Intensive Care Med (2020) 46:2314–2326

https://doi.org/10.1007/s00134-020-06288-9

NARRATIVE REVIEW

Clinical strategies for implementing lung

and diaphragm‑protective ventilation: avoiding
insufficient and excessive effort
Ewan C. Goligher1,2,3, Annemijn H. Jonkman4,5, Jose Dianti1,2, Katerina Vaporidi6, Jeremy R. Beitler7,
Bhakti K. Patel8, Takeshi Yoshida9, Samir Jaber10, Martin Dres11,12, Tommaso Mauri13,14, Giacomo Bellani15,
Alexandre Demoule11,12, Laurent Brochard1,5 and Leo Heunks4* 

© 2020 The Author(s)

Abstract 
Mechanical ventilation may have adverse effects on both the lung and the diaphragm. Injury to the lung is mediated
by excessive mechanical stress and strain, whereas the diaphragm develops atrophy as a consequence of low respira-
tory effort and injury in case of excessive effort. The lung and diaphragm-protective mechanical ventilation approach
aims to protect both organs simultaneously whenever possible. This review summarizes practical strategies for achiev-
ing lung and diaphragm-protective targets at the bedside, focusing on inspiratory and expiratory ventilator settings,
monitoring of inspiratory effort or respiratory drive, management of dyssynchrony, and sedation considerations. A
number of potential future adjunctive strategies including extracorporeal C ­ O2 removal, partial neuromuscular block-
ade, and neuromuscular stimulation are also discussed. While clinical trials to confirm the benefit of these approaches
are awaited, clinicians should become familiar with assessing and managing patients’ respiratory effort, based on
existing physiological principles. To protect the lung and the diaphragm, ventilation and sedation might be applied to
avoid excessively weak or very strong respiratory efforts and patient-ventilator dysynchrony.
Keywords:  Mechanical ventilation’, Lung injury, Diaphragm weakness, Respiratory effort

Introduction Ultimately, the goal of the approach is to reduce the dura-

tion of mechanical ventilation, enhance survival, acceler-
Lung and diaphragm-protective mechanical ventila- ate recovery, and prevent long-term disability in patients
tion is a novel approach that aims to limit side effects with acute respiratory failure.
of mechanical ventilation in critically ill patients. This
approach integrates the principles of lung-protective Principles and rationale
ventilation with the new concept of diaphragm-protec- Principles of lung‑protective ventilation
tive ventilation in an effort to simultaneously protect Lung-protective ventilation can best be understood in
both organs. The approach centers on optimizing patient terms of limiting global and regional mechanical stress
respiratory effort to avoid lung and diaphragm injury (pressure applied to the lung) and strain (deformation
while maintaining acceptable respiratory homeostasis. from resting shape) (Fig. 1). Lung injury may occur from
overdistension (volutrauma/barotrauma), repetitive tidal
recruitment and collapse (atelectrauma), both result-
*Correspondence: [email protected]
4
Department of Intensive Care, Amsterdam UMC, Location VUmc, De ing from heterogeneous insufflation of patchy alveo-
Boelelaan 1117, 1081 HV Amsterdam, the Netherlands lar flooding or collapsed alveoli [1]. Importantly, lung
Full author information is available at the end of the article injury may occur irrespective of whether the ventilator
 2315

