Effects of Prone Positioning on Lung Protection in … of prone positioning on lung protection in...

Effects of prone positioning on lung protection in patients with Acute Respiratory

Distress Syndrome

1Rodrigo A. Cornejo,

2Juan C. Díaz,

1Eduardo A. Tobar,

3Alejandro R. Bruhn,

2Cristobal A. Ramos,

1Roberto A. González,

1Claudia A. Repetto,

1Carlos M. Romero,

1Luis R. Gálvez,

1Osvaldo Llanos

1Daniel H. Arellano,

1Wilson R. Neira,

1Gonzalo A.

Díaz, 1Aníbal J. Zamorano,

2Gonzalo L. Pereira.

1. Unidad de Pacientes Críticos, Departamento de Medicina, Hospital Clínico

Universidad de Chile

2. Departamento de Radiología, Hospital Clínico Universidad de Chile

3. Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad

Católica de Chile

Corresponding author:

Rodrigo Cornejo MD, FACP. Associate Professor Universidad de Chile

Address: Santos Dumont 999, Independencia, Santiago, Chile

E-mail: [email protected] [email protected]

Phone: +562 9788519 Mobile: +569 88399280 FAX: +562 7771373

Author's contributions to the study

Authorship credit was based on: 1.1 Substantial contributions to conception and design:

RC; 1.2 Acquisition of data: RC, JD, CR, RG, CR, DA, WN, GD, AZ, GP; 1.3 Analysis

and interpretation of data: RC, ET, AB, CR, LG, OLl; 2 Drafting the article or revising

it critically for important intellectual content: RC, JD, ET, AB, CR, RG, CR, CR, LG,

OLl, DA, WN, GD, AZ, GP; 3 Final approval of the version to be published: RC, JD,

ET, AB, CR, RG, CR, CR, LG, OLl, DA, WN, GD, AZ, GP

Supported by FONDECYT Grant 11070156, Chile.

Running head: Prone decreases instability and hyperinflation

Subject Code: 4.08 Mechanical Ventilation: Physiology & Pathophysiology

Scientific Knowledge on the Subject

Experimental and clinical studies suggest that high levels of positive end-expiratory

pressure (PEEP) and prone positioning may favor protective mechanical ventilation in

patients with acute respiratory distress syndrome. High PEEP may induce lung

recruitment and decrease cyclic recruitment/derecruitment; however, increasing PEEP

may increase hyperinflation. Prone positioning could have synergistic effects with high

PEEP by providing a more uniform recruitment and better distribution of lung stress.

What This Study Adds to the Field

In ARDS ventilated patients, prone positioning is able to enhance the effects of high

PEEP in terms of lung recruitment and reduction of cyclic recruitment/derecruitment,

while it prevents the negative impact of PEEP on tidal-hyperinflation

of 45 AJRCCM Articles in Press. Published on 24-January-2013 as 10.1164/rccm.201207-1279OC

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ABSTRACT

Rationale: Positive end-expiratory pressure (PEEP) and prone positioning may induce

lung recruitment and affect alveolar dynamics in acute respiratory distress syndrome

(ARDS). However, whether there is any interdependence between the effects of PEEP

and prone positioning on these variables is unknown.

Objectives: To determine the effects of high PEEP and prone positioning on lung

recruitment, cyclic recruitment/derecruitment and tidal-hyperinflation, and how these

effects are influenced by lung recruitability.

Methods: Mechanically ventilated patients (VT 6 ml/kg IBW) underwent whole-lung

computed tomography (CT) during breath-holding sessions at airway pressures of 5, 15,

and 45-cmH2O, and Cine-CTs on a fixed thoracic transverse slice at PEEP 5 and 15-

cmH2O. CT-images were repeated in supine and prone. A recruitment maneuver at 45-

cmH2O was performed before each PEEP change. Lung recruitability was defined as the

difference in percentage of non-aerated tissue between 5 and 45-cmH2O. Cyclic

recruitment/derecruitment and tidal-hyperinflation were determined as tidal changes in

percentage of non-aerated and hyperinflated tissue, respectively

Main Results: 24 ARDS patients were included. Increasing PEEP from 5 to 15-cmH2O

decreased non-aerated tissue (501±201 to 322±132grs, p<0.001) and increased tidal-

hyperinflation (0.41±0.26 to 0.57±0.30%, p=0.004) in supine. Prone positioning further

decreased non-aerated tissue (322±132 to 290±141grs, p=0.028), and reduced tidal-

hyperinflation observed at PEEP 15 in supine (0.57±0.30 to 0.41±0.22%). Cyclic

recruitment/derecruitment only decreased when high PEEP and prone were applied

together (4.1±1.9 to 2.9±0.9%, p=0.003), particularly in patients with high lung

recruitability.


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Conclusions: Prone positioning enhances lung recruitment and decreases alveolar

instability and hyperinflation observed at high PEEP in ARDS patients.


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INTRODUCTION:

Ventilator-induced lung injury (VILI) seems to play an important role in patients with

acute respiratory distress syndrome (ARDS) (1). The mechanisms by which mechanical

ventilation exerts its detrimental effect are not completely understood, but it appears

that hyperinflation of lung units and shear forces generated during cyclic

recruitment/derecruitment of unstable alveoli exacerbate, or even initiate lung injury (1).

High levels of positive end-expiratory pressure (PEEP) and prone positioning have

demonstrated to reduce VILI in experimental models of acute lung injury (ALI) (2-5).

However, analysis of several large clinical trials in ALI/ARDS patients suggests that

these interventions may be effective only in patients with severe ARDS (6-9).

Interestingly, patients who seem to benefit from prone positioning are frequently

subjected to higher levels of PEEP. Thus, there may be a potential interaction between

the effects of both interventions on the mechanisms of VILI.

Regarding VILI, PEEP may have a protective effect by favoring lung recruitment and

by reducing cyclic recruitment/derecruitment (1, 6), but other mechanisms, such as

redistribution of extravascular lung water, redistribution of pulmonary blood flow to

better aerated units or preservation of surfactant activity may also be involved.

