Introduction
Acute respiratory distress syndrome (ARDS) is one of the main causes of mortality
in critically ill patients. Injured lungs can be protected by optimum mechanical ventilator
settings, using low tidal volume (VT) values and higher positive-end expiratory pressure
(PEEP); the benefits of this protective strategy on outcomes have been confirmed in
several prospective randomized controlled trials (RCTs). The question is whether healthy
lungs need specific protective ventilatory settings when they are at risk of injury.
We performed a systematic review of the scientific literature and a meta-analysis
regarding the rationale of applying protective ventilatory strategies in patients
at risk of ARDS in the perioperative period and in the intensive care unit (ICU).
Mechanism of ventilator-induced lung injury in healthy lungs
Several studies have reported the multiple hit theory as the main cause of ARDS in
previously healthy lungs (transfusion, cardiopulmonary bypass [CPB], sepsis etc.).
Recently, many investigators have reported that, in healthy lungs, mechanical ventilation
can aggravate the 'one hit' ventilator-induced lung injury (VILI), even when using
the least injurious settings.
The pathophysiologic principles of VILI are complex and characterized by different
overlapping interactions. These interactions include: (a) high VT causing over distension;
(b) cyclic closing and opening of peripheral airways during tidal breath resulting
in damage of both the bronchiolar epithelium and the parenchyma (lung strain), mainly
at the alveolar-bronchiolar junctions; (c) lung stress by increased transpulmonary
pressure (the difference between alveolar and pleural pressure); (d) low lung volume
associated with recruitment and de-recruitment of unstable lung units (atelectrauma);
(e) inactivation of surfactant by large alveolar surface area oscillations associated
with surfactant aggregate conversion, which increases surface tension [1]; (f) local
and systemic release of lung-borne inflammatory mediators, namely biotrauma [2].
Recent experimental and clinical studies have demonstrated two main mechanisms leading
to VILI: First, direct trauma to the cell promoting releasing of cytokines to the
alveolar space and the circulation; second, the so-called 'mechanotransduction' mechanism.
Cyclic stretch during mechanical ventilation stimulates alveolar epithelial and vascular
endothelial cells through mechano-sensitive membrane-associated protein and ion channels
[3]. High VT ventilation led to an increase in expression of intrapulmonary tumor
necrosis factor (TNF)-α and macrophage inflammatory protein-2 in mice without previous
lung injury [4] and recruited leukocytes to endothelial cells [3]. Tissue deformation
activates nuclear factor-kappa B (NF-κΒ) signaling consequent to the production of
interleukin (IL)-6, IL-8, IL-1β and TNF-α [3]. The cellular necrosis is associated
with an inflammatory response in surrounding lung tissue [3].
Mechanotransduction is the conversion of mechanical stimuli to a biochemical response
when alveolar epithelium or vascular endothelium is stretched during mechanical ventilation.
The stimulus causes expansion of the plasma membrane and triggers cellular signaling
via various inflammatory mediators influencing pulmonary and systemic cell dysfunction
[3]. A high level of mechanical stretch is associated with increased epithelial cell
necrosis, decreased apoptosis and increased IL-8 level [3]. Extracellular matrix (ECM),
a three-dimensional fiber mesh, is composed of collagen, elastin, glycosamino- glycans
(GAGs) and proteoglycans. The ECM represents the biomechanical behavior of the lung
and plays a role in stabilizing lung matrix and fluid content. Mechanotrans- duction
causes the mechanical force on ECM that causes the lung strain (the ratio between
VT and functional residual capacity [FRC]). High VT ventilation causes ECM remodeling,
influenced by the airway pressure gradient and the pleural pressure gradient [2],
[5].
In animal models, VILI, defined by lung edema formation, develops when lung strain
is greater than 1.5-2 [6]. Cyclic mechanical stress causes release and activation
of matrix metalloproteinase (MMP). MMP plays an important role in regulating ECM remodeling
and VILI. Lung strain also leads to modification of proteoglycan and GAGs. The fragmentation
of GAGs may affect the development of the inflammatory response by interacting with
various types of chemokine and acting as ligands for Toll-like receptors [5], [7].
In addition, the ECM has been demonstrated to be the signal of matrikines requiring
proteolytic breakdown. Mechanical strain induces ECM breakdown [5].
