Med Intensiva.

2015;39(6):359---372

www.elsevier.es/medintensiva

ORIGINAL

The effects of prone position ventilation in patients

with acute respiratory distress syndrome. A systematic
review and metaanalysis夽
J.A. Mora-Arteaga a,∗ , O.J. Bernal-Ramírez b , S.J. Rodríguez c

a
Medicina Crítica y Cuidado Intensivo, Universidad del Rosario, Fundación Santa Fe de Bogotá-Hospital Universitario,
Bogotá D.C., Colombia
b
Medicina Crítica y Cuidado Intensivo, Clínica Nueva-Hospital de Suba, Bogotá D.C., Colombia
c
Medicina Crítica y Cuidado Intensivo, Clínica Nueva-Hospital Universitario la Samaritana, Bogotá D.C., Colombia

Received 12 September 2014; accepted 4 November 2014

Available online 26 July 2015

KEYWORDS Abstract
Respiratory distress Introduction: Prone position ventilation has been shown to improve oxygenation and ventila-
syndrome, adult; tory mechanics in patients with acute respiratory distress syndrome. We evaluated whether
Prone position; prone ventilation reduces the risk of mortality in adult patients with acute respiratory distress
Meta-analysis syndrome versus supine ventilation.
Methodology: A meta-analysis of randomized controlled trials comparing patients in supine
versus prone position was performed. A search was conducted of the Pubmed, Embase, Cochrane
Library, and LILACS databases. Mortality, hospital length of stay, days of mechanical ventilation
and adverse effects were evaluated.
Results: Seven randomized controlled trials (2119 patients) were included in the analysis.
The prone position showed a nonsignificant tendency to reduce mortality (OR: 0.76; 95%CI:
0.54---1.06; p = 0.11, I2 63%). When stratified by subgroups, a significant decrease was seen in
the risk of mortality in patients ventilated with low tidal volume (OR: 0.58; 95%CI: 0.38---0.87;
p = 0.009, I2 33%), prolonged pronation (OR: 0.6; 95%CI: 0.43---0.83; p = 0.002, I2 27%), start
within the first 48 h of disease evolution (OR 0.49; 95%CI 0.35---0.68; p = 0.0001, I2 0%) and
severe hypoxemia (OR: 0.51: 95%CI: 0.36---1.25; p = 0.0001, I2 0%). Adverse effects associated
with pronation were the development of pressure ulcers and endotracheal tube obstruction.

夽
Please cite this article as: Mora-Arteaga JA, Bernal-Ramírez OJ, Rodríguez SJ. Efecto de la ventilación mecánica en posición prona en
pacientes con síndrome de dificultad respiratoria aguda. Una revisión sistemática y metanálisis. Med Intensiva. 2015;39:359---372.
∗ Corresponding author.

E-mail address: [email protected] (J.A. Mora-Arteaga).

2173-5727/© 2014 Published by Elsevier España, S.L.U.

360 J.A. Mora-Arteaga et al.

Conclusions: Prone position ventilation is a safe strategy and reduces mortality in patients with
severely impaired oxygenation. It should be started early, for prolonged periods, and should be
associated to a protective ventilation strategy.
© 2014 Published by Elsevier España, S.L.U.

PALABRAS CLAVE Efecto de la ventilación mecánica en posición prona en pacientes con síndrome
Síndrome de de dificultad respiratoria aguda. Una revisión sistemática y metanálisis
dificultad respiratoria
Resumen
del adulto;
Introducción: La ventilación en posición prona ha demostrado mejorar la oxigenación y la
Posición prona;
mecánica pulmonar en pacientes con síndrome de dificultad respiratoria aguda. Nosotros eva-
Metanálisis
luamos si la posición prona disminuye el riesgo de mortalidad en pacientes adultos con síndrome
de dificultad respiratoria aguda versus ventilación en posición supina.
Metodología: Se realizó un metanálisis de ensayos clínicos controlados aleatorizados que com-
pararon pacientes en posición prona versus supina. Se realizó una búsqueda en Pubmed, Embase,
Cochrane Library y LILACS. Se evaluó mortalidad, estancia hospitalaria, días de ventilación
mecánica y efectos adversos.
Resultados: Siete ensayos clínicos controlados aleatorizados (2.119 pacientes) fueron incluidos
en el análisis. La posición prona mostró una tendencia no significativa a disminuir la mortalidad
(OR: 0,76; IC 95%: 0,54---1,06; p = 0,11; I2 63%). Al estratificar por subgrupos se encontró una
disminución significativa en el riesgo de mortalidad en los pacientes ventilados con volumen
corriente bajo (OR: 0,58; IC 95%: 0,38---0,87; p = 0,009; I2 33%), pronación prolongada (OR: 0,6;
IC 95%: 0,43---0,83; p = 0,002; I2 27%), instauración antes de 48 h de evolución de la enfermedad
(OR: 0,49; IC 95%: 0,35---0,68; p = 0,0001; I2 0%) e hipoxemia severa (OR: 0,51; IC 95%: 0,36---1,25;
p = 0,0001; I2 0%). Los efectos adversos relacionados con la pronación fueron el desarrollo de
úlceras por presión y obstrucción del tubo orotraqueal.
Conclusiones: La ventilación en posición prona es una estrategia segura y disminuye la mor-
talidad en los pacientes con compromiso severo de la oxigenación, debe ser instaurada
tempranamente, durante periodos prolongados y asociada a una estrategia de ventilación
protectora.
© 2014 Publicado por Elsevier España, S.L.U.