However, PEEP may induce hyperinflation and increase the risk of VILI, especially in

patients with low recruitability or lobar ARDS (10-12). In fact, some patients exhibit

tidal-hyperinflation despite using low tidal volume and moderate PEEP levels according

to the ARDS-Net strategy (13, 14).

Prone positioning may influence mechanisms of VILI. By recruiting non-aerated tissue,

and by reducing the vertical pleural pressure gradient, prone positioning may provide a


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more uniform distribution of transpulmonary pressures during mechanical ventilation

(15-21). Therefore, prone positioning may act synergistically with high PEEP to protect

the lungs from VILI by enhancing lung recruitment and decreasing the risk of PEEP-

induced hyperinflation.

The objectives of this study were to determine the combined effects of high PEEP and

prone positioning on lung recruitment, cyclic recruitment/derecruitment and tidal-

hyperinflation, as assessed by static and dynamic computed tomography (CT) in ARDS

patients. In addition, we sought to determine whether these responses are influenced by

lung recruitability (22). Some of the results of this study have been previously reported

in the form of abstracts (23, 24).


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METHODS

Study Population

Twenty-four patients were studied in a university hospital. Institutional and

governmental ethical committees granted their approval. Informed consent was obtained

from the patients’ next of kin. Adult patients fulfilling ARDS criteria (25) and on

mechanical ventilation for 24-72 hours, who required lung CT scan for clinical

proposes, were enrolled. Patients younger than 18-years, pregnant, or for whom prone

positioning was contraindicated (26), were excluded.

Study protocol

Patients were evaluated in the ICU and CT-room (Figure 1). During the protocol they

were kept under deep sedation and neuromuscular paralysis, and ventilated in volume-

controlled mode with tidal volume (VT) of 6 ml/kg ideal body weight (IBW).

ICU assessments

Patients were ventilated with PEEP 5 and 15-cmH2O, for 20 minutes each, in supine

and prone (PEEP changes and positioning were applied in random order). Respiratory

mechanics, oxygenation and hemodynamic parameters were assessed at the end of each

setting. Before PEEP changes, a recruitment maneuver at 45-cmH20 airway pressure

was performed to standardize volume history. Quasi-static compliance of the respiratory

system (“compliance”) was calculated by dividing tidal volume by the difference

between plateau pressure and total PEEP.

CT assessments


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i) Patients underwent whole-lung CT during breath-holding sessions at three different

airway pressures: 45-cmH20 end-inspiratory airway pressure, and 5 and 15-cmH20

PEEP. CT scanning (Somaton Sensation®, Siemens, Germany) was performed under

the following protocol: Voltage 120 kVp, Current 200 mA, mAs 100, Rotation time 0.5

seconds, matrix 512x512. Lung compartments were defined according to their CT

density in hyperinflated (-901 to -1000 Hounsfield Units “HU”), well-aerated (-501 to -

900 HU), poorly-aerated (-101 to –500 HU), and non-aerated tissue (-100 to +100 HU)

(22). Lung weight for each compartment was calculated as: (1-[mean CT-number/-

1000]) x volume, where CT-number represents lung density (HU). Percentage of

potentially recruitable lung was defined as ([non-aerated tissue at 5-cmH2O - non-

aerated tissue at 45-cmH2O]/total weight) and high lung recruitability as a percentage of

potentially recruitable lung >13.9% in supine, which corresponds to the median value

observed in 49 ARDS patients in a previous study of lung recruitability (22).

Contiguous axial sections 5-mm thick were reconstructed from the volumetric data

using high definition filter.

ii) A 2.4 mm-thick supra-diaphragmatic CT slice was selected for dynamic-CT.

Respiratory rate was transiently decreased to 10/min during dynamic-CT capture. Cine-

CTs of 12 seconds were performed under the following protocol: Voltage 100 kVp,

Current 80 mA, mAs 40; 0.5 seconds-24 images; matrix 512x512. Lung compartments

were expressed as percentage of tissue weight in the transverse slice. Cyclic

recruitment/derecruitment and tidal-hyperinflation were determined as tidal changes in

percentage of non-aerated and hyperinflated tissue respectively.


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CT-images were repeated in supine and prone, and the sequence of positions and PEEP

levels was applied in random order. Images were analyzed manually by radiologists

using Pulmo® (Siemens, Germany) and MALUNA® (University of Gottingen,

Germany) software. (See additional METHODS in the online supplement).

Statistical analysis

Results are expressed as mean (±SD) or median (interquartile range). The effect of

PEEP level and position was assessed by applying a two-way analysis of variance for

repeated measurements with Sidak’s post-hoc analysis. Comparisons between patients

with low and high lung recruitability were performed with Student's t-test or Wilcoxon-

Mann-Whitney test. SPSS 20.0 software (Chicago, USA) was used for statistical

calculations. Two-sided p<0.05 was considered statistically significant.


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RESULTS:

We included 24 patients (15 male, age 54±18 years) with ARDS. Fourteen patients

presented patchy, six diffuse, and four had lobar CT attenuations. Baseline

characteristics are presented in Table 1.

Prone positioning had no significant effect on gas exchange or compliance, when

compared to supine position at PEEP 5 (Table 2). However, it induced a decrease in

non-aerated tissue and an increase in well-aerated tissue (Table 3).

Increasing PEEP from 5 to 15-cmH2O increased oxygenation and compliance (Table

2), decreased non-aerated tissue, and increased well-aerated tissue (Table 3). However,

it markedly increased hyperinflation. These effects were observed both at supine and

prone positioning. Nevertheless, compared to supine, at prone positioning oxygenation

and compliance tended to be higher at PEEP 15, while non-aerated tissue and

hyperinflation were lower (Table 3 and Figure 2).

The effects of prone positioning and PEEP level on determinants of VILI, namely cyclic

recruitment/derecruitment and tidal-hyperinflation, are shown in Figure 3. Compared to

supine position at PEEP 5, neither prone positioning nor increasing PEEP had a

significant effect on cyclic recruitment/derecruitment. However, both strategies applied

together (prone positioning at PEEP 15) significantly decreased cyclic

recruitment/derecruitment (4.1±1.9 to 2.9±0.9%, p=0.003). Tidal hyperinflation was not

affected by prone positioning at PEEP 5, but it increased in response to PEEP 15 in

supine position (0.41±0.26 to 0.57±0.30%, p=0.004). Noteworthy, PEEP induced tidal-


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hyperinflation observed in supine was markedly decreased by prone positioning

(0.57±0.30 to 0.41±0.22%, p=0.01).