During the perioperative period, general anesthesia and deep sedation with or without
muscle paralysis markedly affect lung structure by reducing the tone of respiratory
muscles and altering diaphragmatic position [8]. A direct effect of anesthetics on
pulmonary surfactant, as well as the weight of the heart and greater intra-abdominal
pressure in the supine position, promotes collapse of dependent lung regions and partial
collapse of mid-pulmonary regions as a consequence of the reduction in end-expiratory
lung volume. These alterations promote: (a) increase in lung elastance; (b) increase
in lung resistance; and (c) impairment in gas exchange. The morphological alterations
of the lungs are sustained at least for the first 24-72 hours postoperatively, particularly
in patients undergoing high-risk surgery. In addition these alterations facilitate
rapid shallow breathing and increased work of breathing as well as impaired gas-exchange
[9] (Figure 1).
Protective ventilation strategies
The previously mentioned mechanisms have encouraged intensive care physicians and
anesthesiologists to consider 'protective ventilation strategies' in vulnerable noninjured
lungs, which use physiologic low VT values, moderate to high levels of PEEP and/or
recruitment maneuvers.
Tidal volume, positive end-expiratory pressure and recruitment maneuvers
In surgery
A recent large prospective cohort study conducted in different types of surgery demonstrated
that the incidence of in-hospital mortality was about as high as the incidence of
postoperative pulmonary complications which were associated with prolonged hospital
stays [10]. Historically, use of large VT (10-15 ml/kg) was advocated during the perioperative
period to prevent impaired oxygenation and re-open collapsed lung units [11]. Nowadays,
lung protective ventilation has become the standard of care in patients with ARDS.
Secondary analysis of the ARDS network trial database revealed that the reduction
in VT from 12 to 6 ml/kg predicted body weight (PBW) yielded benefit, regardless of
the level of plateau pressure [12]. Over the last few decades, clinicians have tended
to decrease VT from 8.8 ml/kg actual body weight (ABW) to 6.9 ml/kg ABW in critically
ill patients [13].
Applying a PEEP > 8 cm H2O and using recruitment maneuvers may increase end-expiratory
lung volume (EELV) beyond airway closure, certainly preventing atelectasis. However,
the adverse effect of PEEP and recruitment maneuvers is a possible reduction in right
ventricular (RV) preload and an increase in RV afterload. These consequences may lead
to lower stroke volume and potentially became problematic during surgery. Therefore,
the role of low VT ventilation and moderate to high PEEP levels with recruitment maneuvers
in previously non-injured lungs is still controversial during surgery.
In terms of lung mechanics and gas exchange, during cardiac surgery protective ventilation
with a VT of 6 ml/ kg and PEEP 5 cm H2O can improve lung mechanics and prevent postoperative
shunting compared to conventional or standard ventilation with VT of 12 ml/kg and
PEEP 5 cm H2O [14].
In patients undergoing CPB surgery, Koner et al. found no differences in plasma levels
of TNF-α or IL-6 in patients ventilated with VT of 6 ml/kg plus PEEP 5 cm H2O, with
VT 10 ml/kg plus PEEP 5 cm H2O or with VT 10 ml/kg but zero end-expiratory pressure
(ZEEP)[15]. Wrigge et al. also reported that ventilation with VT of 6 ml/kg or with
12 ml/kg for 6 hours did not affect serum TNF-α, IL-6, or IL-8 concentrations in CPB
surgery; only bronchoalveolar lavage (BAL) fluid TNF-α levels were significantly higher
in the higher VT group [16]. In contrast, Zupancich et al. showed that serum and BAL
fluid IL-6 and IL-8 levels were elevated in a conventional ventilation group compared
to a protective ventilation group after 6 hours of ventilation [17].
During major thoracic and abdominal surgery, there was no difference in the time course
of tracheal aspirate and plasma TNF-α, IL-1, IL-6, IL-8, IL-12, or IL-10 in patients
receiving conventional ventilation (VT 12-15 ml/ kg ideal body weight [IBW] and PEEP
0 cm H2O) and those receiving protective ventilation (VT 6 ml/kg IBW and PEEP 10 cm
H2O) [18]. In abdominal surgery, Wolthuis et al. demonstrated attenuation of pulmonary
IL-8, myeloperoxidase and elastase in a protective ventilation group [19]. In terms
of clinical outcomes, elderly patients undergoing major abdominal surgery ventilated
with 6 ml/kg PBW, 12 cm H2O PEEP and receiving a recruitment maneuver by sequentially
increasing PEEP in 3 steps to 20 cm H2O had no hemodynamic effects and achieved better
intraoperative PaO2 and dynamic lung compliance compared with patients receiving conventional
ventilation with VT 10 ml/kg without PEEP and recruitment maneuvers. However, this
study showed no differences in IL-6 and IL-8 levels [20].
