Respiratory Medicine 223 (2024) 107541

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Respiratory Medicine
journal homepage: www.elsevier.com/locate/rmed

Rapid review of ventilator-induced diaphragm dysfunction

Huimin Wu a, b, *, Bobby Chasteen b
a
Pulmonary, Critical Care and Sleep Medicine Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, United
States
b
Department of Adult Respiratory Care, University of Oklahoma Medical Center, Oklahoma City, OK, 73104, United States

A R T I C L E I N F O A B S T R A C T

Keywords: Ventilator-induced diaphragm dysfunction is gaining increased recognition. Evidence of diaphragm weakness
Mechanical ventilation can manifest within 12 h to a few days after the initiation of mechanical ventilation. Various noninvasive and
Diaphragm dysfunction invasive methods have been developed to assess diaphragm function. The implementation of diaphragm-
Liberation from mechanical ventilation
protective ventilation strategies is crucial for preventing diaphragm injuries. Furthermore, diaphragm neuro­
stimulation emerges as a promising and novel treatment option. In this rapid review, our objective is to discuss
the current understanding of ventilator-induced diaphragm dysfunction, diagnostic approaches, and updates on
strategies for prevention and management.

1. Introduction evaluation, and management strategies of VIDD.

Mechanical ventilation is an essential, lifesaving therapy for criti­ 2. Diaphragm anatomy, innervation, and function
cally ill patients with respiratory failure. Among patients admitted to
intensive care units (ICU), 33 % required mechanical ventilation [1]. The diaphragm, a dome-shaped structure, serves as a partition be­
The demand for invasive mechanical ventilation has seen a significant tween the thoracic and abdominal cavities [11]. The diaphragm com­
rise during the COVID-19 pandemic [2]. There is a wide range of in­ prises both contracting muscle fibers, including fatigue-resistant
dications for mechanical ventilation, including severe pneumonia, acute slow-twitch type I and fast-twitch type IIa myofibers, as well as a
respiratory distress syndrome, exacerbation of chronic obstructive pul­ non-contractile central tendon. It separates the right and left sides. These
monary disease, cardiogenic shock, neuromuscular diseases, and more. muscle fibers attach to the inner surface of the chest wall, specifically the
While some patients require short-term mechanical ventilation support, lower six ribs laterally, the lumbar vertebrae posteriorly, and the costal
lasting from a few hours to several days, others may require long-term cartilage and sternum anteriorly. Adjacent to the lower rib cage, it forms
mechanical ventilation support, spanning from months to years. the zone of apposition. The diaphragm has three major apertures: the
While mechanical ventilation serves as a critical and sometimes life- aortic, the esophageal, and the inferior vena cava orifices.
saving intervention, its frequently observed complications, such as The diaphragm receives innervation from two phrenic nerves, which
infection, ventilator-induced lung injury, barotrauma, and cardiovas­ arise from the cervical nerve roots at C3 through C5 [12]. These nerves
cular compromise, have been extensively documented [3–6]. pass in front of the pulmonary hilum and descend either along the left
Ventilator-induced diaphragm dysfunction (VIDD) has increasingly ventricle or the right atrium before terminating in the diaphragm.
gained recognition as a significant contributor to prolonged or unsuc­ As the primary muscle responsible for inspiration, the diaphragm
cessful liberation from mechanical ventilation in recent years. VIDD is serves as an essential component of the respiratory pump [13]. During
the phenomenon characterized by a loss of diaphragmatic the process of inhalation, the diaphragm contracts. This action reduces
force-generating capacity that is specifically associated with the use of intrapleural pressure, expands the lower rib cage, causes the lungs to
mechanical ventilation [7]. According to the methods employed to move downward, while simultaneously increasing intraabdominal
measure diaphragm function, the prevalence of diaphragm dysfunction pressure and displacing the abdominal contents downward [14]. The
during liberation from mechanical ventilation ranges from 25 % to 63 % force generated by the diaphragm can be quantified through trans­
[8–10]. This article aims to provide a review of the concept, clinical diaphragmatic pressure (Pdi), which represents the pressure gradient

* Corresponding author: 800 Stanton L Young Blvd, Suite 8400, Oklahoma City, OK, 73104, United States.
E-mail addresses: [email protected] (H. Wu), [email protected] (B. Chasteen).

https://doi.org/10.1016/j.rmed.2024.107541
Received 1 October 2023; Received in revised form 22 January 2024; Accepted 25 January 2024
Available online 28 January 2024
0954-6111/© 2024 Elsevier Ltd. All rights reserved.
H. Wu and B. Chasteen Respiratory Medicine 223 (2024) 107541