Introduction which lessen ventilator-associated lung injury,6,7 the fatality

statistics have remained stable in recent years,2,3,5 without
Clinical studies have found that patients with acute respi- additional reductions in patients of this kind. It is there-
ratory distress syndrome (ARDS) account for approximately fore essential to establish other strategies or treatments
5% of all hospitalized patients subjected to mechanical that may result in further significant reductions in patient
ventilation.1 Most studies have shown that patients with mortality.7
mild ARDS (PaO2 /FiO2 200---300) represent only 25% of the Mechanical ventilation in the prone position has been
cases, while the remaining 75% correspond to patients with used for several decades in patients with ARDS with the
moderate or severe ARDS.1,2 Acute respiratory distress syn- purpose of improving oxygenation.8 It is currently well rec-
drome is associated to an in-hospital mortality rate of ognized that the prone position is associated to important
approximately 40%.2,3 The mortality rate in turn is condi- improvements in the oxygenation indices when compared
tioned to the severity of the oxygenation defect. In the with the supine position. Furthermore, different studies
Berlin definition clinical trial, the mortality rate was found in animals and humans have found that the prone posi-
to be 27% in patients with mild ARDS, 32% in cases of mod- tion can reduce ventilator-associated lung injury.9 A number
erate ARDS, and 45% in those with severe ARDS.4 Although of clinical trials have been made with the aim of extrap-
the deterioration of oxygenation is a mortality risk factor olating these results to the clinical setting,10---15 though
in ARDS, patients generally die as a consequence of multi- none of them have clearly demonstrated a positive impact
organ failure, and only a minority (13---19%) die as a result upon patient survival.16 Likewise, the meta-analyses and
of refractory hypoxemia.3,5 Although the mortality rate has systematic reviews published to date only suggest a ten-
decreased in the last few decades, probably due to the adop- dency to reduce mortality in patients with severely impaired
tion of protective ventilation strategies (low tidal volume, oxygenation.5,9,17---23 However, in the time elapsed from the
optimum PEEP level, and limitation of plateau pressure), first clinical trial10 to the most recent study,16 there have
The effects of prone position ventilation in patients with acute respiratory distress syndrome 361

been important changes in ventilation and pronation strate- --- Tube displacement or selective intubation
gies, as described in the latest study by Guerin et al.,16 --- Tube obstruction
where notorious benefit in terms of survival was documented --- Appearance of pressure ulcers
among patients in the prone position --- with an absolute --- Pneumothorax during pronation
decrease in mortality risk of 37%. --- Venous access loss
In the light of the fact that few strategies have had an
impact upon survival in patients with ARDS, it is important The outcomes were stratified by patient subgroups
that ventilation in the prone position has reappeared with and were predefined taking into account the degree of
strong results. However, because of the changes in prona- hypoxemia,4 the use of protective ventilation,6 the duration
tion strategy and in the patient inclusion criteria in the most of ARDS and the daily pronation time.10,20,25 These factors
recent studies, we considered it necessary to determine the probably have a decisive influence upon the results of ven-
true impact of pronation, and to define which patients can tilation in the prone position.9,17,18,21,22,26---32 The subgroups
benefit from it. A meta-analysis was therefore conducted were stratified as follows:
with the primary objective of determining whether ventila-
tion in the prone position reduces mortality in patients with 1 Severity of ARDS (Berlin classification)
ARDS compared with traditional ventilation in the supine --- Mild (PaO2 /FiO2 200---300 mmHg)
position. As a secondary objective we described the groups --- Moderate (PaO2 /FiO2 100---200 mmHg)
of patients that show a positive impact upon survival and --- Severe (PaO2 /FiO2 < 100 mmHg)
the parameters to be applied during the use of this ventila- 2 Daily duration of pronation
tion strategy (timing of the start, daily duration, associated --- Less than 12 h/day
management strategies, etc.). Lastly, based on the results --- More than 12 h/day
obtained, we aimed to offer a series of evidence-based rec- 3 Start of pronation and duration of ARDS
ommendations on the use of ventilation in the prone position 4 Tidal volume used
in patients with ARDS. --- Less than 8 ml/kg ideal weight
--- More than 8 ml/kg ideal weight
Material and methods
Literature search strategy
Types of studies
A literature search was made of the PubMed, EMBASE,
We included randomized, controlled clinical trials com- Cochrane Library and LILACS databases, combining Mesh
paring mechanical ventilation in the prone position versus terms and Keywords: ‘‘Prone Position’’[Mesh], ‘‘Prone Posi-
conventional mechanical ventilation in the supine position in tioning’’, ‘‘Respiratory Distress Syndrome, Adult’’[Mesh],
adult patients meeting the Berlin criteria for ARDS.4 We also ‘‘Acute Respiratory Distress Syndrome’’, ‘‘ARDS’’, ‘‘Acute
included patients classified as presenting acute lung injury Respiratory Failure’’, ‘‘Acute Lung Injury’’, ‘‘Clinical Trial’’
(ALI)(PaO2 /FiO2 200---300 mmHg) according to the Ameri- [Publication Type], ‘‘Controlled Clinical Trial’’ [Publication
can---European ARDS consensus Conference of 1994.24 Type], ‘‘Randomized Controlled Trial’’ [Publication Type],
‘‘Clinical Trials as Topic’’[Mesh], ‘‘Comparative Study’’
[Publication Type], ‘‘Multicenter Study’’ [Publication Type],
Types of patients ‘‘Multicenter Studies as Topic’’[Mesh]. The search was
limited to the period between 1 January 1974 and 31 Decem-
We included studies that evaluated patients over 16 years ber 2013, with no language restrictions.
of age meeting the diagnostic criteria for ARDS, compared
results between ventilation in the prone position versus the
Data extraction and analysis
supine position, and evaluated mortality.
Studies in the pediatric population (under 16 years of age)
Identification of trials and data extraction
were excluded, as were studies in animals or which used
Two authors (J. Mora and O. Bernal) independently screened
airway pressure release ventilation (APRV), high-frequency
the titles and abstracts identified by the search, selecting
oscillation ventilation (HFOV) or inhaled nitric oxide.
those studies that met the established inclusion crite-
ria. Information was extracted regarding the study design,
Interventions and outcomes randomization procedure, blinding, patient characteristics,
inclusion and exclusion criteria, interventions and results.
The interventions evaluated were ventilation in the prone Any disagreements were resolved through examination of
position and conventional ventilation in the supine position. the information by a third reviewer (S. Rodriguez).
The following outcomes were assessed:
Quality assessment
1. Mortality after maximum follow-up The assessment tool recommended by the Cochrane
2. Stay in intensive care (days) Collaboration33 was used to evaluate the risk of bias that
3. Days on mechanical ventilation referred to:
4. Adverse effects and complications:
--- Ventilator-associated pneumonia (VAP) 1. Random sequence generation
--- Accidental or non-scheduled extubation 2. Allocation concealment
362 J.A. Mora-Arteaga et al.