Potentially recruitable lung was 18.3±11% in supine and 14.9±8% in prone (p=0.036).

Figure 4 shows CT-images from representative patients obtained at airway pressures of

5 and 45-cmH20, in supine and prone positioning. According to our predefined

threshold, fourteen patients presented high lung recruitability.

Increasing PEEP to 15-cmH2O improved oxygenation and compliance only in patients

with high lung recruitability. This subgroup exhibited a 48% relative decrease in non-

aerated tissue when increasing PEEP, while this effect was only 22% in patients with

low lung recruitability (Table 4). In contrast to patients with high lung recruitability,

who showed no additional effect of prone positioning on non-aerated tissue at PEEP 15,

patients with low lung recruitability exhibited a significant decrease in non-aerated

tissue when subjected to prone positioning (20% additional relative decrease).

Cyclic recruitment/derecruitment was significantly lower at baseline in patients with

low lung recruitability (2.8±1.3% vs 5.1±1.8% in patients with high lung recruitability,

p=0.002), and neither increasing PEEP nor prone positioning had any significant effect

on this variable in the former subgroup (Figure 3). In contrast, cyclic

recruitment/derecruitment decreased in patients with high lung recruitability when

increasing PEEP to 15-cmH2O, and a significant additional effect was obtained after

prone positioning at the same PEEP level. Regarding tidal hyperinflation, patients with

low and high lung recruitability had similar values at baseline (0.39±0.25% versus


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0.45±0.24, p=0.568). The effect of high PEEP level on increasing tidal hyperinflation

was prevented by prone positioning in both subgroups of lung recruitability.


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DISCUSSION:

The main finding of the present study is that prone positioning enhances the effects of

high PEEP on lung recruitment and cyclic recruitment/derecruitment, while it prevents

the effects of high PEEP on tidal-hyperinflation. In addition, we found that lung

recruitability, assessed by CT at high airway pressures (22), does not predict lung

recruitment induced by prone positioning.

Effects of prone positioning

Although it has been reported that oxygenation improves after proning (7-9), we only

found a trend, which did not reach statistical significance. This may be explained by the

short sampling period. Data obtained from different series of prolonged prone

positioning in ARDS patients found that oxygenation improves several hours after

turning them into prone (26-30). Other possible explanation is that oxygenation

variation and lung recruitment may be dissociated, because “anatomical” lung

recruitment may differ from “functional” recruitment (22).

We observed that prone positioning was an effective recruitment strategy that, in

contrast to high PEEP, did not increase either hyperinflated tissue or plateau pressures.

This effect may be explained in part by the suppression of the compressive force of the

heart on dorsal lung regions obtained in prone (31, 32). Interestingly, patients with

predominantly basal consolidations, such as patients A and B from Figure 4, were those

who experienced higher recruitment induced by prone (data not shown), which is in line

with the findings of Galiatsu et al. (15). These observations may complement the


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concept by Rouby et al. about lung morphology as a predictor of the response to

increasing airway pressures (33), although this requires confirmation by further studies.

Noteworthy, in patients with low potentially recruitable lung prone positioning was able

to recruit a significant amount of non-aerated tissue, in addition to that already recruited

by high PEEP (Table 4). Therefore, the assessment of potentially recruitable lung

between 5 to 45 cmH2O may correctly predict lung recruitability to increasing airway

pressures, but not the response to prone. Thus, prone positioning may be considered in

severe ARDS patients, even if they have poor response to recruitment maneuvers in

supine position, as assessed by CT.

Effects of positive end-expiratory pressure

Although increasing PEEP from 5 to 15-cmH2O decreased non-aerated tissue and

increased oxygenation, it had no consistent effect on cyclic recruitment/derecruitment in

the overall population. However, in the subgroup of patients with higher lung

recruitability cyclic recruitment/derecruitment significantly decreased when increasing

PEEP to 15-cmH2O (Figure 3). Similar findings were reported in a recent study in

which cyclic recruitment/derecruitment was assessed indirectly with static CT images

(34).

As expected, in supine position high PEEP resulted in higher plateau pressures,

hyperinflated tissue, and tidal-hyperinflation. Hyperinflation is a morphologic

description of the lung areas that appear overfilled with gas in CT images, and it has

been associated to VILI (14). The low values of tidal-hyperinflation may seem

irrelevant (lower than 1%). However, fractional analysis of CT data was based on lung


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weight instead of volume, so the magnitude of real hyperinflated tissue may have been

systematically underestimated (35, 36). We used weight for fractional analysis in

dynamic-CT, because total volume is changing throughout the respiratory cycle. If the

results were expressed as percentage of volume, tidal-hyperinflation would have been

ten times greater (4-6%). PEEP-induced tidal-hyperinflation could be an important

drawback of high PEEP strategies (14), which may explain the lack of consistency in

results of recent clinical trials (6).

The fact that high PEEP levels could favor hyperinflation, without a consistent decrease

in cyclic recruitment/derecruitment, supports the notion that PEEP should be titrated

individually based not only on oxygen exchange, but considering other variables such as

lung recruitability.

Interaction of prone positioning with positive end-expiratory pressure

Few studies have addressed the issue of potential interactions between prone positioning

and PEEP (37, 38). In the present study, we found that prone positioning has a

synergistic effect with high PEEP in increasing respiratory system compliance, likely

because of an increase in well-aerated lung tissue. Previous studies have shown

contradictory data about the effects of prone positioning on respiratory system

compliance (39). These discrepancies may be due to differences in chest wall

compliance and lung recruitability of the study groups.

