Respcare.08280.Full

RESPIRATORY CARE Paper in Press. Published on January 19, 2021 as DOI: 10.4187/respcare.
08280
The Nature of Recruitment and De-Recruitment and Its Implications for

Management of ARDS
Richard H Kallet, Michael S Lipnick, and Gregory D Burns
Introduction
Brief Overview of Recruitment Maneuvers in ARDS
Physics and Physiology of Recruitment: Pressure and Time
Temporal Aspects of Lung Recruitment
Creep: Fast Versus Slow Pulmonary Compartments
Evidence Supporting Creep Phenomenon in ARDS
Selecting Inspiratory Time During Recruitment Maneuver
Mechanics of Recruitment and De-Recruitment
Distribution of TOP and Recruitment
Interpretive Limitations of Mechanistic Studies of Recruitment
Sponge Theory and Superimposed Hydrostatic Pressures
PEEP and De-Recruitment
Superimposed Pressure, De-Recruitment, and ARDS Severity
Elevated Intra-Abdominal Pressure in ARDS
Thoracoabdominal Mechanics, De-Recruitment, and Intra-Abdominal
Hypertension
Intra-Abdominal Hypertension and ARDS
Impact of PEEP on Volume Distribution in ARDS
Ambiguous and Perplexing Nature of Recruitment Phenomena
Radiologic Factors
Rheologic Factors
Histopathologic Factors
Direct Versus Indirect Injury and Injury Severity
Pplat and PEEP During LPV
Optimizing Oxygenation and Minimizing Risk of Atelectrauma
Implications of Slow Pulmonary Compartments
Hemodynamic Consequences of OLV
Potential Risk of Ventilator-Induced Lung Injury
Implications of the ART Study
Summary
Recruitment maneuvers in ARDS are used to improve oxygenation and lung mechanics by
applying high airway pressures to reopen collapsed or obstructed peripheral airways and alveoli.
In the early 1990s, recruitment maneuvers became a central feature of a variant form of lung-
protective ventilation known as open-lung ventilation. This strategy is based on the belief that
repetitive opening and closing of distal airspaces induces shear injury and therefore contributes
both to ventilator-induced lung injury and ARDS-associated mortality. However, the largest
multi-center randomized controlled trial of open-lung ventilation in moderate to severe ARDS
reported that recruitment maneuver plateau pressures of 50–60 cm H2O were associated with
significantly higher mortality compared to traditional lung-protective ventilation. Despite being
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RESPIRATORY CARE Paper in Press. Published on January 19, 2021 as DOI: 10.4187/respcare.08280
RECRUITMENT AND DE-RECRUITMENT IN ARDS MANAGEMENT
based on well conducted preclinical and clinical recruitment maneuver studies, the higher mor-
tality associated with the open-lung ventilation strategy requires re-examining the assumptions
and conclusions drawn from those previous studies. This narrative review examines the evidence
used to design recruitment maneuver strategies. We also review the radiologic, rheologic, and
histopathologic evidence regarding the nature of lung injury and the phenomena of recruitment
and de-recruitment as it informs our perceptions of recruitment potential in ARDS. Major lung-
protective ventilation clinical trial data and other clinical data are also examined to assess the
practical necessity of recruitment maneuvers in ARDS and whether a subset of cases might ben-
efit from pursuing recruitment maneuver therapy. Finally, a less a radical approach to recruit-
ment maneuvers is offered that might achieve the goals of recruitment maneuvers with less risk
of harm. Key words: acute respiratory distress syndrome; alveolar recruitment maneuver; intra-ab-
dominal pressure; plateau pressure; positive end-expiratory pressure; threshold opening pressure; venti-
lator-induced lung injury. [Respir Care 0;0(0):1–. © 0 Daedalus Enterprises]
Introduction Recruitment maneuvers as an adjunct to LPV were first

described in early preclinical studies of high-frequency os-
ARDS is characterized by altered permeability, pulmo- cillatory ventilation for acute lung injury.13 In the early
nary edema, and decreased gas volume (ie, functional resid- 1990s, recruitment maneuvers became a central feature of a
ual capacity [FRC]), which leads to low respiratory system LPV variant known as open-lung ventilation (OLV).14,15
compliance (CRS) and hypoxemia both from intrapulmonary One such technique described brief periods (eg, 10 min) of
shunting and ventilation-perfusion mismatching.1-3 Causes continuous mechanical ventilation at a peak airway pres-
of decreased FRC include underinflated, unstable alveoli sure of 55 cm H2O and PEEP of 16 cm H2O.14 Over the
vulnerable to collapse and atelectatic or de-recruited alveoli.4 intervening years, the mechanics, physiology, and efficacy
With the advent of low-tidal volume lung-protective ventila- of recruitment maneuvers were explored in numerous clini-
tion (LPV), alveolar de-recruitment is exacerbated despite cal and preclinical studies using a variety of strategies, as
moderate levels of PEEP (ie, 10 6 4 cm H2O).5 well as theoretical treatises.16
Recruitment maneuvers reverse lung collapse in ARDS by Some of these findings informed the largest multi-center
applying high airway pressures that overcome a range of randomized controlled trial of OLV, the Alveolar
threshold opening pressures (TOP). Re-opening collapsed or Recruitment for Acute Respiratory Distress Syndrome
obstructed peripheral airways and alveoli often improves oxy- Trial (ART),17 which enrolled > 1,000 subjects with mod-
genation and CRS, and may enhance alveolar fluid clear- erate to severe ARDS. Despite the data-driven protocol, the
ance.6-10 Historically, recruitment maneuvers consisted of ART group17 reported significantly higher mortality in the
inflations of 40 cm H2O sustained for 15 s (ie, the force OLV treatment arm compared to the control arm using
needed to achieve vital capacity in normal subjects) to reverse the National Institutes of Health ARDS Clinical Trials
intraoperative atelectasis and intrapulmonary shunting.11,12 Network (ARDSNet) lower-PEEP protocol.18 Particularly
vexing was that, despite significantly higher oxygenation
and CRS in subjects treated with OLV, the need for rescue
Mr Kallet and Mr Burns are affiliated with the Respiratory Care therapies was not different. This suggests that recruitment
Division, Department of Anesthesia and Perioperative Care, University maneuvers were largely ineffective in stabilizing FRC.
of California San Francisco at San Francisco General Hospital, San Higher mortality in the OLV arm confirmed one of the
Francisco, California. Dr Lipnick is affiliated with the Critical Care major findings of the original ARDSNet LPV trial:
Division, Department of Anesthesia and Perioperative Care, University
of California San Francisco at San Francisco General Hospital, San
improved oxygenation is not necessarily a valid signifier
Francisco, California. for meaningful outcomes.18
Some have interpreted the ART results to suggest aban-
Supplementary material related to this paper is available at http://www. doning recruitment maneuvers in treating ARDS,19
rcjournal.com.
whereas others20 suggest that ART-related methodologi-
Mr Burns presented a version of this paper at AARC Congress 2018, held cal issues still cloud its interpretation and have instead
December 4–7, 2018, in Las Vegas, Nevada. advocated for a thorough post hoc analysis (which, to our
Mr Kallet has disclosed a relationship with Nihon Kohden. The
knowledge, has not yet been published). Furthermore, the
remaining authors have disclosed no conflicts of interest. dramatic failure of a trial based upon numerous well-exe-
cuted physiologic studies behooves re-examining the na-
Correspondence: Richard H Kallet MS RRT FAARC. E-mail: ture of recruitment and de-recruitment as well as the
[email protected].
validity of inferences drawn from them. This narrative
DOI: 10.4187/respcare.08280 review re-examines the physiology and mechanics of
2 RESPIRATORY CARE
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Table 1. Different Recruitment Maneuver Strategies for the Treatment of Moderate to Severe ARDS
Maneuver Description
Sustained inflation CPAP is increased in 5 cm H2O steps every 5–10 s until a target recruitment pressure of 30–50 cm H2O is
achieved, and then sustained for 30–40 s. Deflation is achieved with the same stepwise decrement in airway
pressure until CPAP reaches baseline PEEP level (or a new targeted baseline).
The technique is based upon numerous clinical and preclinical studies.
Intermittent sighs 1–3 programmed, consecutive sigh breaths/min targeting a Pplat of 35–45 cm H2O.
The technique is based upon small clinical studies.
Intermittent PEEP/“fluctuating” Programmed, consecutive breaths in which PEEP is elevated from baseline to a higher level for either a specific
PEEP number of breaths/min (1–3), every few minutes or for an extended time period (6 min).
The technique is based on several preclinical studies without a targeted Pplat and a case report with a targeted Pplat
of 50 cm H2O in ARDS and abdominal compartment syndrome.
Brief recruitment maneuver on Volume or pressure control ventilation producing a Pplat of 45 cm H2O at PEEP of 15 cm H2O.
CMV The technique is based on several clinical studies on the physiologic effects of recruitment maneuver.
Prolonged recruitment Repeated periodic (2 min) PEEP elevation to 15 cm H2O upon which the Pplat was then increased step-wise from
maneuver 30, 35, and 40 cm H2O during successive 2-min maneuvers.
The technique is based on a preclinical study.
Slow moderate pressure recruit- PEEP is increased to 15 cm H2O for 15 min at a VT of 10 mL/kg (producing a Pplat of 27 cm H2O), and a 7-s
ment maneuver end-inspiratory pause is applied every 30 s.
Extended sigh Two approaches:
1) PEEP is increased to 10 cm H2O above LIP and Pplat < upper inflection point; if upper
inflection point is unidentifiable, then VT is adjusted to maintain Pplat # 35 cm H2O for 15 min.
2) PEEP is increased stepwise (5 cm H2O every 30 s) while VT is reduced in 2-mL/kg steps until reaching a PEEP
of 25 cm H2O and a VT of 2 mL/kg; this is followed by CPAP at 30 cm H2O and then a deflationary phase
pattern to return to baseline settings or to PEEP set 2 cm H2O above the lower inflection point.
The technique is based upon several small clinical studies.
RAMP recruitment maneuver Two approaches:
1) CPAP is increased 1 cm H2O/s to reach 40 cm H2O.
2) Peak inspiratory pressure and PEEP increased simultaneously 1–2 cm H2O every 2–3 min. Criteria to stop open
lung are based on reaching oxygenation goals at FIO2 # 0.25 (neonatal model).
Staircase recruitment maneuver Pressure control ventilation with a fixed driving pressure of 15 cm H2O starting at a PEEP of 25 cm H2O. This
strategy uses 2-min periods of alternating increasing and decreasing incremental PEEP steps that ramp up from
5 to 10 and to 15 cm H2O to achieve a Pplat of 60 cm H2O.
Post-recruitment maneuver PEEP is set according to a decremental trial with optimum PEEP defined as the level
just above the threshold when deterioration in either oxygenation or compliance is observed.
Several iterations of this general approach exist using different maximum levels of PEEP and Pplat (eg, 25 and 45–
50 cm H2O, respectively.
The technique is based upon multiple small and large clinical studies as well as preclinical studies.
Pplat ¼ plateau pressure