(ventilator-induced lung injury, VILI), patient breathing

effort (patient self-inflicted lung injury, P-SILI), or both Take‑home message 
together are generating the forces applied to the lung [2].
This review explains the principles of lung and diaphragm-pro-
Bedside measures of stress are available (changes in tective mechanical ventilation. The overall aim of this approach is
transpulmonary pressure, driving pressure), but not for to limit the adverse effects of mechanical ventilation on the lung
measuring the resulting strain, making it challenging to and the diaphragm at the same time. This requires understanding
of the pathophysiology of ventilator-induced lung injury, critical
appropriately individualize mechanical ventilation set- illness-associated diaphragm weakness and especially respiratory
tings to maximize lung protection. Furthermore, even drive. We discuss clinical applicable techniques to monitor lung and
if global stress can be measured quite precisely using diaphragm function, and how to use these techniques to optimize
ventilator settings and sedation. Future techniques that allow to
transpulmonary pressure calculated from airway and control respiratory drive are discussed.
esophageal pressure, the effect of gravity on the edema-
tous lung makes the distribution of collapse and aeration
very uneven between the dependent and non-depend- respiratory muscle pump and limit the consequences of
ent lung regions; therefore, global indices do not reflect high breathing effort (e.g., dyspnea sensation, respira-
regional stress or strain. To minimize total stress and tory failure, possible respiratory muscle injury). However,
strain, dependent regions (usually prone to atelectasis) mechanical ventilation delivered as the predominant
often require recruitment while non-dependent regions breathing source can also lead to diaphragm atrophy and
(usually well ventilated) require relief of overdistension. injury with a substantial deleterious impact on patient
During invasive ventilation, tidal volume ­( VT) is rou- outcome [8]. Clinical studies demonstrate that after 24 h
tinely scaled to predicted body weight (PBW), which of mechanical ventilation, 64% of patients exhibit dia-
correlates with lung volume in healthy subjects. This phragm weakness [9] and at the time of weaning, dia-
correlation is much less accurate in patients with acute phragm weakness is present in up to 80% of patients with
respiratory distress syndrome (ARDS) because of weaning difficulties [10]. While many factors contrib-
alveolar flooding and atelectasis, resulting in a “baby ute to diaphragm weakness in the critically ill [11], both
lung” much smaller than the predicted lung volume excessive and insufficient respiratory muscle unloading
[3, 4]. Using the driving pressure to scale tidal volume rapidly result in deleterious changes in diaphragm struc-
to respiratory system compliance (Crs, V ­ T/Crs = air- ture and function [11]. Low respiratory muscle effort, due
way driving pressure, ΔPaw) is particularly attractive to ventilator over-assist or sedation, may result in mus-
because Crs is affected by the aerated lung size and cle atrophy, while high effort has been associated with
could, therefore, better reflect the global strain ­(VT/ load-induced injury (Fig. 1). In a landmark study, Levine
baby lung). Driving pressure correlates with ARDS out- et al. demonstrated the development of diaphragm disuse
comes among patients with the same V ­ T/PBW [5] and atrophy in brain dead patients on controlled mechani-
may be useful to guide tidal ventilation, although its cal ventilation [12] and subsequent studies confirmed
role remains to be tested in a prospective trial. It should the presence of time-dependent fiber atrophy in the dia-
be acknowledged that static airway pressure is not a phragm of ventilated patients [13, 14]. In line with these
very reliable marker of lung stress (both at end-inspi- findings, ultrasound studies demonstrated that low dia-
ration and end-expiration), because it reflects contribu- phragm effort during mechanical ventilation is associated
tions from both the lung and chest wall (two pressures with time-dependent development of atrophy [15] and
acting in series). Obese patients are an example where that atrophy is associated with poor outcomes [8]. It may
high intrathoracic pressure (and therefore higher pla- be hypothesized that patients are at risk of developing
teau pressure) exist because of the weight imposed by load-induced diaphragm injury, as suggested by the pres-
the chest wall [6]. Lung stress is preferably measured as ence of fiber injury, sarcomeric disruption, inflammation
transpulmonary pressure (­ PL), which allows to quantify and contractile dysfunction in biopsies [13] and acute
the  contribution of the lung and chest wall to changes increases in diaphragm thickness on ultrasound [15]—
in airway pressure. this hypothesis requires further confirmation.
Taken together, these considerations suggest that the
Principles of diaphragm‑protective ventilation diaphragm might be protected by titrating ventilation
The respiratory muscle pump drives alveolar ventilation and sedation to restore early diaphragm activity while
and is composed of a number of skeletal muscles act- avoiding excess respiratory effort. The various lines of
ing in a highly organized fashion. The diaphragm is the physiological and clinical evidence suggesting that a res-
primary muscle of inspiration and the lateral abdominal piratory effort level similar to that of resting quiet breath-
wall muscles are the most prominent expiratory muscles ing is probably optimal for both lung and diaphragm
[7]. Mechanical ventilation is employed to unload the protection were recently summarized elsewhere [16].
2316

Fig. 1  Principles of lung and diaphragm-protective ventilation. ΔP: change in airway pressure during inspiration; PEEP: positive end-expiratory pres-
sure; P-SILI: patient self-inflicted lung injury; VILI: ventilator-induced lung injury; ­VT: tidal volume

Monitoring strategies [24]. The amplitude of Pes or Pdi during tidal breath-
To implement lung and diaphragm-protective mechani- ing provides a simple estimate of the pressure generated
cal ventilation, the variables that mediate injury, prin- by all respiratory muscles (Pes), or the diaphragm (Pdi),
cipally lung stress and respiratory effort, should be whereas the expiratory increase in Pga reflects expiratory
monitored. The available monitoring techniques, their muscle activity. The diaphragm electrical activity (EAdi)
advantages and disadvantages, and proposed specific tar- is the most precise surrogate of respiratory drive and cor-
gets are summarized in Table 1. relates with indices of effort [25] but with considerable
Airway driving pressure, ΔPaw (i.e., plateau pressure— variability between patients. Also, values for peak EAdi
PEEPtot), is a measure that aims to estimate global tidal in young healthy subjects during tidal breathing may
lung stress [5]. ΔPaw can be measured either during con- vary between 4 and 29 μV [26]. Nevertheless, changes in
trolled or assisted ventilation by manual or automated EAdi are useful to monitor changes in patient’s respira-
short end-inspiratory and end-expiratory occlusions tory drive and effort, especially to identify patients at risk
[17–19] Importantly, ΔPaw is determined by transpul- for ventilator  over-assistance. Finally, Pes or EAdi can
monary driving pressure (ΔPL) and driving pressure complement ventilator waveform analysis to facilitate the
across the chest wall (ΔPcw); thus changes in chest wall identification of patient-ventilator dyssynchronies.
elastance affect ΔPaw, without affecting lung stress [20]. Other less invasive techniques are available to monitor
Because pendelluft and regional variations in lung stress patient breathing efforts during mechanical ventilation at
are “dynamic” phenomena that cannot be detected under the bedside. Airway occlusion pressure (­P0.1), the deflec-
static conditions, the risk of excess regional lung stress tion in Paw during the first 0.1 s of an inspiratory effort
during assisted breathing may be more accurately esti- against an occluded airway, is an estimate of the respira-
mated by dynamic ΔPL (ΔPL,dyn, peak ­PL—end-expiratory tory drive and can be used to detect both very low and
­PL) rather than by static measures like ΔPaw [21, 22]. high effort [27]. The maximum deflection of Paw during a
Esophageal pressure (Pes) monitoring, as an estimate of whole breath occlusion (ΔPocc) has been recently shown
pleural pressure, can provide information about both the to accurately detect excessive respiratory muscle pres-
predisposition to end-expiratory collapse and atelectasis sure (Pmus) or ΔPL,dyn; this maneuver can also be used to
(end-expiratory ­PL) and alveolar overdistension within assess different forms of patient-ventilator dyssynchrony
the baby lung (elastance-derived plateau ­PL) [23]. [28, 29]. Ultrasound can be used to visualize and quantify
Monitoring and controlling respiratory muscle effort the thickening of the diaphragm during inspiration in the
are major challenges in implementing lung and dia- zone of apposition (thickening fraction, TFdi) [30]. TFdi
phragm-protective mechanical ventilation. The gold provides an index of diaphragmatic contractility and cor-
standard to quantify global respiratory muscle effort is relates reasonably well with inspiratory effort (ΔPes) and
the esophageal pressure–time product (PTP), while the EAdi [31].
PTP of the transdiaphragmatic pressure (Pdi, i.e., dif- In conclusion, although estimation of pleural pressure
ference between gastric pressure (Pga) and Pes) during using an esophageal balloon appears to be the preferred
inspiration provides a measure of diaphragmatic effort technique to quantify lung stress and respiratory effort,
Table 1  Monitoring strategies and targets for lung and diaphragm-protective ventilation
Parameter Use Advantages Disadvantages Suggested targets for lung and dia‑
phragm-protective ventilation

