Journal of

Personalized
Medicine

Review
Patient Self-Inflicted Lung Injury—A Narrative Review of
Pathophysiology, Early Recognition, and Management Options
Peter Sklienka 1,2,3, *, Michal Frelich 1,2 and Filip Burša 1,2,3

1 Department of Anesthesiology and Intensive Care Medicine, University Hospital Ostrava, 17. listopadu 1790,
70800 Ostrava, Czech Republic
2 Department of Intensive Medicine, Emergency Medicine and Forensic Studies, Faculty of Medicine,
University of Ostrava, Syllabova 19, 70300 Ostrava, Czech Republic
3 Institute of Physiology and Pathophysiology, Department of Intensive Care Medicine and Forensic Studies,
Faculty of Medicine, University of Ostrava, Syllabova 19, 70300 Ostrava, Czech Republic
* Correspondence: [Link]@[Link]; Tel.: +420-59-7372702

Abstract: Patient self-inflicted lung injury (P-SILI) is a life-threatening condition arising from ex-
cessive respiratory effort and work of breathing in patients with lung injury. The pathophysiology
of P-SILI involves factors related to the underlying lung pathology and vigorous respiratory effort.
P-SILI might develop both during spontaneous breathing and mechanical ventilation with preserved
spontaneous respiratory activity. In spontaneously breathing patients, clinical signs of increased work
of breathing and scales developed for early detection of potentially harmful effort might help clini-
cians prevent unnecessary intubation, while, on the contrary, identifying patients who would benefit
from early intubation. In mechanically ventilated patients, several simple non-invasive methods for
assessing the inspiratory effort exerted by the respiratory muscles were correlated with respiratory
muscle pressure. In patients with signs of injurious respiratory effort, therapy aimed to minimize
this problem has been demonstrated to prevent aggravation of lung injury and, therefore, improve
the outcome of such patients. In this narrative review, we accumulated the current information on
pathophysiology and early detection of vigorous respiratory effort. In addition, we proposed a simple
algorithm for prevention and treatment of P-SILI that is easily applicable in clinical practice.

Keywords: patient self-inflicted lung injury; respiratory effort; work of breathing; transpulmonary
Citation: Sklienka, P.; Frelich, M.;
driving pressure; extracorporeal membranous oxygenation
Burša, F. Patient Self-Inflicted Lung
Injury—A Narrative Review of
Pathophysiology, Early Recognition,
and Management Options. J. Pers.
Med. 2023, 13, 593. [Link] 1. Introduction
10.3390/jpm13040593 Continuous oxygen supply and carbon dioxide elimination are the principal physi-
Academic Editor: Eumorfia Kondili
ologic functions of the respiratory system. This gas exchange requires a large epithelial
surface in direct contact with both the external (air) and internal (blood flow through
Received: 25 February 2023 the pulmonary circulation) environments. Lungs and bronchial epithelium also serve as
Revised: 22 March 2023 first-line immune defense organs, including innate and adaptive immune cells capable
Accepted: 27 March 2023
of inducing the local and systemic immune response. The energy needed to generate
Published: 28 March 2023
a pressure gradient between alveoli and atmospheric pressure to pass the inspired gas
through airways and to distend lungs could be produced by respiratory muscles, by a
ventilator, or by a combination of these two sources. The term “biotrauma” was introduced
Copyright: © 2023 by the authors. to describe the translation of energy applied to the respiratory system into biochemical
Licensee MDPI, Basel, Switzerland. signals generating inflammatory response and subsequent dysfunction of distal organs [1].
This article is an open access article The application of excessive mechanical energy on the lung tissue during breathing is trans-
distributed under the terms and lated into biological signals producing systemic inflammation. This explains why most
conditions of the Creative Commons patients dying with acute respiratory distress syndrome (ARDS) die from multiple organ
Attribution (CC BY) license (https:// dysfunction syndrome [2]. During mechanical ventilation (MV), the ventilator provides the
[Link]/licenses/by/ work of breathing; this can, however, result in lung injury—so-called ventilator-induced
4.0/).