formed between the thoracic and abdominal cavities during diaphragm ubiquitination and subsequent proteasome degradation [32]. Titin,
contraction. Pdi is determined by calculating the difference between the serving as a mechanosensory component, regulates muscle protein
pressure in the stomach (referred to as gastric pressure, Pga) and the expression in a sarcomere strain-dependent manner and also plays a
esophageal pressure (Pes, acting as a substitute for intrapleural pres­ crucial role in activating pro-apoptotic pathways in the diaphragm [33].
sure): Pdi = Pga – Pes [15]. As intrapleural pressure decreases, it creates Diaphragm muscle fiber remodeling, including modification of the
a pressure gradient responsible for driving airflow and volume into the overall myosin heavy chain profile, has been observed in animal studies
lungs, known as transpulmonary pressure. Transpulmonary pressure can after controlled mechanical ventilation [7]. There is speculation that
be computed as the difference between airway pressure (Paw) and Pes (i. modifications in the expression of myogenic regulatory transcription
e., Paw – Pes). This transpulmonary pressure plays a key role in alveolar factor proteins, including myogenic determination factor (MyoD) and
ventilation and reflects the stress and strain applied to the lungs due to myogenin, might be implicated in the remodeling process.
the actions of the respiratory muscles and ventilator support.
4. Risk factors of VIDD
3. Evidence for VIDD
Controlled mechanical ventilation is the most common risk factor for
Animal studies have revealed that controlled mechanical ventilation VIDD. Other risk factors contributing to VIDD include excessive venti­
leads to decreased force-generating capacity of the diaphragm. The latory assistance, ventilator asynchrony, overuse of sedatives and
pressure-generating capacity and endurance of the diaphragm decline neuromuscular blocking agents, systemic inflammation and oxidative
by around 40–50 % within only a few days after initiation of controlled stress resulting from critical illness, pre-existing respiratory conditions
mechanical ventilation, and worsen as mechanical ventilation is pro­ (such as chronic obstructive pulmonary disease) or neuromuscular dis­
longed [16–18]. A progressive and severe decline in the rat diaphragm orders, inadequate nutritional support, and advanced age.
contractile function during controlled mechanical ventilation was
evident as early as 12 h [19]. Meanwhile, diaphragm muscle fiber 5. Potential diagnostic approaches in the ICU
remodeling was observed in rats that received controlled mechanical
ventilation. A reduction in diaphragmatic contractility has also been A variety of noninvasive and invasive methods have been employed
noted during assisted ventilation. Histological evidence of diaphragm to assess diaphragm function.
injury has been found in experimental settings where high levels of
pressure support ventilation were used [20]. Pressure support ventila­ 5.1. Transthoracic diaphragm ultrasound imaging
tion also led to a significant decrease in inspiratory effort when
compared to spontaneously breathing animals [20]. Diaphragm thickness increases during inspiration, and this increase
In 2008, Levine et al. conducted a landmark study on ventilated is correlated with the level of inspiratory effort [34,35]. Transthoracic
brain-dead organ donors, providing the first documented evidence of diaphragm ultrasound offers a noninvasive and feasible method to
rapid diaphragm fiber atrophy (both low-twitch and fast-twitch fibers) measure diaphragm thickness, making it a valuable tool for assessing
and enhanced proteolysis after as little as 18 h of mechanical ventilation diaphragm activity and function during mechanical ventilation. For
in humans [21]. A study aimed at evaluating diaphragm thickness and intercostal approach, a linear array ultrasound transducer is positioned
function, with 107 ventilated patients enrolled, found that about 50 % of in the ninth or tenth intercostal space, close to the right midaxillary line,
the patients experienced a 10 % decrease in diaphragm thickness during and angled perpendicular to the chest wall (zone of apposition) [36]. At
the first week of ventilation [22]. The study also observed that low this location, the diaphragm can be identified as a three-layered struc­
diaphragm contractile activity was associated with rapid decreases in ture situated superficial to the liver (Fig. 1). It consists of a relatively
thickness, while high contractile activity was linked to increases in non-echogenic muscular layer, which is enclosed by the echogenic
thickness. Assessing the function of those with increased thickness membranes of the diaphragmatic pleura and peritoneum [37]. Dia­
revealed significant weakness, indicating that the increase in thickness phragmatic thickness is measured using M-mode by determining the
might be indicative of structural injury rather than hypertrophy. distance between the diaphragmatic pleura and the peritoneum at
Furthermore, the study indicated that as ventilator driving pressure end-expiration (Tdi,ee) and peak inspiration (Tdi,pi; i.e., the maximum
increased and controlled ventilator modes were utilized, diaphragm thickness value during inspiration) [38]. Diaphragm thickening during
contractile activity declined. These findings suggest that VIDD is com­ inspiration (DTdi) is calculated as the difference between Tdi,pi and Tdi,
mon within the initial week of mechanical ventilation, and a combina­ ee. Diaphragm thickening fraction is calculated as DTdi/Tdi,ee. These
tion of low contractile diaphragm activity and/or higher ventilator ultrasound measurements of right hemidiaphragm thickness have been
driving pressure increases the risk of developing VIDD. This suggestion proven feasible and highly reproducible in ventilated patients [38].
was also confirmed in a recent meta-analysis [23]. Strenuous inspiratory Another approach is to measure diaphragm excursion by placing the
efforts can also lead to harm. Intense inspiratory efforts can result in probe subcostally [39]. This technique allows for the observation and
increased tidal volume, breath-stacking, and the pendeluft phenomenon measurement of the downward movement of the diaphragm during
[24]. A human study demonstrated sarcomere disruption in diaphragm inhalation. It’s important to note that the interpretation of these findings
samples following inspiratory loading [25]. Sarcomere disruption could is valid exclusively during spontaneous, unassisted breathing. This
be a critical structural injury that leads to diaphragm dysfunction as a distinction is essential because any downward displacement observed
result of high inspiratory loading. during assisted breathing may be attributed to passive lung inflation
The diaphragm muscle fiber changes and molecular mechanisms of caused by the mechanical ventilator. Consequently, diaphragm excur­
VIDD have been investigated. Muscle atrophy is one of the major dia­ sion cannot serve as a reliable indicator of diaphragm effort during
phragm muscle fiber changes associated with VIDD [7]. Decreased mechanical ventilation. Furthermore, it’s important to acknowledge
protein synthesis in the absence of anabolic hormones like insulin-like that the ultrasound technique does not directly measure actual dia­
growth factor-1 [26,27], as well as increased proteolysis due to phragm strength, and concerns about its reliability persist.
heightened expression of proteolytic enzymes such as calpain and
caspase-3 [28,29], constitute the molecular mechanisms at the core of 5.2. Transdiaphragmatic pressure recordings
diaphragmatic atrophy and filament depletion. Oxidative stress is
required for mechanical ventilation induced activation of calpain and The method of invasive transdiaphragmatic pressure (gastric
caspase-3 in the diaphragm and autophagy [30,31]. Mechanical venti­ pressure-esophageal pressure, Pdi = Pga – Pes) recordings by balloon
lation induces oxidative damage to sarcomeric proteins, followed by catheters placed in the stomach and esophagus is considered the gold