Figure 1
Pathophysiology of ventilator-induced lung injury (VILI) in non-injured lungs and
the lung-protective ventilatory approach. VT: tidal volume; PBW: predicted body weight;
PEEP: positive end-expiratory pressure; ARDS: acute respiratory distress syndrome;
ECM: extracellular matrix.
In a prospective study of 3434 cardiac surgery patients, only 21 % of patients received
VT < 10 ml/kg PBW; VT values of more than 10 ml/kg PBW were an independent risk factor
for multiple organ failure [21]. Obesity, female gender and short height are risk
factors for receiving VT of more than 10 ml/kg [22].
Treschan et al. demonstrated that applying VT of 6 ml/ kg PBW during major abdominal
surgery did not attenuate postoperative lung function impairment compared to VT values
of 12 ml/kg PBW with the same PEEP level of 5 cm H2O [23]. However, Severgnini et
al. showed that compared to conventional ventilation (VT 9 ml/kg IBW without PEEP),
application of protective ventilation during abdominal surgery lasting more than 2
hours (VT 7 ml/kg IBW, PEEP 10 cm H2O, and recruitment maneuver) improved pulmonary
function tests for up to 5 days, with reduced modified Clinical Pulmonary Infection
Scores (mCPIS), lower rates of postoperative pulmonary complications, and better oxygenation
[24]. A study conducted by Futier et al. (IMPROVE study) emphasizes the benefits of
low VT with PEEP and recruitment maneuver. This large RCT demonstrated that major
pulmonary and extrapulmonary complications within 7 days after major abdominal surgery
occurred in 21 patients (10.5 %) in the protective ventilation group (VT 6-8 ml/kg
PBW, PEEP 6-8 cm H2O and recruitment maneuver) compared with 55 patients (27.5 %)
in the conventional ventilation group (VT 1012 ml/kg PBW without PEEP); furthermore,
patients in the protective ventilation group had shorter lengths of hospital stay
than those in the conventional group [25].
Higher VT ventilation seems to be an inflammatory stimulus for the lungs. However,
as shown in the studies mentioned earlier, in terms of resultant local and systemic
inflammatory responses processes, results are still debated [15], [16], [18], [26].
Application of lower VT is challenging because it can possibly increase the risk of
atelectasis. Nevertheless, Cai et al. showed that applying ventilation with VT of
6 ml/kg alone was associated with no difference in the amount of atelectasis compared
to ventilation with VT of 10 ml/kg [27] and application of improve lung mechanics,
gas exchange and decrease the PEEP may additionally counteract this effect [24]. Several
incidence of postoperative pulmonary complications studies have shown that protective
ventilation can [24], [25], [28] (Table 1).
Table 1
Characteristics and impact of protective ventilation in surgical patients
Protective ventilation
Standard ventilation
First author, Year[Ref]
No
Design
Patient
population
Tidal
volume
PEEP(cmH2O)
Tidal
volume
PEEP(cmH2O)
Main outcome of protective ventilation
Chaney 2000 [14]
25
RCT
CABG
6 ml/kg
≥ 5
12 ml/kg
≥ 5
Better lung mechanics and less shunt
Wrigge 2004 [18]
62
RCT
Major thoracic or abdominal surgery
6 ml/kg IBW
10
12 or 15 ml/ kg IBW
0
No difference in BAL or plasma cytokines
Koner 2004 [15]
44
RCT
CABG
6 ml/kg
5
10 ml/kg 10 ml/kg
50
No difference in plasma cytokines, better oxygenation in PEEP groups
Wrigge 2005 [16]
44
RCT
CABG
6 ml/kg IBW
9a
12 ml/kg IBW
7a
No difference in BAL and plasma cytokines
Zupancich 2005 [17]
40
RCT
CABG
8 ml/kg
10
10 ml/kg
2-3
Decrease in BAL and plasma cytokines
Cai2006 [27]
16
RCT
Neurosurgery
6 ml/kg
0
10 ml/kg
0
No difference in amount of atelectasis or gas exchange
Determann 2008 [26]
40
RCT
Abdominalsurgery
6 ml/kg IBW
10
12 ml/kg IBW
0
No difference in BAL and plasma of Clara cell protein, advanced glycation end products
and surfactant proteins
Wolthuis 2008 [19]
40
RCT
Abdominalsurgery
6 ml/kg IBW
10
12 ml/kg IBW
0
Attenuated the increase in BAL myeloperoxidase
Weingarten 2010 [20]
40
RCT
Abdominal surgery Age > 65 years
6 ml/kg PBWb
12
10 ml/kg PBW
0
Better intraoperative oxygenation, no difference in biomarkers
Fernandez-Bustamante 2011 [22]
429
Crosssectional
Abdominalsurgery
< 8 ml/kg PBW 8-10 ml/kg PBW
-
10 mL/kg PBW
-
Obesity, female gender or short height risk factors for receiving large VT
Sundar 2011 [28]
149
RCT
Cardiac surgery
6 ml/kg PBW
≥ 5a
10 ml/kg PBW
≥ 5a
Less postoperative reintubation and intubated patients at 6-8 hours after surgery.