Total: 371
PubMed: 134; EMBASE: 16; Cochrane Library: 62; LILACS: 15

Duplicates: 124 Total: 247 references

Screening by titles Pre-selected: 97

Abstract review Discarded: 75

Metaanalyses: 8; Systematic reviews: 2; Comments: 10;
Literature reviews: 16; Observational studies: 5;
Retrospective studies: 5; Comparator other than supine
position or without comparator: 19; Studies in pediatric
patients/neonates: 5; Protocols: 4; Abstracts: 2

Selected for review: 22

Article review

Discarded: 15
No. randomized clinical trials: 12;
ON primary intervention: 1; no evaluation of mortality: 2

References included in the study: 7

Figure 1 Study screening process. ON: nitric oxide.

3. Blinding of participants and evaluators Characteristics of the studies

4. Incomplete results
5. Selective reporting of results The patient population totaled 2119, of which 1088 were
6. Other sources of bias ventilated in the prone position and 1031 in the supine
position. The recruitment period of four studies10,12,13,15 pre-
ceded publication of the results of the ARDS network study6
(which demonstrated a decrease in mortality risk in patients
Statistical analysis ventilated with low tidal volumes). In general, these studies
The data from the included studies were qualitatively and used tidal volumes greater than those currently recom-
quantitatively analyzed per population, intervention and mended.
result using the RevMan 5.2 freeware statistical package The severity of the disease and the mortality risk
from the Cochrane Informatics and Knowledge Management predicted by the SAPS II were similar in all 7 stud-
Department (http://tech.cochrane.org/). The results were ies. The four most recent studies only included patients
quantified and analyzed on an intention-to-treat (ITT) basis; with PaO2 /FiO2 < 200, i.e., with more severely impaired
relative heterogeneity was measured with the I2 statistic; oxygenation.11,12,14,16 Likewise, the number of hours a day
and statistical significance was examined using the chi- in the prone position was found to increase (from 7---11 to
squared test. Dichotomic results were assessed based on the 17---20 h/day). The changes in mechanical ventilation proto-
odds ratio (OR) with the Mantel---Haenszel test and a random col were also seen to be related to the time of publication:
effects model. In the case of continuous variables, we calcu- the three studies that started the recruitment period after
lated the difference in means based on the inverse variance publication of the ARDS network study6 used a tidal volume
method with a random effects model. Publication bias in of 6---8 ml/kg.11,14---16 The administered PEEP was generally
turn was assessed by funnel plot analysis, and a sensitivity low. No single protocol for deciding the time of pronation
analysis was made to assess the certainty of the results. suspension was found. Table 1 shows the general character-
The study protocol was not registered. istics of the studies.

Bias risk assessment

Results
All the included studies were randomized, controlled clin-
A total of 371 literature references were identified: PubMed ical trials. Randomization was carried out on a centralized
n = 134, EMBASE n = 160, Cochrane Library n = 62 and LILACS basis by telephone or sealed and non-transparent envelopes.
n = 15. We discarded 124 due to duplication. Twenty-two ref- Given the nature of the intervention subjected to evalua-
erences were fully reviewed, and of these 7 met the study tion, it was not possible to blind the patients or the treating
inclusion criteria (Fig. 1). medical team---though we consider that this had no effect
 The effects of prone position ventilation in patients with acute respiratory distress syndrome
Table 1 Summarized characteristics of the studies.
Study/characteristics Gatinoni et al. Guerin et al.13 Voggenreiter Mancebo et al.12 Fernandez et al.11 Taccone et al.14 Guérin et al.16
(2001) et al.15
Total patients 304 791 40 136 40 342 466
(no.)
Recruitment December December September December September February January 2008---July
period 1996---October 1998---december 1999---September 1998---September 2003---September 2004---October 2011
1999 2002 2001 2002 2004 2008
Follow-up period 180 days 90 days 90 days Until hospital 60 days 180 days 90 days
discharge
Inclusion criteria PaO2 /FiO2 ≤ 200 PaO2 /FiO2 ≤ 300 PaO2 /FiO2 ≤ 200 PaO2 /FiO2 ≤ 200 PaO2 /FiO2 ≤ 200 PaO2 /FiO2 ≤ 200 PaO2 /FiO2 ≤ 150
with expected with with with with with
PEEP ≥ 5 cmH2 O, mechanical PEEP ≥ 5 cmH2 O, PEEP ≥ 5 cmH2 O, PEEP ≥ 5 cmH2 O, PEEP ≥ 5 cmH2 O, PEEP ≥ 5 cmH2 O,
PaO2 /FiO2 ≤ 300 ventilation time PaO2 /FiO2 ≤ 300 PAOP ≤ 18 mmHg PAOP ≤ 18 mmHg PAOP ≤ 18 mmHg TV 6 ml/kg
with >48 h with
PEEP ≥ 10 cmH2 O, PEEP ≥ 5 cmH2 O,
PAOP ≤ 18 mmHg PAOP ≤ 18 mmHg
Mean age (years) 58 62.2 41.5 54 54.6 60 59
Severity (mean)
PaO2 /FiO2 127.4 152.5 221.5 146.5 155.5 113 100
(mmHg)
APACHE II NR NR NR NR NR NR NR
SAPS II 40 45.6 NR 40.5 38.3 41 46
SOFA NR NR 11.5 NR 9.3 6.8 10
Ventilator settings
PEEP (cmH2 O) 9.65 7.7 11.5 12.4 13.2 10 10
Tidal volume 10.3 8.1 8 8.5 7.3 8 6.1
(ml/kg)
Prone position
Time before NR 50.8 <96 21.3 <48 <72 33
pronation
(hours)
Hours a day 7 8.6 11 17 20 18 17
in pronation
Total days 10 4.1 7 10.1 NR 8.4 4
in pronation

363
 364
Table 1 (Continued)

Study/characteristics Gatinoni et al. Guerin et al.13 Voggenreiter Mancebo et al.12 Fernandez et al.11 Taccone et al.14 Guérin et al.16
(2001) et al.15
Pronation Completion Improvement of PaO2 /FiO2 > 300 Start of weaning PaO2 /FiO2 > 250 Resolution of PaO2 /FiO2 > 150
suspension of 10 days PaO2 /FiO2 > 30% during >48 h from ventilator with ventilation failure PEEP < 10 cmH2 O
criterion with FiO2 < 60% PEEP < 8 cmH2 O and/or 28 days and FiO2 < 0.6
and PEEP < 8 during >12 h from admission
cmH2 O; no sepsis to study
or resolution of
cause of
ventilation failure
Methodology
Allocation Yes, centralized Yes, Yes, centralized Yes, centralized Yes, centralized Yes, centralized
concealment randomization randomization randomization randomization randomization randomization by
by telephone by sealed and by telephone by call center by telephone web-based system
non-transparent
envelopes
Exclusions after Yes, one patient Yes, 7 patients in No Yes, 2 patients in No Yes, one patient in Yes, 5 patients in
randomization in each group supine group and 4 supine group and 4 each group supine group and 3
in prone position in prone position in prone position
group group group
Losses No Yes, one patient No Yes, 2 patients Yes, one patient Yes, two patients No
in each group in prone position in each group in each group
group and one
in supine group
Supine to prone Yes, 12 patients Yes, 81 patients No Yes, 5 patients Yes, 2 patients Yes, 20 patients No
cross-over
Early Yes No No Yes Yes No No
termination

J.A. Mora-Arteaga et al.