J. Pers. Med. 2023, 13, 593. [Link] [Link]

J. Pers. Med. 2023, 13, 593 2 of 14

lung injury (VILI). The identification of the potentially preventable factors of VILI develop-
ment was a logical next step in the research on VILI. Lung-protective ventilatory strategies
based on low tidal volumes, reduced pressures delivered by the ventilator (tidal volume
(Vt ) ≤ 6 mL/kg of predicted body weight (PBW); plateau pressure ≤ 30 cmH2 O; driving
pressure (∆Paw) ≤ 15 cmH2 O), and optimization of positive end-expiratory pressure
(PEEP) were associated with reduced mortality in patients with ARDS [3]. Finally, the
concept of mechanical power was introduced into the clinical practice for calculating the
energy applied to respiratory tissue during mechanical ventilation [4].
In a spontaneously breathing subject, the respiratory effort is generated by inspiratory
muscles and the lung tissue is, therefore, exposed to the same physical forces that cause
lung injury accompanied by VILI. If applied to damaged lung tissue, this can also lead to
further lung injury, and the fact that this is caused by spontaneous breathing is reflected
in the term “patient self-inflicted lung injury” [5]. It is important to mention that P-SILI
might develop in patients on mechanical ventilation with preserved spontaneous effort
as well as in patients breathing without mechanical ventilator support. Because the exact
measurement of driving pressure and tidal volume in a patient breathing spontaneously
has significant limitations, clinicians must be aware of the early signs of excessive work of
breathing and respiratory effort.
In this narrative review, we accumulated the current information on pathophysiology
and, in particular, early detection of P-SILI and options for its treatment. The knowledge
provided in this paper may help clinicians in the early recognition of patients at risk
and, in effect, in applying early interventions to prevent the development of irreversible
lung injury.

2. Experimental Evidence of P-SILI

The early evidence of a detrimental effect of excessive inspiratory effort was described
in the experimental study on pharmacologically induced hyperventilation (central aci-
dosis induced by sodium salicylate injection into the cisterna magna) in spontaneously
breathing animals with healthy lungs. Hyperventilation lasting for a prolonged period
induced subsequent hypoxemia, deterioration of lung mechanics (decrease of compliance),
and macroscopic and histological features consistent with ARDS. These lesions were not
detected in animals in the control arm, where objects were sedated, paralyzed, and me-
chanically ventilated with average tidal volumes immediately after the application of
sodium salicylate injection into the cisterna magna [6]. Yoshida et al. reported the dele-
terious effect of excessive respiratory effort in the lavage-injured lung in animals with
the inserted esophageal balloon and monitored esophageal pressure (Pes ). Animals with
strong spontaneous effort (defined by a greater value of the negative pleural pressure
and increased esophageal pressure switch) developed a significant worsening of the lung
injury as evaluated by the dynamic compliance, neutrophil count in the bronchoalveolar
fluid, and histological lung injury score [7]. The same authors defined the role of lung
injury severity in the development and progression of P-SILI in animals with severe lung
injury induced by repeated lung lavage. Histological lung injury scores were higher in the
subjects with initial severe lung injury who were left to breathe spontaneously compared
to those who were put on mechanical ventilation without spontaneous effort. However,
animals with initial mild lung injury who were left to breathe spontaneously showed the
best results of all groups, thus highlighting the need for individualization and meticulous
evaluation of the suitability of spontaneous breathing for a particular subject with lung
injury [8]. An excessive spontaneous effort with high regional strain was also shown to be
the cause of the increased expression of genes involved in inflammation, coagulation, and
apoptosis [4]. These data from experimental studies, therefore, provide evidence for the
link between excessive respiratory effort and the subsequent development of self-inflicted
lung injury. Some authors advocate the use of the term “effort-induced lung injury” instead
of P-SILI [9].
J. Pers. Med. 2023, 13, 593 3 of 14

