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MCC 260110

REVIEW

CURRENT
OPINION Patient self-inflicted lung injury and positive end-
expiratory pressure for safe spontaneous breathing
Takeshi Yoshida a, Domenico L. Grieco b,c, Laurent Brochard d, and Yuji Fujino a

Purpose of review:
The potential risks of spontaneous effort and their prevention during mechanical ventilation is an important
concept for clinicians and patients. The effort-dependent lung injury has been termed ‘patient self-inflicted
lung injury (P-SILI)’ in 2017. As one of the potential strategies to render spontaneous effort less injurious in
severe acute respiratory distress syndrome (ARDS), the role of positive end-expiratory pressure (PEEP) is
now discussed.
Recent findings:
Experimental and clinical data indicate that vigorous spontaneous effort may worsen lung injury, whereas,
at the same time, the intensity of spontaneous effort seems difficult to control when lung injury is severe.
Experimental studies found that higher PEEP strategy can be effective to reduce lung injury from
spontaneous effort while maintaining some muscle activity. The recent clinical trial to reevaluate systemic
early neuromuscular blockade in moderate–severe ARDS (i.e., reevaluation of systemic early
neuromuscular blockade (ROSE) trial) support that a higher PEEP strategy can facilitate ‘safe’ spontaneous
breathing under the light sedation targets (i.e., no increase in barotrauma nor 90 days mortality versus
early muscle paralysis).
Summary:
To prevent P-SILI in ARDS, it seems feasible to facilitate ‘safe’ spontaneous breathing in patients using a
higher PEEP strategy in severe ARDS.
Keywords
acute respiratory distress syndrome, mechanical ventilation, positive end-expiratory pressure, spontaneous
breathing

INTRODUCTION blockade in moderate–severe ARDS [i.e., reevalua-

Facilitation of spontaneous effort under light seda- tion of systemic early neuromuscular blockade
&&

tion has a central place in mechanical ventilation in
ICU. Such management can bring various benefits to
the patients, for example, better gas exchange, main-
tenance of peripheral muscles, and diaphragm func-
tion. However, it took a long time to recognize that
spontaneous effort could worsen oxygenation [1] and
cause lung injury [2]. In 2010, a randomized clinical
trial revealed that early use of neuromuscular block-
ing agent improved 90-day mortality in severe acute
respiratory distress syndrome (ARDS) [3]. Since then,
the potential risk of spontaneous effort and its pre-
vention during mechanical ventilation have been
extensively discussed [4,5]. In 2017, the concept of
effort-dependent lung injury has been coined
&&
‘patient self-inflicted lung injury (P-SILI)’ [6 ].
The impact of higher positive end-expiratory
pressure (PEEP) during spontaneous effort is indi-
rectly supported by the results of the most recent
trial to reevaluate systemic early neuromuscular
(ROSE) trial] [7 ]. There have been concerns about
the risk of spontaneous effort at higher levels of
PEEP for barotrauma (and therefore the mortality)
especially when breath stacking occurs [8]. The
ROSE trial suggests that patients who were treated
a
Department of Anesthesiology and Intensive Care Medicine, Osaka
University Graduate School of Medicine, Suita, Japan, bDepartment of
Emergency and Intensive Care Medicine and Anesthesia, Fondazione
Policlinico Universitario A. Gemelli IRCCS, cDepartment of Anesthesiol-
ogy and Intensive Care Medicine, Catholic University of The Sacred
Heart, Rome, Italy and dInterdepartmental Division of Critical Care
Medicine, University of Toronto, Toronto, Ontario, Canada
Correspondence to Takeshi Yoshida, MD, Ph.D., Department of Anes-
thesiology and Intensive Care Medicine, Osaka University Graduate
School of Medicine, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Tel.: +81 6 6879 5820;. fax: +81 6 6879 5823;
e-mail: takeshiyoshida@hp-icu.med.osaka-u.ac.jp
Curr Opin Crit Care 2019, 25:000–000
DOI:10.1097/MCC.0000000000000691

