEEP alone in reexpanding atelectasis and in keeping the dependent lung units open.58,59 For thoracic surgery, we found out that the superiority of low VT ventilation with moderate PEEP to CMV in the conventional pairwise comparison lost a significant difference in the NMA. The result should be treated with caution, for there were only five RCTs that reported on PPCs included in this NMA. In spite of the aforementioned strengths, our study has several limitations. First, as PPC was defined as a compositae outcome of minor and major pulmonary complications, a considerable variation in definitions amongst the included studies existed. Second, efforts at reducing PPCs should include a multimodal approach of care, including postoperative ventilation strategies. However, only few of the included RCTs reported the ventilation strategies after surgery. Based on the aforementioned limitaion, the data were insufficient to perform a proper analysis. Third, the recruitment strategies were not uniform in inspiratory pressure, duration, and frequency amongst the included studies. Various RM strategies could have different effects on the result of the NMA. We conclude that the combination of low VT ventilation and moderate-to-high PEEP (5 cm H2O) seems to confer lung protection in surgical patients who receive general anaesthesia compared with conventional mechanical ventilation. High-quality evidence is needed to confirm the beneficial effects of the ventilation strategy. Further investigations are also required to clarify the specific range of optimal levels of PEEP, best recruitment manoeuvre strategies, and the effects of postoperative ventilation strategies on clinical outcomes.

Authors’ contributions QWD and MX: study conception and design, analysis and interpretation of data, drafting the article, revising it critically for important intellectual content; WCT and BCZ: study design, acquisition, analysis and interpretation of data; revising the article critically for important intellectual content; SHW and JTS: acquisition, analysis of data; revising the article critically for important intellectual content. All authors read and approved the final manuscript, and agreed to be accountable for all aspects of the work.

Declarations of interest The authors declare that they have no conflict of interest.

Acknowledgements The authors thank the authors of the 34 selected studies for their contributions to this work, and the medical editor (WordMedex Pty Ltd) for English language editing.

Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.bja.2019.10.024.

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