Prone positioning as well as high PEEP induced lung recruitment, resulting its

combination in the least amount of non-aerated tissue. Prone positioning also reinforced

the effect of high PEEP on cyclic recruitment/derecruitment, especially in patients with


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higher lung recruitability. This interaction did not seem to be a simple additive effect

because in the whole population, neither prone at low PEEP, nor high PEEP on supine,

decreased cyclic recruitment/derecruitment. Thus, prone positioning and high PEEP

together showed a synergistic effect on cyclic recruitment/derecruitment.

Prone positioning prevented the increase in hyperinflated tissue and in tidal-

hyperinflation induced by high PEEP levels in supine. Likewise, the increase in plateau

pressures induced by high PEEP was lower in prone. These findings may be related to

the effects of prone positioning in decreasing pleural pressure gradients and

homogenizing transpulmonary pressures in the ARDS lungs (15, 16, 18, 20). A regional

analysis of CT images, as performed by Grasso et al (40), would be a valuable

complement to the present study in order to assess the effects of prone positioning on

inhomogeneity and recruitment of individual lung regions.

The results of the present study suggest that a high PEEP strategy applied in prone

positioning, instead of supine, could have more benefitial and less adverse effects in

terms of respiratory mechanics and determinants of VILI. These findings are consistent

with the observations of metaanalysis, which indicate that patients with severe forms of

ARDS, who are usually ventilated with high levels of PEEP, may have a survival

benefit when treated in prone positioning (7-9).

Recruitment and cyclic recruitment/derecruitment: Methodological issues

Computed tomography has been the gold standard to assess lung recruitment, although

different definitions have been applied (10, 41). We chose the original definition of

recruitment based on the decrease of non-aerated tissue expressed in lung weight, as we


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have already used in the past (22, 42), and because it may be applied to analyze cyclic

recruitment/derecruitment in dynamic-CT. Other authors have defined recruitment as

the reaeration of the nonaerated and poorly aerated compartment (10). As we applied a

definition limited to the nonaerated compartment we acknowledge that our results for

PEEP-induced recruitment may appear as subestimated compared to studies which

include the poorly aerated compartment, as shown in a recent study using transthoracic

ultrasound (43).

The threshold of 13.9% used in the present study to classify patients as having high or

low lung recruitability in supine position was predefined arbitrarily based on the median

value of the subgroup of 49 ARDS patients from Gattinoni’s study. The original lung

recruitability threshold of Gattinoni’s study was 9%, which corresponded to the median

value of the whole ALI/ARDS population (68 patients). We are aware that by applying

a different threshold our subgroups of higher and lower lung recruitability are not

comparable to the subgroups defined in the original study of Gattinoni (22).

There is controversy whether cyclic recruitment/derecruitment, as assessed by CT,

corresponds really to intra-tidal opening and closing of lung units, or whether it

corresponds to flooded alveoli that become partially inflated during inspiration (44, 45).

Whatever the underlying phenomenon (cyclic mechanical deformation, or cyclic

recruitment/derecruitment of lung units), a reduction of instability produced by prone

positioning at high PEEP, as supported by our study, appears as theoretically positive in

terms of lung protection.


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Several approaches to assess cyclic phenomena have been used (46). A cine-CT

analysis of a fixed transverse slice allows dynamic imaging without mechanical

ventilation interruption. This method has been recently validated by experimental and

clinical studies to determine cyclic recruitment/derecruitment, tidal hyperinflation and

dynamic lung strain (18, 35, 36, 47, 48). The main limitations of this method are: a) the

more inhomogeneous the lung impairment, the less representative the slice may be (this

handicap is particularly true in patients with lobar pattern, but only four of our patients

had such pattern); b) it is impossible for dynamic-CT to scan exactly the same

anatomical structure in different settings, although the careful definition of anatomical

landmarks and fractional analysis used for dynamic-CT may avoid artifacts created by

the cranio-caudal motion, and c) the absolute amount of grams of lung tissue

undergoing either recruitment/derecruitment or tidal-hyperinflation cannot be

determined. The alternative approach of using static CT images of the whole lung after

end-expiratory and end-inspiratory breath holds (15, 16, 18-20, 22, 34) also has several

limitations, being the time dependency of the recruitment and derecruitment phenomena

the most important (49, 50). Despite limitations of both methods, a previous study

comparing them showed no major differences (48).

In conclusion, prone positioning induces lung recruitment even in patients classified as

having low potential for lung recruitment. In addition, prone positioning applied

together with high PEEP levels in ARDS patients act synergistically to decrease

mechanical determinants of VILI such as cyclic recruitment/derecruitment and tidal-

hyperinflation.

ACKNOWLEDGMENTS


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We thank Dr. Jerónimo Graf, Dr. Gastón Murias and Dr. Guillermo Bugedo for their

critical comments and suggestions for the manuscript, as well as the nurses, respiratory

therapists, medical staff and medical technologists from Hospital Clínico Universidad

de Chile for their precious support during the execution of the studies. We acknowledge

the role of Dr. Hector Gatica, for the statistical advice in the present article. We are

indebted to Daniel Castro, medical biophysics and radiation protection officer, who

assessed and adjusted the level of radiation per CT, allowing that the total dose per

patient did not exceed the equivalent of 1 coronary CT Angiography study.


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38. Walther SM, Johansson MJ, Flatebo T, Nicolaysen A, Nicolaysen G. Marked

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47. Doebrich M, Markstaller K, Karmrodt J, Kauczor HU, Eberle B, Weiler N,

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25

Table 1: Baseline Characteristics of the Study Population.