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H. Wu and B. Chasteen Respiratory Medicine 223 (2024) 107541

Fig. 1. Ultrasonography image of the right hemidiaphragm obtained in the zone of apposition. The probe is positioned between the ribs over the lateral chest wall. B-
mode imaging reveals the diaphragm can be identified as a three-layered structure just superficial to the liver bounded by pleural and peritoneal membranes. M-mode
imaging reveals the variation in diaphragm thickness over time. (Tdi,ee: distance between the diaphragmatic pleura and the peritoneum at end-expiration, Tdi,pi:
distance between the diaphragmatic pleura and the peritoneum at peak inspiration).

standard of diaphragm muscle strength testing. The pressure measured diaphragm dysfunction, such as shock, sepsis, and electrolyte distur­
in the stomach equals gastric (Pga), and hence abdominal pressure. The bances. Additionally, a comprehensive differential diagnosis should
pressure measured in esophagus (Pes) equals pleural pressure. The encompass other potential causes of diaphragm dysfunction, including
transdiaphragmatic pressure is measured following supramaximal critical illness myopathy and polyneuropathy, pleural effusion, myop­
magnetic stimulation of the phrenic nerve roots. Using this invasive athy or neuropathy due to medications (especially neuromuscular
measurement, it was shown that ventilated patients had impaired blocking agents or corticosteroids), Guillain-Barré Syndrome, amyo­
contractility of the diaphragm compared with healthy individuals [38]. trophic lateral sclerosis, myasthenia gravis, and congenital diaphrag­
Although this technique is able to evaluate the diaphragm strength matic hernia. Conducting a thorough clinical assessment, including a
directly, given the invasive feature, it has been applied in very limited review of medical history, physical examination, and diagnostic tests, is
clinical studies in ventilated patients [40,41]. The alternative is to crucial for differentiating VIDD from these diverse conditions.
measure the negative airway pressure at the tip of the endotracheal tube
following a magnetic supramaximal stimulation [23]. 7. Management of VIDD

5.3. Diaphragm electrical activity monitoring There is currently no established approach for directly treating or
reversing VIDD. Employing diaphragm-protective ventilation and
The utilization of specialized nasogastric tubing equipped with implementing inspiratory muscle training could potentially prevent
electromyography electrodes has significantly enhanced the ability to diaphragm weakening and facilitate the successful liberation from me­
monitor the electrical activity of the crural diaphragm (EAdi) at the chanical ventilation. Additionally, diaphragm neurostimulation is
bedside [42]. By assessing the ratio of the tidal EAdi change to the emerging as an innovative therapeutic method.
maximum EAdi, it becomes possible to estimate the patient’s respiratory
effort. Importantly, it should be noted that the maximum EAdi varies 7.1. Diaphragm-protective ventilation
among individuals, which makes establishing a definitive reference
range for EAdi challenging. Both animal and human studies have indicated the potential for
diaphragm atrophy when using controlled mechanical ventilation and
5.4. Maximum inspiratory pressures excessive ventilatory assistance in assisted modes (over-assistance
myotrauma). Conversely, attempting to avoid passive ventilation and
Maximum inspiratory pressures (PImax) can be conducted to eval­ excessive ventilatory assistance can pose a risk of high inspiratory efforts
uate global respiratory strength [42]. The test should be performed by for patients [43] which may lead to sarcomere disruption and dia­
an experienced operator who should strongly urge the patient to make phragm injury (under-assistance myotrauma). Therefore, it is crucial to
maximum inspiratory efforts at or near residual volume. The test is titrate inspiratory efforts to prevent VIDD (Table 1) [44].
volitional and requires full patient cooperation. It’s crucial to interpret In spontaneously breathing patients receiving assisted ventilation,
the results in conjunction with the patient’s complete clinical context. A there can be a difference in timing between mechanical breath delivery
low result may be due to lack of motivation and should not automati­ and diaphragmatic contraction. This asynchrony has the potential to
cally be seen as a sign of reduced inspiratory muscle strength. result in diaphragmatic injury (eccentric myotrauma) [45].
Applying higher positive end-expiratory pressure (PEEP) may reduce
6. Differential diagnosis the risk of both lung and diaphragm injury in some patients [44]. PEEP
serves to decrease atelectatic lung regions, promoting a more uniform
The techniques outlined above are employed to assess diaphragm distribution of inspiratory stress. This, in turn, can reduce the harmful
function in the ICU. Before establishing the diagnosis of VIDD, it is effects of uneven lung inflation associated with spontaneous breathing
crucial to address other acute conditions that may contribute to efforts [46]. Furthermore, an increase in PEEP can mitigate the force