CMV ¼ continuous mechanical ventilation
VT ¼ tidal volume
recruitment and de-recruitment in ARDS, the results of amplitude-modulated ventilation) posited that following a
which might suggest when and how recruitment maneu- deep inflation the time constants for alveolar closure (of
vers might be incorporated more reasonably into clinical previously collapsed units) were substantially longer than
practice. the ventilatory cycle, so that recruitment achieved from a
single deep inflation (or short periods of elevated PEEP)
Brief Overview of Recruitment Maneuvers in ARDS could be sustained for a period of time afterwards.25,26 This
was hypothesized to allow alveolar stabilization without
Different approaches to recruitment maneuvers have requiring sustained levels of higher PEEP. Strategies based
T1,AQ:F been developed over the past 30 years (Table 1). One of the on this approach include intermittent sigh breaths27,28 and
earliest and most popular strategies has been the sustained intermittent or fluctuating PEEP.29-31 Another approach
inflation maneuver using CPAP.15,21-24 Another strategy (ie, is a less intense variation of the recruitment maneuver
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technique described by Lachmann,14 in which a brief (2 necrosis/sloughing and the rupturing of bronchiolar-alveolar
min) period of ventilation at a plateau pressure (Pplat) of 45 attachments that promotes distal airway instability.45,46 This
cm H2O and PEEP of 15 cm H2O is used.32 Other, more in turn increases airways resistance and expiratory flow limi-
extended iterations of this approach include the prolonged tation.2,47 Opening collapsed small airways in ARDS is a
recruitment maneuver33 and the slow moderate pressure dynamic process with a variable time course that depends
recruitment maneuver.34 Other prolonged approaches upon several factors, including airway radius, the fraction of
include the extended sigh maneuver35-37 and the RAMP functional alveoli providing regional airway stability (ie,
technique.38,39 These last 4 techniques most closely resem- axial wall traction or tethering), airway fluid characteristics
ble what is currently the most widely investigated technique (ie, surface tension and viscous forces, as well as film thick-
(and the primary focus of this review): the staircase recruit- ness) and the presence of biologically active surfactant.48-51
ment maneuver.40 The impact of these techniques will be As lining fluid surface tension increases, so too does the
discussed in varying detail throughout the course of this TOP to overcome it, with additional pressure required to
review in terms of what they reveal about the nature of overcome viscous forces. As airway fluid viscosity increases,
recruitment in ARDS. both yield pressure and time required to effect airway open-
Recruitment maneuver studies have categorized ARDS ing also increase, which may be particularly difficult to
subjects as either responders or nonresponders according achieve in peripheral and terminal airways.50
to the presence and magnitude of improvement in Regarding normal alveolar response to recruitment, an
oxygenation,26 resting lung volume,26 or reduction in experimental microimaging study of deflated healthy lungs
nonaerated lung tissue by computed tomography (CT) undergoing stepwise inflation from 0 to 35 cm H2O
scan, electrical impedance tomography, or ultrasonogra- observed an unusual U-shaped pattern, whereby mean alve-
phy.34,41 This implies recruitment maneuvers have a lim- olar size first increased, stabilized (at 25 cm H2O), and then
ited application under specific conditions not always decreased. The number of inflated alveoli decreased and
discernable at the bedside. ARDS associated with either then markedly increased again at pressures of 25–35 cm
direct epithelial injury (ie, pulmonary or primary ARDS) H2O, causing a doubling of lung volume size.52 In other
or indirect endothelial injury (ie, extrapulmonary or sec- words, at higher pressures, alveoli paradoxically become
ondary ARDS) both demonstrate improved oxygenation both smaller and more plentiful. It was hypothesized that
following the maneuver: those with indirect injury tended stretching the alveolar wall increases the diameter of the
to be more responsive both in the degree of recruitment pores of Kohn. This in turn thins the alveolar lining fluid
and oxygenation and of reductions in both lung resistance normally covering the pores, thus facilitating pressure
and elastance.21,27,42 Indirect injury typically coincides transmission between adjacent mother-daughter alveoli and
with early interstitial edema and higher chest wall elastic resulting in the latter’s recruitment.
forces,43,44 suggesting that recruitment maneuvers are These experimental conditions, however, diverge from
most effective when compressive and congestive atelecta- those encountered in ARDS such that similar behavior (if
sis are major factors versus alveolar flooding and tissue it in fact occurs during a recruitment maneuver) might
consolidation, which are more prominent in direct injury require a prolonged time period. In early ARDS altered
such as pneumonia (see below). permeability pulmonary edema fluid contains protein con-
centrations similar to plasma.53,54 Protein and fibrin-rich
Physics and Physiology of Recruitment: Pressure alveolar edema, along with oxygen radicals, inactivates
and Time surfactant, resulting in higher TOP for both distal airways
and alveoli.55
The focus of recruitment has been on alveolar re- Depending upon the severity of pulmonary capillary
inflation. This is a matter of conversational convenience leakage, when alveolar flooding involves the alveolar ducts,
that unintentionally results in an underappreciation of liquid bridge formation rises exponentially, particularly
the fact that distal airway injury and inflammation is a when FRC decreases and elastic recoil forces increase.56
prominent feature of ARDS and cannot be separated Bronchiolar epithelial damage and inflammation also are
from alveolar injury.45 What follows is a description of present and associated with ARDS severity,45,57 thereby
the interplay between distal airway and alveolar injury increasing the likelihood of inflammatory exudate obstruct-
as it relates to recruitment phenomena. In a later section ing both the airway lumen and the pores of Kohn. Because
describing the ambiguities surrounding recruitment fluid viscosity increases with increasing protein concentra-
maneuvers, a more in-depth description of associated tions,58 enhanced viscosity of airway and alveolar lining
tissue-related factors (ie, rheology and histopathology) fluid (along with other cellular debris accumulating in the
will be provided. peripheral airspaces) may prolong the time necessary to
Injury in distal airways (ie, airways with a diameter < 2 achieve maximum recruitment for any targeted Pplat during
mm) in ARDS is characterized by bronchiolar epithelial a recruitment maneuver.
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200
Inflation 1
180 Inflation 2
160
Creep volume (mL)