Tidal volume ­( VT) Indirect surrogate marker of risk of Readily available Strain is quantified by ­VT/EELV (end- VT 4–8 ml/PBW
ventilator-induced lung injury expiratory lung volume), thus ­VT
Expired tidal volume may be used to alone is not a precise measure of
detect volumes delivered above set lung strain
volume in volume-controlled mode Does not reflect lung stress and does
not correct for “baby lung” size
Airway driving pressure (ΔPaw) Monitor lung stress and strain result- Readily available Does not reflect regional lung stress ΔPaw < 15 ­cmH2O
ing from inflation with tidal volume when respiratory effort is high
Overestimates the transpulmonary
pressure ­(PL) if chest wall elastance
is increased and in the presence of
expiratory muscle activity
Paw and flow waveforms Detect patient-ventilator dyssynchro- Readily available Some dyssynchronies may not be Maintain patient-ventilator synchrony
nies Readily detects flow starvation, breath immediately evident without close
stacking, and premature cycling inspection and additional monitor-
dyssynchronies ing of effort
Airway occlusion pressure ­(P0.1) Monitor respiratory drive and detect Non-invasive Elevated respiratory drive does not P0.1 1–4 cmH2O
presence of low or high respiratory Automated measurement available always result in elevated respiratory
effort on most ventilators effort (i.e., in the presence of res-
piratory muscle weakness or short
inspiratory time)
Airway pressure swing during a whole Assess for excessive respiratory effort Non-invasive Though sensitive and specific for Predicted Pmus 5–10 cmH2O (ΔPocc
breath  occlusion (ΔPocc) and tidal lung stress Easily measured at the bedside high respiratory effort and dynamic 8–20 ­cmH2O)
Can predict respiratory muscle effort lung stress, the technique is not suf- Predicted ΔPL,dyn < 15–20 ­cmH2O
(Pmus) and transpulmonary pres- ficiently accurate to replace direct
sure swing (ΔPL,dyn) measurement
Detect apnea, auto-triggering
Differentiate different forms of dys-
synchrony
Esophageal pressure (Pes) and Directly measure and monitor respira- Minimally invasive Requires equipment and training ΔPes 3–15 ­cmH2O (diaphragm protec-
transpulmonary pressure ­(PL) tory effort and tidal lung stress Provides gold standard information Balloon must be calibrated before tive)
about lung stress (ΔPL) and respira- each measurement ΔPL,dyn < 15–20 ­cmH2O (lung protec-
tory effort (ΔPes, PTPes) Absolute values of Pes of unclear tive)
utility
Transdiaphragmatic pressure swing Directly measure and monitor Minimally invasive Requires equipment and training ΔPdi–15 cmH2O
(ΔPdi) and gastric pressure swing diaphragmatic effort and expiratory Provides direct measurement of Balloon must be calibrated before
(ΔPga) effort diaphragmatic effort each measurement
Provides information about expiratory No calibration for Pga
muscle activity Difficult to assess post-inspiratory
effort (eccentric loading)
2317
 2318

the technique is currently not widely implemented;