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H. Wu and B. Chasteen Respiratory Medicine 223 (2024) 107541

Table 1 reverse triggering leads to potentially harmful consequences such as

Mechanisms of mechanical ventilation induced diaphragm injury [44]. double cycling, breath stacking, or strong inspiratory efforts, adjust­
Type of Diaphragm Causes ments to ventilator settings or transitioning the patient to a spontaneous
myotrauma injury ventilation mode should be considered. In some cases, reducing the
Over-assistance disuse and Excessive ventilator assistance respiratory rate can eliminate reverse triggering. Minimizing excessive
myotrauma atrophy Excessive sedation sedation, decreasing ventilatory support, and addressing metabolic
Under-assistance Load-induced Insufficient ventilator assistance alkalosis may alleviate ineffective efforts [52,54].
myotrauma injury Insufficient sedation Using neurally adjusted ventilatory assist (NAVA), the ventilator
Eccentric Load-induced Expiratory dyssynchrony (reverse
myotrauma injury triggering, premature cycling, ineffective
provides positive pressure in direct correlation to the electrical activity
efforts) of the diaphragm on a breath-by-breath basis [55]. The duration of each
Insufficient PEEP breath’s inspiration is determined by the patient’s effort, making NAVA
Expiratory Longitudinal Excessive PEEP effective in reducing asynchronies. Additionally, because the level of
myotrauma atrophy
assistance is proportionate to the patient’s effort, this allows the pa­
tient’s control-of-breathing system to regulate ventilation, preventing
generated by diaphragm contractions, making spontaneous efforts both over-assistance and under-assistance, and thereby enhancing dia­
potentially less harmful [47]. Conversely, it’s worth noting that the use phragm recovery [56].
of PEEP has also been observed to lead to longitudinal atrophy in dia­
phragm fibers (expiratory myotrauma) [48]. PEEP causes a caudal 7.1.3. Sedation strategies
displacement of the diaphragm, subsequently reducing the length of the Sedation can promote diaphragm-protective ventilation by allevi­
fibers. During spontaneous breathing trials, these shortened diaphragm ating excessive inspiratory effort and addressing asynchronies. Howev­
fibers are stretched to excessive sarcomere lengths, resulting in reduced er, it’s important to note that completely suppressing respiratory drive
muscle force generation. Additionally, PEEP might contribute to dia­ and effort through sedation can lead to diaphragm disuse atrophy.
phragm injury by increasing vascular resistance and reducing both total Therefore, a thoughtful and balanced approach to sedation is crucial.
and regional diaphragm perfusion [49]. Therefore, the possibility of Prior to administering sedation, it is important to address other factors
diaphragm weakness resulting from excessive PEEP should be that can elevate respiratory drive, such as metabolic acidosis or pain.
considered. Recent clinical practice guidelines have advocated for an “analgesia-first
A ventilation strategy aimed at protecting the diaphragm involves approach” to minimize the risk of excessive sedation [57]. This is based
avoiding controlled ventilation, extremely low or high inspiratory ef­ on findings that opioids have been linked to fewer instances of asyn­
forts, asynchronies, inappropriate PEEP levels, and ensuring appropriate chronies and reduced levels of consciousness compared to approaches
sedation. that primarily use sedatives. Propofol is the preferred sedative for
managing high respiratory drive. To prevent over-sedation, strategies
7.1.1. Titration of inspiratory effort involving the careful adjustment of sedatives or the interruption of
It is recommended to regularly monitor respiratory effort during sedation on a daily basis should be employed, with close monitoring of
mechanical ventilation [44,50]. Intensivists are encouraged to acquire respiratory drive and effort. For patients with no excessive respiratory
expertise in various techniques for assessing respiratory effort, including effort, dexmedetomidine can provide sedation, anxiety relief, and pain
esophageal manometry, diaphragm electrical activity measurement, management without inducing respiratory depression [58].
diaphragm ultrasound, airway occlusion pressure and trans­
diaphragmatic pressure assessment. Maintaining a respiratory effort 7.2. Inspiratory muscle training (IMT)
level similar to that of resting quiet breathing is likely optimal for dia­
phragm protection. The exact upper limit for acceptable respiratory IMT focuses on improving the strength and endurance of the dia­
effort remains uncertain. It is recommended to aim for esophageal phragm and accessory inspiratory muscles. IMT techniques include
pressure swings below 10–15 cmH2O and a diaphragm thickening threshold loading, resistive loading, and whole-body mobilization [59].
fraction in the intermediate range of 15–30 %. In a clinical trial Threshold loading and resistive loading represent the two primary types
including 40 patients who were intubated and mechanically ventilated of inspiratory muscle training techniques applied in critically ill pa­
in a partially supported mode, adjusting inspiratory support based on tients. In threshold loading, a threshold valve is applied to the airway,
diaphragm effort within a predefined “diaphragm-protective” range designed so that the patient’s respiratory muscles must generate a spe­
(mean transdiaphragmatic pressure between 3 and 12 cmH2O) was cific training pressure before it opens, allowing for inspiratory flow. The
successful [51]. Respiratory drive is closely linked to the magnitude of threshold load can be applied directly to the ventilator by configuring a
inspiratory efforts [52]. Evaluating the reasons behind low respiratory pressure trigger at the desired threshold pressure level. Resistive loading
drive, such as hyperoxemia, sedation, and metabolic alkalosis, as well as involves the application of a resistor to the airway, which raises the
the causes of high respiratory drive, such as hypoxemia, metabolic pressure requirement for the respiratory muscles to generate a specific
acidosis, anxiety, and pain, should precede any ventilation adjustments. flow.
Further research is required to develop implementation strategies that IMT regimens may vary widely in terms of load, frequency, and
promote maintaining modest inspiratory effort in clinical practice. duration. Studies have shown that IMT can improve inspiratory muscle
strength, exercise performance, and overall quality of life in patients
7.1.2. Identification and management of asynchronies with chronic pulmonary or cardiac diseases [60–63]. In a randomized
Asynchronies can manifest at various stages of mechanical respira­ controlled trial aiming to assess whether IMT could improve the liber­
tion. Diaphragm eccentric contractions can be associated with different ation from mechanical ventilation of patients who had previously failed
types of asynchronies, such as premature cycling, reverse triggering, and to wean, 69 patients were enrolled. IMT was conducted on 35 subjects
ineffective efforts during expiration [44]. Careful examination of the using a threshold inspiratory device, set at the highest pressure toler­
airway pressure and flow waveforms, along with direct monitoring of ated, and progressed daily [64]. Subjects completed 4 sets of 6–10
respiratory effort, can aid in the identification of these asynchronies. training breaths, 5 days per week. This trial demonstrated that IMT
The termination of asynchronies due to premature cycling off can be could result in increased Pimax and improved liberation from mechan­
accomplished by extending the mechanical inspiration time, increasing ical ventilation in patients who had previously failed to wean. A recent
the flow rate, and reducing the flow threshold for cycling off [53]. If meta analysis, which included 28 studies (N = 1185 patients), concluded
that IMT is feasible and well tolerated in critically ill patients and