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KEY POINTS
 Experimental and clinical data support that
spontaneous effort is difficult to control within a safe
range when lung injury is more severe and vigorous
spontaneous effort may worsen lung injury.
 The global concept of ‘ventilation’-induced lung injury
includes both VILI with P-SILI and lung injury occurs
from overdistension either caused by a mechanical
ventilator (i.e., VILI) or patient’s own breathing (i.e., P-
SILI).
 Higher levels of PEEP seem to enable patients with
moderate–severe ARDS preserve ‘safe’ spontaneous
breathing during mechanical ventilation, considering
recent experimental studies and clinical studies.
with a higher PEEP strategy can have a ‘safe’ spon-
taneous breathing under light sedation targets (i.e.,
no increase in barotrauma nor 90 days mortality
&&
versus early muscle paralysis) [7 ].
Here, we summarize the concept of P-SILI and
the potential roles of higher PEEP to render sponta-
neous effort less injurious.
PATIENT SELF-INFLICTED LUNG INJURY
Evidence
In 1985, case series of patients with adult respiratory
distress syndrome reported marked increases in oxy-
genation after muscle relaxation concomitant with
reduced respiratory efforts as indicated by the shape
of airway pressure–time curves [1]. The authors
concluded that a trial of paralysis should be consid-
ered in patients with adult respiratory distress syn-
drome who exhibit vigorous activity of the
respiratory muscles [1]. In 1988, an experimental
study convincingly demonstrated the harm associ-
ated with spontaneous effort [2]. In sheep, sponta-
neous effort was increased by instillation of sodium
salicylate (acid, respiratory stimulant) into the cis-
terna magna, leading to increased tidal volume (VT)
and minute ventilation [2]. This, alone, induced
severe lung injury both clinically and at autopsy.
Subsequent to these, laboratory studies, case series,
and clinical studies to support the concept of P-SILI
are summarized as follows.
First, laboratory data provided the most direct
evidence. In mechanically ventilated rabbits and pigs
with established lung injury, vigorous spontaneous
effort worsened lung injury despite the limitation of
VT and plateau pressure [9,10]. Severe ARDS was asso-
ciated with stronger spontaneous effort compared
with mild ARDS, and the injurious effects of
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spontaneous breathing during mechanical ventilation
were more prominent in severe disease [11]. In the
severest form of ARDS which required extracorporeal
carbon dioxide removal, even mild spontaneous effort
increased inflammation despite ultralow VT [12].
Second, individual case reports revealed that
vigorous effort during mechanical ventilation was
associated with poor oxygenation, pulmonary
edema and barotrauma [1,13–15]. A multicenter
trial demonstrated that the use of neuromuscular
blocking agent with cisatracurium induced a signif-
icant increase in oxygenation in hypoxemic
patients (P/F < 200 mmHg) under mechanical venti-
lation [16]. In patients with severe ARDS during
extracorporeal membrane oxygenation, a clinical
study demonstrated that ‘safe’ spontaneous breath-
ing (as defined by the thresholds for respiratory rate
and delta esophageal pressure: Pes) was unlikely in
&
patients with ARDS [17 ]. In accordance with labo-
ratory findings [11], this observation was more evi-
&
dent in more severe ARDS patients [17 ]. Further,
carbon dioxide removal (by increasing sweep gas
flow) was not sufficient to prevent harmful sponta-
neous respiratory effort and thus keep transpulmo-
&
nary pressure (PL) within a safe limit [17 ,18].
Finally, clinical data provide mostly indirect
evidence. First, two single-center and one multicen-
ter randomized clinical trials reported that neuro-
muscular blockade (to prevent spontaneous effort)
results in improved lung function, decreased inflam-
mation, and increased survival in severe ARDS
[3,19,20]. In the randomized clinical study, early
use of neuromuscular blockade resulted in signifi-
cantly lower crude mortality at 90 days (30.8 versus
44.6%; P ¼ 0.04) when patients were confined to
those with PaO2/FiO2 less than 120 mmHg (i.e., more
severe injury) [3]. Data from a large database (>7000
patients) suggested that among mechanically venti-
lated patients with severe sepsis and respiratory infec-
tion, early treatment with a neuromuscular blocking
agent is associated with lower in-hospital mortality
[21]. In addition, a secondary analysis of patients
enrolled in the ARDS network low tidal volume ven-
tilation (Assessment of Respiratory. Management in
ALI and ARDS) study showed that muscle paralysis
was associated with less epithelial and endothelial
lung injury (evidenced by lower serum surfactant
protein-D and lower von Willebrand factor), and
less systemic inflammation (evidenced by lower
interleukin-8) in patients with PaO2/FiO2 less than
120 mmHg (i.e., more severe lung injury) [22]. Last,
clinical data about spontaneous breathing are mixed
but in children with ARDS, vigorous spontaneous
effort – in the setting of airway pressure release
ventilation – doubled mortality, compared modest
effort during pressure-controlled ventilation [23].
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Patient self-inflicted lung injury Yoshida et al.