Suggested targets for lung and dia‑

Normalize target EAdi based on Pocc,

moreover, the potential impact on patient outcome

EAdi diaphragm electrical activity, EELV end-expiratory lung volume, P0.1 airway occlusion pressure during 0.1 s, Paw airway pressure, Pdi transdiaphragmatic pressure, Pes esophageal pressure, Pga gastric pressure, PL
transpulmonary pressure, PL,dyn change in transpulmonary pressure during tidal inflation, Pmus respiratory muscle pressure, Pocc whole breath airway occlusion pressure, PTP pressure-time product, TFdi diaphragm
phragm-protective ventilation

remains to be determined in clinical studies. We suggest

routine monitoring of tidal volume, inspiratory plateau
pressures and airway driving pressure to limit lung injury,
and P0.1 to monitor respiratory drive and prevent inad-
ΔPdi, or ΔPes
equate effort (Table 1).
TFdi 15–30%

Clinical strategies to facilitate lung

and diaphragm‑protective ventilation
Several strategies can be used to facilitate lung and dia-
phragm protective ventilation, including modulation of
effort during mechanical ventilation Continuous monitoring is not feasible

ventilator inspiratory and expiratory assist, drugs that

Requires equipment and training

Requires equipment and training

modify respiratory drive and/or effort, extracorporeal

­CO2 removal  (ECCO2R) and electrical stimulation of
the respiratory muscles, as shown in Fig. 2. Here, we will
No reference values

briefly discuss these different strategies.

Disadvantages

Inspiratory ventilator settings

A lung and diaphragm-protective ventilation approach
aims to minimize lung stress and strain while limit-
ing diaphragm atrophy and injury. To achieve these
Variation in EAdi correlates with varia-

goals, inspiratory ventilator settings can be adjusted to

Non-invasive assessment of diaphrag- Provides an index of diaphragmatic

Provides an index of diaphragmatic

Continuous information with auto-

(1) modulate the patient’s inspiratory effort, (2) mini-

mize the dynamic lung stress, and (3) prevent or correct
tion in respiratory effort
function (maximal TFdi)

patient-ventilator dyssynchrony or any form of mismatch

between needs and support.
Minimally invasive

Titrating the inspiratory ventilator settings to optimize

mated output

respiratory effort requires a thorough understanding

Advantages

(tidal TFdi)

of the control of breathing under mechanical ventila-

tion [32, 33], acknowledging that the control of breath-
ing system responds to changes in ventilatory demands
by modifying inspiratory effort (and thus tidal volume)
to a greater extent than respiratory rate [34]. Therefore,
Monitor electrical activity of the

the inspiratory ventilator settings will affect the inspira-

tory effort by modifying the delivered tidal volume, and
thus, in spontaneously breathing patients, increasing
matic contractility

pressure or volume assist will increase the delivered tidal

volume and reduce the inspiratory effort (as respiratory
diaphragm

drive depends mainly on the chemoreflex control of arte-

rial pH). Excessive assist, resulting in a tidal volume that
is higher than the patient’s demands, may almost abolish
Use

the patient’s the inspiratory effort, and as such promote

diaphragmatic atrophy. However, increasing inspiratory
Diaphragm electrical activity (EAdi)
Diaphragm inspiratory thickening

support may not attenuate inspiratory effort in the pres-

thickening fraction, V T tidal volume
fraction on ultrasound (TFdi)

ence of high respiratory drive due to stimuli other than

arterial pH/PaCO2, such as pain, anxiety, or stimulation
Table 1  (continued)

of peripheral lung receptors by lung edema or inflam-

mation [32]. In such case, transpulmonary pressure (and
hence dynamic lung stress) may progressively increase
Parameter

with increasing inspiratory support. Increasing ­FiO2 to

 2319

Fig. 2  Map of interventions to achieve lung and diaphragm-protective mechanical ventilation. ­ECCO2R: extracorporeal carbon dioxide removal