NR: not reported; PAOP: pulmonary artery occlusion pressure; PaO2 /FiO2 : ratio between partial pressure of oxygen in arterial blood and fraction of inspired oxygen; PEEP: positive
end-expiratory pressure; TV: tidal volume.
The effects of prone position ventilation in patients with acute respiratory distress syndrome 365

upon the results. Furthermore, with the exception of a Four studies11,14---16 used a tidal volume 8 ml/kg ideal weight,
single study,13 the group handling the information of the showing a decrease in mortality risk of 36% (OR: 0.58; 95%CI:
patients and the results of the analyses was independent and 0.38---0.87; p = 0.009; I2 33%). This finding was not obtained
blinded to the treatment groups. No significant losses were when using a tidal volume >8 ml/kg ideal weight (OR: 1.01;
reported in the studies, and exclusions after randomization 95%CI: 0.77---1.32; p = 0.94; I2 18%) (Fig. 3).
were also few (being mainly due to secondary withdrawal
of consent and inclusion error). Three studies ended pre-
Mortality and number of hours a day in the prone
maturely. 10---12 We therefore could not obtain an adequate
position
sample for identifying probable differences with optimum
All the studies reported and analyzed data regarding
statistical power.
the duration of pronation. In the four most recent
publications11,12,14,16 the number of daily hours was
Prone position and mortality increased (18 h on average)---this resulting in a significant
decrease in event risk in favor of the group of patients placed
Global mortality in the prone position for more than 12 h (OR: 0.6; 95%CI:
A total of 456 events were recorded in the prone posi- 0.43---0.83; p = 0.002; I2 27%) (Fig. 4).
tion group (41.9%), versus 483 in the supine position group
(46.8%), with an OR of 0.76 (95%CI: 0.54---1.06; p = 0.11;
I2 63%) showing a tendency in favor of the prone posi- Mortality and start of pronation
tion group---though statistical significance was not reached In the same way that the number of hours in the prone
(Fig. 2). Since the studies had different follow-up periods, position appears to be important, so does the timing of
and we used the final report on events at the end the start of patient placement in the prone position. In
of this period for the global result, the findings were effect, greater benefit was observed when the patients were
stratified and evaluated in different time periods: after 28 placed in the prone position within the first 48 h after the
days (OR: 0.73; 95%CI: 0.41---1.32; p = 0.3; I2 85%), after start of mechanical ventilation, with an OR of 0.49 (95%CI:
90 days (OR: 0.64; 95%CI: 0.29---1.40; p = 0.26; I2 84%) and 0.35---0.68, p = 0.0001; I2 0%) (Fig. 5).
after 180 days (OR: 0.97; 95%CI: 0.67---1.40; p = 0.26; I2 28%),
together with mortality in intensive care (OR: 0.86; 95%CI: Mortality and severity of hypoxemia
0.61---1.22; p = 0.4; I2 31%)---no significant differences being The studies were stratified according to the severity
found in each of the groups. of hypoxemia: moderate (PaO2 /FiO2 100---200) or severe
(PaO2 /FiO2 < 100). Taccone et al. stratified the population
Mortality and protective ventilation into these two groups; their data were therefore taken
On examining the association between mortality and the separately for analysis. The study published by Voggen-
administered tidal volume, stratification into two groups reiter et al. reported patients with PaO2 /FiO2 > 200. Five
was made according to whether a low tidal volume was used studies10---14 documented patients with moderate hypoxemia,
as part of a protective ventilation strategy, or a high tidal while two studies14,16 reported patients with severe hypox-
volume was administered (the latter appearing to be related emia. On performing the meta-analysis, the group with
to the development of ventilator-associated lung injury). severely impaired oxygenation showed clear benefit with the

Prono Supino Odds ratio Odds ratio Risk of bias

Study or subgroup Events Total Events Total Weight M–H, Random, 95% CI Year M–H, Random, 95% CI A B CD EF G
1.1.1 General mortality
Gattinoni et al., 2001 95 152 89 152 18.1% 1.18 [0.74, 1.87] 2001
Guerin et al., 2004 179 413 159 378 22.7% 1.05 [0.79, 1.40] 2004
Voggenreiter et al., 2005 1 21 3 19 1.9% 0.27 [0.03, 2.81] 2005
Mancebo et al., 2006 38 76 37 60 12.8% 0.62 [0.31, 1.24] 2006
Fernandez et al., 2008 8 21 10 19 5.8% 0.55 [0.16, 1.95] 2008
Taccone et al., 2009 79 168 91 174 19.0% 0.81 [0.53, 1.24] 2009
Guerin et al., 2013 56 237 94 229 19.7% 0.44 [0.30, 0.66] 2013
Subtotal (95% CI) 1088 1031 100.0% 0.76 [0.54, 1.06]
Total events 456 483
Heterogeneity: Tau2 = 0.11; Chi2 = 16,37, df = 6 (P = 0.01); l2 = 63%
Test for overall effect: Z = 1.60 (P = 0.11)

0.01 0.1 1 10 100

Test for subgroup differences: not applicable Prono supino
Risk of bias legend
(A) Random sequence generation (selection bias)
(B) Allocation concealment (selection bias)
(C) Blinding of participants and personnel (performance bias)
(D) Blinding of outcome assessment (detection bias)
(E) Incomplete outcome data (attrition bias)
(F) Selective reporting (reporting bias)
(G) Other bias

Figure 2 Global mortality and bias risk. Mortality was evaluated up until the end of follow-up in each study. The bias risk of each
study was scored as high (−), intermediate (?) or low (+).
366 J.A. Mora-Arteaga et al.