140
120
100
80
60
40
20
0
P-3 P-9 P-15 P-27 P-33
Tracheal pressure (cm H2O)
Fig. 1. Association between increasing driving pressures and alveolar stress adaptation in an animal model with normal chest mechanics. Data
from Reference 60.
The time necessary to reopen collapsed or obstructed fibers in smooth muscle, skeletal muscle, ligaments, and
small airways also depends upon the extent of menisci for- tendons) as well as abdominal organs.61
mation or plugs in sequentially collapsed or obstructed Under normal physiology, a 2-phase process consist-
airways, which may be amplified either by the presence of ing of fast and slow compartments was described in ani-
mucus in pneumonia-associated ARDS or in patients with mals.60 During a 10-s inflation hold, an initial rapid (2 s)
substantial smoking histories.48,50,59 In other words, the phase is followed by a slow (8 s) phase of continued
level of recruitment reported at a specific Pplat cited in tissue stretching; the latter was attributed primarily to al-
recruitment maneuver studies that were sustained for 1–2 veolar recruitment and reduced alveolar surface tension,
min is not definitive proof of maximum efficacy at that and to a lesser degree alterations in tissue viscoelastic
level of applied pressure (see below). properties.62 Stress adaptation was directly associated
with increasing driving pressures and reaching maxi-
Temporal Aspects of Lung Recruitment mum creep at 33 cm H2O. Increasing sustained inflation
intensity (ie, 120 s at 33 and 39 cm H2O) effected addi-
Two temporal aspects influence the effectiveness of tional stress adaptation (Fig. 1).60 F1,AQ:H
recruitment: (1) the duration of any particular recruitment Stress adaptation has been observed in anesthetized nor-
maneuver itself, and (2) the clinician-set inspiratory time mal subjects undergoing step inflations (similar to con-
chosen during the maneuver. Some of what is discussed structing a pressure-volume curve), stabilizing at 5–7 s at
below reflects this ambiguity as to precisely what occurs different volumes.61 Two thirds of stress adaptation was
when we observe recruitment. Some of this (but by no attributed to the lungs, with the chest wall exhibiting a
means all) has been clarified by the advent of lung paren- smaller, slower time course. This was ascribed to tissue
chymal microimaging in animal models, as discussed properties in both structures rather than alveolar recruit-
above. The following 2 sections provide a historical narra- ment and gas redistribution.61
tive on the development of our understanding as well as the
persistent ambiguity surrounding recruitment from the Evidence Supporting Creep Phenomenon in ARDS
1960s to the 1990s.
In ARDS, slow volume changes following a 10 cm H2O
Creep: Fast Versus Slow Pulmonary Compartments PEEP increase were first reported by Katz et al,4 whereby
67% of volume change occurred during the first breath and
The term “creep” was coined in the 1960s to describe the 90% by the fifth breath. The remaining increase occurred
progressive increase in volume over time when the lungs over 40 min and was attributed either to stress adaptation or
are subjected to “constant” pressure inflations.60,61 More alveolar recruitment. Similar to other findings,61 62% of the
broadly referred to as hysteresis or stress adaptation, creep changes were attributed to the lungs and 38% to the chest
expresses how tissue, once deformed, resists returning to its wall.4
former shape. This is attributed to adaptive surface tension Slowly distensible pulmonary compartments in severe
forces in the lungs and intrinsic viscoelastic properties of ARDS have been reported by others.63 Using a 5 cm H2O
both lung and chest wall tissue (eg, the presence of elastic PEEP increment, only 37% of subjects exhibited a slow

recruitment compartment, whereas 79% displayed a slow improvement in oxygenation typically occurred within 30–
de-recruitment compartment, consistent with other studies 60 min, yet it is not uncommon for improvements to
reporting delayed de-recruitment following step-decreases become apparent only after 6 h, with continuing improve-
in PEEP.26 The mean inflation time constant (t ) of the slow ments sometimes observed over 20–36 h.69 Prolonged
compartment was 9.4 6 7.3 s. As 95% equilibration occurs recruitment maneuver (ie, 6–14 h) reversing profound re-
at 3 t and 99% at 5 t ,64 recruitment (or stress adaptation) fractory hypoxemia has been reported anecdotally in
of slow pulmonary compartments would reach 95–99% ARDS complicated by abdominal compartment syndrome70
volume equilibration at mean times of 28–47 s with an and in pronounced obesity when combined with prone
upper 95% confidence limit of 43–72 s. As a reference, in position.69
normal subjects under general anesthesia, atelectasis rever- These findings underscore the considerable difference in
sal occurs at t of 2.6 s (95–99% reversal at 8–13 s).12 the time frames chosen to evaluate oxygenation response
In contrast, when oxygenation is the variable of interest, following a recruitment maneuver. Several recruitment ma-
the temporal impact on recruitment is exaggerated. Several neuver studies that will be discussed in the next section
studies examined the time required to establish steady state used 2-min equilibration periods between all or some of the
oxygenation in ARDS following a PEEP increase or after PEEP steps,17,40,71-73 which is consistent with classic physi-
initiating sigh breaths.27,65,66 Setting PEEP above the lower ologic studies.60,67,74 While the 2-min limit allows for stress
inflection point (PEEP 14 6 3 cm H2O), 90% of maximal adaptation, it also limits exposure to severe respiratory
improvement occurred at 20 6 19 min.65 However, in acidemia40 and potential cardiovascular instability from
another study, a 10 cm H2O PEEP increase produced alterations in right and left ventricular function.75-78 Most
no apparent oxygenation plateau (ie, PaO2 progressively importantly, these necessary time constraints imposed by
increased by 5–60 min).66 When augmenting LPV with very high pressure recruitment maneuver techniques limits
intermittent sigh breaths (Pplat 45 cm H2O; PEEP 14 cm our ability to fully understand the actual recruitment poten-
H2O) maximum improvements occurred at 30 min for both tial in ARDS.
PaO2 and end-expiratory lung volume.27
An intriguing aspect of recruitment are transient (pul-
monary) states observed in ARDS when the ventilatory Selecting Inspiratory Time During Recruitment
pattern was altered.67 Prolonged effects of recruitment Maneuver
were noted after various manipulations, including a sin-
gle PEEP step, a PEEP wave maneuver, and an undulat- The other temporal aspect is whether the inspiratory time
ing PEEP pattern. One hour following a PEEP increase per breath impacts the overall effectiveness of a recruitment
from 13 to 21 cm H2O, FRC rose 150% greater than that maneuver. This is likely dependent upon whether the clini-
predicted by CRS of the fast pulmonary compartment (ie, cian-set inspiratory time is appropriate for the inspiratory
baby lung).68 These results were similar to those reported time constant of individual patients. In general, ARDS sub-
by Katz et al.4 jects have an inspiratory t of 0.17–0.41 s,2 which (depend-
In the PEEP wave study, a brief repetitive cycle of incre- ing upon syndrome severity) would result in 95% and 99%
mental ascending and descending PEEP with a maximum estimated equilibration between airway and alveolar pres-
PEEP change of 10 cm H2O was repeated 5 times over sev- sures at 0.5–1.2 s and 0.9–2.1 s, respectively. However,
eral hours. When PEEP was returned to the initial settings, these estimates are based on assumptions of mono-expo-
PaO2 stabilized at 10 mm Hg above the previous baseline. nential functions of constant elastances and resistances
The phenomenon occurred with each successive PEEP throughout inspiration, and therefore neglect the impact of
wave so that, at the end of the experimental run, PaO2 was mechanical inhomogeneity in ARDS.79 Moreover, they
80 mm Hg higher than at the initial baseline.67 ignore the impact of continued gas mixing and redistribu-
The undulating PEEP study assessed the upper limit of tion (ie, pendelluft motion) and increased diffusion time on
time constant distributions using a PEEP cycle above and both oxygenation and dead-space ventilation by which
below a baseline PEEP of 14 cm H2O. PEEP was titrated in recruitment maneuver efficacy often is assessed.
increments of 7 cm H2O up to 29 cm H2O and down to 0 The range of inspiratory time reported in recruitment
cm H2O over 9 h. FRC measured 1 h following any PEEP maneuver studies have varied: 1.5 s (single PEEP step),63
change did not indicate a steady state in terms of recruit- 2.5 6 1.1 s (for sigh breaths), 27 2–3 s17,71,72,80 (for staircase
ment or de-recruitment. The overall impression was that recruitment maneuver studies or unspecified),40 whereas
“the length of individual time constants in ARDS may exist others used an end-inspiratory pause of 5–7 s.34,81 In a lung
in the region of hours.”67 lavage model of acute lung injury, in vivo microscopic
Slow, progressive lung recruitment frequently observed studies of subpleural alveoli during a recruitment maneuver
during prone position therapy supports the existence at 40 cm H2O found that, over a period of 40 s, 85% of
of slow pulmonary compartments in ARDS.69 Initial recruitment occurred by 2 s.82 These data support clinical
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PEEP
60 P drive
55
50
Paw (cm H2O) 45