3. Pathophysiology of P-SILI
The pathophysiology of P-SILI is complex and involves factors related to the underly-
ing lung pathology and respiratory mechanics. From the physiological point of view, three
distinct factors determine the respiratory mechanics: (i) respiratory drive (i.e., neural output
to respiratory muscles), (ii) respiratory effort (i.e., the activity of respiratory muscles), and
(iii) breathing pattern (i.e., the mechanics of respiration).
Respiratory drive. The respiratory drive is defined as the intensity of the neural
output of the respiratory centers, which determines the effort of the respiratory muscles.
The respiratory drive is determined by signals from central chemoreceptors, peripheral
chemoreceptors, stretch receptors from the thoracic wall and lung tissue, irritant receptors
of the airway epithelium, and, finally, cortical and emotional feedback. In a pathological
condition, the tissue of the respiratory system produces vital positive feedback, further
increasing the respiratory drive through hypoxemia, hypercarbia, and vagal C-fibers acti-
vation by inflammation and congestion [10,11].
Inappropriate lung stress and strain. Lung stress is the pressure distending the lung
and chest wall. Numerically, the stress applied to the lung parenchyma is represented
by the transpulmonary pressure (PL ). Strain is the change in lung volume above the end-
expiratory lung volume in response to an applied stress (i.e., tidal volume). Inappropriate
stress and strain are both related to the development of VILI and P-SILI. In injured lungs
with reduced compliance, higher transpulmonary pressure and work of breathing are
needed to provide an appropriate tidal volume and minute ventilation. Moreover, the
distribution of stress and strain becomes significantly non-homogeneous under pathologic
conditions, causing further deleterious regional amplification of stress and strain between
regions with different mechanical properties [12–14].
Pendelluft is characterized by redistributing the tidal volume from the non-dependent
to the dependent lung regions due to the higher negative pressure in the dependent areas.
Moreover, in patients with substantial expiratory effort, the de-recruitment of dependent
lung regions during exhalation may increase the pendelluft during the subsequent inspira-
tion [15,16]. Intraparenchymal air shift causes significant regional over-distension of the
dependent regions. It increases the work of breathing irrespective of the tidal volume, and
the frequency and magnitude of pendelluft correlate with increased blood concentrations
of inflammatory biomarkers [17].
Lung edema. Vigorous inspiratory effort and excessive intrathoracic negative pressure
result in an increase in venous return. The subsequent elevation of left ventricular end-
diastolic and pulmonary capillary pressures creates a high trans-capillary pressure gradient.
In acute lung injury, capillary permeability is increased due to the dysfunction of the
endothelial cell layer. This combination of elevated trans-capillary pressure gradient and
increased capillary permeability facilitate fluid leakage from the pulmonary capillaries into
the interstitial and alveolar space [18]. Lung edema, in turn, increases respiratory effort
because of worsening hypoxemia and hypercarbia and due to direct stimulation of vagal
C-fibers [10].
Diaphragmatic injury. Atrophy due to prolonged disuse in controlled mechanical
ventilation was considered the primary mechanism of ventilation-induced diaphragmatic
injury (VIDI). However, concentric load-induced injury caused by excessive muscle fibers
contraction in patients with high respiratory effort (both inspiratory and expiratory) may
also contribute to VIDI development. Because the activity and function of the diaphragm
are the main factors influencing lung volume and pressure changes during spontaneous
breathing, avoiding insufficient and/or excessive respiratory effort became the cornerstones
of the so-called lung- and diaphragm-protective ventilation strategies [19,20].
Patient–ventilator dyssynchrony during mechanical ventilation is defined as a situa-
tion when the parameters of breath delivered by the ventilator do not match the patient’s
respiratory drive and effort. Dyssynchronies are of clinical relevance because the number
and intensity of patient–ventilator dyssynchronies are related to parameters of poor out-
come, such as increased mortality or prolonged ventilation due to slower weaning [21–23].
J. Pers. Med. 2023, 13, x FOR PEER REVIEW 4 of 14

J. Pers. Med. 2023, 13, 593 4 of 14

Injured lungs are susceptible to subsequent insults. Paradoxically, respiratory insuf-

ficiency increases the respiratory drive through the central and peripheral receptor back
loop and Injured lungsstimulation
the direct are susceptible to subsequent
of pulmonary vagalinsults. Paradoxically,
C-fibers respiratory
by inflammation insuffi-
and edema
ciency
[10,11] increases
. The the respiratory
excessive respiratorydrive
drivethrough the centrallung-protective
may overwhelm and peripheral receptor
reflexes,back loop
which,
inand theleads
turn, direct
tostimulation
the breathingof pulmonary vagal self-inflicted
pattern causing C-fibers by inflammation
lung injury and edema
exposes[10,11].
the
The excessive
lungs to the riskrespiratory drivethe
of aggravating may overwhelmlesions—the
pre-existing lung-protective reflexes,
vicious cycle which, in turn,
of P-SILI [5]
leads to
[Figure 1]. the breathing pattern causing self-inflicted lung injury and exposes the lungs to
the risk of aggravating the pre-existing lesions—the vicious cycle of P-SILI [5] [Figure 1].