Lellouche 2012 [21]
3434
Observational
Cardiac surgery
< 10 ml/kg PBW
-
10-12 ml/kg PBW > 12 ml/kg PBW
- -
VT > 10 ml/kg independent risk factor for organ failure and prolonged ICU stay
Treschan 2012 [23]
101
RCT
Upperabdominalsurgery
6 ml/kg PBW
5
12 ml/kg PBW
5
Did not improve lung function
Severgnini 2013 [24]
56
RCT
Open abdominal surgery
7 ml/kg IBWb
10
9 ml/kg IBW
0
Better pulmonary function test and mCPIS score, fewer chest X-ray findings.
Futier 2013 [25]
400
RCT
Major abdominal surgery
6-8 ml/kg PBWb
6-8
10-12 ml/kg PBW
0
Less postoperative pulmonary and extra pulmonary complications.
No: number of patients; CABG: coronary artery bypass surgery; BAL: bronchoalveolar
lavage; IBW: ideal body weight; PBW: predicted body weight; RCT: randomized control
trial; ICU: intensive care unit; MV: mechanical ventilation; tidal volume; mCPIS:
modified Clinical Pulmonary Infection Score.
a Level of PEEP set according to the sliding scale based on PaO2/FiO2 ladder.
b With recruitment maneuver.
To better investigate the impact of protective ventilation itself involving low VT
or PEEP and recruitment maneuvers, a large RCT including 900 patients and investigating
the effect on postoperative pulmonary complications of an open lung strategy with
high PEEP and recruitment maneuvers in short term mechanical ventilation has recently
been completed (PROVHILO) [29]. Finally, the impact of current mechanical ventilatory
practice during general anesthesia on postoperative pulmonary complications will be
revealed by another large prospective observational study (LAS VEGAS) [30].
In the intensive care unit
In a study comparing mechanical ventilation with VT of 6 ml/kg and 12 ml/kg but with
the same level of PEEP (5 cm H2O) in a surgical ICU, the low VT group had a lower,
but not significantly, incidence of pulmonary infections, duration of intubation,
and duration of ICU stay [31]. Pinheiro de Oliveira et al. demonstrated in trauma
and general ICU patients that protective ventilation (VT 5-7 ml/kg PBW and PEEP 5
cm H2O) attenuated pulmonary IL-8 and TNF-α compared with high VT ventilation (10-12
ml/kg PBW and PEEP 5 cm H2O) after 12 hours of mechanical ventilation. Nevertheless,
there were no differences in number of days on mechanical ventilation, length of ICU
stay or mortality between the 2 groups [32]. Determann et al. also reported that conventional
ventilation with VT ml/kg was associated with a significantly lower clearance rate
of plasma IL-6 compared to protective ventilation with a VT 6 ml/kg PBW [33]. This
trial was stopped early because more patients in the conventional ventilation group
developed acute lung injury (ALI, 10 patients [13.5 %] vs. 2 patients [2.6 %], p =
0.01) [33].
Not only a high VT but also the time of exposure can lead to the release of pro-inflammatory
mediators and an increase in the wet-to-dry ratio in the lung [34]. In a large retrospective
cohort study in ICU patients who received mechanical ventilation for > 48 hours, 24
% of 332 patients developed acute lung injury (ALI) within 5 days. A VT > 6 ml/kg
PBW (OR 1.3 for each ml above 6 ml/kg PBW, p < 0.001), history of blood transfusion,
acidemia, and history of restrictive lung disease were independent risk factors for
development of ALI [35]. The incidence of ARDS decreased from 28 % to 10 % when applying
a quality improvement intervention, namely setting VT at 6-8 ml/kg PBW in patients
at risk of ARDS plus using a restrictive protocol for red blood cell (RBC) transfusion
[36]. Lower VT ventilation was also not associated with differences in sedative drug
dosage [37].