40
35
30
25
20
15
10
5
0
RM Base Step 1 RM Base Step 2 RM Base Step 3 RM Base Step 4 RM Base
Fig. 2. Representation of a “staircase” recruitment maneuver inflation steps. P drive ¼ driving pressure (plateau pressure – PEEP); Paw ¼ airway
pressure; RM ¼ recruitment maneuver. Data from Reference 84.
use of inspiratory times of 2–3 s to maximize per-breath observations that TOP (Pplat being the clinical correlate)
recruitment potential during an recruitment maneuver. progressively increases from nondependent to dependent
lung between 20–60 cm H2O.40,85 A variation of this tech-
Mechanics of Recruitment and De-Recruitment nique was used in the ART trial but with stabilization peri-
ods of only 1 or 2 min between steps (Fig. 3).17
The majority of physiologic and clinical studies investi- When absorption atelectasis is pervasive, Pplat up to 70
gating recruitment in ARDS began in earnest in the first cm H2O is required,85 and pressures up to 80 cm H2O have
decade of this century and has produced the majority of our been used in ARDS associated with blunt chest trauma86 or
current knowledge base and clinical evidence. Because of abdominal compartment syndrome.70 To place these extra-
this, the narrative in this section mostly derives from select ordinary pressures into perspective, the first few post-natal
studies we believe constitute the most important findings breaths, which expand gasless, partially liquid-filled lungs
regarding recruitment maneuver and PEEP titration inform- (ie, 100 times more viscous than air), require TOP of 40 cm
ing current practice. H2O and peak transpulmonary pressures of 60–100 cm
In 2000, a variant of the original recruitment maneuver H2O to achieve full inflation.87,88 The unique circumstances
used in OLV,14 was introduced by Medoff et al,83 who in the moments following birth, in which completely
applied pressure control ventilation at a Pplat of 60 cm H2O deflated, non-injured lungs are initially expanded, are
and PEEP of 40 cm H2O for 2 min. In a subsequent study markedly different from that of heterogenous lung and dis-
comparing pressure control ventilation recruitment maneu- tal airway injury present in ARDS (in addition to pathologi-
vers to sustained inflation recruitment maneuvers (CPAP of cal alterations in chest wall mechanics). Nonetheless, the
45 cm H2O), a 2-min trial pressure control ventilation physics illustrates the circumstantial necessity that some-
recruitment maneuver (using a lower Pplat of 45 cm H2O times requires applying extraordinarily high transpulmo-
and inspiratory time of 2.5 s) produced substantially greater nary pressures to displace liquid and re-expand the lungs
oxygenation improvement (80% vs 19%).75 under extreme conditions.
Since the case report by Medoff et al,83 the pressure con-
trol ventilation recruitment maneuver has become a popular Distribution of TOP and Recruitment
approach and was the basis of the strategy used in the ART
trial.17 A generalized description of this approach is as fol- Small physiologic studies suggest varying degrees of
lows: an initial Pplat of 40 cm H2O is slowly increased in recruitment occur throughout the lung. An early CT study
increments of 5 cm H2O to levels of 50 or 60 cm H2O. The reported that potentially recruitable lung in moderate-to-
recruitment maneuver is done using 2–3 min stepwise esca- severe ARDS averaged 21 6 10% and required a Pplat of 45
lation/de-escalation of super-PEEP (ie, 20–45 cm H2O) cm H2O (whereas 25% remained collapsed).80 Also,
with a fixed driving pressure (ie, the difference between there may exist nodal points whereby full recruitment tran-
Pplat and PEEP) of 15 cm H2O (Fig. 2).40,84 This is based on sitions down the lungs from mid-to-dorsal regions when

60
PEEP
55 P drive
50
45
Paw (cm H2O)

40
35
30
25
20
15
10
5
0
RM Base Step 1 Step 2 RM Base
Fig. 3. Representation of a “staircase” recruitment maneuver inflation steps as used initially during the ART trial. P drive ¼ driving pressure
(plateau pressure – PEEP); Paw ¼ airway pressure; RM ¼ recruitment maneuver. Data from Reference 17.
Pplat of 30, 35, and 45 cm H2O are reached (with the least current definition of ARDS, a Pplat of 40 cm H2O and PEEP
amount of nonaerated tissue observed at 45 cm H2O).40,85 of 18 cm H2O were needed to return FRC to normal.4 Thus,
Subsequent studies have reaffirmed that TOP varies down in the context of refractory hypoxemia even at moderate to
the ventral-dorsal axis in ARDS. Upper zones had a negli- high levels of PEEP, a recruitment maneuver Pplat of at least
gible TOP of 0–4 cm H2O, whereas middle zones had a 40 cm H2O probably should be targeted.
TOP of 4–7 cm H2O and dorsal lung recruitment com- Furthermore, there is speculation that the recruitable
menced at 20 cm H2O.81 lung represents a penumbra of inflamed tissue surrounding
Similar to initial post-natal breaths, achieving a TOP in a core nidus of compartmentalized injury, constituting a
ARDS is not synonymous with full recruitment. Early mixture of collapsed or partially flooded air spaces.21,92 The
pressure-volume curve studies of ARDS interpreted the remaining 25% of nonaerated lung tissue, despite recruit-
lower inflection point as the TOP needed to recruit col- ing pressures of 45 cm H2O,80 likely signifies consolidated
lapsed peripheral airways and alveoli, but it was miscon- tissue, at least in those with normal body habitus (see
strued as the anchoring point for setting best PEEP.89 It below).
later became apparent that recruitment merely com-
menced in the upper lung zones at the lower inflection
point and continued throughout the inspiratory pressure- Interpretive Limitations of Mechanistic Studies of
volume limb.90,91 Likewise, despite TOPs of 4–7 cm Recruitment
H2O (middle) and 20 cm H2O (dorsal), maximum
recruitment in these regions occurs at 20–30 cm H2O and Interpreting these recruitment maneuver studies raises
45 cm H2O, respectively.81,85 several issues. First, confounding factors influence the
Other CT imaging studies reported that nonaerated lung potential effectiveness of recruitment maneuvers in ARDS.
tissue progressively decreased from 55% (at a baseline ven- These may include: (1) the inherently heterogenous nature
tilation with 10 cm H2O of PEEP) to 23% at a Pplat of 40 and unique spatial patterns of acute lung injury among
cm H2O and to 10% at a Pplat of 50 cm H2O.71 Improved individual patients; (2) apparent differences in the
recruitment was observed even when Pplat increased from a response to recruitment maneuver related either to initiat-
baseline of 28–32 cm H2O to 36–41 cm H2O at essentially ing pathways (direct vs indirect, interstitial vs alveolar
the same PEEP level.5 Most importantly (in light of the edema) or the severity of injury (eg, the degree of inflam-
ART study results), extending a recruitment maneuver to a mation and magnitude of edema formation); (3) timing of
Pplat of 60 cm H2O only reduced nonaerated tissue by 5%. recruitment maneuver relative to syndrome onset; (4) the
Full recruitment has been reported at Pplat of 40–51 cm ventilatory strategy used prior to initiating recruitment
H2O,72 whereas others have reported increasing percentages maneuver; (5) alterations in chest wall mechanics; and (6)
of subjects achieving full recruitment as Pplat increased: hemodynamic status (eg, various vasoactive drugs that
46% at 40 cm H2O, 60% at 45 cm H2O, and 70% at 50 might affect cardiac output and pulmonary blood flow
cm H2O).40 In the seminal study on the time course of FRC distribution).24,93-98 Moreover, mechanistic recruitment
improvement with PEEP in subjects with acute respiratory maneuver studies require highly complex, clinically
failure, the majority of whom likely would have met the impractical methodologies that limit the number of
8 RESPIRATORY CARE VOL NO