Taking all of the experimental and clinical data
together, accumulating evidence indicates that spon-
taneous effort is difficult to control within a safe range
when lung injury is severe; spontaneous effort may
worsen lung injury in specific situations when the
initial injury is severe and/or the effort is vigorous.
&&
Although the concept of P-SILI is new [6 ], the
underlying mechanism for P-SILI is similar to that
for VILI [5,28]. In the case of P-SILI, global (and
local) overdistension is caused by patients’ own
spontaneous effort (i.e., negative pleural pressure)
more or less amplified by the ventilator.

Concept of ventilator-induced lung injury Mechanism

versus patient-self-inflicted lung injury
Mechanical ventilation is a life-saving, supportive
therapy, but mechanical ventilation itself is known
to cause lung injury, termed as ventilator-induced
lung injury (VILI). The concept of VILI has appeared
in the around 1970s [24,25] and now this is a well-
accepted concept and term. The main mechanism
for VILI is considered as overdistension because of
volume [26]. Therefore, low VT is a standard venti-
latory strategy to minimize the risks of VILI [27].
Three potential mechanisms of lung injury from
spontaneous effort exist (Fig. 1): global and local
overdistension, increased lung perfusion, and
patient–ventilator asynchrony.
Overdistension
In pressure assist-control or pressure support, pleu-
ral pressure (Ppl) is reduced by spontaneous breath-
ing and PL and VT will be increased. Global
overdistension reflected by high PL can then worsen

Spontaneous Effort at Lower PEEP Spontaneous Effort at Higher PEEP

• More efficient diaphragmatic contraction • Less efficient diaphragmatic contraction
• Maldistribution of Lung stress • Even distribution of Lung stress
• Global & Local Overdistension • Homogeneous Distension
∆Ppl -10
∆Ppl -10
• More Asynchrony • Better gas exchange
• More Perfusion

∆Ppl -20 (dorsal) ∆Ppl -13 (dorsal)

18F-FDG

uptake scale
More Inflammation Less Inflammation 0.022 Ki (min-1)

PET Scan
0.000

FIGURE 1. Lower PEEP in severe ARDS presents more lung collapse, resulting in less end-expiratory lung volume (Left panel).
Since the presence of atelectatic lung tissue could block the pressure transmission of DPpl following diaphragmatic contraction,
more negative DPpl is localized in the dorsal lung regions (DPpl 20 cmH2O vs. 10 cm H2O in dorsal vs. ventral lung regions).
The higher local (dorsal) lung stress then causes local overdistension by drawing gas from other lung regions and/or a
mechanical ventilator. The bulk of P-SILI occurs in the dorsal lung, i.e., the same region in which vigorous effort caused greater
inspiratory stress and stretch (Lower in Left panel). Higher PEEP in severe ARDS decreases lung collapse, resulting in higher end-
expiratory lung volume (Right panel). The higher end-expiratory lung volume is, the less force the diaphragm can generate by
changing the force-length relationship of the diaphragm and reducing the curvature of the diaphragm. Less atelectatic lung tissue
could achieve more even distribution of DPpl following diaphragmatic contraction (DPpl 13 cmH2O vs. 10 cm H2O in dorsal
vs. ventral lung regions), leading to more even distribution of lung ventilation (lines in Right panel). Therefore, higher PEEP
reduced lung inflammation from spontaneous effort in severe ARDS (Lower in Right panel). ARDS, Acute respiratory distress
syndrome; PEEP, positive end-expiratory pressure; Ppl, pleural pressure; P-SILI, patient self-inflicted lung injury.