Recent meta-analyses
Serpa Neto et al. [38] performed a meta-analysis of 20 trials that compared higher
and lower VT ventilation in critically ill patients and surgical patients who did
not meet the consensus criteria for ARDS. Patients who received lower VT ventilation
showed a decrease in the development of ATLI (risk ratio [RR] 0.33, 95 % CI 0.23-0.47,
number needed to treat [NNT] 11), pulmonary infection (RR 0.45, 95 % CI 0.22-0.92,
NNT 26), atelectasis (RR 0.62, 95 % CI 0.41-0.95) and mortality (RR 0.64, 95 % CI
0.46-0.86, NNT 23) [38]. However, there are some limitations that need to be addressed
in the design of this meta-analysis. Some of the included studies were small, five
studies were observational and studies included various types of clinical settings,
such as sepsis in the ICU and one-lung ventilation in the operating room [36], [39].
Therefore, the results of this study cannot be considered as definitive.
To better specify the effect of protective ventilation in cardiac and abdominal surgical
patients, excluding ICU patients, Hemmes et al. [40] performed a meta-analysis focusing
on the effects of protective ventilation on the incidence of postoperative pulmonary
complications and included eight articles. These authors demonstrated that applying
protective ventilation decreased the incidence of lung injury (RR 0.40, 95 % CI 0.22-0.70,
NNT 37), pulmonary infection (RR 0.64, 95 % CI 0.43-0.97, NNT 27) and atelectasis
(RR 0.67, 95 % CI 0.47-0.96, NNT 31). When comparing lower PEEP and higher PEEP, higher
PEEP also attenuated postoperative lung injury (RR 0.29, 95 % CI 0.14-0.60, NNT 29),
pulmonary infection (RR 0.62, 95 % CI 0.40-0.96, NNT 33) and atelectasis (RR 0.61,
95 % CI 0.41-0.91, NNT 29).
The most recent systematic review was performed by Fuller et al. [41]. These authors
hypothesized that low VT is associated with a decreased incidence in the progression
to ARDS in patients without ARDS at the time of initiation of mechanical ventilation.
Thirteen studies were included and only one was a RCT. The majority of these studies
showed that low VT could decrease the progression of ARDS. However, a formal meta-analysis
was not conducted because of the marked heterogeneity and variability of baseline
ARDS among included patients [41].
Meta-analysis including the most recent trials
From the results of two additional recently published RCTs, which included overall
more than 400 patients [24], [25], we hypothesized that the use of a protective ventilator
strategy, defined as physiologically low VT with moderately high PEEP with or without
recruitment maneuvers, could lead to a substantial decrease in pulmonary complications
in non-injured lungs and may affect mortality. Therefore, we conducted a new metaanalysis
restricted to RCTs in patients undergoing surgery and critically ill patients, and
excluding one-lung ventilation. Studies were identified by two authors through a computerized
blind search of Pubmed using a sensitive search strategy. Articles were selected for
inclusion in the systematic review if they evaluated two types of ventilation in patients
without ARDS or ALI at the onset of mechanical ventilation in the operating room or
ICU. Protective ventilation was defined as low VT with or without high PEEP, and standard
ventilation was defined as high VT with or without low PEEP. Articles not reporting
outcomes of interest were excluded. Data were independently extracted from each report
by two investigators using a data recording form developed for this purpose. We extracted
data regarding study design, patient characteristics, type of ventilation, and mean
change in arterial blood gases, lung injury development, and ICU and hospital length
of stay, overall survival, and incidence of atelectasis. The longest follow-up period
in each trial up to hospital discharge was used in the analysis. After extraction,
the data were reviewed and compared by a third investigator. Whenever needed, we obtained
additional information about a specific study by directly questioning the principal
investigator. We assessed allocation concealment, the baseline similarity of groups
(with regard to age, severity of illness, and severity of lung injury), and early
treatment cessation.
The primary endpoint was the development of lung injury in each study group. Secondary
endpoints included incidence of lung infection, atelectasis, length of ICU stay, length
of hospital stay and mortality. Continuous outcome data were evaluated with a meta-analysis
of risk ratio performed with a fixed-effects model according to Mantel and Haenszel.
