ORIGINAL ARTICLE. Abstract

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Potential for Lung Recruitment Estimated by the

Recruitment-to-In

ﬂ

ation Ratio in Acute Respiratory

Distress Syndrome

A Clinical Trial

Lu Chen1,2,3, Lorenzo Del Sorbo3,4, Domenico L. Grieco5, Detajin Junhasavasdikul6, Nuttapol Rittayamai7, Ibrahim Soliman8, Michael C. Sklar3, Michela Rauseo9, Niall D. Ferguson3,4, Eddy Fan3,4,

Jean-Christophe M. Richard10, and Laurent Brochard1,2,3*

1_{Keenan Research Centre and Li Ka Shing Institute, Department of Critical Care, St. Michael’s Hospital, Toronto, Ontario,}

Canada;2Interdepartmental Division of Critical Care Medicine, and3Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada;4_{Division of Respirology and Critical Care Medicine, Toronto General Hospital, Toronto, Ontario, Canada;}5_{Istituto di Anestesia e} Rianimazione, Universit `a Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy;6Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, and7Division of Respiratory Diseases and Tuberculosis, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand;8Critical Care Department, King Saud Medical City, Riyadh, Saudi Arabia;9Anestesia e Rianimazione, Ospedali Riuniti di Foggia, Foggia, Italy; and10Emergency Department, General Hospital of Annecy, Annecy, France ORCID ID: 0000-0002-7512-1865 (L.C.).

Abstract

Rationale:Response to positive end-expiratory pressure (PEEP) in acute respiratory distress syndrome depends on recruitability. We propose a bedside approach to estimate recruitability accounting for the presence of complete airway closure.

Objectives:To validate a single-breath method for measuring recruited volume and test whether it differentiates patients with different responses to PEEP.

Methods:Patients with acute respiratory distress syndrome were ventilated at 15 and 5 cm H2O of PEEP. Multiple

pressure–volume curves were compared with a single-breath

technique. Abruptly releasing PEEP (from 15 to 5 cm H2O) increases expired volume: the difference between this volume and the volume predicted by compliance at low PEEP (or above airway opening pressure) estimated the recruited volume by PEEP. This recruited volume divided by the effective pressure change gave the compliance of the recruited lung; the ratio of this compliance to the compliance at low PEEP gave the

recruitment-to-inﬂation ratio. Response to PEEP was compared

between high and low recruiters based on this ratio.

Measurements and Main Results:Forty-ﬁve patients were enrolled. Four patients had airway closure higher than high PEEP, and thus recruitment could not be assessed. In others, recruited volume measured by the experimental and the reference methods

were strongly correlated (R2= 0.798;P,0.0001) with small bias

(221 ml). The recruitment-to-inﬂation ratio (median, 0.5; range,

0–2.0) correlated with both oxygenation at low PEEP and the

oxygenation response; at PEEP 15, high recruiters had better

oxygenation (P= 0.004), whereas low recruiters experienced lower

systolic arterial pressure (P= 0.008).

Conclusions:A single-breath method quantiﬁes recruited volume.

The recruitment-to-inﬂation ratio might help to characterize lung

recruitability at the bedside.

Clinical trial registered with www.clinicaltrials.gov (NCT02457741).

Keywords:acute respiratory distress syndrome; artiﬁcial respiration; mechanical ventilators; positive-pressure respiration; respiratory mechanics

( Received in original form February 12, 2019; accepted in final form October 1, 2019 )

*L.B. is Deputy Editor ofAJRCCM. His participation complies with American Thoracic Society requirements for recusal from review and decisions for authored works.

Author Contributions: L.C., L.D.S., J.-C.M.R., and L.B. conceived the study. L.C., L.D.S., N.R., N.D.F., E.F., and L.B. participated in its design and coordination. L.C., L.D.S., D.L.G., D.J., N.R., I.S., M.C.S., and M.R. made substantial contributions to data acquisition. L.C. conducted the signal and statistical analysis. L.C. and L.B. drafted the manuscript. All authors helped to revise the draft of the manuscript. All authors read and approved the final manuscript.

Correspondence and requests for reprints should be addressed to Laurent Brochard, M.D., St. Michael’s Hospital in Toronto, Li Ka Shing Knowledge Institute, Keenan Research Centre, 209 Victoria Street, Room 408, Toronto, ON, M5B 1T8 Canada. E-mail: [email protected].

This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org. Am J Respir Crit Care Med Vol 201, Iss 2, pp 178–187, Jan 15, 2020

Originally Published in Press as DOI: 10.1164/rccm.201902-0334OC on October 2, 2019 Internet address: www.atsjournals.org

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Since theﬁrst description of the acute respiratory distress syndrome (ARDS), positive end-expiratory pressure (PEEP) has remained an essential component of its management (1). The rationale of using PEEP is to keep airways and alveoli open. The response to positive pressure, however, varies enormously among patients (2). Increasing PEEP may improve or worsen gas exchange (3, 4), depending on the corresponding reaeration of nonaerated

and poorly aerated lung tissue, also deﬁned

as lung recruitability (2, 5, 6), and alterations in intrapulmonary and intracardiac shunt (7, 8). Although improved oxygenation can be explained by lung recruitment (9, 10), the relationship between oxygenation and recruitment is often weak owing to the complex circulatory effects of PEEP (7, 8). Application of excessive PEEP in the absence of

recruitability can lead to lung overdistension, cardiac dysfunction, and a reduction in oxygen delivery to tissues (2, 11). In lowly recruitable lungs, higher PEEP may provide

only minimal beneﬁt or cause harm by

increasing strain (12). In highly recruitable lungs, higher PEEP may increase the size of the aerated lung and reduce alveolar strain, and also reduce the cyclic closing-reopening

of alveoli and small airways during tidal

breaths (“atelectrauma”) (13). Knowing

whether PEEP has an effect on lung recruitment is thus fundamental.