increase ­PaO2 and reduce the hypoxic stimulus to breathe several, generally resulting in 15 ± 4  cmH2O) is cur-
may alleviate increased respiratory drive in some patients rently recommended over lower PEEP (approximately
(hyperoxemia is not required to achieve this effect) [35]. 9 ± 3 cmH2O) in moderate and severe ARDS [44]. In the
In a volume-targeted mode, the patient’s effort will presence of spontaneous breathing during mechanical
be modified mainly by the set tidal volume and the flow ventilation, a higher PEEP strategy offers several addi-
delivery profile (flow pattern and peak flow). In pressure- tional potential advantages to facilitate lung and dia-
targeted modes, the delivered tidal volume, and thus phragm-protective ventilation (Fig.  1). First, in patients
the patient’s inspiratory effort, is influenced by the set with significant lung recruitability, PEEP reduces the
inspiratory pressure, rise time and cycling-off criterion, amount of atelectatic ‘solid-like’ lung and, therefore, can
and of course the mechanical properties of the respira- achieve a more homogeneous distribution of the tidal
tory system [36]. Irrespective of the mode of assist, the pleural pressure swing (∆Ppl) over the whole lung surface
delivered tidal volume and respiratory effort will together following a diaphragmatic contraction. The even distri-
determine global and regional lung stress, depending on bution of inspiratory dynamic stress can diminish inju-
the mechanical properties of the respiratory system [37]. rious asymmetric inflation associated with spontaneous
Neurally adjusted ventilatory assist (NAVA) delivers effort (i.e., pendelluft), reducing regional lung stress in
inspiratory assist proportional to the electrical activity dependent lung regions [45]. Second, by increasing end-
of the diaphragm [38]. Increasing inspiratory assist will expiratory lung volume, forcing the diaphragm to oper-
reduce diaphragm electrical activity (and vice versa) over ate at a shorter length and thereby impairing diaphragm
a wide range of respiratory demand, and consequently neuromuscular coupling [46, 47], increased PEEP can
tidal volume remains relatively stable over a wide range attenuate the force generated by diaphragmatic contrac-
of assist [39]. In theory, pulmonary reflex mechanisms tion [48]. Indeed, several clinical studies provide indirect
prevent patients from spontaneously inspiring large tidal evidence to suggest that higher PEEP may render sponta-
volumes and NAVA may therefore facilitate lung-protec- neous effort less injurious in patients with acute respira-
tive ventilation. Also, diaphragm inactivity due to over- tory failure before intubation [49], in patients with ARDS
assistance is unlikely in NAVA, as low diaphragm activity [45, 50], and in pediatric patients with lung injury [51].
will immediately reduce inspiratory assist. Future studies On the other hand, preliminary experimental evidence
should confirm the role of NAVA in lung and diaphragm- suggests that if the diaphragm is maintained at a shorter
protective ventilation, but recent randomized trials length during acute mechanical ventilation, the dia-
suggest clinical benefit of NAVA (reduced time on  the phragm muscle fibers could adapt to the reduced length
ventilator) compared to pressure support mode [40, 41]. by absorbing sarcomeres in series (i.e., longitudinal atro-
phy) [52]. This may result in fibers overstretching with
Expiratory ventilator settings the release of PEEP during a T-tube weaning trial or after
The expiratory ventilator setting (i.e., positive end-expir- extubation. The possibility of diaphragm weakness result-
atory pressure, PEEP) has been traditionally adjusted to ing from excess PEEP should therefore be borne in mind.
optimize oxygenation and/or lung mechanics [42, 43].
A higher PEEP ventilation strategy (of which there are
2320

Resolving dyssynchrony oscillations transmitted to the Paw or airflow signal is

Patient-ventilator dyssynchronies may cause lung and/or more likely to occur when the respiratory system time
diaphragm injury by increasing dynamic lung stress and/ constant is low, such as in ARDS. Air leaks and mois-
or injurious diaphragmatic contractions, respectively. ture in the ventilator circuit are also common causes of
Dyssynchronies may occur during inspiration (flow star- auto-triggering.
vation, short cycles, prolonged insufflation and reverse Ineffective triggering (or  ineffective efforts)  develops
triggering), during expiration (auto-triggering, ineffective when a patient’s effort fails to trigger a ventilator-deliv-
effort) or both during inspiration and expiration (reverse ered breath. Ineffective triggering is generally the con-
triggering and double triggering). We will briefly discuss sequence of weak inspiratory efforts, either from low
dyssynchronies most relevant for lung and diaphragm- respiratory drive due to sedation, metabolic alkalosis
protective ventilation; for more extensive discussion of or excessive ventilatory assist, or because of diaphragm
dyssynchronies we refer to other reviews [53]. weakness. When the respiratory system time constant is
Reverse triggering, a diaphragmatic contraction trig- high, (i.e., obstructive lung disease), ventilator over-assis-
gered by mechanical inflation, is common in fully sedated tance results in delayed cycling, dynamic hyperinflation,
patients (in whom drive is abolished) [54]. Reverse trig- and increased intrinsic PEEP, predisposing to ineffec-
gering can induce breath stacking resulting in excessive tive triggering. Decreasing the level of assist can there-
tidal volumes and high dynamic lung stress [55], and it fore alleviate ineffective efforts [57]. Over-assistance in
may create eccentric diaphragm loading conditions with assisted ventilation can also induce apneas during sleep.
resultant muscle injury [56]. When necessary to avoid Interestingly, several studies have demonstrated that
breath stacking, reverse triggering can be abolished by NAVA improves patient-ventilator interaction, especially
neuromuscular blocking agents. Alternatively, the devel- reducing the risks of ineffective efforts and over-assist
opment of reverse triggering may indicate that sedation [39, 58]. Whether the reduced duration of mechanical
should be stopped to allow the patient to take control of ventilation reported in some NAVA trials [40, 41] results
ventilation. from improved patient-ventilator interaction remains to
In patients with relatively high respiratory drive and a be investigated.
low respiratory system time constant, the neural inspi-
ration time may exceed the mechanical inflation (pre- Sedation strategies
mature cycling). In such cases, the contraction of the Sedation can facilitate lung and diaphragm-protective
inspiratory muscles continues during mechanical expi- ventilation by ameliorating, when present, excessive
ration and the diaphragm is forced to contract while respiratory effort. Complete suppression of respira-
lengthening (eccentric contraction). In volume-targeted tory drive and effort with sedation can also contribute
modes, unmet high demands appear as ‘flow-starvation’, to diaphragm disuse atrophy. A judicious approach to
a downward curvature of inspiratory Paw, and the patient sedation is key and monitoring of respiratory drive and
may experience dyspnea and distress, which can be effort may be helpful in selecting the sedation strategy
resolved by increasing inspiratory flow rate using a decel- that facilitates lung and diaphragm-protective ventila-
erating flow pattern. Strong inspiratory efforts may result tion. Before administering sedation to address excessive
in double-triggering, breath stacking and, therefore, deliv- respiratory drive or ventilator dyssynchrony, ventilator
ery of high tidal volumes. A better match of mechanical settings should be adjusted and other factors increas-
and neural inspiratory time can be achieved by increasing ing respiratory drive such as metabolic acidosis or
ventilator inspiratory time and using a decelerating flow pain should be addressed. Relying on sedation alone
pattern in volume-assist control mode, by decreasing the to enhance patient–ventilator interaction without
cycling-off criterion in pressure support mode, or using addressing these issues can paradoxically exacerbate
proportional modes of assist. Importantly, in patients dyssynchrony, prolong mechanical ventilation, and
with high respiratory drive, modification of inspiratory exacerbate diaphragm dysfunction [59]. Recent clini-
time may not suffice to resolve dyssynchrony. Increasing cal practice guidelines have recommended an “anal-
the level of assist to match the patient’s demands should gesia-first approach” to minimize the risk of excessive
be considered, but, if that results in an injurious high sedation as opioids during mechanical ventilation were
ventilation, other means to decrease the patient’s respira- associated with less dyssynchrony and depressed con-
tory drive, such as sedation, may be required. sciousness in comparison to sedative-based approaches
Another dyssynchrony occurring in patients with [60].
absent or low respiratory drive is auto-triggering, i.e., Nevertheless, when elevated respiratory drive cannot
the delivery of a ventilator-assisted breath in the absence otherwise be resolved, sedatives can attenuate the ven-
of patient effort. Auto-triggering due to strong cardiac tilatory response to hypoxemia and hypercapnia and
 2321