When heterogeneity was > 25 %, we performed a meta-analysis with mixed random effect
using the DerSimonian and Laird method. Results were graphically represented using
Forest plot graphs. The homogeneity assumption was measured by the I2, which describes
the percentage of total variation across studies that is due to heterogeneity rather
than to chance; a value of 0 % indicates no observed heterogeneity, and larger values
show increasing heterogeneity. Parametric variables are presented as mean and standard
deviation, and nonparametric variables as median and interquartile range (IQR). All
analyses were conducted with OpenMetaAnalyst (version 6), Prism 6 (GraphPad software)
and SPSS version 20 (IBM SPSS). For all analyses, 2-sided p values less than 0.05
were considered significant. To evaluate potential publication bias, a weighted linear
regression was used, with the natural log of the OR as the dependent variable and
the inverse of the total sample size as the independent variable. This is a modified
Macaskill's test, which gives more balanced type I error rates in the tail probability
areas in comparison to other publication bias tests [42].
Seventeen articles were included in the meta-analysis [14-20], [23-28], [31-33], [43].
Three studies were conducted in critically ill patients and the others in surgical
patients. Six of the studies were in cardiac surgery, 6 in major abdominal surgery,
1 in neurosurgery, and 1 in thoracic surgery. A total of 1362 patients, comprising
682 patients with protective ventilation and 680 patients with conventional ventilation,
were analyzed. Characteristics of the included RCTs are shown in Table 2. Nine studies
evaluated inflammatory mediators as their primary outcome. The development of pulmonary
complications was the primary outcome in three studies. The average VT values in the
protective ventilation and conventional ventilation groups were 6.1 ml/kg IBW and
10.7 ml/kg, respectively. The average plateau pressures were < 20 cm H2O in both groups,
significantly lower in the protective ventilation group than in the conventional ventilation
group. The protective ventilation groups had higher levels of PaCO2 and more acidemia,
although within the normal ranges (Table 3).
Table 2
Characteristics of the studies included in the meta-analysis
Protective ventilation
Standard ventilation
First author, Year [Ref]
Number of patients
VT (ml/kg)
N
VT (ml/kg)
N
Setting
Design
Primary outcome
Lee 1990 [31]
103
6
47
12
56
ICU
RCT
Duration of MV
Chaney 2000 [14]
25
6
12
12
16
Surg
RCT
Lung mechanics
Wrigge 2004 [18]
62
6
30
12
32
Surg
RCT
Cytokines in BAL
Koner 2004 [15]
44
6
15
10
29
Surg
RCT
Cytokines in blood
Wrigge 2005 [16]
44
6
22
12
22
Surg
RCT
Cytokines in BAL
Zupancich 2005 [17]
40
8
20
10
20
Surg
RCT
Cytokines in BAL
Michelet 2006 [43]
52
5
26
9
26
Surg
RCT
Cytokines in blood
Cai 2007 [27]
16
6
8
10
8
Surg
RCT
Atelectasis
Wolthius 2008 [19]
40
6
21
12
19
Surg
RCT
Pulmonary Inflammation
Determan 2008 [26]
40
6
21
12
19
Surg
RCT
Cytokines in BAL
Weingarten 2010 [20]
40
6
20
10
20
Surg
RCT
Oxygenation
Determann 2010 [33]
150
6
76
10
74
ICU
RCT
Cytokines in BAL
Pinheiro de Oliveira 2010 [32]
20
6
10
12
10
ICU
RCT
Cytokines in BAL
Sundar 2011 [28]
149
6
75
10
74
Surg
RCT
Duration of MV
Treschan 2012 [23]
101
6
50
12
51
Surg
RCT
Spirometry
Severgnini 2013 [24]
55
7
27
9
28
Surg
RCT
Change in mCPIS
Futier 2013 [25]
400
6-8
200
10-12
200
Surg
RCT
Pulmonary and extrapulmonary complications
BAL: bronchoalveolar lavage; ICU: intensive care unit; MV: mechanical ventilation;
Surg: surgical; VT: tidal volume; mCPIS: modified Clinical Pulmonary Infection Score.
Table 3
Demographic, ventilation and laboratory characteristics of the patients included in
the different studies
Protective ventilation (n = 682)
Standard ventilation (n = 680)
p
Age, years
61 (8.4)
61 (7.7)
0.96
Weight, kg
77.5 (10.1)
77.2 (9.5)
0.82
Tidal volume, ml/kg
6.1 (0.63)
10.7 (1.2)
0.00
PEEP, cm H2O
7.6 (2.4)
2.5 (2.6)
0.00
Plateau pressure, cm H2O
17.2 (2.2)
19.9 (3.9)
0.03
Respiratory rate, breaths/min
16.7 (3.2)
10.1 (3.5)
0.00
PaO2/FiO2
331.6 (62.3)
332.5 (64.3)
0.94
PaCO2, mmHg
42.6 (5.5)
38.4 (4.8)
0.01
pH
7.37 (0.3)
7.40 (0)
0.01
Results are shown as mean (±SD). FiO2: fraction of inspired oxygen; PEEP: positive
end-expiratory pressure.