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Respiratory system
lung injury, either caused by a mechanical ventila-
tor or a patient’s effort or both.
It is important to note that even if VT and global
PL are limited by using volume-controlled ventila-
tion, spontaneous effort can cause lung injury by
increasing local lung stress and overdistension
[10,29–31]. Injured lung does not exhibit a liquid-
like behavior; the inspiratory Ppl swing following
diaphragm contraction is not fully dissipated but is
mostly localized to the dependent regions in which it
is generated (by contraction of the diaphragm)
[29,31]. Thus, strong effort results in negative local
‘swings’ in Ppl in the dependent lung more than in the
remainder of the lung. The higher local (dependent)
lung stress then causes local overdistension [29]; it
also results in substantial tidal recruitment (and der-
ecruitment at expiration) in the dependent lung
[30,31] by drawing gas from other lung regions, for
example, nondependent lung (this is called pendel-
luft [29]). Recent data confirmed that the bulk of
effort-dependent lung injury occurs in the dependent
lung, that is, the same region in which vigorous effort
caused greater inspiratory stress and stretch [10,32].
Increased lung perfusion
Spontaneous effort generates a more negative Ppl
which in turn increases transmural vascular pres-
sure, that is, the difference between intravascular
and extramural pressure. Transmural vascular pres-
sure is the net pressure distending the intrathoracic
vessels; indeed vigorous spontaneous effort during
volume-controlled low VT ventilation (where Ppl
becomes extremely negative because inspiratory
effort continues but airflow into the lungs is
arrested) can cause pulmonary edema in ARDS
[13]. Finally, vigorous spontaneous effort was
recently shown to increase lung perfusion and pro-
pensity to edema, as well as worsen outcome in
children with acute exacerbations of asthma [33].
Patient–ventilator asynchrony
Asynchrony can potentially worsen lung injury.
Indeed, the association with adverse outcome of
patient–ventilator asynchrony is increasingly rec-
ognized, and data from 50 ventilated patients sug-
gests an association with higher mortality [34]. For
example, ‘Double triggering’, the occurrence of two
consecutive inspirations following a single respira-
tory effort [35], is potentially injurious because the
delivered VT has been increased. Double triggering is
more common in patients with higher respiratory
drive [36]. In contrast to vigorous effort which is
easy to detect and widely recognized to be harmful
[5,36], reverse triggering can occur in heavily
sedated patients, a scenario in which clinicians con-
sider the risk of asynchrony to be minimal [37].
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Reverse triggering can increase PL and/or VT, and
– through pendelluft – may increase dependent
lung stress and stretch [38].
POSITIVE END-EXPIRATORY PRESSURE
FOR SAFE SPONTANEOUS BREATHING
Evidence
Higher PEEP may render spontaneous effort less
injurious. First, ‘classic’ articles showed that DPes
(or Ppl) following phrenic nerve stimulation is
known to be lessened as the end-expiratory lung
volume is increased [39–42]. This phenomenon is
consistently observed in normal animal and human
(i.e., noninjured lungs). Second, more recently, the
same observation was confirmed in ARDS model
(i.e., injured lungs). Higher PEEP (and thus higher
end-expiratory lung volume) was associated with
less spontaneous effort (estimated by DPes or DPpl)
in ARDS model (rabbits and pigs) [10,30,32]. There-
fore, higher PEEP reduced P-SILI in ARDS model
(rats, rabbits, and pigs) [10,30,32,43]. Third, in sev-
eral case series, higher PEEP restored end-expiratory
lung volume, resulting in less spontaneous effort
and less pendelluft in an obese patient with ARDS
and a pediatric patient with ARDS [44,45]. Fourth,
beneficial effects of higher PEEP were suggested by
several clinical trials. In the randomized clinical
study to compare the delivery of noninvasive venti-
lation with helmet versus face mask in patients with
ARDS, noninvasive ventilation with helmet could
deliver higher PEEP levels, resulting in less sponta-
neous effort (suggested by lower respiratory rate),
less intubation rate, and better survival [46]. Impor-
tantly, lower spontaneous effort was observed in
helmet group (versus face mask group) despite lower
pressure support level [46].
The most recent randomized clinical trial to
reevaluate systemic early neuromuscular blockade
in moderate–severe ARDS (i.e., ROSE trial) indirectly
supports that higher PEEP may render spontaneous
effort less injurious. The trial showed that among
patients who were treated with a strategy involving
a high PEEP, there was no difference in mortality at
90 days between patients who received early use of
neuromuscular blockade and those who preserved
&&
spontaneous effort [7 ]. It is important to highlight
a key difference between the ARDS et Curarisation
&&
Systematique (ACURASYS) [3] and ROSE [7 ] trials.
The ACURASYS trial employed a lower PEEP on the
basis of low PEEP/FiO2 table [27], whereas the ROSE
trial employs a higher PEEP ‘open-lung’ strategy,
based on previous high PEEP strategies [47,48].
The results of the ROSE trial are consistent with
the hypothesis of lower injury from spontaneous
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Patient self-inflicted lung injury Yoshida et al.