Prono Supino Odds ratio Odds ratio

Study or subgroup Events Total Events Total Weight M-H, Random, 95% CI Year M-H, Random, 95% CI
1.3.1 1 Mortality and tidal volume 6-8 ml/kg
Voggenreiter et al., 2005 1 21 3 19 2.9% 0.27 [0.03, 2.81] 2005
Fernandez et al., 2008 8 21 10 19 9.3% 0.55 [0.16, 1.95] 2008
Taccone et al., 2009 79 168 91 174 42.7% 0.81 [0.53, 1.24] 2009
Guerin et al., 2013 56 237 94 229 45.1% 0.44 [0.30, 0.66] 2013
Subtotal (95% CI) 447 441 100.0% 0.58 [0.38, 0.87]
Total events 144 198
Heterogeneity: Tau2 = 0.06; Chi2 = 4.51, df = 3 (P = 0.21); l2 = 33%
Test for overall effect: Z = 2.63 (P = 0.009)

1.3.2 2 Mortality and tidal volume > 8 ml/kg

Gattinoni et al., 2001 95 152 89 152 28.0% 1.18 [0.74, 1.87] 2001
Guerin et al., 2004 179 413 159 378 58.2% 1.05 [0.74, 1.87] 2004
Mancebo et al., 2006 38 76 37 60 13.8% 0.62 [0.31, 1.24] 2006
Subtotal (95% CI) 641 590 100.0% 1.01 [0.77, 1.32]
Total events 312 285
Heterogeneity: Tau2 = 0.01; Chi2 = 2.43, df = 2 (P = 0.30); l2 = 18%
Test for overall effect: Z = 0.08 (P = 0.94)

0.01 0.1 1 10 100

Prono supino
Test for subgroup differences: Chi2 = 5.04, df = 1 (P = 0.02), l2 = 80.1%

Figure 3 Mortality and protective ventilation. The prone position exerted a protective effect in patients ventilated with a tidal
volume <8 ml/kg ideal weight.

prone position (OR: 0.51; 95%CI: 0.36---1.25; p = 0.0001; I2 0%) Prone position and adverse effects
(Fig. 6). Pressure ulcers were the most frequent adverse events
(34%), followed by ventilator-associated pneumonia (21.4%),
orotracheal tube obstruction (14.6%), accidental extubation
Prone position, stay in intensive care and days
(10.9%), venous access loss (10.9%), pneumothorax (5.8%),
on mechanical ventilation
and displacement of the orotracheal tube (3.7%).
Four studies reported the stay in intensive care,11,12,14,16 and
The prone position was associated to a significantly
5 studies11,13---16 recorded the days on mechanical ventila-
increased risk of orotracheal tube obstruction (OR: 2.19;
tion. Analysis was discarded in both cases,14 since different
95%CI: 1.55---3.09; p < 0.0001; I2 0%) and the development
measurement units were used. The study published by
of pressure ulcers (OR: 1.53; 95%CI: 1.21---1.94; p = 0.0003;
Guerin et al.16 reported the results in subgroups of survivors
I2 0%). No differences were observed in relation to the rest
and non-survivors. No differences were found in the results
of the described events (Fig. 8).
between the two studied groups (stay in intensive care:
difference of means −0.05; 95%CI: −2.98---2.89; p = 0.00001;
I2 95%, and days on mechanical ventilation: difference of Assessment of publication bias
means −1.19; 95%CI: −2.74---0.35; p = 0.00001; I2 91%) Visual inspection of the funnel plots revealed no evidence
(Fig. 7). of publication bias (Fig. 9).

Prono Supino Odds ratio Odds ratio

Study or subgroup Events Total Events Total Weight M-H, Random, 95% CI Year M-H, Random, 95% CI
1.4.1 Mortality and prone position >12 h/day
Mancebo et al., 2006 38 76 37 60 18.3% 0.62 [0.31, 1.24] 2006
Fernandez et al., 2008 8 21 10 19 6.3% 0.55 [0.16, 1.95] 2008
Taccone et al., 2009 79 168 91 174 36.3% 0.81 [0.53, 1.24] 2009
Guerin et al., 2013 56 237 94 229 39.1% 0.44 [0.30, 0.66] 2013
Subtotal (95% CI) 502 482 100.0% 0.60 [0.43, 0.83]
Total events 181 232
Heterogeneity: Tau2 = 0.03; Chi2 = 4.11, df = 3 (P = 0.25); l2 =27%
Test for overall effect: Z = 3.09 (P = 0.002)

1.4.2 Mortality and prone position <12 h/day

Gattinoni et al., 2001 95 152 89 152 27.0% 1.18 [0,74, 1.87] 2001
Guerin et al., 2004 179 413 159 378 72.0% 1.05 [0,79, 1.40] 2004
Voggenreiter et al., 2005 1 21 3 19 1.0% 0.27 [0,03, 2.81] 2005
Subtotal (95% CI) 586 549 100.0% 1.07 [0,84, 1.36]
Total events 275 251
Heterogeneity: Tau2 = 0.00; Chi2 = 1.52, df = 2 (P = 0.47); l2 =0%
Test for overall effect: Z = 0.56 (P = 0.57)

0.01 0.1 1 10 100

Test for subgroup differences: Chi2 = 8.00, df = 1 (P = 0.005), l 2 = 87.5% Prono supino

Figure 4 Mortality and hours a day in the prone position. Significant differences were found in favor of the group placed in the
prone position during more than 12 h a day.
The effects of prone position ventilation in patients with acute respiratory distress syndrome 367

Prono Supino Odds ratio Odds ratio

Study or subgroup Events Total Events Total Weight M-H, Random, 95% CI Year M-H, Random, 95% CI
1.5.1 Mortality and prone position before 48 h
Mancebo et al., 2006 38 76 37 60 23.4% 0.62 [0.31, 1.24] 2006
Fernandez et al., 2008 8 21 10 19 7.0% 0.55 [0.16, 1.95] 2008
Guerin et al., 2013 56 237 94 229 69.6% 0.44 [0.30, 0.66] 2013
Subtotal (95% CI) 334 308 100.0% 0.49 [0.35, 0.68]
Total events 102 141
Heterogeneity: Tau2 = 0.00; Chi2 = 0.73, df = 2 (P = 0.70); l2 = 0%
Test for overall effect: Z = 4.22 (P < 0.0001)

1.5.2 Mortality and prone position after 48 h

Guerin et al., 2004 179 413 159 378 65.8% 1.05 [0.79, 1.40] 2004
Voggenreiter et al., 2005 1 21 3 19 1.2% 0.27 [0.03, 2.81] 2005
Taccone et al., 2009 79 168 91 174 33.0% 0.81 [0.53, 1.24] 2009
Subtotal (95% CI) 602 571 100.0% 0.95 [0.73, 1.23]
Total events 259 253
Heterogeneity: Tau2 = 0.01; Chi2 = 2.17, df = 2 (P = 0.34); l2 = 8%
Test for overall effect: Z = 0.39 (P = 0.70)

0.01 0.1 1 10 100

Prono supino
Test for subgroup differences: Chi2 = 9.61, df = 1 (P = 0.002), l2 = 89.6%

Figure 5 Mortality and timing of the start of pronation. Pronation within the first 48 h was associated to a decrease in mortality
risk.