Figure 2
Effect of protective ventilation on lung injury and infection in surgical and ICU
patients.
Figure 3
Effect of protective ventilation on atelectasis and mortality in surgical and ICU
patients.
Figure 4
Effect of protective ventilation on ICU and hospital lengths of stay in surgical and
ICU patients.
The protective ventilation group had a lower incidence of ALI (RR 0.27, 95 % CI 0.12-0.59)
and lung infection (RR 0.35, 95 % CI 0.25-0.63); however, application of protective
ventilation did not affect atelectasis (RR 0.76, 95 % CI 0.33-1.37) or mortality (RR
1.03; 95 % CI 0.67-1.58) compared with conventional ventilation (Figures 2 and 3).
There were no differences in length of ICU stay (weighted mean difference [WMD] -0.40,
95 % CI -1.02; 0.22) or length of hospital stay (WMD 0.13, 95 %CI -0.73; 0.08) (Figure
4) between the protective ventilation and conventional ventilation groups. The I
2
test revealed no heterogeneity in the analysis of lung injury and mortality, but there
was heterogeneity in the analysis of atelectasis and length of stay.
Our meta-analysis including the most recent trials suggests that among surgical and
critically ill patients without lung injury, protective mechanical ventilation with
use of lower VT, with or without PEEP, is associated with better clinical pulmonary
outcomes in term of ARDS incidence and pulmonary infection but does not decrease atelectasis,
mortality or length of stay. The plateau pressure in the conventional group was less
than 20 cm H2O, indicating that ARDS can occur even below the previously-believed
safe plateau pressure level. The meta-analysis by Serpa Neto et al. [38] demonstrated
that mortality was significantly lower with protective ventilation than in our study.
This finding can be explained by the fact that we included only RCTs in our meta-analysis
and the two most recent RCTs were not analyzed in the previous study. We summarize
the characteristics of each recent meta-analysis Table 4
Table 4
Characteristics and outcomes of three recent meta-analyses
Author, year [ref]
Serpa Neto et al. 2012 [38]
Hemmes et al. 2013 [40]
Our meta-analysis
Number of studies
20 articles
8 articles
17 articles
Number of RCTs
15 articles
6 articles
17 articles
Populations
ICU and surgical patients
Only surgical patients
ICU and surgical patients
Search strategy until (year)
2012
2012
2013
Statistical analysis
Fixed effect + Mantel and Haenszel
Fixed effect + Mantel and Haenszel
Fixed effect + Mantel and Haenszel, when P > 25 % random effect plus DerSimonian and
Laird
Number of patients
2833
1669
1362
PV group
CV group
PV group
CV group
PV group
CV group
VT (ml/kg)
6.5
10.6
6.1
10.4
6.1
10.7
PEEP (cm H2O)
6.4
3.4
6.6
2.7
7.6
2.5
Plateau pressure (cmH2O)
16.6
21.4
16.6
20.5
17.2
19.9
Main outcome
ALI
RR 0.33; 95 %CI 0.23-0.47
RR 0.40; 95 % CI 0.22-0.70
RR 0.27; 95 % CI 0.12-0.59
Pulmonary infection
RR 0.52; 95 %CI 0.33-0.82
RR 0.64; 95 % CI 0.43-0.97
RR 0.35; 95 % CI 0.25-0.63
Atelectasis
RR 0.62; 95 %CI 0.41-0.95
RR 0.67; 95 % CI 0.47-0.96
RR 0.76; 95 % CI 0.33-1.37
Mortality
RR 0.64; 95 %CI 0.46-0.86
No data
RR 1.03; 95 % CI 0.67-1.58
ICU length of stay
No data
No data
WMD -0.40; 95 %CI -1.02; 0.22
Hospital length of stay
No data
No data
WMD 0.13; 95 %CI -0.73; 0.08
Homogeneity test
Found heterogeneity in pulmonary infection outcome
Found heterogeneity in atelectasis outcome
Found heterogeneity in atelectasis, ICU length of stay and hospital length of stay
outcome
RCT: randomized control trial; VT: tidal volume; PEEP: positive end-expiratory pressure;
PV: protective ventilation; CV: conventional ventilation; ICU: intensive care unit;
RR: risk ratio; 95 % CI: 95 % confidence interval. WMD: weighted mean difference.