Until now, clinicians have had no reliable and easily accessible tool to assess lung recruitment at the bedside. Computed tomography (CT) has been used in research but is infeasible in clinical practice, not the least because of risks of transport (2, 5, 14). The measurements require repeated CT examinations at different pressures, the analysis is time-consuming, and also the

deﬁnition of lung recruitment by CT is

controversial (15, 16). Other morphological approaches, such as ultrasound and electrical impedance tomography, seem to

be promising but require speciﬁc

equipment and validation with other established methods. Alternatively, the

multiple pressure–volume (P–V) curves

technique is based on a“hysteresis-like”

behavior of the lung and has been proposed to assess recruitment. Although this technique does not require patient transport, it is still relatively complex owing

to the need for merging two or more P–V

curves starting from different lung volumes. Setting PEEP based on tidal compliance has been shown to be unreliable (17). Randomized clinical trials comparing different levels of PEEP did not determine

the potential for lung recruitment (18–21)

and patients having different responses to

PEEP could not be stratiﬁed or phenotyped

in subgroup analyses. The inconsistent results from these trials and the likelihood of heterogeneity of treatment effect raise an urgent need for developing a reliable and valid bedside tool to assess lung recruitability.

We propose to validate a simpliﬁed

single-breath method to quantitate lung recruitment at the bedside that does not require any specialized equipment. We propose the concept of the compliance of the recruited lung (Crec) as the recruited volume divided by the effective change in pressure accounting for patients with complete airway closure, as recently

described (22–24). We propose a new

approach to deﬁne lung recruitability by

measuring the ratio of the Crec to the

compliance of the“baby lung.”We

hypothesized that our new deﬁnition of

lung recruitability would reliably differentiate patients with different response to PEEP in terms of gas exchange, lung mechanics, and hemodynamics.

Methods

Design

This was a prospective clinical study (clinicaltrials.gov NCT02457741) conducted in two quaternary academic

ICUs at St. Michael’s Hospital and Toronto

General Hospital (Toronto, Canada), with approval by the relevant institutional research ethics boards. Informed consent was obtained from each patient or their legal substitute decision-maker before onset of any study procedures.

Patients

All mechanically ventilated patients in the ICUs were screened Monday to Friday.

Inclusion criteria were1) age older than

16 years,2) presence of moderate or severe

ARDS (PaO2/FIO2 <200 mm Hg) (25) and

within 10 days of onset,3) assist/control

mechanical ventilation with continuous

sedation, and4) an arterial line in place.

Exclusion criteria were1) undrained

pneumothorax or ongoing air leak,2)

hemodynamic instability (.30% increase

in vasopressors in the last 6 h or

norepinephrine.0.5mg/kg/min),3)

PaO2/FIO2,80 mm Hg, 4) severe or very

severe chronic obstructive pulmonary disease according to the Global Initiative for Chronic Obstructive Lung Disease

criteria (26), and5) clinically suspected

elevated intracranial pressure

(.18 mm Hg).

Measurements

During the study, all patients were ventilated with a dedicated ventilator (Engstrom Carestation; General Electric). Airway

pressure (Paw),ﬂow, carbon dioxide (CO2),

and oxygen concentrations were measured

byﬂowmeters (D-Lite; GE) integrated in

the ventilator. If an esophageal balloon catheter was already available (4),

esophageal pressure (Pes) was measured by connecting the catheter with the auxiliary pressure transducer on the ventilator and was validated by performing an occlusion

test (27). Pressure andﬂow transducers

were calibrated (error,4%) before the

measurements. Potential gas leak was carefully excluded before and after

connecting the ventilator (seeonline

supplement).

Changes in lung volume, such as VT and change in end-expiratory lung volume

between two PEEP levels (ΔEELV) were

At a Glance Commentary

Scientiﬁc Knowledge on the Subject: In acute respiratory distress syndrome, the effect of positive end-expiratory pressure (PEEP) depends on the amount of nonaerated and poorly aerated lung tissue that can be reopened or recruited. There is no simple accessible and reliable method to assess recruitability at the bedside.

What This Study Adds to the Field:

Using a drop in PEEP over a single-breath maneuver, one can measure the recruited volume over a given range of PEEP. Taking into account the possible presence of airway closure and, therefore, of the effective change in pressure permits one to calculate the compliance of the recruited lung; the latter is compared to the baby lung compliance using the

recruitment-to-inﬂation ratio, which helps to

differentiate recruiters and nonrecruiters.

(3)

measured with theﬂowmeter (i.e., the

integral ofﬂow); for example,ΔEELV

was measured by comparing the

difference in expiratory VTwhen reducing

PEEP from high PEEP (PEEPhigh) to low PEEP (PEEPlow) over a 9-second expiration

(seeSINGLE-BREATH EXPERIMENTAL METHOD).

Similarly, we measuredΔEELV when

reducing PEEPlowto zero end-expiratory

pressure. In addition, we measured the absolute end-expiratory lung volume using the nitrogen wash-out/in technique integrated on the ventilator (28).

An elastic P–V curve was obtained by

performing a low-ﬂow (5 L/min) inﬂation,

ensuring that the resistive pressure was negligible (29).