subjects who can be studied and thus limits the generaliz- removed through the lymphatic system and does not freely
ability of results to individual patients. redistribute through lung tissue.99
Second, variables chosen to signify full recruitment dif-
fered between studies, which introduces interpretative PEEP and De-Recruitment
ambiguity. Borges et al40 used PaO2 + PaCO2 > 400 mm Hg.
Adjusting for the range of mean PaCO2 across recruitment A recurring and relatively uniform finding in many of
maneuver steps (70–95 mm Hg) yields a corresponding the early recruitment maneuver studies was that, when
PaO2 of 300–330 mm Hg. Povoa et al72 used a PaO2 of ventilation was resumed at the previous PEEP level, ox-
250 mm Hg on an FIO2 of 1, and de Matos et al71 reported ygenation improvements dissipated rapidly over time
the Pplat at which nonaerated alveoli was minimal. Studies despite relatively high baseline PEEP ( 12–15 cm
by both Crotti et al85 and Caironi et al92 merely reported the H2O).22,23,27,101,102 In contrast, oxygenation improve-
degree of recruitment observed at a fixed Pplat of 45 cm ments could be sustained following recruitment maneu-
H2O as a surrogate measure of total lung capacity. ver when higher post-recruitment maneuver PEEP levels
Third, over the years, recruitment maneuver studies were maintained (eg, 6–7 cm H2O above baseline).21
have utilized different measurement techniques that have Acute lung injury models also reported that oxygenation
influenced both the results and their interpretation.32 after a recruitment maneuver was PEEP-dependent, with
Recruitment inferred from chest mechanics (eg, change in the highest sustained improvement occurring at PEEP of
end-expiratory lung volume measured during construction 16 cm H2O (vs 12 or 8 cm H2O).77 That the sustained
of pressure-volume curves or after step changes in PEEP) improvement was independent of recruitment maneuver
reflects increased aeration of partially and fully inflated methodology suggests recruitment and de-recruitment
alveoli, as well as recruitment of previously collapsed or occur through different mechanisms.
noncommunicating alveoli. In this review, we have focused When pleural pressure exceeds alveolar pressure at end-
on CT-based studies. Although ambiguities exist with this expiration, de-recruitment occurs over time irrespective of
technique, it nonetheless provides a high degree of differen- previous volume history.73 In ARDS, de-recruitment is a
tiation between non-, poorly and well-inflated alveoli (see continuous process that becomes prominent at PEEP < 15
below). As would be anticipated, recruitment inferred from cm H2O.85 De-recruitment appears to cease in the upper
chest mechanics analysis estimate much greater recruitment and hilar lung zones at PEEP of 10 cm H2O, whereas it con-
than those based on CT analysis.32 tinues in dorsal regions, reaching a maximum collapse rate
Taken together, these potential confounding variables at 5 cm H2O.85 De-recruitment modeling suggests the speed
(ie. relatively small numbers of study subjects, variations of collapse also increases as PEEP decreases.59 Similarly, a
in both technique and primary endpoints) limit the general- decremental PEEP study noted that pleural pressure
izability of recruitment maneuver study results to individual exceeded alveolar pressure once PEEP decreased below
patients, let alone navigating the contentious discourse 9 6 5 cm H2O, whereas in some subjects de-recruitment
regarding their interpretation. occurred at PEEP < 20 cm H2O.73
These findings suggest 3 potential PEEP targets that
Sponge Theory and Superimposed Hydrostatic might reduce de-recruitment during the acute phase of
Pressures ARDS: (1) minimum PEEP of 10–12 cm H2O, (2) a general
target of 16 cm H2O, and (3) $ 20 cm H2O in very severe
Setting aside common clinically induced causes (eg, cir- cases, particularly those with reduced chest wall compli-
cuit disconnection, endotracheal suctioning), lung de- ance. This is similar to the better PEEP strategy proposed
recruitment in ARDS is thought to be caused largely by by Gattinoni and colleagues.103
super-imposed hydrostatic pressure of overlying edematous
lung tissue and mediastinal structures, as well as increased Superimposed Pressure, De-Recruitment, and ARDS
weight of the chest wall (eg, thoracic anasarca, ascites).94 Severity
This is based upon the sponge theory posited to explain
rapid redistribution of lung densities on CT scans from dor- The largest and perhaps most comprehensive CT
sal to ventral regions during placement in prone position.76 study reported the maximum range of ventral-dorsal
Two facts support the notion that this represents a shift in superimposed hydrostatic pressure was 6–18 cm H2O.94
gravitational forces applied to the lungs. First, overall lung Interestingly, the mean hydrostatic pressure was similar
density was unchanged, suggesting lung tissue mass (ie, between Berlin classifications of mild, moderate, and
edema, blood, cellular content or debris) had remained sta- severe ARDS (12 6 3, 12 6 2, 13 6 1 cm H2O, respec-
ble.99 Second, although pulmonary edema clearance in tively, P ¼ .053). Factoring in PEEP required to counter
ARDS is severely impaired (6%/h),100 edema fluid is both superimposed hydrostatic pressure and chest wall
RESPIRATORY CARE
VOL NO 9
elastance yielded PEEP estimates of 16 6 8, 16 6 5, and as displacement of resting lung and chest wall tissues,
18 6 5 cm H2O, respectively (P ¼ .48). including the abdominal contents.109
A particularly interesting finding was that PEEP require- During quiet breathing with normal body habitus, inert-
ments did not differ between those characterized as having ance accounts for < 5% of driving pressure.113 In morbid
low or high recruitment potential and based on the observa- obesity, inertance is 4-fold higher, and up to 68% can be
tion that maximum superimposed hydrostatic pressure accounted for by chest wall tissue.109 Although its rele-
between the 2 groups differed by only 1–2 cm H2O. Thus, vance to ARDS is unknown, it is notable that, in morbidly
neither superimposed hydrostatic pressure nor chest wall obese subjects, the driving pressure required to overcome
elastance correlated appreciably with recruitment potential. inertance alone during maximal ventilation maneuvers
This implies that superimposed hydrostatic pressure reaches 40 cm H2O.109 In a case of ARDS and abdominal
enters the calculus of setting PEEP to preserve lung stabil- compartment syndrome, a similar driving pressure (Pplat 80
ity following recruitment rather than causing recruitment. cm H2O and PEEP 45–50 cm H2O) was required to
These observations led the authors to dissuade clinicians increase PaO2 from 23 to 350 mm Hg when surgical decom-
from reflexively treating low recruitability (ie, lobar pression could not be attempted.70
ARDS) with PEEP levels of 15 cm H2O simply to pre-
vent shear injury in “a few grams of lung tissue,” given the Intra-Abdominal Hypertension and ARDS
greater risk of hemodynamic compromise and regional
overdistention in middle and ventral lung zones.94 Intra-abdominal hypertension is common in severe
ARDS108 and is particularly prevalent in extrapulmonary
cases.43 It occurs in pulmonary ARDS complicated by mor-
Elevated Intra-Abdominal Pressure in ARDS
bid obesity (ie, mass loading), where IAP is 12–19 cm
H2O,114 as well as other conditions such as ascites from ab-
The ventral-dorsal pleural pressure gradient in the supine
dominal sepsis, pancreatitis, or hepatic failure.115,116 In acute
position determines resting alveolar size and largely reflects
lung injury models, IAP of 20 cm H2O greatly exacerbated
gravitational forces imposed by the abdomen, which is a
pulmonary edema formation and increased intrapulmonary
more dense, fluid-like compartment with a volume twice
shunting.117,118 Mean IAP of 22 cm H2O43,116,119 and end-
that of an air-filled thorax.104,105 Normal intra-abdominal
expiratory esophageal pressures of 20 cm H2O have been
pressure (IAP) is 5–7 mm Hg (7–10 cm H2O), whereas
reported in cases of severe ARDS.120
intra-abdominal hypertension is defined as IAP > 12 mm
IAP is particularly relevant in treating refractory hypoxe-
Hg (16 cm H2O) with 20–60% pressure transmission to the
mia. A preclinical study reported that, at IAP of 24–35 cm
thorax.106 Therefore, severe hypoxemia coinciding with
H2O, high PEEP (ie, 15 cm H2O) was equally ineffective as
intra-abdominal hypertension is a compelling indication for
low to moderate PEEP (ie, 5–12 cm H2O) in improving
OLV.
FRC and PaO2 =FIO2 .121 This led to a follow-up study of
IAP-matching PEEP in acute lung injury with intra-abdom-
Thoracoabdominal Mechanics, De-Recruitment, and inal hypertension (ie, 16–25 cm H2O). Higher levels of Pplat
Intra-Abdominal Hypertension and PEEP used in the pressure control ventilation recruit-
ment maneuver strategies described above were needed to
Elevated IAP displaces the diaphragm cephalad into the improve FRC and oxygenation (Fig. 4).117
thorax and stiffens the abdominal portion of the chest wall, Adding half of the measured IAP to the recruitment ma-
such that pleural pressure becomes more positive. This is neuver pressure targets has been suggested.106 For example,
particularly acute in the dorsal-caudal regions in the supine a recruitment maneuver of 45 cm H2O92 applied to IAP rep-
position, causing reduced lung and chest wall compliance, resenting conditions of intra-abdominal hypertension (16
increased tissue and airways resistance, and compressive cm H2O), average IAP in reported in ARDS (22 cm H2O)
atelectasis.107-109 Under these conditions, alveolar de-recruit- or severe abdominal compartment syndrome ($ 50 cm
ment from tissue compression (vs alveolar consolidation) is H2O)110,122 would require adjusting Pplat upward to 53, 56,
more likely the primary cause of refractory hypoxemia, and 70 cm H2O, respectively.
hence a recruitment maneuver is more likely to be effective. Attempting a recruitment maneuver in a patient with
Abdominal compartment syndrome (IAP > 25 mm Hg; intra-abdominal hypertension requires assessing overall
> 34 cm H2O)110 is associated with substantial nonaerated risk/benefit ratio. Elevated pleural and intra-abdominal
and poorly aerated lung tissue (23% and 18%, respec- pressures impede hemodynamic function and lymphatic
tively).111 At these extraordinary pressures, respiratory drainage and therefore carries the risk of worsening both
system inertance, normally considered negligible, may pulmonary edema and intra-abdominal hypertension as
become significant and therefore would increase TOP.112 well as risking hemodynamic collapse.123 In the context of
Inertance refers to the acceleration of gas molecules as well abdominal compartment syndrome, it should probably be
10 RESPIRATORY CARE
VOL NO
Paw (cm H2O) and Elastance (cm H2O/L)