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H. Wu and B. Chasteen Respiratory Medicine 223 (2024) 107541

improves both inspiratory and expiratory muscle strength [59]. The System) was placed to sedated, mechanically ventilated patients just
adverse events were uncommon during IMT sessions. Seven studies re­ before an elective atrial septal defect repair procedure [67]. The goal
ported no adverse events. Paradoxical breathing, tachypnea, and desa­ was to decrease the inspiratory pressure required from the ventilator to
turation were infrequent. Severe bradycardia, hemodynamic instability, maintain ventilation, with the aim of preventing VIDD. The decrease in
and syncope were rare. The impact of IMT on clinical outcomes will applied positive pressure during paced breaths demonstrated the active
require further confirmation in the future. contribution of the diaphragm. Among all 22 paced subjects, substantial
reductions in ventilator pressure-time-product were consistently ach­
ieved (range, 9.9–48.6 %; p < 0.001). No adverse events were observed
7.3. Diaphragm neurostimulation either immediately or during the two-week follow-up period.
The first randomized controlled trial to evaluate diaphragm neuro­
Stimulation of the phrenic nerve to pace the diaphragm is a tech­ stimulation to treat difficult to wean patients was published in 2022
nique in which a nerve stimulator delivers electrical impulses to the [74]. In this multicenter, open-label, randomized, controlled study, 112
phrenic nerve, inducing diaphragmatic contraction (Fig. 2.). This pro­ patients with prolonged mechanical ventilation and having failed at
cess may help prevent the decline in the diaphragm’s pressure- least two weaning attempts received transvenous diaphragm neuro­
generating capacity that can be induced by mechanical ventilation stimulation or usual care. In the intervention group (n = 43), patients
[18,65]. Since its first documentation in the 18th century, the applica­ received bilateral phrenic stimulation via a multielectrode central
tions of diaphragm neurostimulation have evolved, shifting from its venous catheter (Lungpacer Diaphragm Pacing Therapy System, Lung­
initial use in cardiopulmonary resuscitation to its current role in pacer Medical, Inc.) until extubation. Pacing sessions consisted of either
providing long-term ventilatory support [66]. The primary indications four sets of 10 or six sets of 10 consecutive manual stimulations, syn­
for this approach have expanded to include central alveolar hypo­ chronized with the ventilator, with a < 1-min separation between sets.
ventilation and high quadriplegia. Nevertheless, the application of dia­ Two to three sessions, totaling 120 stimulations per day, were conducted
phragm neurostimulation for assisted ventilation represents an for up to 30 days and stopped when patients successfully passed the SBT
innovative strategy aimed at promoting diaphragm-protective ventila­ and were extubated. Although no difference in successful liberation
tion and preventing VIDD [66]. from mechanical ventilator between groups was noticed, there was a
Animal studies revealed that diaphragm neurostimulation is associ­ dose-response relationship between the number of stimulations actually
ated with less diaphragm atrophy, damage and fiber disorganization delivered and increase in Pimax. A larger multicenter randomized
[68,69]. In an animal study, unilateral diaphragm neurostimulation was controlled trial, using the same technology with both liberation from
implemented in three mechanically ventilated sheep [69]. Hemi­ mechanical ventilation after 30 days and Pimax as primary endpoints,
diaphragms that were mechanically ventilated without diaphragm may provide more data (ClinicalTrials.gov ID NCT03783884).
neurostimulation exhibited severe damage, including hypercontracted Diaphragm neurostimulation can be established by cervical, thoracic
fibers with noticeable lipid droplet accumulation and a significant or abdominal approaches [66]. There are two types of neurostimulation:
edematous infiltrate within the interstitium, resulting in fiber disorga­ temporary and permanent. Temporary neurostimulation is more prac­
nization. These structural abnormalities were not observed in hemi­ tical in the ICU due to less invasive and feasible for critically ill patients.
diaphragms on the side receiving diaphragm neurostimulation. Transvenous phrenic nerve stimulation is one of the temporary neuro­
Additionally, signs of diaphragm fiber atrophy were markedly less stimulations that has been systematically evaluated in ICU patients.
pronounced in all the hemidiaphragms that received diaphragm neu­ Phrenic nerves are close to the superior vena cava on the right side and
rostimulation. Furthermore, the surface area of type 2 fibers was the innominate vein on the left side. A transvenous catheter with elec­
significantly larger in the hemidiaphragms that received diaphragm trodes can be placed and used to stimulate one or both phrenic nerves.
neurostimulation compared to those not receiving diaphragm Because of the potential risks linked to inserting the transvenous cath­
neurostimulation. eter, there is an ongoing investigation into the use of non-invasive
Case reports and cohort studies demonstrated that diaphragm neu­ electrical stimulation on the phrenic nerve in the neck [75].
rostimulation increases diaphragm thickness and diaphragm pressure Although diaphragm neurostimulation is a novel method under
generating capacity and may contribute to liberation from mechanical investigation to manage VIDD, it has limitations. Special training for
ventilation in ventilator dependent patients [70–73]. In the clinicians and support teams is needed, limiting its use to a few large
first-in-human series, diaphragm neurostimulation (Lungpacer© Intra­ academic medical centers. This method may potentially cause ventilator
Venous Electrode catheter and the Lungpacer© Diaphragm Pacing

Fig. 2. Diaphragm neurostimulation, adopted from S. Reynolds et al. [67]. A, Illustration of device set-up; B, Placement of a diaphragm neurostimulation catheter in
a subject.

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H. Wu and B. Chasteen Respiratory Medicine 223 (2024) 107541