In specific populations
Donors
A prospective multicenter study in brain death patients reported that 45 % of potential
lung donors have a PaO2/ FiO2 < 300, making them ineligible for lung donation. The
authors suggest that mechanical ventilation management should be changed to protective
ventilation settings to improve the supply of donor lungs [44]. Mascia et al. compared
a protective mechanical ventilation strategy, including VT of 6-8 ml/kg PBW, PEEP
of 8-10 cm H2O, apnea tests performed by using continuous positive airway pressure
(CPAP), closed circuit for airway suction and recruitment maneuver performed after
each ventilator disconnection, with conventional ventilation, mely VT of 10-12 ml/kg
PBW, PEEP 3-5 cm H2O, apnea test performed by disconnecting the ventilator and open
circuit airway suctioning, in potential donors. The authors clearly demonstrated that
the number of lungs that met lung donor eligibility criteria after the 6-hour observation
period and the number of lungs eligible to be harvested were nearly two times higher
with protective ventilation compared to traditional mechanical ventilation [45]. The
authors concluded that these strategies can prevent the lungs from ARDS caused by
brain injury and can recruit atelectasis.
One-lung ventilation
Michelet et al. demonstrated that during one-lung ventilation, protective ventilation
resulted in higher PaO2/FiO2 ratios and shortened duration of postoperative mechanical
ventilation in patients undergoing esophagectomy compared to conventional ventilation
[43]. In patients undergoing esophagectomy, protective ventilation during one-lung
ventilation causes lower serum levels of IL-1, IL-6, and IL-8 [43], [46]. In lobectomy
patients, during one lung ventilation, Yang et al. reported that applying VT of 6
ml/kg PBW, PEEP 5 cm H2O and FiO2 0.5 decreased the incidence of pulmonary complications
and improved oxygenation indices compared to conventional ventilation [47].
Obesity
Obesity can aggravate atelectasis formation and is one of the risk factors for receiving
high VT values [21]. In morbid obesity, the forced vital capacity, maximal voluntary
ventilation and expiratory reserve volume are markedly reduced. During anesthesia,
an increase in body mass index correlates well with decreasing lung volume, lung compliance
and oxygenation [48] but increasing lung resistance. The decrease of FRC is linked
with atelectasis formation consequent to hypoxemia [49]. Ventilator management during
anesthesia in obesity should be set as follows: (a) low VT; (b) open lung approach
with PEEP and recruitment maneuvers; (c) low FiO2, less than 0.8 [49]. Because of
the effects of chest wall and intra-abdominal pressure, we recommend careful monitoring
of airway plateau pressure, intrinsic PEEP and transpulmonary pressure. Further studies
are warranted to define protective ventilation settings in this group and particularly
during the perioperative period.
Conclusions
Although, mechanical ventilation is a supportive tool in patients with respiratory
failure and during the perioperative period, it has proved to be a double-edged sword.
Mechanisms of VILI are now better understood. Implementation of protective ventilator
strategies, consisting of VT of 6 ml/kg, PEEP of 6-12 cm H2O and recruitment maneuvers
can decrease the development of ARDS, pulmonary infection and atelectasis but not
mortality in previously non-injured lungs in the perioperative period and the ICU.
List of abbreviations used
ABW: actual body weight; ALI: acute lung injury; ARDS: acute respiratory distress
syndrome; BAL: bronchoalveolar lavage; CABG: coronary artery bypass surgery; CI: confidence
interval; CPB: cardiopulmonary bypass; CV: conventional ventilation; ECM: extracellular
matrix; EELV: end-expiratory lung volume; FRC: functional residual capacity; GAGs:
glycosaminoglycans; IBW: ideal body weight; ICU: intensive care unit; IL: interleukin;
mCPIS: modified Clinical Pulmonary Infection Score; MMP: matrix metalloproteinase;
MV: mechanical ventilation; NF-KB: nuclear factor-kappa B; NNT: number needed to treat;
OR: odds ratio; PBW: predicted body weight; PEEP: positive-end expiratory pressure;
PV: protective ventilation; RBC: red blood cell; RCTs: randomized controlled trials;
RR: risk ratio; RV: right ventricular; TNF: tumor necrosis factor; VILI@ ventilator-induced
lung injury; V- tidal volume; WMD: weighted mean difference; ZEEP: zero end-expiratory
pressure.
Competing interests
The authors declare that they have no competing interests.