Figure 1. The pathophysiology of P-SILI—a “vicious circle” of self-aggravating lung injury; yellow
Figure 1. The pathophysiology of P-SILI—a “vicious circle” of self-aggravating lung injury; yellow
arrow—vagal signalization (according to [5,10,18]).
arrow—vagal signalization (according to [5,10,18]).
The COVID-19 outbreak triggered intensive research in the field of self-inflicted lung
The COVID-19
injury. In the early outbreak
phase oftriggered intensive
the pandemic, research
several in the field of
“phenotypes” ofself-inflicted
COVID-19-relatedlung
injury. In the early phase of the pandemic, several “phenotypes”
ARDS were believed to exist; however, with a growing knowledge of COVID-19-related of COVID-19-related
ARDS
ARDS, were believedapparent
it became to exist; that
however, with a growing
the differences knowledge
observed in lung of COVID-19-related
pathology and clinical
ARDS, it became apparent that the differences observed in
presentation were rather manifestations of disease development in time than lung pathology and clinical
different
presentation
phenotypeswere rather
[24,25]. manifestations
Moreover, of disease
these differences maydevelopment in time
have also arisen than
due to different
a combination
phenotypes [24,25]. Moreover,
of disease-related conditionsthese differences may
and respiratory have alsoinjury
effort-related arisen[26].
due to a combination
COVID-19-related
ofARDS
disease-related
was specific conditions
becauseand respiratory
patients effort-related
frequently toleratedinjury
severe[26]. COVID-19-related
hypoxemia (“silent hy-
ARDS was specific
poxemia”) due to thebecause patients
impaired frequently
function tolerated
of central severe hypoxemia
and peripheral (“silent
chemoreceptors hy-
[27–29].
poxemia”) due to the impaired function of central and peripheral chemoreceptors
Patients, therefore, often developed excessive respiratory effort inducing severe P-SILI [27–29].
Patients, therefore, period.
for an extended often developed
In most excessive respiratory
severe cases, effort inducing
the pressure gradient severe
applied P-SILI forin-
to the
anjured
extended
lungperiod.
duringIn most severe breathing
spontaneous cases, the pressure gradient
was capable applied tocausing
of eventually the injured lung
structural
during spontaneous
disruption breathing was
of the pulmonary capable
tissue, of eventually
resulting causing
in the most structural
severe forms ofdisruption of
P-SILI associ-
the pulmonary
ated tissue,mortality—spontaneous
with increased resulting in the most severe forms of P-SILI
pneumothorax, associated with in-
pneumomediastinum, and
pneumopericardium
creased mortality—spontaneous[30,31]. In retrospective studies
pneumothorax, describing the and
pneumomediastinum, incidence and clin-
pneumoperi-
ical features
cardium [30,31].ofInspontaneous
retrospectivepneumothorax and pneumomediastinum
studies describing the incidence and clinical in patients
featureswith
of
COVID-19-related pneumonia, a significant portion of patients presented pneumothorax
J. Pers. Med. 2023, 13, 593 5 of 14

or pneumomediastinum at admission or during the hospital stay before initiation of any

form of invasive ventilation, suggesting the association between vigorous spontaneous
ventilation and progression of lung injury [32,33].

4. Identification of Risk Factors for the P-SILI Development

Early identification of markers of vigorous effort is of fundamental importance for
treating patients at high risk of P-SILI. Below, we will focus on characteristics that can be
monitored at the bedside with standard equipment and minimal invasiveness.
Work of breathing scale. Modern intensive medicine is based on precise monitoring
and therapeutic algorithms arising from the results of clinical trials. However, physiology,
pathophysiology, and clinical examination remain the cornerstones of the best clinical prac-
tice. In an excellent review, Tobin focused on simple clinical signs of increased respiratory
effort and work of breathing, such as nasal flaring, sternomastoid muscle phasic contraction,
tracheal tug (downward motion of the trachea with inspiratory effort), suprasternal fossa
excavation during inspiration, and abdominal muscle use [34]. Nasal flaring, sternoclei-
domastoid muscle activity, abdominal muscle use, and respiratory rate are also included
in the so-called work of breathing (WOB) scale, a simple tool for non-invasive respiratory
effort monitoring and prediction of need for intubation in spontaneously breathing patients.
Apigo et al. have shown in a small sample study that the use of respiratory accessory
muscles resulting in WOB > 4 represents a relevant signal of subsequent high-flow nasal
(HFNC) therapy failure [35].
The ROX index is a clinical tool defined as ROX index = (SpO2 /FiO2 )/RR, where
SpO2 —peripheral oxygen saturation; FiO2 —fraction of inspired oxygen; and RR—respiratory
rate. The ROX index was proposed as a tool for predicting the failure of HFNC in pneu-
monia patients with hypoxemic respiratory failure [36]. The validity of the ROX index
was repeatedly confirmed in clinical studies, and its correlation with HFNC failure was
confirmed in the meta-analyses of studies in patients with COVID-19-related respiratory
failure [37,38].
The HACOR score, taking into account the hemodynamic response (heart rate; HR),
acid-base status (pH value), consciousness (Glasgow Coma Scale; GCS), arterial oxygena-
tion (PaO2), and respiratory rate (RR), was designed to predict a non-invasive ventilation
failure [39]. In moderate to severe ARDS patients on noninvasive ventilation (NIV) as a
first-line therapy, the reduction of HACOR score after 1–2 h of NIV identified the patients
who responded well to NIV, indicating a lower risk of need for intubation as well as of
mortality [40].
Although the WOB scale, ROX index, and HACOR score are not tools for direct
measurement of the respiratory effort, such combinations of the parameters of gas exchange
and respiratory mechanics might suggest an increased risk of P-SILI in spontaneously
breathing patients or in patients on NIV. Moreover, analyzing the temporal trend of the
WOB scale, ROX index, and/or HACOR score in a patient might help clinicians prevent
unnecessary intubation and identify patients who, on the contrary, would benefit from
early intubation before severe P-SILI develops.
Esophageal and transpulmonary pressure. The inspiratory effort exerted by the res-
piratory muscles is a crucial physiological mechanism contributing to P-SILI development
in patients with spontaneous breathing activity. The esophageal pressure monitoring
is considered clinical gold standard for the measurement of the pressure generated by
the respiratory muscles (i.e., the respiratory muscle pressure, Pmus ). The changes in Pes
(esophageal pressure swings; ∆Pes ) mirror the changes in pleural pressure, and the differ-
ence between the airway pressure (Paw ) and Pes represents the transpulmonary driving
pressure [41,42]. However, routine bedside Pes monitoring is limited by its invasiveness
(esophageal balloon manometry) and potential confounding factors (misplacement of the
probe, technical complications, risk of esophageal pressure ulcers, etc.). Therefore, alterna-
tive Pmus assessment tools were developed and validated in experimental and clinical trials.
Among these methods, the monitoring of nasal pressure swings, airway occlusion pressure
J. Pers. Med. 2023, 13, 593 6 of 14