Assessment of Recruitment

The multiple P–V curve method: reference method.The multiple P–V curve was the reference method to assess lung

recruitment. This method wasﬁrst

proposed to interpret the hysteresis-like behavior of the respiratory system (30) and then used to detect lung recruitment (9, 31). The rationale is to detect a difference in lung volume for a given elastic pressure

between two P–V curves starting from two

PEEP levels. If the ventilated, open, lung units are the same (no recruitment) after a higher PEEP, the lung volume at a given elastic pressure should remain unchanged. If the higher PEEP applied for several minutes results in improved respiratory mechanics due to recruitment

(i.e., increased number of aerated lung

units), an upward volume shift on P–V

curves is observed, the difference between the two volumes at a given pressure indicating recruited volume.

We measured two elastic P–V curves

traced along the VTand starting from

PEEPhighand PEEPlow. We plotted these

two curves starting from different end-expiratory lung volumes on the same graph.

To do this, we measured theΔEELV

between PEEPhighand PEEPlow(Figures 1

and 2]) with a single prolonged expiration,

as explained above. Theﬁgures started from

zero end-expiratory pressure and its corresponding volume, the FRC. The

recruited volume (ΔVrec) was calculated as

the amount of upward shift in volume

between two P–V curves at a same pressure

(PEEPhigh).

Of note, to simplify the terminology and although we went down from PEEPhigh to PEEPlow, we do not use the term

“derecruitment”(9).

Complete airway closure: a confounder.ΔVrec assessed lung

recruitability over a certain range of PEEP.

We neededﬁrst to identify if complete

airway closure, a confounder for measurement of alveolar pressure, was present (22). During an interim analysis of this study, we found that 8 out of 30 patients had complete airway closure (22). Their lungs required an airway opening pressure (AOP) between 5 and 20 cm H2O to reopen airways before initiating lung

inﬂation. In such cases, the airways are not

communicating with the alveoli below the AOP, until the airways reopen. The real change in alveolar pressure can therefore be remarkably different from the change in Paw (32). When AOP was higher than

PEEP, we considered the AOP to be the nearest measurable alveolar pressure. Depending on AOP, the same change in alveolar pressure could not be applied to all patients. For assessing lung recruitment

reliably, we thus indexedΔVrec by the

effective pressure change.

Crec. We deﬁned the Crec as theΔVrec divided by the effective change in pressure

over which recruitment is assessed (ΔPrec):

Crec¼DVrec

DPrec:

In patients without complete airway closure

at PEEPlow,ΔPrec is the difference between

PEEPhighand PEEPlow:

Crec¼ DVrec

PEEPhigh2PEEPlow:

In patients with complete airway closure and an AOP greater than the PEEPlow,

ΔPrec is then the difference between

PEEPhighand AOP:

slope: circuit compliance

Vrec = 143 ml

Prec = 10 cmH2O

slope:  ”baby lung” compliance

0 5 10 15 20 25 30 35

Elastic Airway Pressure (cmH₂O) 0 100 200 300 400 500 600 700 800 900 1000

Lung Volume above FRC (ml)

Patient at PEEPhigh Patient at PEEPlow Blocked circuit at bench

slope: Crec = Vrec Prec

= 14 ml/cmH₂O

Figure 1.Measurement of the recruited volume (ΔVrec) and compliance of the recruited lung (Crec) using the reference method (multiple pressure–volume [P–V] curves) in a representative patient (#27) without complete airway closure. The blue line stands for elastic P–V curve of the patient ventilated at 5 cm H2O of positive end-expiratory pressure (PEEP), the green line stands

for P–V curve at 15 cm H2O of PEEP, and the red line stands for P–V curve of a blocked

circuit measured in a bench model. Elastic P–V curves were obtained by low-flow (5 L/min) inflation. The lung volume above FRC was obtained by measuring the change in lung volume when reducing PEEP from 15 to 5 cm H2O and from 5 to 0 cm H2O. At 8 cm H2O of PEEP,

the slope of the patient’s P–V curve was much higher than the blocked circuit’s P–V curve at the beginning of inflation, suggesting the absence of complete airway closure._ΔVrec was the volume difference between two P–V curves of the patient and the pressure over which

recruitment is assessed (_ΔPrec) was the difference between the two PEEP levels. Crec was then the quotient ofΔVrec andΔPrec; compliance of respiratory system at low PEEP was used as a surrogate for the compliance of the baby lung. Of note, PaO2/FIO2dropped by 4 mm Hg with PEEP

15 in this patient.

(4)

Crec¼ DVrec

PEEPhigh2AOP:

We explain this concept in Figures 1 and 2 using two representative patients without and with airway closure, respectively.

Crec is essentially an indexedΔVrec. This

denomination represents how much volume can be regained from the recruitable lung by each centimeter of water of pressure increment.