Patient Age Gender APACHE SOFA Lung MV Pre-study Etiology PaO2/FiO2 PEEP Compliance

(N) (y.o.) (M/F) infiltrates (hours) position ARDS (mmHg) (cmH2O) (ml/cmH2O)

1 25 F 18 5 diffuse 62 SP SS+Asp. P 195 12 30

2 67 F 14 7 patchy 28 SP SS 178 8 37

3 47 F 22 10 diffuse 32 SP SS 154 10 39

4 78 F 26 12 diffuse 64 SP HS 88 12 44

5 66 M 29 17 patchy 68 SP SS 190 8 40

6 80 M 27 13 lobar 66 SP BP 170 8 43

7 64 F 12 9 lobar 67 SP SS 186 6 28

8 83 M 20 8 patchy 26 SP BP 175 12 28

9 30 M 31 15 diffuse 38 PP Asp. P 101 14 32

10 66 M 23 8 diffuse 40 PP SS 155 12 32

11 41 F 18 8 patchy 69 SP SS 177 8 32

12 63 M 21 8 patchy 26 SP BP 183 8 35

13 39 M 16 8 patchy 33 PP H1N1 100 12 43

14 36 M 6 5 patchy 29 PP H1N1 97 14 43

15 52 F 18 9 diffuse 52 PP H1N1 78 13 29

16 45 M 10 9 patchy 36 PP BP 198 6 30

17 53 M 17 12 patchy 34 PP H1N1+BP 91 12 45

18 74 M 22 11 patchy 31 SP BP 185 7 38

19 17 F 22 12 patchy 24 SP SS 195 8 35

20 47 M 19 10 lobar 38 SP AP 193 10 35

21 65 M 19 10 lobar 44 SP AP 105 13 29

22 64 M 24 11 patchy 67 PP H1N1 112 12 25

23 51 F 19 8 patchy 69 SP SS 183 8 32

24 37 M 15 8 patchy 33 SP H1N1 86 11 43

mean±DS 53±18 20±6 10±3 45±17 149±44 10±3 35±6

APACHE: Acute Physiology and Chronic Health Evaluation II score; SOFA:

Sequential Organ Failure Assessment score; Lung infiltrates: type of lung infiltrates

according to computed tomography; MV: mechanical ventilation; SP: supine position;

PP: prone position; ARDS: acute respiratory distress syndrome; SS: severe sepsis; Asp.

P: aspirative pneumonia; HS: hemorrhagic shock; H1N1: Influenza H1N1; BP: bacterial

pneumonia; AP: acute pancreatitis; PaO2/FiO2: partial pressure of oxygen in arterial

blood/inspired oxygen fraction ratio; PEEP: end-expiratory pressure; Compliance:

Quasi-static compliance of respiratory system.


26

Table 2: Effects of PEEP levels and prone position on respiratory variables

SUPINE 5 SUPINE 15 PRONE 5 PRONE 15

PaO2:FiO2 [mmHg] 143 ± 58 235 ± 68* 170 ± 71 259 ± 63†

PaO2 [mmHg] 90 ± 34 155 ± 73* 114 ± 68 175 ± 79†

PaCO2 [mmHg] 47 ± 7 46 ± 8 46 ± 6 46 ± 7

Compliance [ml/cmH2O] 34 ± 6 40 ± 9* 35 ± 8 44 ± 10†‡

plateau pressure [cmH2O] 18 ± 3 27 ± 3* 18 ± 2 26 ± 2†‡

driving pressure [cmH2O] 13 ± 3 12 ± 3 13 ± 2 11 ± 2†‡

PaO2:FiO2: partial pressure of oxygen in arterial blood/inspired oxygen fraction ratio;

PEEP 5: Positive end-expiratory pressure 5 cmH2O; PEEP 15: Positive end-expiratory

pressure 15 cmH2O; PaCO2: partial pressure of carbon dioxide; Compliance:

compliance of the respiratory system; Driving pressure: difference between plateau

pressure and positive end-expiratory pressure; ∆: delta between parameters at PEEP 15

and PEEP 5 cmH2O

*P<0.05, between parameters at supine 5 and supine 15 cmH2O

†P<0.05, between parameters at prone 5 and prone 15 cmH2O

‡ P<0.05, between parameters at supine 15 and prone 15 cmH2O


27

Table 3: Effects of PEEP levels and prone position on lung compartment

distribution

SUPINE 5 SUPINE 15 PRONE 5 PRONE 15

total lung volume [ml] 2140 ± 643 3271 ± 900 2240 ± 614 3268 ± 821

total lung weight [g] 1201 ± 307 1282 ± 316 1216 ± 341 1261 ± 321

volume of non-aerated compartment [ml] 503 ± 201 324 ± 133* 431 ± 193‡ 291 ± 143†§

weight of non-aerated tissue [g] 501 ± 201 322 ± 132* 431 ± 192‡ 290 ± 141†§

volume of poorly-aerated compartment [ml] 623 ± 210 753 ± 314 657 ± 207 724 ± 289

weight of poorly-aerated tissue [g] 446 ± 149 517 ± 216 467 ± 157 497 ± 203

volume of well-aerated compartment [ml] 872 ± 406 1767 ± 661* 1027 ± 456‡ 1893 ± 617†

weight of well-aerated tissue [g] 254 ± 103 485 ± 148* 324 ± 148‡ 535 ± 152†

volume of hyperinflated compartment [ml] 144 ± 160 434 ± 318* 125 ± 105 362 ± 220†§

weight of hyperinflated tissue [g] 5,6 ± 6 19 ± 15* 4,4 ± 4 14 ± 8†




§ P<0.05, between parameters at supine 15 and prone 15 cmH2O


28

Table 4: Comparisons between Patients with High and Low Lung Recruitability

High Lung Recruitability Low Lung Recruitability

SUPINE PRONE SUPINE PRONE

PaO2/FiO2 at PEEP 5 [mmHg] 128±61 156±62 164±49 191±80

PaO2/FiO2 at PEEP 15 [mmHg] 230±69* 272±70*§ 244±70 241±49§

PaCO2 at PEEP 5 [mmHg] 49±7 47±7 45±6 45±6

PaCO2 at PEEP 15 [mmHg] 47±8 46±8 46±6 46±5

Compliance at 5 cmH2O [ml/cmH2O] 34±6 33±8 35±6 37±9

Compliance at 15 cmH2O [ml/cmH2O] 40±7* 45±11*§ 40±12 43±10§

Total lung weight at 5 cmH2O [ml] 1307 ± 240 1312 ± 292 1052 ± 334 1083 ± 376

NAT at 5 cmH2O [g] 576 [410-797] 448 [354-646]† 372 [305-472]# 325 [181-390]#

NAT at 15 cmH2O [g] 301 [230-400]* 296 [231-329]*§ 290 [250-334]* 215 [163-330]*‡§