cortical input to the respiratory centres [33] (Table  2). alveoli, reducing lung stress. This is the putative basis
Propofol and benzodiazepines are gamma-aminobu- for the observed mortality benefit of prone positioning
tyric acid (GABA) agonists known to cause respiratory in patients with ARDS [68]. The mechanistic benefits
depression, primarily by reducing the amplitude of res- of prone positioning may also apply under assisted ven-
piratory effort [61–63]. Because benzodiazepines are tilation with spontaneous breathing, because the lung
associated with a high risk of delirium and prolonged recruitment accrued by prone positioning may attenuate
mechanical ventilation [64], propofol is the preferred ‘solid-like’ lung behaviour and reduce effort-dependent
sedative of choice for controlling high respiratory drive. regional lung stress. Prone positioning improves oxygen-
Because propofol or benzodiazepines reduce the ampli- ation in spontaneously breathing patients with COVID-
tude of inspiratory effort, ineffective triggering may 19 pneumonia [69]; it is possible that prone positioning
develop as sedation depth increases [61]. Inhalational could also reduce the risk of patient self-inflicted lung
sedation offers a potential alternative for controlling injury [70]. Thus, prone positioning might facilitate safe
respiratory effort though clinical experience is limited spontaneous breathing and diaphragm-protective venti-
to date [65]. To avoid excessive sedation, strategies lation as well as lung protection.
aimed at active titration of sedatives or daily interrup-
tion of sedation should be employed and respiratory Future approaches to lung and respiratory
drive and effort should be monitored closely. muscle‑protective ventilation
For patients without excessive breathing effort Extracorporeal carbon dioxide removal
(Table  2), a multimodal analgesia approach that mini- Eliminating ­CO2 is the primary purpose of alveolar
mizes opiate use is recommended to avoid diaphragm ventilation. ­ECCO2R reduces the ventilatory demands,
inactivity. Dexmedetomidine is a selective alpha-2 decreasing the respiratory effort, and thus may ame-
agonist which, in contrast to propofol and benzodi- liorate dynamic lung stress. E ­ CCO2R is feasible and
azepines, provides sedation, anxiolysis, and analge- effective in reducing tidal volume, driving pressure, and
sia without respiratory depression [66]. This property mechanical power in patients with ARDS [71]. In spon-
makes it an interesting drug of choice to preserve taneously breathing patients, E ­ CCO2R can dampen res-
awareness and diaphragm contractility and at the same piratory drive and effort [72], theoretically reducing the
time limiting excess delirium risk in agitated patients requirement for ventilatory support or sedation to con-
without elevated respiratory drive. trol respiratory effort. Karagiannidis et al. showed that
increasing sweep gas flow, increasing ­CO2 elimination,
Prone positioning in ARDS patients undergoing extracorporeal mem-
The prone position has been used for decades in early brane oxygenation (ECMO) reduced respiratory drive,
ARDS to improve oxygenation and over time an appreci- estimated by EAdi [73]. Mauri et  al. [7] also showed
ation for the lung-protective benefit of prone positioning that higher ­ECCO2R support reduced ­P0.1, respiratory
has emerged [67]. As the amount of lung tissue is larger muscle effort, and transpulmonary pressure in spon-
in dorsal lung regions, gravitational forces generate more taneously breathing patients recovering from severe
dependent atelectasis in the supine position compared to ARDS [74]. Pilot clinical studies have explored the
prone position. Therefore, ventilation-perfusion match- extreme possibility of extubating severe ARDS patients
ing is improved in the prone position and, more impor- early after intubation by means of E ­ CCO2R: prelimi-
tantly, the energy applied to the lung by mechanical nary results were encouraging but they also recognized
ventilation is distributed among more (non-atelectatic)