at 100 ms, expiratory occlusion pressure, flow index, the electrical activity of the diaphragm,
ventilator waveform analysis, and electrical impedance tomography (EIT) represent simple,
non-invasive or minimally invasive tools that are easy to use in daily practice.
Nasal pressure swings. Tonelli et al. evaluated the correlation between ∆Pes and
nasal pressure swings (∆Pnos ) in 61 consecutive spontaneously breathing patients with
acute respiratory failure. One nostril was hermetically closed by the monitoring system
(“nasal plug”), and HFNC was placed into the remaining patent nostril. Patients then
breathed with their mouths closed, and nasal pressure swings were monitored. Interestingly,
the insertion of the nasal plug did not affect inspiratory effort and respiratory rate. ∆Pes
and ∆Pnos strongly correlated on admission and 24 h apart, suggesting the possibility of
estimating esophageal pressure swings from minimal invasive nasal pressure swings [43].
Airway occlusion pressure at 100 ms (P0 .1 ). P0 .1 is defined as the negative airway
pressure developed during a brief (100 ms after the onset of the inspiration) airway oc-
clusion. Levels of P0 .1 less than 1.0 cm H2 O suggest an inappropriate respiratory effort
and values greater than 3.5 cm H2 O suggest a vigorous respiratory effort [44]. Recently,
pooled data from clinical studies showed P0 .1 to be a reliable bedside tool for monitoring
the respiratory drive and detecting potentially injurious inspiratory effort [45]. Thanks to
its non-invasiveness and simple monitoring, P0 .1 has become a routine parameter automat-
ically monitored by modern ventilators.
Expiratory occlusion pressure (∆Pocc ) is defined as the total swing in airway pressure
generated by respiratory muscle effort on assisted ventilation when the airway is oc-
cluded. Bertoni et al. studied the relationship between ∆Pocc and parameters derived from
esophageal manometry (Pmus ) and dynamic transpulmonary driving pressure (∆PL,dyn ) in
sixteen patients ventilated in pressure support mode. Excessive respiratory effort (Pmus > 10 cm
H2 O) and transpulmonary driving pressure (∆PL,dyn > 15 cm H2 O) were quite common.
The authors found a significant correlation between ∆Pocc and both of Pmus and ∆PL,dyn ,
and concluded that measuring ∆Pocc allows non-invasive detection of elevated respiratory
muscle pressure and transpulmonary driving pressure [46]. Similar results were reported
by Roesthuis et al. in a study on mechanically ventilated patients with COVID-19-related
respiratory failure. Although only a weak correlation was generally found between the mea-
sured and computed ∆PL and Pmus , excessive effort (∆PL > 20 cm H2 O and Pmus > 15 cm
H2 O) was detected with high sensitivity and specificity [47].
Flow index is a novel non-invasive method based on the analysis of the flow–time
curve in patients on pressure-support ventilation (PSV) to estimate the inspiratory effort.
In these patients, the concavity of the inspiratory flow-time waveform recorded during
pressure support ventilation reflects the inspiratory effort because the effort-induced pres-
sure difference between the airway opening and the alveoli determines the intensity of
the inspiratory flow. Flow index can be calculated using relatively simple software. In
small-sample clinical trials, the calculation of inspiratory effort by flow index agreed with
esophageal-pressure-based methods [48,49].
Electrical Activity of the Diaphragm. Electrical activity of the diaphragm (EAdi)
provides important information about the crural diaphragm. The Pmus /EAdi (PEI) index
characterizes the pressure generated by the respiratory muscles in relation to the electrical
activity of the diaphragm, which facilitates the discrimination between the respiratory drive
(electrical activity) and the respiratory effort (generated pressure) [50,51]. The limitation of
EAdi measurement lies in its invasiveness, but small-sample clinical studies confirmed a
significant correlation between EAdi and the diaphragmatic electrical activity measured by
surface electromyography [52,53]. Surface diaphragmatic electromyography may, therefore,
serve as a non-invasive alternative for inspiratory effort monitoring.
Ventilator waveforms analysis provides crucial information on patient-ventilator phys-
iology and interaction. Visual analysis of flow/time and pressure/time curves alongside
clinical examination provide information on patient–ventilator interaction and dyssynchrony.
Electrical impedance tomography (EIT) is a non-invasive, bedside functional imaging
modality allowing breath-to-breath visualization of lung ventilation. During spontaneous
 Ventilator waveforms analysis provides crucial information on patient-ventilator
physiology and interaction. Visual analysis of flow/time and pressure/time curves along-
side clinical examination provide information on patient–ventilator interaction and dys-
synchrony.
J. Pers. Med. 2023, 13, 593 7 of 14
Electrical impedance tomography (EIT) is a non-invasive, bedside functional imag-
ing modality allowing breath-to-breath visualization of lung ventilation. During sponta-
neous breathing, EIT can detect the non-homogeneous distribution of lung ventilation and
breathing, EIT can detect the non-homogeneous distribution of lung ventilation and the
the pendelluft phenomenon [54].
pendelluft phenomenon [54].
In Figure2,2,noninvasive
In Figure noninvasive or minimally
or minimally invasive
invasive bedside
bedside tools
tools for for detection
detection of poten-
of potentially
tially injurious respiratory effort are summarized.
injurious respiratory effort are summarized.