PAT at 5 cmH2O [gr] 454 [360-546] 443 [411-561] 387 [281-431] 457 [275-561]

PAT at 15 cmH2O [gr] 486 [422-786] 459 [410-681] 378 [241-572] 407 [263-577]

WAT at 5 cmH2O [g] 208 [163-347] 255 [191-434]† 240 [210-351] 324 [239-343]†

WAT at 15 cmH2O [g] 468 [388-593]* 534 [458-630]*‡§ 461 [377-581]* 483 [336-593]*

HIT at 5 cmH2O [gr] 3.6 [2.1-5.4] 2.7 [2.0-4.9] 5.8 [4.7-6.9] 6.0 [4.8-7.9]#

HIT at 15 cmH2O [gr] 15 [7.3-18]* 12 [9.0-18]* 17 [14-26]* 15 [10-24]*


29

PaO2/FiO2: pressure of oxygen in arterial blood/inspired oxygen fraction ratio; PEEP 5:

Positive end-expiratory pressure 5 cmH2O; PEEP 15: Positive end-expiratory pressure

15 cmH2O; PaCO2: partial pressure of carbon dioxide; NAT: non-aerated tissue; PAT:

poorly- aerated tissue; WAT: well-aerated tissue; HIT hyperinflated tissue

*P<0.05, between parameters at 5 cmH2O (or PEEP 5) and 15 cmH2O (or PEEP 15)

†P<0.05, comparing parameters at 5 cmH2O (or PEEP 5) between supine and prone

‡ P<0.05, comparing parameters at 15 cmH2O (or PEEP 15) between supine and prone

§ P<0.05, between parameters at 5 cmH2O (or PEEP 5) in supine, and 15 cmH2O (or

PEEP 15) in prone

# P<0.05, comparing patients with high lung recruitability versus low lung recruitability

at the same level of PEEP and position


30

LEGENDS

Figure 1: Study Protocol

The protocol was performed in ICU and CT room. In ICU, patients were ventilated with

PEEP 5 and then 15 cmH2O, for 20 minutes each, starting with a recruitment maneuver

at 45 cmH2O before each period. Respiratory mechanics, oxygenation and

hemodynamic parameters were assessed at the end of each setting. Thereafter, in the

CT-room, patients underwent whole-lung CT during breath-holding sessions at

consecutive airway pressures of 5, 45, and 15 cmH20; afterwards, Cine-CTs were

performed on a fixed thoracic transverse slice at PEEP 5 and 15 cmH2O. CT-images

were repeated in supine and prone, and the sequence of positions and PEEP levels was

applied in random order.

Figure 2: Distribution of lung compartments expressed in weight and volume

Proportion of total lung weight (A) and volume (B) of each compartment classified as

non-aerated (NAT), poorly-aerated (PAT), well-aerated (WAT), and hyperinflated

(HIT) tissue, at end expiration with PEEP 5 and 15-cmH2O, assessed in supine (supine

5 and supine 15) and prone positioning (prone 5 and prone 15). Data is presented for the

overall population (left, n=24), for the subgroup of patients with high lung recruitability

(center, n=14) and for the subgroup of patients with low lung recruitability (right,

n=10).




§ P<0.05, between parameters at supine 15 and prone 15 cmH2O


31

Figure 3: Effects of PEEP and prone positioning on cyclic

Recruitment/Derecruitment (R/D) and Tidal-Hyperinflation (TH).

Cyclic Recruitment/Derecruitment (R/D) and Tidal-Hyperinflation (TH) with PEEP 5

and 15-cmH2O, assessed in supine (supine 5 and supine 15) and prone positioning

(prone 5 and prone 15). Data is presented for the overall population (A; n=24), for the

subgroup of patients with high lung recruitability (B; n=14) and for the subgroup of

patients with low lung recruitability (C; n=10).

*P<0.05, between parameters at supine 5 and prone 15 cmH2O

†P<0.05, between parameters at supine 5 and supine 15 cmH2O


Figure 4: Representative chest CT images obtained during breath-holding sessions.

Representative CT slices of the lungs obtained 2 cm above the diaphragm dome at

airway pressures of 5-cmH2O (left) and 45-cmH2O (right) from four patients in supine

(upper) and prone positioning (lower). The percentage of potentially recruitable lung

was defined as the proportion of non-aerated tissue in which aeration is restored when

increasing airway pressures from 5 to 45 cmH20. In patient A, percentage of potentially

recruitable lung was 24% in supine and 18% in prone; in patient B, 24% in supine and

15% in prone; in patient C, 14 % in supine and 21% in prone; and in patient C, 27% in

supine and 24% in prone.


Figure 1. Study Protocol

ICU CT ROOM

PEEP 5

PEEP 15

RM

1° CT 5 cmH2O 3° CT

15 cmH2O

5 min

2 cicles

(12 sec)

DYNAMIC CT

(MV unterrupted)

PEEP 25

2° CT 45 cmH2O

5 min

2 cicles

(12 sec)

RM

RM

RM

STATIC CT

(Holding sesions)

PEEP 5

PEEP 15

20 min.

20 min.

Assessment of:

-Respiratory

mechanics

-Oxygen

exchange

-Hemodynamic

parameters

ZEEP

RM 45 cmH2O

Assessment of:

-Respiratory

mechanics

-Oxygen

exchange

-Hemodynamic

parameters

RM


Fig 2

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

% HIT

% WAT

% PAT

% NAT

sup

ine

5

sup

ine

15

pro

ne

5

pron

e 1

5

Tis

sue W

eig

ht

(%

of

tota

l lu

ng w

eigh

)

sup

ine

5

sup

ine

15

pro

ne

5

pron

e 1

5

sup

ine

5

sup

ine

15

pro

ne

5

pron

e 1

5

Overall

population

Patients with high

lung recruitability

Patients with low

lung recruitability

∗∗∗∗ †

‡∗∗∗∗

∗∗∗∗†

‡

∗∗∗∗†

∗∗∗∗

†

‡∗∗∗∗

†∗∗∗∗

†

∗∗∗∗ †‡

∗∗∗∗ †

∗∗∗∗†

†

‡

∗∗∗∗

A

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

% HIT

% WAT

% PAT

% NAT

sup

ine

5

sup

ine

15

pro

ne

5

pron

e 1

5

Lu

ng c

om

partm

en

ts

(% o

f to

tal

lun

g v

olu

me)

sup

ine

5

sup

ine

15

pro

ne

5

pron

e 1

5

sup

ine

5

sup

ine

15

pro

ne

5

pron

e 1

5

Overall

population

Patients with high

lung recruitability

Patients with low

lung recruitability

∗∗∗∗ †‡

∗∗∗∗

†‡

∗∗∗∗†

∗∗∗∗ †∗∗∗∗ †

‡

†

∗∗∗∗†

‡

∗∗∗∗ †

∗∗∗∗†

∗∗∗∗†

∗∗∗∗†

B


Figure 3. Effects of PEEP and prone position on cyclic Recruitment/Derecruitment

(R/D) and Tidal-Hyperinflation (TH).

A.- Overall population (n = 24)

R/D (%)

B.- Patients with high lung recruitability (n = 14)

R/D (%)

C.- Patients with low lung recruitability (n = 10)

supine 5 supine 15 prone 5 prone 150

2

4

6

8

supine 5 supine 15 prone 5 prone 150.0

0.5

1.0

1.5

∗∗∗∗ ‡

†

† †

‡ ∗∗∗∗

‡

†

‡


Figure 4. Representative chest CT images obtained during breath-holding sessions

Patient A Patient B

5 cm H2O 45 cm H2O 5 cm H2O 45 cm H2O

Patient C Patient D

5 cm H2O 45 cm H2O 5 cm H2O 45 cm H2O


Effects of prone positioning on lung protection in patients with Acute Respiratory

Distress Syndrome

Rodrigo A. Cornejo, Juan C. Díaz, Eduardo A. Tobar, Alejandro R. Bruhn, Cristóbal A.

Ramos, Roberto A. González, Claudia A. Repetto, Carlos M. Romero, Luis R. Gálvez,

Osvaldo Llanos, Daniel H. Arellano, Wilson R. Neira, Gonzalo A. Díaz,

Aníbal J. Zamorano, Gonzalo L. Pereira.

ONLINE DATA SUPPLEMENT


Additional Methods

Study population

Twenty-four patients were studied at the Hospital Clínico Universidad de Chile. This

prospective single center study was approved by the institutional review board and the

ethical committee from CONYCIT (Comisión Nacional de Investigación Científica y

Tecnológica, Gobierno de Chile). Written informed consent was obtained from the next

of kin.

Inclusion criteria included patients with i) acute respiratory distress syndrome (ARDS),

i.e., ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen

(PaO2:FiO2) of less than 200 mmHg, the presence of bilateral pulmonary infiltrates on

the chest radiograph, and no clinical evidence of left atrial hypertension (defined by

pulmonary-capillary wedge pressure of 18 mmHg or less, if measured) (E1); ii) time on

mechanical ventilation more than 24 and less than 72 hours (early phase of ARDS); and,

iii) who required lung computed tomography (CT) scan for clinical proposes.

Exclusion criteria were an age below 18 years, pregnancy, haemodynamic instability,

evidence of barotrauma, history of chronic bronchitis, emphysema or pulmonary

fibrosis, and contraindications for prone positioning: intracranial hypertension,

abdominal compartment syndrome, severe septic shock, unstable spinal injury, recent

abdominal or chest surgery, open or flail chest, and inability to tolerate prone

positioning (eg, pelvic fracture, unstable long bone fracture) (E2).

Ventilatory setting

During the protocol, all patients were in volume-controlled mode, under deep sedation

(fentanyl and midazolam) and neuromuscular paralysis (rocuronium). Tidal volume

(VT) was kept constant at 6 ml/kg ideal body weight (IBW) during the protocol.

Fraction of inspired oxygen (FiO2) and respiratory rate were adjusted to maintain


oxygen saturation higher than 93%, and partial pressure of arterial carbon dioxide

(PaCO2) lower than 55 mmHg. Inspiration: expiration time ratio (I:E) was set at 1:2.

Respiratory flow and airway pressures were monitored continuously using a

pneumotachometer (Hans Rudolph 3700; Kansas City, MO), and data was collected on

a personal computer-based data acquisition system (Research Pneumotach System

3.07.08, Korr Medical Technologies Inc.).

Protocol

Protocol was performed in two areas: intensive care unit (ICU) and CT room. Before

the protocol, we verified that PEEP 15 cmH2O did not induce plateau pressure higher

than 30 cmH2O nor hemodynamic instability.

In the ICU, patients were evaluated at two levels of PEEP (5 and 15), first in one

position, and later in the other one (i.e. supine and prone positioning, in random order).

Respiratory mechanics (quasi-static compliance of the respiratory system and driving

pressure), oxygenation and hemodynamic parameters (central venous pressure, heart

rate, and mean arterial pressure) were measured at the end of each 20-minute period

with PEEP 5 and PEEP 15 cmH2O, both applied in random order also. Quasi-static

compliance of the respiratory system was calculated by dividing tidal volume by the

difference between plateau pressure and total PEEP (including auto-PEEP if present).

In the CT room patients were scanned in supine and prone positioning. The sequence of

positions and PEEP levels was applied randomly. Static and dynamic CT images were

acquired at each setting after 5-min of ventilations for stabilization. Immediately before

each stabilization period, a recruitment maneuver performed at 45 cmH2O (Pressure-

controlled mode with inspiratory pressure of 25 cmH2O over PEEP 20 cmH2O, I:E ratio

1:1, respiratory rate 15 breaths/min, for 1 minute) was applied to standardize volume

history (E3). Patients remained in the CT room at least 1 hour. The delay time between


ICU and CT assessments was less than two hours. Each patient was transported to the

CT room by the intensive care research team, composed by two intensivists, two nurses,

two respiratory therapists and one nursing assistant.