Table 2  Effect of sedation on respiratory drive, effort and breathing pattern

Drug class Inspiratory effort Respiratory rate Ventilatory response Effect on diaphragm function and patient-ventilator
and tidal volume to hypercapnia and hypox‑ interaction
emia

Benzodiazepines ↓ ⟷ or ↑ ↓ Delay restoration of diaphragm activity

↓ at high doses
Propofol ↓ ⟷ or ↑ ↓ May ↑ dyssynchrony (i.e., ineffective efforts because of
↓ at high doses lower respiratory effort)
Opioids ⟷ or ↑ ↓ ↓ May ↓ dyssynchrony (i.e., fewer ineffective efforts
because of slower, deeper respiratory efforts)
Dexmedetomidine ⟷ ⟷ ⟷ ↓ dyssynchrony by decreasing agitation/delirium
2322

the need to identify the subgroup of patients with a of dependent lung regions [82]. Pacing must be synchro-
high probability of success [75–77]. nized with the ventilator and potentially injurious inspir-
Despite the appeal and physiological rationale of this atory efforts must be avoided.
strategy, there are relevant limitations. First, in some There is as yet no clinical evidence of benefit from dia-
patients, non-chemoreceptive stimuli (pain, agitation, phragm pacing in ICU patients. Direct stimulation of
discomfort, metabolic acidosis, lung mechanical stimuli) the phrenic nerves by surgically implanted electrodes
may predominate and high respiratory drive may per- has been employed to restore spontaneous ventilation
sist despite E
­ CCO2R [78]. Second, E ­ CCO2R requires full in patients with high-level spinal cord injury and cen-
anticoagulation and the risk of bleeding is not insubstan- tral hypoventilation syndrome [83]. The feasibility of
tial [79]. Third, the application of ­ECCO2R may exacer- direct pacing using temporary implanted electrodes for
bate hypoxemia by various mechanisms [80]. the prevention of diaphragm dysfunction is currently
under investigation in cardiac surgery patients identi-
fied to be at risk for prolonged mechanical ventilation
Partial neuromuscular blockade (NCT04309123). Preclinical work showed that this tech-
Complete neuromuscular blockade may increase the nique could reduce the development of diaphragm type II
risk for diaphragm disuse atrophy and increases seda- fiber atrophy [84, 85]. Recently, Reynolds et al. presented
tion requirements. Low-dose neuromuscular blockers a first-in-human series of temporary transvenous phrenic
(“partial neuromuscular blockade”) is an interesting com- nerve pacing in surgical patients and showed that this
promise between total paralysis and strenuous breathing technology delivered safe and effective diaphragm con-
efforts, particularly when respiratory effort does inad- tractions [86]. This strategy is currently being studied as
equately respond to titration of ventilatory support or potential intervention for improving diaphragm strength
sedation. The feasibility of partial neuromuscular block- in difficult-to-wean patients (NCT03096639). The role of
ade has been evaluated in a proof of concept study in transvenous phrenic nerve pacing for the prevention of
patients with moderate ARDS and high respiratory drive diaphragm disuse atrophy remains to be investigated.
on partially supported modes [81]. Titration of rocuro- Neuromuscular stimulation strategies targeting the
nium decreased tidal volume from approximately 9 mL/ expiratory muscles of ICU patients are less well stud-
kg to approximately 6  mL/kg while maintaining Pdi at ied. This is surprising, as stimulation of the expiratory
approximately 5 ­cmH2O (within the physiological range abdominal wall muscles can be employed noninvasively
for diaphragm activity in healthy subjects). These pre- via surface electrodes placed over the abdominal wall.
liminary findings suggest that partial neuromuscular Feasibility of a breath-synchronized expiratory muscle
blockade could be a feasible approach to achieving lung stimulation technique during the early phase of mechani-
and diaphragm-protective ventilation targets in patients cal ventilation was recently demonstrated with prom-
with high respiratory effort. Importantly, partial neuro- ising results [87] and its efficacy is under investigation
muscular blockade does not reduce respiratory drive, (NCT03453944).
but only the mechanical consequences of high drive.
This dissociation between central drive and respiratory
muscle mechanical output may result in dyspnea [33]; Summary and future directions
adequate relief of dyspnea and distress must be ensured Clinicians caring for mechanically ventilated patients are
by judicious application of sedatives and opioids. Future generally well aware of the risk of causing barotrauma,
clinical studies should confirm the safety and efficacy of volutrauma, and atelectrauma. Given the mounting evi-
prolonged partial neuromuscular blockade in ventilated dence of clinically important diaphragm atrophy and
patients. injury, consideration must also be given to protecting the
diaphragm. Based on the foregoing discussion about ven-
Neuromuscular stimulation tilation and sedation, a basic algorithm and approach to
Neuromuscular stimulation (“pacing”) uses electrical lung and diaphragm-protective ventilation is presented
currents to generate muscle contraction in the absence in Fig. 3. Clinical trials testing new ventilation algorithms
of volitional efforts, making it an attractive intervention and sedation strategies targeted at optimizing respiratory
in incapacitated critically ill patients. There is growing effort are required to confirm the benefit of the lung and
interest in neuromuscular stimulation as a novel strategy diaphragm-protective approach outlined in this paper.
to preserve or restore respiratory muscle activity and, in The benefit of adjunctive strategies such as ­ECCO2R, par-
turn, to prevent or treat ICU-acquired diaphragm weak- tial neuromuscular blockade and phrenic nerve stimula-
ness. In addition, by inducing diaphragm contractions, tion requires further evaluation, in particular to identify
neuromuscular stimulation may improve lung aeration the subpopulations of patients most likely to benefit
 2323