efforts in patients with moderate–severe ARDS ven-
tilated with higher PEEP.
Mechanism for high positive end-expiratory
pressure
First, higher PEEP can reduce the amount of atelec-
tatic ‘solid-like’ lung, which can achieve more
homogeneous distribution of DPpl over the whole
lung surface, following diaphragmatic contraction.
The even distribution of inspiratory stress can
diminish injurious inflation associated with sponta-
neous effort (i.e., pendelluft), resulting in the avoid-
ance of local overdistension in dependent lung
regions (Fig. 1).
Second, higher PEEP can potentially help to
decrease forces generated by spontaneous effort
(reflected by DPes or DPpl) in ARDS (Fig. 2). The
impact on the force–length relationship and curva-
ture of the diaphragm may be important. High PEEP
increases end-expiratory lung volume, changing the
force–length relationship of the diaphragm and
reducing the curvature of the diaphragm, thus lead-
ing to change in the neuromechanical coupling
[10,39,41,42,49]. The lower end-expiratory lung vol-
ume is, the more force the diaphragm can generate
[39,41,42,49]. DPes (or Ppl) following phrenic nerve
stimulation is lessened as the end-expiratory lung
volume increases [39,41,42]. At a given level of
DEAdi, DPes was less negative at higher PEEP in
lung-injured pigs [10]. This mechanism can explain,
at least in part, why high PEEP reduced
spontaneous effort.
Third, higher PEEP often improves gas
exchange, which in turn can potentially help to
reduce respiratory drive.

FIGURE 2. Higher PEEP decreased negative swing in esophageal pressure. One-minute recording of flow, Paw, Pes and PL
(calculated as Paw  Pes) in an intubated patient with moderate ARDS undergoing pressure support ventilation (pressure
support ¼ 10 cmH2O). After 20 s, PEEP was increased from 8 to 15 cmH2O, yielding reduced inspiratory effort (i.e., the
negative swing in Pes) and lower dynamic transpulmonary driving pressure (i.e., the positive swing in PL). Flow and Paw were
recorded (sample rate ¼ 200 Hz) through a Fleisch-type pneumotacograph (n. 2, Metabo, Switzerland) placed at the
mouthpiece. Signals were transmitted to an analog–digital converter together with Pes, which was measured by an
esophageal catheter (Nutrivent, Sidam, Italy). All signals were reviewed offline through a dedicated software (ICU Lab,
Kleistek, Italy). ARDS, Acute respiratory distress syndrome; Paw, airway pressure; PEEP, positive end-expiratory pressure; Pes,
esophageal pressure; PL, transpulmonary pressure.

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Respiratory system
Finally, external PEEP may act as a counterbal-
ancing force and minimize the pressure differences
across the dynamic small airways’ obstruction,
reducing the effort to trigger the ventilator and
the increased load of inspiratory muscles [50].
CONCLUSION
We provide an update on the concept of P-SILI in
ARDS. As lung injury occurs from overdistension
either caused by a mechanical ventilator (i.e., VILI)
or patient’s own breathing (i.e., P-SILI), or both, we
describe the global concept of ‘ventilation’-induced
lung injury. Higher levels of PEEP seem to enable
patients with moderate–severe ARDS preserve ‘safe’
spontaneous breathing during mechanical ventila-
tion, considering recent experimental studies and
clinical studies.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
T.Y. declares no conflicts of interest. D.L.G. has received
payments for travel expenses by Maquet, Getinge, and
Air Liquide and discloses a research grant by General
Electric healthcare. LB’s laboratory has received funding
and/or equipment from Medtronic Covidien, Fisher Pay-
kel, Air Liquide, Sentec, and Philips.
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