Discussion a second change was the prolongation of pronation time

to over 16 consecutive hours a day. A third change was
The primary objective of our study was to examine the the utilization of protective ventilation strategies with a
impact of mechanical ventilation in the prone position upon tidal volume of <8 ml/kg ideal weight, the maintenance of
mortality in patients with ARDS. Global assessment of the a plateau pressure of <30 cmH2 O, and titration of the opti-
results revealed a nonsignificant tendency to reduce mor- mum PEEP level according to the recommendations of the
tality risk in favor of the prone position group. However, ARDS network. On examining the studies linearly over time,
on individually analyzing the studies, we found that the we observed a tendency to gradually favor the prone posi-
most recent trials11,12,14,16 incorporated a number of changes tion, culminating in the study published by Guerin et al.,16
in both the inclusion criteria and in the prone position where a strong reduction in mortality risk was recorded in
protocol, based on the analysis of the probable causes favor of pronation (HR 0.44; 95%CI: 0.29---0.67; p = 0.001
underlying the discouraging results recorded in the ear- after 90 days). These findings are consistent with those
lier studies.10,13,15 A first change was the inclusion of more of two recent meta-analyses. The first study was carried
severely compromised patients, with PaO2 /FiO2 < 200, while out by Beitler et al.,34 who conducted a meta-analysis of

Prono Supino Odds ratio Odds ratio

Study or subgroup Events Total Events Total Weight M-H, Random, 95% CI Year M-H, Random, 95% CI
1.6.1 Mortality and prone position in severe ARDS(PaO2 /FiO2 <100)
Taccone et al., 2009 (1) 39 74 48 76 27.3% 0.65 [0.34, 1.25] 2009
Guerin et al., 2013 56 229 94 229 72.7% 0.46 [0.31, 0.69] 2013
Subtotal (95% CI) 303 305 100.0% 0.51 [0.36, 0.72]
Total events 95 142
Heterogeneity: Tau2 = 0.00; Chi2 = 0.74, df = 1 (P = 0.39); l2 =0%
Test for overall effect: Z = 3.87 (P = 0.0001)

1.6.2 Mortality and prone position in moderate ARDS (PaO2 /FiO2 100-200)
Gattinoni et al., 2001 95 152 89 152 24.4% 1.18 [0.74, 1.87] 2001
Guerin et al., 2004 179 378 159 413 35.4% 1.44 [1.08, 1.91] 2004
Mancebo et al., 2006 38 76 37 60 15.2% 0.62 [0.31, 1.24] 2006
Fernandez et al., 2008 8 21 10 19 5.8% 0.55 [0.16, 1.95] 2008
Taccone et al., 2009 (2) 40 94 43 98 19.3% 0.95 [0.54, 1.68] 2009
Subtotal (95% CI) 721 742 100.0% 1.05 [0.76, 1.45]
Total events 360 338
Heterogeneity: Tau2 = 0.06; Chi2 = 7.15, df = 4 (P = 0.13); l2 =44%
Test for overall effect: Z = 0.31 (P = 0.75)

0.01 0.1 1 10 100

Prono supino
Test for subgroup differences: Chi2 = 9.18, df = 1 (P = 0.002), l = 89.1%
2

Footnotes
(1) Severe hypoxemia subgroup
(2) Moderate hypoxemia subgroup

Figure 6 Mortality and severity of hypoxemia. Taccone et al. stratified the patients into individuals with moderate or severe
hypoxemia. The data of each group were taken separately to the effects of analysis.
368 J.A. Mora-Arteaga et al.

Experimental Control Mean Difference Mean Difference

Study or subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI Year IV, Random, 95% CI
2.1.1 Ventilation in prone position and stay in intensive care
Mancebo et al., 2006 20,5 18,2 1558 19,1 23.1 1146 24.7% 1.40 [–0.21, 3.01] 2006
Fernandez et al., 2008 14,7 9,7 309 17,5 16.1 332 23.6% –2.80 [–4.84, –0.76] 2008
Guerin et al., 2013 (1) 21 20 3801 18 15 2430 26.0% 3.00 [2.13, 3.87] 2013
Guerin et al., 2013 (2) 24 22 4344 26 27 3510 25.7% –2.00 [–3.11, –0.89] 2013
Subtotal (95% CI) 10012 7418 100.0% –0.05 [–2.98, 2.89]
Heterogeneity: Tau2 = 8.41; Chi2 = 61.51, df = 3 (P < 0.00001); l2 =95%
Test for overall effect: Z = 0.03 (P = 0.97)

2.1.2 Ventilation in prone position and days on mechanical ventilation

Guerin et al., 2004 13.7 7.8 5658 14.1 8.6 5330 24.0% –0.40 [–0.71, –0.09] 2004
Voggenreiter et al., 2005 30 17 630 33 23 627 16.1% –3.00 [–5.24, –0.76] 2005
Fernandez et al., 2008 11.9 9.2 250 15.7 16.9 298 16.1% –3.80 [–6.03, –1.57] 2008
Guerin et al., 2013 (3) 18 14 1008 16 11 1504 21.9% 2.00 [0.97, 3.03] 2013
Guerin et al., 2013 (4) 17 16 3077 19 21 2565 22.0% –2.00 [–2.99, –1.01] 2013
Subtotal (95% CI) 10623 10324 100.0% –1.19 [–2.74, –0.35]
Heterogeneity: Tau2 = 2.57; Chi2 = 45.00, df = 4 (P = 0.00001); l2 =91%
Test for overall effect: Z = 1.51 (P = 0.13)