Figure 2. Noninvasive or minimally invasive bedside tools for detection of potentially injurious
respiratory effort. Blue square—methods of indirect detection of vigorous spontaneous effort in
J. Pers. Med. 2023, 13, 593 8 of 14

patients breathing spontaneously or on noninvasive ventilation. White square—methods applicable

both during spontaneous breathing and mechanical ventilation. Green square—methods applicable
under mechanical ventilation. Abbreviations: WOB—work of breathing; HFNC—high-flow nasal can-
nula; NIV—noninvasive ventilation; SpO2 —peripheral oxygen saturation; FiO2—fraction of inspired
oxygen; RR—respiratory rate; HR—heart rate; GCS—Glasgow Coma Scale; paO2 —arterial partial
pressure of oxygen; Pes —esophageal pressure; ∆Pes —esophageal pressure swings; Pmus —respiratory
muscle pressure; PL —transpulmonary pressure; Vt—tidal volume; IBW—ideal body weight;
P0 .1 —airway occlusion pressure at 100 ms; Pocc —expiratory occlusion pressure.

5. Prevention and Treatment of P-SILI

Awake-prone position. The effect of early prolonged prone position (PP) was evalu-
ated in 81 awake patients with acute COVID-19-associated respiratory failure requiring
noninvasive ventilatory support. Prone position was associated with fewer incidences of
NIV failure (defined as the need for intubation) and mortality. Moreover, physiological
effects arising from PP were observed—lung tissue aeration (defined by lung ultrasound
score), paO2 /FiO2 , respiratory rate, and plasma levels of inflammatory biomarkers signifi-
cantly improved in patients who underwent PP [55]. These effects of pronation strongly
suggest that the prone position is associated with a reduced risk of self-inflicted lung
injury [56]. The favorable effect of awake prone positioning on paO2 /FiO2 and respiratory
rate in patients with spontaneous breathing was confirmed in recent meta-analyses [57,58].
Sedation reduces the respiratory drive and may protect the lung from further ag-
gravation of P-SILI. However, long-term sedation is accompanied with increased risk of
ventilator-associated pneumonia, muscle weakness (including diaphragm), and subse-
quent delirium. During the COVID-19 pandemic, high doses of intravenous sedatives
and opioids were reported to achieve sedation and suppress patient–ventilator dyssyn-
chronies [59]. It is noteworthy that sedation scales used in intensive medicine are markers
of arousal but do not correspond to the intensity of respiratory drive. In patients on
mechanical ventilation, respiratory drive monitored by P0 .1 did not correlate with the
Richmond Agitation–Sedation Scale [60]. The approach of personalized sedation aiming at
maintaining safe levels of dyssynchrony and patient effort while simultaneously allowing
spontaneous ventilation is termed “lung-protective sedation” [61].
In mechanically ventilated patients with ARDS who were (according to the mechanical
parameters of the respiratory system) considered eligible for partial support ventilation,
a reduction in intravenous sedation was accompanied by excessive respiratory effort in
as much as 80% of cases [62]. Therefore, alternative sedation strategies, such as partial
neuromuscular blockade or inhalation sedation, should be considered.
Inhalation sedation allows spontaneous breathing in patients on mechanical venti-
lation while in deep sedation. Landoni et al.’s meta-analysis found a reduced need for
intravenous sedatives and opioids when using inhalation sedation [58]. Alongside seda-
tion, inhaled anesthetics may provide other clinical benefits—bronchodilatation, reduced
inflammation, improved gas exchange, and facilitated awakening [63,64].
Partial neuromuscular blockade is a pharmacological strategy to treat high tidal
volumes and negative pressure swings caused by excessive respiratory effort in patients on
partial ventilatory support. This is achieved by applying neuromuscular blocking agents in
low doses to maintain diaphragm activity and spontaneous ventilation [65,66].
Early protective mechanical ventilation. Although evidence from experimental and
clinical studies suggests that P-SILI is a severe and life-threatening clinical condition, inten-
sivists have no consensus on when to intubate a patient with excessive respiratory effort.
In animal studies with artificially induced lung injury, early use of mechanical ventilation
eventually led to less severe lung injury than leaving them to ventilate spontaneously with
vigorous effort, and mechanical ventilation prevented self-inflicted lung injury if applied
early but not when applied late [6,7,67,68]. Some authors, therefore, advocate that in the