PEEP
Pplat
60 Ecw
50
40
30
20
10
0
25 25 25 30 30 30
Intra-abdominal pressure (cm H2O)
Fig. 4. Relationship between PEEP, plateau pressure (Pplat) and chest wall elastance (Ecw) at increasing levels of intra-abdominal pressure in an
animal model of acute lung injury. Data from Reference 118.
considered only when surgical decompression carries an Table 2. Interpretation of Lung Function Based on Computed
even greater risk. Tomography Imaging
Radiologic Quantification,
Impact of PEEP on Volume Distribution in ARDS Used to Signify
Hounsfield Units
+1,000 Bone
Finally, regardless of Pplat or PEEP, gas distribution in
0 Tissue (defined as 50% tissue, 50% air)
ARDS steadily decreases down the ventral-dorsal axis with
1,000 Air
an upper-to-lower lung volume distribution ratio of 2.2:1 at 1,000 to 900 Hyperinflated tissue
ambient end-expiratory pressure. At PEEP of 20 cm H2O 900 to 500 Normally aerated tissue
ventral-dorsal gas distribution was essentially equivalent 500 to 100 Poorly aerated tissue
(1.1:1).81 For the dorsal regions (ie, those having the great- 100 to +100 Non-aerated tissue
est impact on gas exchange) this volume redistribution
translated into increased end-expiratory lung volumes from
10% to 25% and increased end-inspiratory lung volumes in ARDS, inferred by the lungs ability to attenuate x-
from 15% to 35%. These findings were supported by an rays.125 The radiologic definition of consolidation is mark-
electrical impedance tomography study of OLV wherein edly increased lung attenuation obscuring pulmonary ves-
ventral/dorsal tidal volume ratio decreased from 2.01 6 sels caused by atelectasis or alveolar filling, whereas in
0.36 to 1.19 6 0.10 (P < .01).124 pathology the term specifically refers to the latter.126
Attenuation is measured by the Hounsfield linear density
Ambiguous and Perplexing Nature of Recruitment scale that assigns a numeric value (Hounsfield units [HU])
Phenomena differentiating between bone (+1,000 HU), water (0 HU)
and air (–1,000 HU).127 Values between these 3 points are
In ARDS, improvements in radiologic imaging, gas used to convey various states of pulmonary tissue, with val-
exchange, and lung mechanics during and following ues between 100 HU and +100 HU considered to repre-
recruitment maneuver represent complex, histopathologic sent collapsed tissue (Table 2).12,81,94,128
responses of injured lungs and chest wall forces to applied From these interpretations, pulmonary gas-tissue ratios
pressure, and thus are open to interpretation. This section are calculated and used to infer the response to recruitment
describes some of the vagaries that limit our interpretation maneuver and PEEP. Yet, the designation of lung “tissue”
of the efficacy of recruitment maneuver. also includes extravascular fluid and blood.127 Thus, CT
imaging represents “the quantity of air being introduced
Radiologic Factors into a diseased lung,” hence the statement, “one pixel is not
an alveolus.”115 Lung CT imaging interpretation relies
CT scans are the gold standard for evaluating topo- upon an unprovable assumption of homogenous alveolar
graphic distribution of aerated and nonaerated lung tissue filling in condensed lung tissue, whereas in reality it likely