–100 –50 0 50 100

Prono supino
Test for subgroup differences: Chi2 = 0.46, df = 1 (P = 0.50), l 2 = 0%
Footnotes
(1) Not survivors
(2) Survivors
(3) Survivors
(4) Not survivors

Figure 7 Ventilation in the prone position, stay in intensive care and days on mechanical ventilation. No significant differences
were found between the groups of patients.

individual patient data, including the PROSEVA study,16 volume and the relative risk of death after 60 days during
assessing mortality after 60 days, with the identification pronation. Specifically, a decrease in mean basal tidal vol-
of a nonsignificant tendency in favor of pronation (RR: ume of 1 ml/kg ideal weight was seen to be associated to a
0.83; 95%CI: 0.68---1.02; p = 0.073). The second study was 16.7% mortality risk.34
published by Lee et al.,35 based on broader inclusion The degree of alveolar recruitment in the prone posi-
criteria and a larger number of studies, and identified a tion also requires consideration. Acute respiratory distress
global decrease in mortality risk, though with a confidence syndrome is characterized by disruption of the alveolar-
interval very close to one (OR: 0.77; 95%CI: 0.59---0.99; capillary barrier, with increased permeability of the latter
p = 0.039). and the production of flooding and alveolar edema further-
However, interesting data were obtained on stratifying more associated to the depletion of surfactant---thus giving
the results by subgroups, supporting our theory regarding rise to alveolar instability and collapse.38 Pulmonary involve-
the evolution and optimization of the prone position ven- ment is heterogeneous, with well aerated lung regions
tilation strategy based on plausible physiology and clear that participate in gas exchange, and other regions that
clinical characteristics. Firstly, the utilization of a low have collapsed as a result of the overpressure exerted
tidal volume (<8 ml/kg ideal weight) in patients with ARDS by the interstitial edema and alveolar flooding39,40 ---these
became generalized after publication of the ARDS network mechanisms explaining the decrease in lung volume in
study6 , which revealed a decrease in mortality risk prob- these patients.40 Pronation makes it possible to recruit
ably related to the generation of lesser mechanical stress these affected zones,37 redistributing and homogenizing
upon the alveolar membrane by preventing overdistension ventilation,30 reducing the intrapulmonary shunt effect and
and improving alveolar stability.36 This, being associated to improving oxygenation, ventilation and lung mechanics.41
recruitment capacity and homogenization of the distribu- However, the degree of recruitment depends on factors such
tion of ventilation, flow and airway pressures attributed as the severity of lung involvement,25 the pronation time39
to pronation,37 probably also produce an additive effect and the time elapsed from lung injury to patient placement
in the prevention and reduction of ventilator-associated in the prone position.19
lung injury. Thus, on evaluating the subgroup of patients Although the prone position can effectively increase oxy-
in which a tidal volume of <8 ml/kg ideal weight was genation when used several days after onset of the disease,10
used,11,14---16 a significant decrease in mortality risk was its application during the early stages was found to offer
noted in comparison with the group receiving a greater tidal betters results. During these early stages, all the condi-
volume10,13,15 ---these findings possibly being attributable to tions favoring the effectiveness of pronation are present,
the decrease in ventilator-associated lung injury. Beitler such as alveolar edema, reversible collapse and the absence
et al.34 and Lee et al.35 also recorded a significant decrease of pulmonary structural alterations.37 In these stages, the
in mortality risk in those studies that used low tidal vol- reduction in ventilator-associated lung injury risk proba-
umes (RR: 0.66; 95%CI: 0.5---0.86; p = 0.002 and OR: 0.62; bly exceeds that obtained when pronation is used in later
95%CI: 0.48---0.69; p = 0.015, respectively). Beitler et al.34 stages of ARDS, when the damage has already been caused.42
in turn performed a metaregression analysis that revealed This has been clearly demonstrated in our study, where the
a dose---response relationship between the mean basal tidal patients placed in the prone position within the first 48 h
The effects of prone position ventilation in patients with acute respiratory distress syndrome 369

Prono Supino Odds ratio Odds ratio

Study or subgroup Events Total Events Total Weight M–H, Random, 95% CI Year M–H, Random, 95% CI
3.1.1 Ventilation in the prone position and development of pressure ulcers
Gattinoni et al., 2001 55 152 42 152 23.1% 1.49 [0.91, 2.41] 2001
Guerin et al., 2004 208 413 155 378 68.9% 1.46 [1.10, 1.93] 2004
Mancebo et al., 2006 2 76 0 60 0.6% 4.06 [0.19, 86.19] 2006
Taccone et al., 2009 18 168 8 174 7.4% 2.49 [1.05, 5.89] 2009
Subtotal (95% CI) 809 764 100.0% 1.53 [1.21, 1.94]
Total events 283 205
Heterogeneity: Tau2 = 0.00; Chi2 = 1.74, df = 3 (P = 0.63); l2 =0%
Test for overall effect: Z = 3.59 (P = 0.0003)

3.1.2 Ventilation in the prone position and orotracheal tube obstruction

Guerin et al., 2004 34 413 12 378 26.1% 2.74 [1.40, 5.37] 2004
Mancebo et al., 2006 1 76 0 60 1.1% 2.40 [0.10, 60.07] 2006
Taccone et al., 2009 85 168 59 174 62.4% 2.00 [1.29, 3.09] 2009
Guerin et al., 2013 11 237 5 229 10.3% 2.18 [0.75, 6.38] 2013
Subtotal (95% CI) 894 841 100.0% 2.19 [1.55, 3.09]
Total events 131 76
Heterogeneity: Tau2 = 0.00; Chi2 = 0.60, df = 3 (P = 0.90); l2 =0%
Test for overall effect: Z = 4.47 (P < 0.00001)

3.1.3 Prone position and risk of orotracheal tube displacement

Gattinoni et al., 2001 12 152 15 152 32.2% 0.78 [0.35, 1.73] 2001
Guerin et al., 2004 0 413 6 378 6.9% 0.07 [0.00, 1.23] 2004
Voggenreiter et al., 2005 1 21 1 19 7.1% 0.90 [0.05, 15.47] 2005
Taccone et al., 2009 18 168 8 174 30.6% 2.49 [1.05, 5.89] 2009
Guerin et al., 2013 6 237 5 229 23.2% 1.16 [0.35, 3.87] 2013
Subtotal (95% CI) 991 952 100.0% 1.04 [0.46, 2.37]
Total events 37 35
Heterogeneity: Tau2 = 0.38; Chi2 = 7.83, df = 4 (P = 0.10); l2 =49%
Test for overall effect: Z = 0.10 (P = 0,92)