context of high respiratory drive and vigorous respiratory effort, mechanical ventilation
J. Pers. Med. 2023, 13, 593 9 of 14

with lung-protective parameters might be considered a protective therapy to minimize

P-SILI [5,69].
Spontaneous breathing during mechanical ventilation in patients with severe lung
injury remains subject to an ongoing debate amongst intensivists. Active insufflation
of the lung by inspiratory muscle activity improves gas exchange and lung aeration,
mainly in dependent regions, optimizes ventilation–perfusion matching, and prevents
the loss of end-expiratory lung volume (i.e., of the functional residual capacity) [70,71].
Moreover, spontaneous breathing during mechanical ventilation promotes the recovery of
the diaphragmatic thickness and can partially reverse respiratory muscle atrophy. However,
it is still necessary to consider the prevention of excessive effort that can lead to P-SILI
and consequent diaphragmatic myoinjury. In experimental study, spontaneous breathing
was beneficial in animals with mild lung injury; however, in animals with severe lung
injury, spontaneous breathing was associated with a significant increase in atelectasis with
cyclic collapse, higher plateau pressure, and more excessive spontaneous breathing effort,
resulting in the highest transpulmonary pressure and the highest driving pressure. On
the other hand, muscle paralysis in severe lung injury resulted in better oxygenation and
less histological lung injury [8]. Currently, the data from clinical trials are insufficient to
make evidence-based recommendations and guidelines on the strategy of spontaneous
ventilation in mechanically ventilated subjects in the acute phase of ARDS. According to the
expert panel opinion, ventilation with a pressure mode allowing spontaneous ventilation
can be used when ensuring that the tidal volume generated is close to 6 mL/kg predicted
body weight (PBW) and does not exceed 8 mL/kg PBW [72,73].
Extracorporeal membrane oxygenation (ECMO). It is essential to mention that the
beneficial effects of ECMO rather lie in facilitating lung rest and healing than in acting as a
modality of lung treatment per se. Extracorporeal oxygenation and elimination of carbon
dioxide could significantly reduce the patient’s respiratory drive and, therefore, reduce the
risk of excessive respiratory effort in spontaneously breathing patients [74,75]. An “awake
ECMO approach” is based on the implantation of venovenous ECMO in spontaneously
breathing patients to avoid undesirable effects associated with mechanical ventilation
and continuous deep sedation. Avoiding mechanical ventilation could be advantageous,
especially in patients at high risk of pneumothorax or pneumomediastinum [76–78].
Hypoxemia and hypercarbia are the main reasons for instituting mechanical venti-
lation in patients with acute respiratory failure. During the COVID-19 pandemic, large
numbers of COVID-19 patients presented with severe hypoxemia and hypercarbia but
were fully conscious and without subjectively perceived severe discomfort. Lung visualiza-
tion by computed tomography or ultrasound verified severe structural injury of the lung
parenchyma, and the respiratory mechanics of these patients was characterized by vigorous
respiratory effort. A significant portion of patients with COVID-19-related respiratory
failure finally had to be put on mechanical ventilation or ECMO, and the mortality of these
patients was in excess. Therefore, it is important to recognize situations when sponta-
neous respiration with vigorous effort becomes dangerous, further aggravating preexisting
lung injury.
Preventing P-SILI in mechanically ventilated patients with preserved spontaneous
breathing activity is another important issue. Dianti et al. performed an elegant study
on the strategy for minimizing the risk of P-SILI in 30 mechanically ventilated patients.
The approach used to achieve lung- and diaphragm-protective targets (−3 to −8 cm H2 O;
dynamic transpulmonary driving pressure 15 cm H2 O) was based on (i) successive steps
of titration of sedation, (ii) adjustment of ventilation parameters (including the titration
of the PEEP value to the maximum dynamic compliance) and sweep gas flow (in patients
on ECMO), and (iii) the application of partial neuromuscular blockade. Initially, only six
patients met the goals of lung- and diaphragm-protective targets, but following the study
protocol, these goals were achieved in all monitored patients [62]. P-SILI prevention should
be, therefore, viewed as a complex approach combining different therapeutic modalities
J. Pers. Med. 2023, 13, x FOR PEER REVIEW 10 of 14