Crec allowed us to compareΔVrec measured

in patients with or without airway closure. Recruitment-to-inﬂation ratio. Conceptually, Crec can be integrated in a three-compartment model of the ARDS lung, with a nonrecruitable part, a recruitable part, and the baby lung. The term

“baby lung”is used to describe the lung

tissue that remains aerated at PEEPlowor at

FRC. A recruitable part refers to the lung tissue that can be recruited over a clinically

acceptable range of PEEP. An analogy of this model is three serially connected springs with different stiffness. By comparing Crec with the compliance of the baby lung, one might predict the likelihood of the distribution of volume

between the recruited lung (recruitment) and

the baby lung (inﬂation/hyperinﬂation). The

respiratory system compliance (Crs) at PEEPlow or above AOP (depending on the presence of

airway closure;see below) can be used as a

surrogate for the compliance of the baby lung. The ratio of Crec to the compliance of the baby

lung was called the recruitment-to-inﬂation

ratio (R/I ratio): R

I ratio¼

Crec

Crs at PEEPlowor above AOP

:

The higher the R/I ratio is, the higher the potential for lung recruitment is. For

example, an R/I ratio of 1.0 indicates that the likelihood of recruitment (volume distributed in the recruited lung) is the

same as inﬂation/hyperinﬂation (volume

distributed in the already aerated baby

lung). Note, however, that hyperinﬂation

can coexist with recruitment. Single-breath experimental

method. Our simpliﬁed method mainly requires a single-breath PEEP reduction. It has

a similar rationale as the multiple P–V curve

method but does not require complex ofﬂine

analysis and can be performed without

additional equipment. TheΔEELV is

measured by theﬂowmeter during a PEEP

reduction maneuver using the expired VT (Figure E2 in the online supplement). In

parallel, the predictedΔEELV in the absence

of PEEP-induced recruitment can be calculated under the assumption of a linear recoil process of the respiratory system without any change in aerated lung units. The

difference between the measuredΔEELV and

the predicted one is the recruitment caused or maintained by higher PEEP:

ΔVrec¼measured ΔEELV

2predicted ΔEELV:

In patients without airway closure, the

predictedΔEELV is the product of the Crs

at PEEPlowand the change in PEEP (4):

Predicted DEELV

¼ VT

ðPplat at PEEPlowÞ2PEEPlow

3 PEEPhigh2PEEPlow;

where Pplat is plateau pressure. In patients with airway closure, we measured the Crs

above AOP when lungs were“effectively”

ventilated:

Predicted DEELV

¼ VT

ðPplat at PEEPlowÞ2AOP 3 PEEPhigh2AOP

:

AOP can be identiﬁed by either a P–V

curve or by a pressure–time curve on the

ventilator at lowﬂow (seeFigure E4). Crec

can then be calculated as the quotient of

ΔVrec andΔPrec. We previously showed

the feasibility of assessingΔVrec (4). Finally,

the R/I ratio is calculated by normalizing the

Crec to the Crs at PEEPlowor above AOP.

We provide a Web page including videos to

0 5 8 AOP 25 30 35

Elastic Airway Pressure (cmH₂O) 0 100 200 300 400 500 600 700 800 900 1000

Lung Volume above FRC (ml)

18 slope: circuit

compliance

'V_rec = 191 ml

'Prec = 3.2 cmH2O slope: | baby lung

compliance slope: Crec =

'Vrec

'Prec

= 60 ml/cmH2O Patient at PEEPhigh

Patient at PEEPlow Blocked circuit at bench

Figure 2.Measurement of the recruited volume (_ΔVrec) and compliance of the recruited lung (Crec) using the reference method (multiple pressure–volume [P–V] curves) in a representative patient (#15) with complete airway closure. The blue line stands for elastic P–V curve of the patient ventilated at 8 cm H2O of positive end-expiratory pressure (PEEP), the green line stands

for P–V curve at 18 cm H2O of PEEP, and the red line stands for P–V curve of a blocked

circuit measured in a bench model. Elastic P–V curves were obtained by low-flow (5 L/min) inflation. The lung volume above FRC was obtained by measuring the change in lung volume when reducing PEEP from 18 to 8 cm H2O and from 8 to 0 cm H2O. Airway opening pressure

(AOP) was defined as the elastic airway pressure at which gas volume delivered to a patient became 4 ml greater than the volume compressed in an occluded circuit. The presence of AOP suggests complete airway closure because the initial part of the patient’s P–V curve (red line) completely overlapped with the blocked circuit’s P–V curve (22). In this case,ΔVrec was the volume difference between two P–V curves of the patient butΔPrec was the difference between higher PEEP and the AOP. Crec was then the quotient ofΔVrec byΔPrec; compliance of respiratory system above AOP was used as a surrogate for the compliance of the baby lung. Of note, in this patient, PaO2/FIO2increased by 16 mm Hg for 3 cm H2O increase

in pressure.

(5)

demonstrate the measurements in patients with or without airway closure, and to perform the calculations (https:// crec.coemv.ca).

Protocol

A detailed protocol and aﬂow chart

(seeFigure E1) are provided in the online

supplement. Brieﬂy, all patients were

passively ventilated (no spontaneous effort) in a standardized volume control mode (4). After a baseline assessment at a PEEP preset by clinicians, we used the following

steps:1) PEEPhigh, being 15 to 18 cm H2O;

2) PEEPlow, being 5 to 8 cm H2O; and3)

PEEPhigh. The difference between PEEPhigh

and PEEPlowwas 10 cm H2O but the exact

level of PEEP was adjusted slightly to allow better clinical tolerance. Each step lasted 30 minutes. At each step, the following order was used: arterial blood gases at 10 minutes after initiation of the PEEP level, end-expiratory and end-inspiratory occlusions,

absolute lung volume, and low-ﬂow

inﬂation. FIO2was planned to be kept

unchanged during the study but some

patients required increased FIO2at

PEEPlow(oxygen saturation as measured by

pulse oximetry [SpO2],88%). Because

PaO2/FIO2usually changes with FIO2(33),

SpO2at the same FIO2was also used for

comparisons.