Fig. 3  Clinical-physiological pathway for achieving lung and diaphragm-protective ventilation targets. It should be stressed that at each step clini-
cal evaluation of the patient, including signs of high breathing effort, agitation, and over-sedation is of major importance and should be interpreted
together with clinical-physiological measurements as outlined in this pathway. ΔP: change in airway pressure during inspiration; P0.1: decrease in
airway pressure during the first 100 ms of inspiratory effort against an occluded airway; P­ aCO2: arterial carbon dioxide tension; PEEP: positive end-
expiratory pressure; Pes: esophageal pressure; ­PL: transpulmonary pressure; Pocc: airway pressure deflection during a whole breath occlusion; RR:
respiratory rate; ­VT: tidal volume

from these more costly and invasive interventions. For Compliance with ethical standards
the present, we encourage clinicians to incorporate rou- Conflicts of interest
tine monitoring of respiratory drive and effort in their EG is supported by an Early Career Investigator award from the Canadian
clinical practice and to adjust the ventilator to achieve a Institutes of Health Research (AR7-162822). He has received research support
in the form of equipment from Getinge and Timpel and personal fees from
physiological level of effort where possible while carefully Getinge. SJ reports receiving consulting fees from Drager, Medtronic, Baxter,
attending to the effect on lung stress. Fresenius Medical and Fisher & Paykel. TM received personal fees from Fisher
and Paykel, Drager, Mindray, Braun outside of the submitted work. LB’s labora-
tory reports grants from Medtronic Covidien, grants and non-financial support
Author details from Fisher Paykel, non-financial support from Air Liquide, non-financial
1
 Interdepartmental Division of Critical Care Medicine, University of Toronto, support from Sentec, non-financial support from Philips, a patent with General
Toronto, Canada. 2 Department of Medicine, Division of Respirology, University Electric, outside the submitted work. LH received research grants from Liber-
Health Network, Toronto, Canada. 3 Toronto General Hospital Research ate Medical and Orion Pharma, and travel and speakers fee from Getinge and
Institute, Toronto, Canada. 4 Department of Intensive Care, Amsterdam UMC, Orion Pharma.
Location VUmc, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands.
5
 Keenan Centre for Biomedical Research, Li Ka Shing Knowledge Institute, St. Open Access
Michael’s Hospital, Toronto, Canada. 6 Department of Intensive Care Medicine, This article is licensed under a Creative Commons Attribution-NonCommercial
University Hospital of Heraklion, Medical School, University of Crete, Heraklion, 4.0 International License, which permits any non-commercial use, sharing,
Greece. 7 Center for Acute Respiratory Failure, Division of Pulmonary, Allergy, adaptation, distribution and reproduction in any medium or format, as long as
and Critical Care Medicine, Columbia University College of Physicians and Sur- you give appropriate credit to the original author(s) and the source, provide a
geons, New York, NY, USA. 8 Department of Medicine, Section of Pulmonary link to the Creative Commons licence, and indicate if changes were made. The
and Critical Care, University of Chicago, Chicago, IL, USA. 9 Department images or other third party material in this article are included in the article’s
of Anesthesiology and Intensive Care Medicine, Osaka University Graduate Creative Commons licence, unless indicated otherwise in a credit line to the
School of Medicine, Suita, Japan. 10 Critical Care and Anesthesia Department material. If material is not included in the article’s Creative Commons licence
(DAR B), Hôpital Saint-Éloi, CHU de Montpellier, PhyMedExp, Université de and your intended use is not permitted by statutory regulation or exceeds the
Montpellier, Montpellier, France. 11 Sorbonne Université, INSERM, UMRS1158 permitted use, you will need to obtain permission directly from the copyright
Neurophysiologie Respiratoire Expérimentale et Clinique, 75005 Paris, France. holder. To view a copy of this licence, visit http://creat​iveco​mmons​.org/licen​
12
 Service de Pneumologie, Médecine Intensive et Réanimation (Département ses/by-nc/4.0/.
R3S), AP-HP, Groupe Hospitalier Universitaire APHP-Sorbonne Université, Site
Pitié-Salpêtrière, 75013 Paris, France. 13 Department of Anesthesiology, Inten-
sive Care and Emergency, Fondazione IRCCS Ca’ Granda Ospedale Maggiore
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
Policlinico, Milan, Italy. 14 Department of Pathophysiology and Transplanta-
lished maps and institutional affiliations.
tion, University of Milan, Milan, Italy. 15 Department of Medicine and Surgery,
University of Milan-Bicocca, Via Cadore 48, Monza, MB, Italy.
Received: 2 September 2020 Accepted: 8 October 2020
2324

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