includes already aerated alveoli.56,115 In addition, estimating thickness of airway edema, and overcoming strain energy
the reduction in nonaerated tissue is dependent upon the in collapsed small airways (see below).48-50,56,139,141
number of CT sections sampled (compared to whole lung Even sponge model proponents acknowledge that com-
scans). For example, a single juxta-diaphragmatic section pression atelectasis likely represents a mixture of alveolar
may result in either over- or underestimation of recruit- and small airway collapse.81 What remains undisputed is
ment, whereas adding samples of apical and hilar regions that specific and reproducible ranges of airway pressures
tends to overestimate recruitment.129 transmitted to the lung parenchyma are required to improve
In spite of the strong association found between radiologic regional aeration and gas exchange in ARDS, and that the
assessment of alveolar recruitment and oxygenation,40,130 a recruitment of collapsed or obstructed airways and alveoli
complex interaction of other factors contributes to improved invariably involves epithelial cell deformation and there-
oxygenation (eg, increased ventilation-perfusion match- fore likely causes shear injury139,140 and exacerbates base-
ing,131 decreased cardiac output with redistribution of pulmo- line airway epithelial injury associated with ARDS.45
nary perfusion,132 reduced edema formation,133 and its Greater injury is thought to occur with reopening collapsed
redistribution to the perivascular spaces56,134). Skeptics claim versus obstructed airways.140
radiologic evidence supporting lung recruitment are “infer-
ences about alveolar micromechanics from measurements
Histopathologic Factors
made on a scale several orders of magnitude greater than
that of the structures of interest.”135 The volume element of a
Ambiguity surrounding the effectiveness and appropriate-
CT image (ie, the voxel) is 22.6 mm3,32,127 whereas a
ness of recruitment maneuvers partly depends upon whether
single alveolus is 0.12 mm3.136 Thus, a single voxel may
atelectasis (ie, degassed alveoli), intra-alveolar edema (ie,
represent a tissue section consisting of 15 discrete alveoli.
flooded alveolar units and peripheral airways), or interstitial
The importance of this limitation becomes apparent in
edema is the predominant lesion causing refractory hypoxe-
lung microimaging of gas dynamics within alveolar clus-
mia, as well as the intensity of edema.98 Historically the
ters. Animal models of acute lung injury observed pro-
most prominent autopsy findings in early ARDS included
nounced pendelluft motion between adjacent alveoli (some
some combination of interstitial and alveolar edema or hem-
slowly inflating during expiration, some deflating during
orrhage and hyaline membranes,142-152 along with a substan-
inspiration), as well as paradoxically simultaneous recruit-
tial subset reporting atelectasis.144,145,147,149,153 In what
ment and de-recruitment, while still others either synchro-
eventually would be called ARDS, the term congestive ate-
nously inflate and deflate or appear stunned (ie, remaining
lectasis was used to describe “diffuse non-obstructive col-
motionless at a constant volume).137,138 This localized inter-
lapse of pulmonary alveoli and intense interstitial edema
alveolar asynchrony and instability results from mechanical
and pulmonary capillary congestion,”147 leading to exces-
interdependency between neighboring alveoli and increases
sive surface tension forces causing collapse.148 More
with the severity of injury.138 Although CT imaging studies
recently, this has been redefined as inflammatory (ie, con-
provide invaluable information on the nature of recruitment
gestive) atelectasis versus compression atelectasis.154
and de-recruitment, they are clinically impractical for rou-
These characteristics defined diffuse alveolar damage,
tine use; in addition, there remains assumptive ambiguity
the histopathologic hallmark of ARDS.142 During the first
and therefore a risk of over-interpretation.
week of ARDS confirmed with diffuse alveolar damage,
intra-alveolar edema tends to be highest (90% of cases) but
Rheologic Factors remains prevalent during subsequent weeks (74% of
cases).155 Only 50% of ARDS cases now present with
During expiration, distal airway de-recruitment occurs as diffuse alveolar damage,156 its decrease coinciding with the
increasing surface tension causes liquid bridges to reform, emergence of LPV.157 ARDS without diffuse alveolar dam-
drawing airway and alveolar walls together.56,139 An in vivo age has been associated primarily associated with pneumo-
study of acute lung injury confirmed the presence of liquid nia. This is characterized less by intense interstitial edema
menisci forming dense bridges across small peripheral air- and alveolar neutrophil infiltration localized in the terminal
ways.138 Therefore, the perception of alveolar recruitment bronchioles.156,158
in acutely injured lungs may be explained as the breaking A study that matched PEEP responsiveness to lung bi-
of foam bridges and displacement of pulmonary edema opsy and autopsy samples reported that subjects exhibiting
fluid, resulting in increased alveolar ventilation.56,135,140 minimal oxygenation response had complete alveolar fill-
Thus, other factors determine the force required to re-open ing with purulent or hemorrhagic material. Those exhibit-
the lungs: surface-tension forces (accounting for 50–60% ing the greatest oxygenation response had less intense
of lung elastance), the presence of biologically active sur- alveolar edema and were distinguished by hyaline mem-
factant (in both alveoli and distal airways), viscosity and brane formation, interstitial edema, and atelectasis.159
12 RESPIRATORY CARE
VOL NO
Direct Versus Indirect Injury and Injury Severity Second, the duration and fidelity to LPV prior to initiating
a recruitment maneuver will influence recruitment poten-
Both direct and indirect forms of ARDS include alveolar tial regardless of injury mechanism. Third, the higher cor-
collapse,42 yet direct (ie, alveolar epithelial) injury has relation between direct injury and ARDS severity may
been characterized more by intense collapse and alveolar reflect the degree of bacterial diffusion throughout the
edema but minimal interstitial edema, whereas indirect lung parenchyma.93 This in turn suggests relatively greater
(ie, capillary endothelial) injury is associated with more consolidation in direct injury (with a corresponding brisk
intense interstitial edema than alveolar edema.160 Similar reactive edema formation) possibly producing greater
findings were reported in other studies.126 Moreover, edema than that caused by distant organ injury. However,
direct injury has been associated with higher pulmonary the investigators stressed that extrapulmonary injury or
microvascular permeability that, over a period of days, infection can cause equivalent severity. Thus, when only a
coincides with higher levels of extravascular lung small number of subjects are studied (ie, selection bias),
water.161 Some evidence suggests that recruitment maneu- the results may suggest equivalence, relatively greater, or
ver (at least when using the sustained inflation technique) relatively lesser lung recruitability between direct versus
might be ineffective in the presence of high extravascular indirect injury.
lung water ( 16 mL/kg).98
Inconsistencies between histologic findings in ARDS Pplat and PEEP During LPV
likely have many sources due to the limited number of
samples, the heterogeneous nature of ARDS and associated Oxygenation goals in LPV tend to align with the least-
lesions, and its timing relative to syndrome onset. PEEP philosophy, whereby the objective is using the lowest
Irrespective of these, such inconsistencies suggest that sim- PEEP that provides a reasonable PaO2 ($ 70 mm Hg) at a
plistic conceptual models guiding recruitment maneuver relatively non-toxic FIO2 (# 0.60).168 Only when clearly
have limited utility because the varied histopathologic toxic levels of FIO2 ($ 0.70)169 are necessary are higher
changes in ARDS coexist across a spectrum and that lesions PEEP levels generally used (> 10 cm H2O).18
evolve over time.159 Moreover, direct injury from pneumo- In traditional LPV, tidal volume is titrated to achieve a
nia disrupting alveolar membrane integrity (ie, loss of bac- Pplat # 30 cm H2O.18 Slightly more stringent LPV variants
terial compartmentalization) can induce indirect, secondary have focused on minimizing the risk of right-ventricular
injury to noninfected lung regions through systemic cyto- dysfunction and cor pulmonale (Pplat # 26 cm H2O)170,171
kine release.162 In fact, a substantial number of subjects or the risk of tidal overdistention (Pplat # 27 cm H2O).172
with ARDS with either aspiration or pneumonia as primary Given the heterogeneity of ARDS and large variability in
etiology also have sepsis as a secondary source of lung oxygenation dysfunction, it is important to have some per-
injury (20% and 40%, respectively).163 spective as to how often traditional LPV goals fall short of
Furthermore, secondary analysis of several recruitment securing adequate oxygenation at relatively non-toxic lev-
maneuver CT studies concluded that recruitment is likely els of FIO2 .
determined more by the severity of injury and correspond- The mechanistic studies reviewed above suggest that a
ing edema formation than injury mechanism per se.93 As Pplat of 30 cm H2O effects almost complete recruitment in
lung injury severity increases, so too does the degree of the mid-lung (CT regions 4–7) and simultaneously the larg-
pulmonary capillary permeability and the magnitude of est incremental changes in the dorsal lung (regions 8–10). In
extravascular lung water.164 In general, regardless of addition, de-recruitment becomes apparent at PEEP < 15
injury mechanisms, greater recruitment potential is pres- cm H2O and is particularly prominent in the dorsal regions
ent in ARDS characterized by diffuse versus predomi- only at PEEP < 10 cm H2O.85,92 Therefore, assuming normal
nant dorsal opacities.101,165-167 Unfortunately, this is not body habitus, a PEEP of 10–15 cm H2O and Pplat of 26–30
a distinction that can be made by clinicians when chest cm H2O appears sufficient to ensure adequate oxygenation
radiographs are the only practical tool available when at relatively non-toxic levels of FIO2 in the majority of
contemplating whether to pursue treating refractory hy- ARDS cases.
poxemia with recruitment maneuver. Data from 3 major LPV trials173-175 involving > 2,300
In a secondary analysis of recruitment maneuver studies subjects with early ARDS compared 2 PEEP strategies sup-
evaluated with CT, estimates of recruitability were actually port this interpretation. These studies found that: (1) moder-
higher in direct injury.93 Several factors were cited that pro- ate PEEP of 8–10 cm H2O produced a mean Pplat of 21–25
vide important insights into the interpretation of recruit- cm H2O and was generally sufficient to achieve an adequate
ment maneuver studies. First, the timing of recruitment to normal PaO2 on relatively non-toxic levels of FIO2 ; (2)
maneuver relative to ARDS onset influences recruitability. higher PEEP (ie, 15 cm H2O) with mean Pplat < 30 cm
Over time, edema fluid is slowly reabsorbed while concur- H2O further improved PaO2 at a decidedly less toxic levels of
rently fibrotic and tissue repair mechanisms evolve. FIO2 ; and (3) by the third study day, oxygenation had either
RESPIRATORY CARE
VOL NO 13
Table 3. Oxygenation and Pplat Differences in 3 Trials of Lower vs Higher PEEP During Lung-Protective Ventilation
Day 1 Day 3
Study
Lower PEEP Higher PEEP Lower PEEP Higher PEEP
173
ALVEOLI
PEEP, cm H2O* 964 15 6 4 964 13 6 5
Pplat, cm H2O 24 6 7 27 6 6 24 6 6 26 6 7
FIO2 0.54 6 0.18 0.44 6 0.17 0.52 6 0.18 0.40 6 0.14
PaO2 , mm Hg 78 6 22 85 6 28 77 6 22 74 6 20
PaO2 =FIO2 168 6 66 220 6 89 169 6 69 206 6 76
EXPRESS174
PEEP, cm H2O† 862 16 6 3 862 15 6 4
Pplat, cm H2O 21 6 5 28 6 2 21 6 5 27 6 4
FIO2 0.66 6 0.21 0.55 6 0.19 0.58 6 0.20 0.46 6 0.17
PaO2 , mm Hg 89 6 34 108 6 43 91 6 37 102 6 38
PaO2 =FIO2 150 6 69 218 6 97 175 6 81 245 6 98
LOVS175
PEEP, cm H2O‡ 10 6 3 16 6 4 963 12 6 4
Pplat, cm H2O 25 6 5 30 6 6 25 6 6 29 6 6
FIO2 0.58 6 0.17 0.50 6 0.16 0.41 6 0.12 0.52 6 0.16
PaO2 , mm Hg 80 6 26 88 6 32 76 6 16 75 6 15
PaO2 =FIO2 149 6 61 187 6 69 164 6 64 197 6 61
* After the first interim analysis, the Higher PEEP protocol was amended to require a minimum PEEP of 14 cm H2O for 48 h due to a lack of difference in PEEP requirements in the 2 treatment arms. In
addition, the first 80 subjects in the Higher PEEP arm underwent 1–2 sustained inflation recruitment maneuvers with CPAP at 35–40 cm H2O for 30 s during the first 4 study days. This sub-study was dis-
continued for lack of sustained oxygenation response.
†
Total PEEP rather than set PEEP reported. Pplat was limited to 30 cm H2O in the Higher PEEP arm.
‡
The Higher PEEP arm included a Pplat limit of 40 cm H2O and use of a sustained inflation recruitment maneuver with CPAP at 40 cm H2O for 40 s.
Pplat ¼ end-inspiratory plateau pressure
stabilized or improved regardless of PEEP strategy. Optimizing Oxygenation and Minimizing Risk of
These findings strongly suggest that a recruitment Atelectrauma
maneuver is unnecessary to manage the majority of
ARDS cases and needlessly increases the risk/benefit ratio FRC represents the alveolar volume and is the primary de-
(Table 3). terminant of PaO2 .177 Therefore, increased PaO2 in response to
Mean data, however, cannot elucidate whether Pplat gen- increased PEEP or recruitment maneuver is a bedside con-
erated by PEEP levels used during traditional LPV would: venience to infer changes in FRC and, by extension, shear
(1) likely reach suggested nodal points of TOP associated injury risk. Unfortunately, the logic linking these 3 phenom-
with full recruitment of dorsal regions; (2) estimate the per- ena is precarious.
centage of subjects requiring toxic levels of FIO2 ; and (3) Depending upon Pplat, a substantial portion of early FRC
gauge how many subjects would be reasonable candidates increase (ie, the fast pulmonary compartment) represents
for recruitment maneuver therapy. We examined these expansion of normally inflated or underinflated alveoli and
issues by querying databases used in our prior studies.163,176 not recruitment.4 In addition, arbitrary PaO2 =FIO2 thresholds
Our results are discussed in detail in online supplementary used to signify full recruitment (ie, 250–330 mm Hg)40,72
materials (see the supplementary materials at http://www. are literally false. Full recruitment implies normal pulmo-
rcjournal.com); however, the 2 main findings are: (1) tidal nary oxygen diffusion function (eg, PaO2 =FIO2 $ 450 mm
volume titration effectively limited Pplat to desired levels Hg). This does not occur in ARDS because of varying
despite high PEEP levels; and (2) this limited the likelihood degrees of tissue consolidation and slow resolution of pul-
for substantial dorsal lung recruitment in severe refractory monary edema. Thus, the PaO2 =FIO2 thresholds of 250–330
hypoxemia, as even at PEEP > 16 cm H2O only 5% of sub- mm Hg used to evaluate recruitment maneuver effective-
jects reached a sufficiently high recruitment threshold of 45 ness suggest a tacit acknowledgment that the term full
cm H2O. Thus, there is a subset of severe ARDS cases in recruitment is meant figuratively.
which traditional LPV is insufficient and a recruitment ma- Beyond these vagaries lies the crux of the debate: Does
neuver would appear to be a reasonable option to reverse OLV materially reduce the risk of repetitive shear injury
refractory hypoxemia. compared to traditional LPV? This is unlikely for the