Analysis

Signal analysis. We recorded real-time

ventilator signals (Paw,ﬂow, Pes, CO2,

and oxygen) by connecting the ventilator to a computer. Recordings were processed and analyzed automatically by a

customized program in MATLAB (Mathworks). Auto-PEEP was measured by performing end-expiratory hold. All other parameters of respiratory

mechanics, such as airway Pplat, and Pes at the end of inspiration (using a brief set inspiratory pause) and at the end-expiration, were measured by a 40-breath

ensemble averaging process (seeFigure

E3) (34, 35). This allowed cancelling out the cardiac artifacts, particularly in the Pes signal. The alveolar dead space fraction was calculated by

(PaCO22PETCO2)/PaCO2, where PETCO2

is the partial pressure of end-tidal CO2.

An average of PETCO2 during 40

consecutive breaths was used for each

patient. The AOP was identiﬁed as

previously described (22).

Endpoints and statistical analysis. The primary endpoints were the correlation and

agreement in measuringΔVrec between our

experimental method and the reference method. The correlation was assessed by simple linear regression. Bias and limits of agreement were compared by Bland-Altman analysis (36). We separated patients as low-recruiters and high-low-recruiters using the median of the R/I ratio measured by our experimental method and compared the response to PEEP within group by the paired

ttest. In particular, we compared tidal

respiratory system compliance and lung compliance to see how they would be changed by altering PEEP. Statistical analyses were conducted in R version 3.5.1 (37).

Results

Forty-ﬁve consecutively identiﬁed patients

were enrolled into this study. Their characteristics are reported in Table 1.

Airway Closure

One-third (n= 15) of the 45 patients

presented with complete airway closure with AOP ranging from 5 to 20 cm H2O

(seecharacteristics in Table 1). All

patients with airway closure displayed auto-PEEP during regular tidal breath at PEEPlow. The level of auto-PEEP was always lower than the AOP and could be

“eliminated”after prolonged expiration

(seeFigures E4 and E5). Pes was measured

in 13 of the 15 patients with airway closure (87%), allowing us to calculate transpulmonary pressure. At AOP,

transpulmonary pressure ranged from29

to 3 cm H2O. Four patients had AOP greater than PEEPhigh. In these four patients, no analysis of recruitability could

be performed because PEEPhighwas

insufﬁcient to keep the airways open at

end-expiration. We report their characteristics in Table 1. DVrec by Experimental versus Reference Method

In 41 patients with or without airway

closure,ΔVrec values measured with the

experimental and the reference methods

were strongly correlated (R2= 0.798;

P,0.0001) (Figure 3A). The bias was

221 ml with limits of agreement from

2119 to 76 ml (seeFigure 3B).

Crec to IndexDVrec and R/I Ratio to Normalize Crec

Figures 1 and 2 showΔVrec and Crec in

two patients. Both have a lowΔVrec (143

and 191 ml) compared with the median

level of the cohort (228 ml). One (see

Figure 2) had complete airway closure and the effective change in pressure was only about 3 cm H2O. The calculated Crec were remarkably different (14 vs. 60 ml/cm H2O), as well as the R/I ratio (0.37 vs. 1.67).

R/I Ratio to Deﬁne Lung Recruitability

The median value of the R/I ratio measured by our experimental method in all 41 analyzed patients was 0.5, ranging from 0 to 2.0. We dichotomized the R/I ratio by using

the median to deﬁne lung recruitability: high

recruiters were deﬁned by an R/I ratio

greater than or equal to 0.5 and low

recruiters were deﬁned by an R/I ratio less

than 0.5 (seegrouped characteristics in

Table E1). Average R/I ratios were

0.9060.39 in high recruiters and 0.3060.15

in low recruiters (seeTable E2 forΔVrec

and Crec). We compared their response to PEEP (Table 2). At PEEPhigh, only high

recruiters had a signiﬁcant oxygenation

response, whereas only low recruiters had a lower systolic arterial pressure. Tidal

Crs [VT/(Pplat2total PEEP)] and tidal

lung compliance (VT/lung driving

pressure) were higher at PEEPlowin

both groups.

Continuous R/I Ratio Correlates with Gas Exchange

At PEEPlow, the R/I ratio was inversely

correlated with PaO2/FIO2and correlated

with alveolar dead space fraction

(R2= 0.223 andR2= 0.164, respectively)

(Figures 4A and 4B). Four patients required

a higher FIO2at PEEPlow. All were high

recruiters with a median of R/I ratio of 1.04

(range, 0.87–1.15). Overall, the response to

PEEP in SpO2 and in alveolar dead space

both correlated with the R/I (R2= 0.315 and

R2

= 0.284, respectively) (seeFigures 4C and

4D). The changes in SpO2and alveolar dead

space were normalized by the effective change in pressure because the effective changes in alveolar pressure varied depending on AOP. The correlations

remained signiﬁcant when the changes in

SpO2and alveolar dead space were not

normalized (P= 0.009 andP= 0.014,

respectively).

(6)

Discussion

The mainﬁndings of this study are:

1) complete airway closure is not rare

in patients with moderate or severe ARDS, especially at PEEPlow, and can confound the assessment of respiratory

mechanics and lung recruitment;2)

a single-breath method provides a reliable and accurate estimation for

recruited volume in one maneuver;3)

the R/I ratio differentiates patients with different responses to PEEP;

and4) the R/I ratio correlates

with oxygenation and alveolar dead space, both at baseline and in response to PEEP.