J. Pers. Med. 2023, 13, 593 10 of 14

should be, therefore, viewed as a complex approach combining different therapeutic mo-
dalities according to respiratory mechanics and gas exchange parameters. A proposal of
therapeutic algorithm in prevention of P-SILI is presented in Figure 3.
according to respiratory mechanics and gas exchange parameters. A proposal of therapeutic
algorithm in prevention of P-SILI is presented in Figure 3.

Figure 3. Proposal of an algorithm for P-SILI prevention and treatment. CMV—controlled mechanical
Figure 3. Proposal
ventilation; of an algorithm
HFNC—high-flow nasalfor P-SILINIV—noninvasive
cannula; prevention and treatment.
ventilation; CMV—controlled
PNX—pneumothorax; mechan-
icalPNM—pneumomediastinum;
ventilation; HFNC—high-flow nasal cannula;
ECMO—extracorporeal NIV—noninvasive
membranous oxygenation. ventilation; PNX—
pneumothorax; PNM—pneumomediastinum; ECMO—extracorporeal membranous oxygenation.
The COVID-19 pandemic provided insight into the field of self-inflicted lung injury, but
manyTherelevant
COVID-19topicspandemic
remain unsolved.
provided Further research
insight should
into the fieldbeoffocused on identifying
self-inflicted lung injury,
criteria strictly associated with injurious respiratory effort, defining the strategies balancing
but many relevant topics remain unsolved. Further research should be focused on identi-
the benefits and risks between early and delayed intubation, and interventions minimizing
fying criteria strictly associated with injurious respiratory effort, defining the strategies
the disadvantages arising from vigorous effort in patients on mechanical ventilation.
balancing the benefits and risks between early and delayed intubation, and interventions
minimizing the disadvantages arising from vigorous effort in patients on mechanical ven-
6. Conclusions
tilation.
Self-inflicted lung injury represents a life-threatening complication in patients with
acute respiratory failure. During vigorous spontaneous breathing, lung tissue is exposed to
6. the
Conclusions
physical forces producing inappropriate stress, strain, pendelluft, and lung congestion,
which induces histopathological and clinical features that further aggravate lung injury.
Self-inflicted lung injury represents a life-threatening complication in patients with
Clinicians must be aware of the early signs of excessive work of breathing and respiratory
acute respiratory failure. During vigorous spontaneous breathing, lung tissue is exposed
effort. Incorporating clinical signs of the increased work of breathing alongside with WOB
to scale,
the physical forces
ROX index, producing
or HACOR scoreinappropriate stress,
in spontaneously strain,
breathing pendelluft,
patients andclinicians
may help lung conges-
tion, which induces histopathological and clinical features that further aggravate
prevent unnecessary intubation while also identifying patients who would benefit from lung in-
jury. Clinicians
early intubationmust
beforebesevere
aware of the
P-SILI early signs
develops. of mechanical
During excessive work of breathing
ventilation, and res-
parameters
piratory effort.
estimating PmusIncorporating clinical signsrespiratory
may suggest inappropriate of the increased work of breathing
effort. Prevention alongside
and treatment
with WOB scale, ROX index, or HACOR score in spontaneously breathing patients may
help clinicians prevent unnecessary intubation while also identifying patients who would
J. Pers. Med. 2023, 13, 593 11 of 14

of P-SILI are multimodal and require detailed evaluation of respiratory mechanics and
mechanisms causing the excessive effort.

Author Contributions: All authors have read and agreed to the published version of the manuscript.
Funding: This research was supported by MH CZ-DRO-FNOs/2022.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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