asynchronies which attribute to excessive vital volume and diaphragm Writing – original draft. Bobby Chasteen: Resources, Writing – review
injury [66]. It may also lead to a pendulluft phenomenon (movement of & editing.
air within the lung from nondependent to dependent regions without
change in tidal volume) by strong spontaneous breathing during me­ Declaration of competing interest
chanical ventilation which may enhance lung damage. Large human
studies are needed to evaluate the effects of diaphragm contractions on None
hemodynamics, lung stress, lung strain, and gas exchange [66]. The
optimal approach to delivering and titrating therapy, including in­ References
tensity, frequency, and duration, has yet to be determined. Use of the
transvenous catheter for transvenous phrenic nerve stimulation may [1] A. Esteban, A. Anzueto, F. Frutos, I. Alía, L. Brochard, T.E. Stewart, et al.,
Characteristics and outcomes in adult patients receiving mechanical ventilation: a
increase the risk of central venous catheter-related bloodstream in­ 28-day international study, JAMA 287 (3) (2002) 345–355.
fections. Overcoming these issues presents a challenging task. [2] H. Wunsch, Mechanical ventilation in COVID-19: interpreting the current
epidemiology, Am. J. Respir. Crit. Care Med. 202 (1) (2020) 1–4.
[3] A.C. Kalil, M.L. Metersky, M. Klompas, J. Muscedere, D.A. Sweeney, L.B. Palmer, et
8. Knowledge gaps and future research on VIDD al., Management of adults with hospital-acquired and ventilator-associated
pneumonia: 2016 clinical practice guidelines by the infectious diseases society of
In recent decades, our understanding of VIDD has significantly America and the American thoracic society, Clin. Infect. Dis. 63 (5) (2016)
e61–e111.
advanced, and it is heartening to witness the emergence of novel in­ [4] A.S. Slutsky, V.M. Ranieri, Ventilator-induced lung injury, N. Engl. J. Med. 369
terventions for its prevention and treatment. Nevertheless, several (22) (2013) 2126–2136.
knowledge gaps persist and require further exploration. The acquisition [5] M.D. Eisner, B.T. Thompson, D. Schoenfeld, A. Anzueto, M.A. Matthay, Airway
pressures and early barotrauma in patients with acute lung injury and acute
of data to quantify the natural recovery of diaphragm function following
respiratory distress syndrome, Am. J. Respir. Crit. Care Med. 165 (7) (2002)
mechanical ventilation, coupled with an investigation of associated risk 978–982.
factors, takes on paramount importance in both current clinical practice [6] M.R. Pinsky, The hemodynamic consequences of mechanical ventilation: an
evolving story, Intensive Care Med. 23 (5) (1997) 493–503.
and future VIDD research due to the scarcity of such data. Ultrasound, a
[7] T. Vassilakopoulos, B.J. Petrof, Ventilator-induced diaphragmatic dysfunction, Am.
readily accessible and noninvasive tool in clinical practice, proves J. Respir. Crit. Care Med. 169 (3) (2004) 336–341.
invaluable for diagnosing VIDD. It offers potential advantages when [8] E. DiNino, E.J. Gartman, J.M. Sethi, F.D. McCool, Diaphragm ultrasound as a
integrated into decision-making algorithms that need development. predictor of successful extubation from mechanical ventilation, Thorax 69 (5)
(2014) 423–427.
Despite transdiaphragmatic pressure recording being considered the [9] W.Y. Kim, H.J. Suh, S.B. Hong, Y. Koh, C.M. Lim, Diaphragm dysfunction assessed
gold standard for assessing diaphragm function, its widespread adoption by ultrasonography: influence on weaning from mechanical ventilation, Crit. Care
faces barriers and challenges due to the need for clinicians to possess Med. 39 (12) (2011) 2627–2630.
[10] M. Dres, B.P. Dubé, J. Mayaux, J. Delemazure, D. Reuter, L. Brochard, et al.,
specialized procedural skills and for institutions to provide specific Coexistence and impact of limb muscle and diaphragm weakness at time of
support. Investigating these obstacles and formulating strategies to liberation from mechanical ventilation in medical intensive care unit patients, Am.
enhance its utilization becomes essential. Additionally, there is a need to J. Respir. Crit. Care Med. 195 (1) (2017) 57–66.
[11] P. Richard Drake, A. Wayne Vogl, Adam W.M. Mitchell, Richard Tibbitts,