Airway Closure

The prevalence of airway closure found in this cohort is consistent with recent reports (23, 38). This phenomenon, ignored until recently, needs to be assessed before any measurement of

respiratory mechanics and for deﬁning

lung recruitability as well because it

makes airway and alveolar pressure different. The concern that Paw could

poorly reﬂect alveolar pressure has

been raised previously (32) but was mostly considered for auto-PEEP. Auto-PEEP can coexist but differs from AOP, and we assumed that AOP was the closest estimate

of the alveolar pressure (seejustiﬁcations

in the online supplement). The classical auto-PEEP needs the presence of

expiratoryﬂow at end-expiration. When

the expiratory time is modiﬁed, AOP

remains constant, whereas auto-PEEP greatly varies. Auto-PEEP can be easily suppressed by prolonging the expiratory time without altering the level of AOP

at the next insufﬂation (seeFigures E5

and E6A from the same patient). The difference between and the coexistence of auto-PEEP and airway closure is

further discussed in the online supplement.

Deﬁnition of Recruitment

Different techniques and deﬁnitions

exist to assess recruitment (15, 39–42).

We discussed their important differences and associations in the online

supplement. The recruited volume measured by the hysteresis-like behavior methods include reversal of lung collapse and improved mechanical properties of an already partially

inﬂated lung. Such recruitment reduces

regional transpulmonary pressure; stress; and, probably to a certain extent, strain on the lung.

When assessing lung recruitability, we implicitly mean recruitability over a clinically acceptable range of PEEP (9,

40–42). Greater recruitment can be

achieved by higher and often excessive positive pressure (43, 44), but this might result in lung overdistension, right ventricular dilatation, severe hypotension, and potentially worse outcomes

(2, 12, 21).

Lung Recruitability and Gas Exchange

Our experimental method was strongly correlated with the reference method in

Table 1. Characteristics of the Patients

Characteristics Overall (N=45)

Non–Airway Closure (n=30)

Airway Closure (All,n=15)

Airway Closure and AOP>PEEPhigh

(n=4)

Sex, M,n(%) 36 (80.0) 24 (80.0) 12 (80.0) 3 (75.5)

Age, yr 58616 60617 55614 48611

Height, cm 171616 174613 165620 154631

Body mass index, kg/m2 33 (27–39) 31 (26–39) 36 (30–40) 35 (30–37)

COPD/asthma/smoking history,n(%) 15 (33.3) 9 (30.0) 6 (40.0) 0 (0.0)

APACHE II at admission 2569 2668 24610 23612

ICU stay before enrollment, d 4 (2–8) 4 (2–9) 6 (3–8) 9 (8–10)

Totalﬂuid balance from admission, L 7.3 (3.7–14.2) 7.3 (3.4–12.7) 8.9 (4.7–16.2) 15.6 (12.0–19.0)

SOFA at the day of enrollment 1363 1364 1363 1262

Clinical PEEP at enrollment, cm H2O 15 (12–16) 14 (12–16) 16 (15–17) 15 (14–16) PaO2/FIO2at clinical PEEP, mm Hg 145 (105–168) 151 (106–170) 120 (104–149) 115 (106–126)

_

VE,corr, L/min 12.2 (10.2–14.0) 12.3 (10.5–14.4) 12.0 (9.7–13.2) 11.0 (8.0–14.3) Estimated shunt at high PEEP*, % 39 (29–45) 36 (27–45) 41 (34–48) 41 (39–44) Risk factors of ARDS,n(%)

Pneumonia 15 (33.3) 10 (33.3) 5 (33.3) 2 (50.0) Aspiration 7 (15.6) 3 (10.0) 4 (26.7) 1 (25.0) Extrapulmonary sepsis 8 (17.8) 8 (26.7) 0 (0.0) 0 (0.0) Trauma 2 (4.4) 1 (3.3) 1 (6.6) 0 (0.0) Other 13 (28.9) 8 (26.7) 5 (33.3) 1 (25.0) Severity of ARDS,n(%) Moderate 36 (80.0) 25 (83.3) 11 (73.3) 3 (75.0) Severe 9 (20.0) 5 (16.7) 4 (26.7) 1 (25.0) ICU mortality,n(%) 18 (40.0) 14 (46.7) 4 (26.7) 1 (25.0)

Definition of abbreviations: AOP = airway opening pressure; APACHE II = Acute Physiology and Chronic Health Evaluation II score; ARDS = acute respiratory distress syndrome; COPD = chronic obstructive pulmonary disease; PEEP = positive end-expiratory pressure; SOFA = Sepsis-related Organ Failure Assessment;V_E,corr = expired volume per minute corrected by arterial carbon dioxide.

Dichotomous or nominal categorical variables are described as number (percentage); continuous variables are described as mean6SD or median (interquartile range), as appropriate.V_E,corr was calculated using the method described in Reference 25.

*Intrapulmonary shunt was estimated by using the PaO2when FIO2was set at 1.0, proposed by Reske and colleagues (48). We performed this

measurement at the end of the study at the high PEEP level to avoid alternation in FIO2during other measurements.

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measuringΔVrec in patients with and without airway closure. The biases were small and the limits of agreement acceptable. Airway closure was not previously considered, and not considering the effective pressure change to interpret

ΔVrec may be misleading. To assess

recruitment reliably, the determination of

AOP isﬁrst required, which is also essential

for any calculation of respiratory mechanics.