3.1.4 Prone position and risk of accidental extubation

Guerin et al., 2004 44 413 47 378 56.4% 0.84 [0.54, 1.30] 2004
Mancebo et al., 2006 6 76 1 60 3.2% 5.06 [0.59, 43.21] 2006
Fernandez et al., 2008 1 21 1 19 1.8% 0.90 [0.05, 15.47] 2008
Guerin et al., 2013 31 237 25 229 38.5% 1.23 [0.70, 2.15] 2013
Subtotal (95% CI) 747 686 100.0% 1.03 [0.70, 1.52]
Total events 82 74
Heterogeneity: Tau2 = 0.02; Chi2 = 3.34, df = 3 (P = 0.34); l2 =10%
Test for overall effect: Z = 0.16 (P = 0.88)

3.1.5 Prone position and risk of pneumothorax

Guerin et al., 2004 22 413 28 378 55.5% 0.70 [0.40, 1.25] 2004
Mancebo et al., 2006 7 76 4 60 11.3% 1.42 [0.40, 5.10] 2006
Fernandez et al., 2008 0 21 1 19 1.7% 0.29 [0.01, 7.47] 2008
Guerin et al., 2013 15 237 13 229 31.5% 1.12 [0.52, 2.41] 2013
Subtotal (95% CI) 747 686 100.0% 0.87 [0.57, 1.33]
Total events 44 46
Heterogeneity: Tau2 = 0.00; Chi2 = 1.96, df = 3 (P = 0.58); l2 =0%
Test for overall effect: Z = 0.64 (P = 0.52)

3.1.6 Prone position and risk of ventilator associated pneumonia

Guerin et al., 2004 85 413 91 378 49.9% 0.82 [0.58, 1.14] 2004
Voggenreiter et al., 2005 12 21 17 19 13.3% 0.16 [0.03, 0.86] 2005
Mancebo et al., 2006 14 76 9 60 29.0% 1.28 [0.51, 3.20] 2006
Fernandez et al., 2008 3 21 1 19 7.8% 3.00 [0.28, 31.63] 2008
Subtotal (95% CI) 531 476 100.0% 0.83 [0.41, 1.68]
Total events 114 118
Heterogeneity: Tau2 = 0,23; Chi2 = 5.70, df = 3 (P = 0.13); l2 =47%
Test for overall effect: Z = 0,52 (P = 0.60)

3.1.7 Prone position and risk of venous access loss

Gattinoni et al., 2001 8 152 14 152 49.8% 0.55 [0.22, 1.35] 2001
Taccone et al., 2009 27 168 7 174 50.2% 4.57 [1.93, 10.81] 2009
Subtotal (95% CI) 320 326 100.0% 1.59 [0.20, 12.75]
Total events 35 21
Heterogeneity: Tau2 = 2.06; Chi2 = 11.19, df = 1 (P = 0.0008); l2 = 91%
Test for overall effect: Z = 0.44 (P = 0.66)

0.01 0.1 1 10 100

Prono supino
Test for subgroup differences: Chi2= 16.80, df = 6 (P = 0.01), l2 = 64.3%

Figure 8 Ventilation in the prone position and adverse effects. A direct relationship was found between pronation and the risk
of pressure ulcers and orotracheal tube obstruction.
370 J.A. Mora-Arteaga et al.

SE (log[OR])
0

0.5

1.5

OR
2
0.01 0.1 1 10 100
Subgroups
General mortality

Figure 9 Funnel plot. Visual inspection reveals no selection bias.

of the evolution of the disease showed a clear protective the incidence of adverse events is low, we think that it is
effect referred to mortality risk. largely conditioned by treating team experience with the
In clinical practice, the severity of ARDS has been rated prone position, and the existence of guides and protocols
according to the PaO2 /FiO2 ratio,4 though in disorders as with the indications, contraindications and safety measures
complex as this syndrome, the PaO2 /FiO2 ratio depends on to be adopted during the procedure.
the PEEP level and FiO2 administered, as well as on the pre-
scribed treatments and/or interventions, the comorbidities,
and the innate compensatory mechanisms of the disease.43 Conclusions
Despite the presence of these variables, the results obtained
allow us to clearly establish that the prone position is indi- The prone position offers clinical benefits such as improved
cated in patients with severely impaired oxygenation, as oxygenation, by optimizing lung recruitment and the
has already been demonstrated in other studies.5,17---19,21---23 ventilation---perfusion ratio, and probably also prevents and
Furthermore, prolongation of the prone position to over 12 reduces ventilator-associated lung injury by homogenizing
consecutive hours a day (18 h on average) in patients with the stress and strain upon the lung parenchyma, resulting in
severe ARDS is a highly recommended strategy.11,12,14,16 It is a decrease in mortality risk.
important to note that in patients with mild ARDS, pronation Based on the results obtained, the prone position
has not been found to offer clinical advantages and is there- can be recommended in patients with severe hypoxemia
fore not advised.15 In cases of moderate ARDS, the clinical (PaO2 /FiO2 < 100), associated to a low tidal volume (<8 ml/kg
recommendation is likewise not clear, though the results of ideal weight), during a period of over 16 h a day, and starting
the post hoc analysis of a meta-analysis9 revealed a certain early during the course of the disease (<48 h). These conse-
tendency to benefit patients with PaO2 /FiO2 < 140. Conse- quently would be the indications and associated strategies
quently, when taken in combination with the results of the to be included in pronation protocols.
PROSEVA study,16 these data allow us to consider the use of Pronation requires no special equipment, but should be
this strategy in this patient subgroup.37,44 carried out by trained personnel and adopting the required
safety measures in order to avoid associated complications.
Adverse events
Financial support
In general, ventilation in the prone position is safe,
and its complications are infrequent. The most common The authors declare that no financial support has been
adverse effects are pressure ulcers and orotracheal tube received for this study from any government or private
obstruction. Accidental extubation, displacement of the organism.
orotracheal tube, the risk of pneumothorax, and venous
access loss exhibited a similar distribution between the two
groups. The development of ventilator-associated pneumo- Conflicts of interest
nia (VAP) was not related to pronation, and its frequency
was similar to that reported in previous reviews.45 Although The authors declare that they have no conflicts of interest.
The effects of prone position ventilation in patients with acute respiratory distress syndrome 371

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