develop alternative noninvasive, accurate, and easily implemented Paul Richardson, Gray’s Atlas of Anatomy, third ed., 2021.
techniques for evaluating diaphragm function. Ventilator asynchronies [12] S.C. Fell, Surgical anatomy of the diaphragm and the phrenic nerve, Chest Surg
pose common challenges for patients on mechanical ventilation. While Clin. 8 (2) (1998) 281–294.
[13] F.D. McCool, G.E. Tzelepis, Dysfunction of the diaphragm, N. Engl. J. Med. 366
recent technological advancements allow for the synchronization of the
(10) (2012) 932–942.
stimulator with the ventilator, additional studies are needed to identify [14] A.D. Troyer, T.A. Wilson, Action of the diaphragm on the rib cage, J. Appl. Physiol.
optimal strategies for minimizing the risk of patient-ventilator asyn­ 121 (2) (2016) 391–400, 1985.
chronies, including the use of volume control ventilation, deep sedation, [15] D. Laporta, A. Grassino, Assessment of transdiaphragmatic pressure in humans,
J. Appl. Physiol. 58 (5) (1985) 1469–1476, 1985.
and alternative approaches. Managing diaphragm neurostimulation, a [16] A. Anzueto, J.I. Peters, M.J. Tobin, R. de los Santos, J.J. Seidenfeld, G. Moore, et
promising novel strategy for addressing VIDD, requires guidance al., Effects of prolonged controlled mechanical ventilation on diaphragmatic
regarding its initiation, titration, and the assessment of tolerance and function in healthy adult baboons, Crit. Care Med. 25 (7) (1997) 1187–1190.
[17] P.J. Radell, S. Remahl, D.G. Nichols, L.I. Eriksson, Effects of prolonged mechanical
feasibility during continuous diaphragm neurostimulation. Further­ ventilation and inactivity on piglet diaphragm function, Intensive Care Med. 28 (3)
more, experimental drugs, including antioxidant agents, warrant further (2002) 358–364.
investigation. [18] C.S. Sassoon, V.J. Caiozzo, A. Manka, G.C. Sieck, Altered diaphragm contractile
properties with controlled mechanical ventilation, J. Appl. Physiol. 92 (6) (2002)
2585–2595, 1985.
9. Conclusions [19] L. Yang, J. Luo, J. Bourdon, M.C. Lin, S.B. Gottfried, B.J. Petrof, Controlled
mechanical ventilation leads to remodeling of the rat diaphragm, Am. J. Respir.
Crit. Care Med. 166 (8) (2002) 1135–1140.
VIDD has recently been recognized as an important factor compli­ [20] M.B. Hudson, A.J. Smuder, W.B. Nelson, C.S. Bruells, S. Levine, S.K. Powers, Both
cating the liberation from mechanical ventilation process. Research has high level pressure support ventilation and controlled mechanical ventilation
been dedicated to elucidating its mechanisms, developing diagnostic induce diaphragm dysfunction and atrophy, Crit. Care Med. 40 (4) (2012)
1254–1260.
approaches, and enhancing management strategies. Nevertheless, there
[21] S. Levine, T. Nguyen, N. Taylor, M.E. Friscia, M.T. Budak, P. Rothenberg, et al.,
are still knowledge gaps that require further investigation. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans,
N. Engl. J. Med. 358 (13) (2008) 1327–1335.
[22] E.C. Goligher, E. Fan, M.S. Herridge, A. Murray, S. Vorona, D. Brace, et al.,
Funding
Evolution of diaphragm thickness during mechanical ventilation. Impact of
inspiratory effort, Am. J. Respir. Crit. Care Med. 192 (9) (2015) 1080–1088.
This research did not receive any specific grant from funding [23] M. Dres, A. Demoule, Diaphragm dysfunction during weaning from mechanical
agencies in the public, commercial, or not-for-profit sectors. ventilation: an underestimated phenomenon with clinical implications, Crit. Care
22 (1) (2018) 73.
[24] T. Yoshida, V. Torsani, S. Gomes, R.R. De Santis, M.A. Beraldo, E.L. Costa, et al.,
Note Spontaneous effort causes occult pendelluft during mechanical ventilation, Am. J.
Respir. Crit. Care Med. 188 (12) (2013) 1420–1427.
[25] M. Orozco-Levi, J. Lloreta, J. Minguella, S. Serrano, J.M. Broquetas, J. Gea, Injury
Color does not need to be used for any figures in print. of the human diaphragm associated with exertion and chronic obstructive
pulmonary disease, Am. J. Respir. Crit. Care Med. 164 (9) (2001) 1734–1739.
CRediT authorship contribution statement [26] G. Gayan-Ramirez, M. Decramer, Effects of mechanical ventilation on diaphragm
function and biology, Eur. Respir. J. 20 (6) (2002) 1579–1586.