majority of ARDS cases. First, a Pplat of $ 40 cm H2O is fast pulmonary compartment.180 In light of studies describ-
needed to reopen distal airways and alveoli deep within the ing transient [pulmonary] states, as well as those on prone
dorsal lung; these units remain closed and protected from positioning, it is worth considering whether more clinically
shear injury when Pplat is limited to # 30 cm H2O. Second, appropriate inspiratory times used during LPV, if not opti-
in ARDS substantial portions of lung tissue appear to reach mal, might be sufficient to effect sufficient recruitment
full recruitment at Pplat # 30 cm H2O, and its stability over time to reach oxygenation goals.
appears to be maintained when PEEP is set at 10–15 cm
H2O. In addition, evidence from several preclinical studies Hemodynamic Consequences of OLV
suggests that atelectatic areas are relatively protected from
shear injury by intra-alveolar edema, with most damage Although it is not the focus of this review, the unex-
caused by excessive stress developed in the peripheral air- pectedly higher mortality in the OLV arm of the ART
ways.178 In these studies, tidal overdistention was a more study, and its association with a higher incidence of hemo-
important contributor to pro-inflammatory cytokine expres- dynamic impairment, requires a brief review of cardio-
sion than shear injury. Third, microimaging of subpleural thoracic inter-relationships in ARDS and the potential
alveoli in acute lung injury models revealed that, despite impact of OLV strategies. The pulmonary vasculature
stable levels of driving pressure and PEEP, there exist pat- functions as a low-resistance, high-capacitance system
terns of recruitment and de-recruitment between interde- reflected in the thin-walled right ventricle, which readily
pendent alveoli, even at high PEEP levels, that appear to shows signs of dysfunction and eventually fails under sus-
fluctuate minute by minute.138 Thus, the notion of eliminat- tained work demands imposed by high pulmonary vascu-
ing de-recruitment and atelectrauma in ARDS appears lar resistance in ARDS.170
illusory. Acute pulmonary hypertension commonly develops in
ARDS due to hypoxemia, hypercapnia, acidosis, and pul-
Implications of Slow Pulmonary Compartments monary vascular obstruction from interstitial edema, and
disseminated arterial and microvascular embolization.181-184
Integrating the temporal issues involved in recruitment, Under mechanical ventilation, conditions of high end-
with evidence that most recruitment occurs at # 50 cm inspiratory volume (eg, high PEEP, driving pressure, or a
H2O, and the increased mortality risk reported in the ART combination of both) markedly increase pulmonary vas-
study,17 it behooves us to reflect upon the need for a cular resistance negatively impacts right-ventricular
recruitment maneuver and how it might be approached function.185-187 Right-ventricular function is further com-
going forward. Compelling evidence of slow pulmonary promised due to the simultaneous reduction in venous
compartments in ARDS is at odds with the current recruit- return and ventricular preload. Acute cor pulmonale
ment maneuver strategy and raises questions of whether develops when the right ventricle becomes ischemic
brief recruitment periods reflect the actual effectiveness from sustained excessive workloads; this occurs in 22–
of a specific Pplat. By extension, this influences the deci- 25% of patients with ARDS, with the incidence increas-
sion to use higher pressures with increasing risk of injury ing to 50% in patients with severe ARDS.188 Thus higher
and hemodynamic compromise. Moreover, limited inten- PEEP strategies and the potential for recruitment maneu-
sity recruitment maneuver studies such as the extended ver overuse in response to incidents of desaturation risks
sigh, the prolonged, and the slow moderate recruitment the development of either short-term transient hemodynamic
maneuvers cited above all observed substantial recruit- instability, which is a common finding in recruitment maneu-
ment at pressures # 40 cm H2O over a period of several ver studies,189 or, more importantly, the potential for longer-
minutes.33-35,37,38 To date, no study has investigated term problems of right-ventricular dysfunction and the devel-
whether an extended trial of super-PEEP limited to 25–30 opment of cor pulmonale, which increases mortality risk in
cm H2O and driving pressures of 15 cm H2O might pro- patients with ARDS.190
vide sufficiently stable oxygenation over a period of sev-
eral hours. Potential Risk of Ventilator-Induced Lung Injury
Also, the relative importance of using an inspiratory time
of 2–3 s during a recruitment maneuver, while supported A brief comment also seems appropriate regarding the
by preclinical data, has not been evaluated clinically. This potential risk of pressure control ventilation recruitment
strategy substantially limits recruitment maneuvers because maneuver strategies for ventilator-induced lung injury.
it restricts minute ventilation in more severe manifestations Although driving pressure is controlled at a seemingly
of ARDS that are associated with highly elevated physio- safe level during stepwise increases of super-PEEP (ie,
logic dead space179 and places additional strain on right- 15 cm H2O), the overall magnitude of step-changes in
ventricular function.78,170 In preclinical studies, an inspira- airway pressure increase abruptly from 5 or 10 cm H2O
tory time of 1.4 s is generally sufficient for recruiting the to 20 cm H2O as PEEP increases from 25 to 45 cm
RESPIRATORY CARE
VOL NO 15
H2O40,72 or by continuous incremental changes of 10 cm cases with persistent or recurring bouts of hypoxemia that
H2O.17 Regardless, these manipulations culminate in ex- occur despite PEEP levels of 15–20 cm H2O and require
traordinarily high end-inspiratory pressures of 60 cm prolonged exposure (ie, days) to FIO2 $ 0.70 to stabilize ox-
H2O. More concerning is that, during the subsequent ygenation, particularly patients with either intra-abdominal
PEEP decrement trials in some studies, once the optimal hypertension or severe obesity. Under these circumstances,
PEEP level is determined, “patients underwent another the risk of exacerbating lung injury from oxidative stress
recruitment maneuver using the same recruiting pres- from prolonged exposure to toxic levels of FIO2 enters
sures used in the last step of the maximum recruitment prominently into the calculus.169 When elevated IAP is not
maneuver.”40 This procedure was incorporated into the a prominent factor, a prolonged trial of super-PEEP and
ART trial.17 As others have noted, regardless of the per- low driving pressures that generate a Pplat of 40–45 cm H2O
ceived safety of limiting driving pressure to 15 cm H2O, (perhaps in concert with prone position) may be a more pru-
there is an upper limit of lung stress that can be tolerated dent approach to stabilize oxygenation. Finally, a recruit-
without resulting in severe lung injury.140 As described in ment maneuver in those with direct injury and a higher
this review, there appears to exist highly circumspect sit- likelihood of pronounced tissue consolidation is probably
uations in which this might be appropriate (eg, morbid of limited benefit and has been associated with greater mor-
obesity, abdominal compartment syndrome), although tality risk.
clinicians should always be cognizant of this danger.
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RESPIRATORY CARE Paper in Press. Published on January 19, 2021 as DOI: 10.4187/respcare.

The Nature of Recruitment and De-Recruitment and Its Implications for

RECRUITMENT AND DE-RECRUITMENT IN ARDS MANAGEMENT

Introduction Recruitment maneuvers as an adjunct to LPV were first

RECRUITMENT AND DE-RECRUITMENT IN ARDS MANAGEMENT

Pplat ¼ plateau pressure

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RECRUITMENT AND DE-RECRUITMENT IN ARDS MANAGEMENT

Creep volume (mL)

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RECRUITMENT AND DE-RECRUITMENT IN ARDS MANAGEMENT

RECRUITMENT AND DE-RECRUITMENT IN ARDS MANAGEMENT

Paw (cm H2O) 45

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Paw (cm H2O)

8 RESPIRATORY CARE VOL NO

RECRUITMENT AND DE-RECRUITMENT IN ARDS MANAGEMENT

RECRUITMENT AND DE-RECRUITMENT IN ARDS MANAGEMENT

RECRUITMENT AND DE-RECRUITMENT IN ARDS MANAGEMENT

Paw (cm H2O) and Elastance (cm H2O/L)

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RECRUITMENT AND DE-RECRUITMENT IN ARDS MANAGEMENT

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RECRUITMENT AND DE-RECRUITMENT IN ARDS MANAGEMENT

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