Static computed tomography

Lung scanning was performed from the apex to the diaphragm at an inspiratory-plateau

pressure of 45 cmH2O during an end-inspiratory pause (ranging from 15 to 20 seconds)

and thereafter at PEEP values of 5 and 15 cmH2O applied in a random sequence during

an end-expiratory pause (ranging from 15 to 20 seconds). Airway pressure was

monitored during the CT scan acquisition to ensure that the target pressures (end-

inspiratory 45 cmH2O and end-expiratory 5 and 15 cmH2O) were actually applied.

Multidetector CT scanning (Somaton Sensation®, Siemens Medical Systems Germany)

was performed as follows: tube voltage: 120 kVp, tube reference current: 200 mA,

mAs: 100, collimation: 24 x 1.2 mm, bed speed: 80.64 mm per second, rotation time:

0.5 sec, pitch: 1.4, matrix was 512x512, and pixel 0.55 mm. Contiguous axial sections

5-mm thick were reconstructed from the volumetric data using the B70 convolution

Kernel, a high definition filter (Very Sharp, Siemens®). All sections were recorded on

an optical disk for later computerized analysis

Dynamic computed tomography

During this phase respiratory rate was reduced to 10 breaths per minute. A 2.4 mm-

thick CT slice, 2 cm above the dome of the diaphragm was selected for the dynamic

protocol. Cine-CTs of 12 seconds was performed as follows: tube voltage: 100 kVp,

tube current: 80 mA, mAs: 40, collimation: 24 x 1.2 mm; 0.5 sec-24 images, 0.36

sec./rotation; matrix: 512x512, and pixel 0.55 mm.


CT-scan images analysis

CT-scan images analysis was performed by three radiologists (JD, CR and GP), blinded

to the patient data and airway pressure applied, using Pulmo® (Siemens Medical

Systems Germany), and MALUNA® (University of Gottingen, Germany) software for

CT images analysis.

In the case of static CT images, analysis was performed on each one of the contiguous

axial 5-mm thick sections, from the apex to the diaphragm. The outline of each CT-slice

was established visually and delineated manually, including all lung parenchima and

excluding bones, mediastinal organs, pleaural effusions and large vessels of lung hilum.

The respective volumes of gas and tissue were measured according to a previously

described analysis (E4-E7), based on the correlation between the CT attenuation and

physical density (E8).

We used the classic definition for lung compartments according to their different CT

thresholds, identifying the following lung compartments: hyperinflated (pixels with CT

numbers between -1.000 and -900 Hounsfield units [HU]), well-aerated (between -900

and -500 HU), poorly aerated (between -500 and -100 HU), nonaerated (between -100

and +100 HU) (E4-E7).

The weight of the corresponding lung tissue in each lung compartment was calculated

as follows:

Tissue weight [compartment] = Volume [compartment]*(1- (CT[compartment] /-1000))

E4

Where “Tissue weight [compartment]” corresponds to the lung tissue weight of the

compartment, “Volume [compartment]” its entire volume, and “CT [compartment]”

corresponds to the average CT number of the compartment, expressed in HU.

The percentage of potentially recruitable lung was defined as:


([non-aerated tissue at 5 cmH2O - non-aerated tissue at 45 cmH2O] / total weight) (E5)

Patients with high lung recruitability were defined as those with a percentage of

potentially recruitable lung higher than 13.9% in supine. For sample size determinations

we defined this recruitability threshold “a priori” based on the median value of

recruitability for the subgroup of ARDS patients from Gattinoni’s study (49 of the 68

patients) (E5). The original threshold of Gattinoni’s study was 9%, which corresponded

to the median value of the whole ALI/ARDS population (68 patients). We acknowledge

that by applying a different threshold, our subgroups of higher and lower lung

recruitability are not comparable to the subgroups defined in the original study of

Gattinoni.

In the case of dynamic CT, each 2.4 mm-thick cine-CT slice was analyzed. Each lung

was manually outlined drawing ROIs in each of the 24 images (frames) that

encompassed two respiratory cycles. The weight of each tissue compartment was

divided by the total lung weight contained in the transverse slice and expressed as

percentage. Each dynamic CT captured two respiratory cycles. In each respiratory cycle

within the 12 sec-dynamic CT, maximal (max), minimal (min), and cyclic variation (∆,

with ∆=max-min) of the four density compartments were registered and averaged to

obtain the corresponding values for each level of PEEP, in supine and prone

positioning. Anatomical landmarks were carefully defined to obtain CT slices at the

same level and comparable between different levels of PEEP and positions. Cine-CT

was performed at each ventilator setting at least after 5 minutes of stable airway

pressures and pulse oximetry readings. Cyclic recruitment/derecruitment was defined as

∆ non-aerated tissue, and tidal-hyperinflation was defined as ∆ hyperinflated tissue

measured (E7) at each PEEP level (5 and 15 cmH2O) while VT was held constant.


Given the potential for radiation exposure, a medical biophysics and radiation

protection officer (DC) was included in the study team to reduce the level of radiation

per CT. Finally, the total dose per patient did not exceed the equivalent of 1 coronary

CT Angiography study (1500 - 1800 mGy*cm).


References

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E2. Messerole E, Peine P, Wittkopp S, Marini JJ, and Albert RK. The Pragmatics of

Prone Positioning. Am J Respir Crit Care Med 2002; 165: 1359 - 1363

E3. Perchiazzi G, Rylander C, Vena A, Derosa S, Polieri D, Fiore T, Giuliani R,

Hedenstierna G. Lung regional stress and strain as a function of posture and ventilatory

mode. J Appl Physiol 2011; 110: 1374 - 1383.

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E5. Gattinoni, L., P. Caironi, M. Cressoni, D. Chiumello, V. M. Ranieri, M. Quintel, S.

Russo, N. Patroniti, R. Cornejo, and G. Bugedo. Lung recruitment in patients with

the acute respiratory distress syndrome. N.Engl.J.Med. 2006; 354: 1775 - 1786.

E6. Bugedo G, Bruhn A, Hernández G, Rojas G, Varela C, Tapia JC, Castillo L. Lung

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E7. Bruhn A, Bugedo D, Riquelme F, Varas J, Retamal J, Besa C, Cabrera C, Bugedo

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