In two representative patients (see

Figures 1 and 2), they both would be

classiﬁed as“low recruiters”if one simply

used the median ofΔVrec to deﬁne lung

recruitability as described in the literature. Crec and R/I ratio are new concepts proposed in this study and thus no available threshold exists yet. We decided to use the median of R/I ratio by

the experimental method to deﬁne lung

Table 2. Response to Postive End-Expiratory Pressure in High Recruiters (Recruitment-to-Inﬂation Ratio>0.5) and Low Recruiters (Recruitment-to-Inﬂation Ratio,0.5)

High Recruiters (n=21*) Low Recruiters (n=20†)

High PEEP Low PEEP PValue High PEEP Low PEEP PValue

PEEP, cm H2O 1661 661 — 1661 661 —

Gas exchange

SpO2atﬁxed FIO2, % 9562 9364 0.002 9663 9564 0.340

FIO2where ABG was measured 0.6960.21 0.7360.21 0.115 0.5660.10 0.5660.10 0.330

PaO2/FIO2, mm Hg 132652 111651 0.004 181662 178660 0.853 VD,alv/VT, % 33610 35611 0.109 2169 2169 0.616 Mechanics Absolute EELV, ml 1,7656556 1,1036416 <0.001 1,9226773 1,3416593 <0.001 PL,end-exp, cm H2O 063 2763 <0.001 063 2764 <0.001 Elastance-derived PL,plat, cm H₂O 2464 1563 <0.001 2062 1263 <0.001 Tidal Crs, ml/cm H2O 2968 3568 <0.001 3269 39613 <0.001 Tidal CL, ml/cm H2O 38614 46613 <0.001 49614 62618 0.006 Tidal Ccw, ml/cm H2O 139660 151652 0.342 126662 154684 0.080 Hemodynamics

Heart rate, beats/min 88621 88621 0.693 87618 84618 0.882

SBP, mm Hg 123624 123614 0.178 118624 124622 0.008

DBP, mm Hg 60611 61611 0.762 60610 6168 0.492

Definition of abbreviations: ABG = arterial blood gas; DBP = diastolic blood pressure; EELV = end-expiratory lung volume; elastance-derived

PL,plat = elastance-derived transpulmonary plateau pressure, calculated using airway plateau pressure times the ratio of lung elastance to respiratory system elastance; PEEP = positive end-expiratory pressure; PL,end-exp = transpulmonary pressure at end-expiration; SBP = systolic blood pressure; SpO2= oxygen saturation as measured by pulse oximetry; tidal Ccw = chest wall compliance during tidal breath; tidal CL= lung compliance during tidal

breath; tidal Crs = respiratory system compliance during tidal breath; VD,alv/VT= alveolar dead space fraction.

Continuous variables are described as mean6SD and were compared using the pairedttest. Bold indicates significantPvalues.

*n= 19 (90% of high recruiters) for those parameters requiring esophageal pressure, such as transpulmonary pressures, tidal lung, and chest wall compliances.

†

n= 16 (80% of low recruiters) for those parameters requiring esophageal pressure. A

0 100 200 300 400

'Vrec by reference method (ml)

'

Vrec by experimental method (ml) P<0.0001, R2=0.798 400 0 300 100 200 B 0 100 200 300 400 Mean Mean + 2SD Mean− 2SD Diff in '

Vrec (exp − ref) (ml)

200

−200 100

−100 0

Average 'Vrec by two methods (ml)

Figure 3. (A) Linear regression and (B) Bland-Altman plot of recruited volume (ΔVrec) measured by the reference method and the experimental method (N= 41). Each dot represents one patient: red dots denote patients with airway closure and blue dots denote patients without airway closure. Of note, there is one slightly negativeΔVrec (239 ml) estimated by the experimental method (i.e., the measured change in end-expiratory lung volume is less than the predicted one). We did not arbitrarily set it as zero to avoid any artificial modification on the linear regression and to show that the value is positive in all remaining patients. exp = experimental; ref = reference.

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recruitability in this series and then

checked if this deﬁnition could

differentiate patients with different PEEP responses.

Our deﬁnition of recruitability was able

to separate patients having opposite oxygenation and hemodynamic responses to PEEP. At PEEPlow, there was a negative correlation between the R/I ratio and

PaO2/FIO2, and a positive correlation

between this ratio and the alveolar dead space. These are consistent with Gattinoni

and colleagues’(2) study, which showed that

the high recruiters had worse oxygenation and dead space. The correlations between

the normalized change in SpO₂at constant

FIO2and the R/I ratio, and between the

normalized change in alveolar dead space and the ratio, also support this concept. The correlation with gas exchange is expected to be weak owing to the circulatory effects

of PEEP and the complex shunt Q:

relationship. Chiumello and colleagues (45) have demonstrated that the oxygenation-based PEEP strategy was the only bedside method correlated with lung recruitability

deﬁned by CT scan and the correlation was

weak (R2= 0.29;P,0.0001). Oxygenation

or oxygenation response is thus an indirect indicator of lung recruitment, which can be individually misleading.

Changes in Tidal Compliance

It might be counterintuitive that the Crs and lung compliance during tidal breathing decreased at higher PEEP, especially in high recruiters. This can be explained by a greater tidal recruitment at lower PEEP (17, 46). A low tidal compliance at higher PEEP can be caused by less ongoing tidal recruitment

during the insufﬂation. On the other hand,

tidal hyperinﬂation is also possible, making

the interpretation of tidal compliance even more complicated. Moreover, the lung

tissue that is recruited by a higher PEEP level could have different mechanical properties than the baby lung, as already suggested from experimental work (47). The recruited lung improves lung aeration but may present different regional compliances. The Crec tissue could therefore be lower than that of the preexisting baby lung.

Clinical Implications

The single-breath method permits an

easy assessment ofΔVrec and does not

need additional complex analysis. Our

study is theﬁrst to distinguish patients

with and without airway closure in the assessment of lung recruitability. A

low-ﬂow inﬂation is mandatory to detect

airway closure (seeVideo E1) but a

simple pressure–time curve starting

from PEEP 5 is sufﬁcient to detect

and measure it (seeFigure E4). Overall,

D 0.0 0.5 1.0 1.5 2.0 −1.5 −1.0 −0.5 0.0 0.5

Normalized change in dead

space (%/cmH 2 O) P=0.0002, R2_=0.284 Recruitment−to−Inflation Ratio B 10 20 30 40 50 60

Alveolar dead space at low PEEP (%) 0.0 0.5 1.0 1.5 2.0 P=0.0050, R2_=0.164 Recruitment−to−Inflation Ratio C 0.0 0.5 1.0 1.5 2.0

Normalized change in SpO

2 (%/cmH 2 O) P<0.0001, R2_=0.315 −0.5 0.0 0.5 1.0 1.5 2.0 2.5 Recruitment−to−Inflation Ratio A 50 100 150 200 250 300 0.0 0.5 1.0 1.5 2.0 P=0.0011, R2_=0.223 Recruitment−to−Inflation Ratio

PaO2/FiO2 at low PEEP (mmHg)

Figure 4.(A) Linear regression between PaO2/FIO2at low positive end-expiratory pressure (PEEP) and the recruitment-to-inflation ratio. (B) Linear

regression between alveolar dead space fraction at low PEEP and the recruitment-to-inflation ratio. (C) Correlation between the recruitment-to-inflation ratio and the normalized change in oxygen saturation as measured by pulse oximetry (SpO2) at fixed FIO2. (D) Correlation between the

recruitment-to-inflation ratio and the normalized change in alveolar dead space. Changes in SpO2and alveolar dead space were normalized by the effective

change in pressure between the two PEEP levels. Each dot represents one patient: red dots denote patients with airway closure and blue dots denote patients without airway closure.

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our technique permits a direct assessment

of the“potential for recruitment.”

The R/I ratio, mathematically, reﬂects

the proportion of volume distributed into the recruited lung to that into the baby lung when PEEP is changed. For example, the lower the R/I ratio, the greater the volume that will be distributed into the already aerated baby lung and therefore the greater

the risk of hyperinﬂation. This will need

future validation and may need to be tested prospectively as a new method to titrate PEEP in ARDS. Indeed, the R/I ratio may provide an indicator for both the risk of

atelectrauma (setting PEEPlowin patients

with a high R/I ratio) and hyperinﬂation

(setting PEEPhighin patients with a low R/I

ratio), and can help in developing a strategy for preventing ventilator-induced lung injury. Increasing PEEP in high recruiters does

not guarantee the absence of hyperinﬂation.

It is reassuring to see a lack of negative hemodynamic effect in the high recruiters,

but any inﬂation of the baby lung can coexist

with hyperinﬂation.

Limitations

Our study involves careful measurements to assess lung recruitability and respiratory

mechanics. We calibratedﬂowmeters and

carefully excluded potential leaks. Ideally, this should also be recommended during

clinical practice in which less accurateﬂow

sensors may be used and unrecognized leaks could exist. Implementing our single-breath method into clinical practice may require a careful check on ventilators (e.g., pretest and leak-test).

Our experimental method assumes

a linear P–V relationship. To increase

the chance of keeping the measurements

within a linear P–V relationship, we

kept the recruitability test within 10 cm H2O of changes in pressure (e.g., from 15 to 5 cm H2O of PEEP) and kept the

inﬂated volume at 6 ml/kg predicted body

weight. In addition, we used the tidal Crs

above AOP [i.e., VT/(Pplat2AOP)] to

overcome the nonlinearity of the P–V curve

due to airway closure.

Aﬁxed order of measurements (see

online supplement) is a potential limitation. Also, lung recruitability was tested

over aﬁxed change in PEEP and the

lack of a wider range of PEEP is a limitation to completely assess the potential for recruitment. Four patients were excluded from analyses on lung recruitability.

Setting a PEEPhighgreater than AOP is

thus necessary if one wants to use the recruitability test. Other limitations in this study include the lack of biological or imaging correlations to support the

ﬁndings, and the lack of investigation on

the regional versus global distribution of recruitment or the effects of positioning.

Conclusions

Our single-breath method can accurately

measureΔVrec at the bedside and, to

avoid the confounding effect of airway closure, Crec needs to be calculated. By comparing Crec with the compliance of the baby lung, the R/I ratio

differentiates patients with, on average, different oxygenation and circulation responses to PEEP. This ratio correlates with both oxygenation and alveolar dead space, indicating further validity of this index. It provides clinicians a bedside tool to characterize lung recruitability over a clinical range of PEEP, which can be used to personalize

PEEP.n

Author disclosuresare available with the text of this article at www.atsjournals.org.

Acknowledgment:The authors thank Jianing Gu and Audery Kim for their essential work on data collection and organization. They also thank Gyan Sandhu, Jennifer Hodder, Thomas Piraino, and Orla Smith for their help with the research coordination. Thomas Piraino also dedicated his precious time to make the video for demonstration and the Web page for automating calculations. This study is a part of L.C.’s Ph.D. program, supervised by L.B. and the Program Advisory Committee: Drs. Brian Kavanagh, John Laffey, and Haibo Zhang. Brian Patrick Kavanagh passed away on June 15, 2019, and we will greatly miss his immense talent.

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