Huimin Wu: Conceptualization, Data curation, Methodology,

6
H. Wu and B. Chasteen Respiratory Medicine 223 (2024) 107541

[27] G. Gayan-Ramirez, K. de Paepe, P. Cadot, M. Decramer, Detrimental effects of inspiratory support to diaphragm effort: a randomized clinical trial, Crit. Care Med.
short-term mechanical ventilation on diaphragm function and IGF-I mRNA in rats, 50 (2) (2022) 192–203.
Intensive Care Med. 29 (5) (2003) 825–833. [52] K. Vaporidi, E. Akoumianaki, I. Telias, E.C. Goligher, L. Brochard,
[28] R.A. Shanely, M.A. Zergeroglu, S.L. Lennon, T. Sugiura, T. Yimlamai, D. Enns, et D. Georgopoulos, Respiratory drive in critically ill patients. Pathophysiology and
al., Mechanical ventilation-induced diaphragmatic atrophy is associated with clinical implications, Am. J. Respir. Crit. Care Med. 201 (1) (2020) 20–32.
oxidative injury and increased proteolytic activity, Am. J. Respir. Crit. Care Med. [53] D. Chiumello, P. Pelosi, E. Calvi, L.M. Bigatello, L. Gattinoni, Different modes of
166 (10) (2002) 1369–1374. assisted ventilation in patients with acute respiratory failure, Eur. Respir. J. 20 (4)
[29] X. Zhu, H.W.H. van Hees, L. Heunks, F. Wang, L. Shao, J. Huang, et al., The role of (2002) 925–933.
calpains in ventilator-induced diaphragm atrophy, Intensive Care Med Exp 5 (1) [54] J.A. Esperanza, L. Sarlabous, C. de Haro, R. Magrans, J. Lopez-Aguilar, L. Blanch,
(2017) 14. Monitoring asynchrony during invasive mechanical ventilation, Respir. Care 65 (6)
[30] M.A. Whidden, A.J. Smuder, M. Wu, M.B. Hudson, W.B. Nelson, S.K. Powers, (2020) 847–869.
Oxidative stress is required for mechanical ventilation-induced protease activation [55] W. Verbrugghe, P.G. Jorens, Neurally adjusted ventilatory assist: a ventilation tool
in the diaphragm, J. Appl. Physiol. 108 (5) (2010) 1376–1382, 1985. or a ventilation toy? Respir. Care 56 (3) (2011) 327–335.
[31] S.N. Hussain, M. Mofarrahi, I. Sigala, H.C. Kim, T. Vassilakopoulos, F. Maltais, et [56] R. Di Mussi, S. Spadaro, L. Mirabella, C.A. Volta, G. Serio, F. Staffieri, et al., Impact
al., Mechanical ventilation-induced diaphragm disuse in humans triggers of prolonged assisted ventilation on diaphragmatic efficiency: NAVA versus PSV,
autophagy, Am. J. Respir. Crit. Care Med. 182 (11) (2010) 1377–1386. Crit. Care 20 (2016) 1.
[32] P.E. Hooijman, A. Beishuizen, C.C. Witt, M.C. de Waard, A.R. Girbes, A. [57] J.W. Devlin, Y. Skrobik, C. Gélinas, D.M. Needham, A.J.C. Slooter, P.
M. Spoelstra-de Man, et al., Diaphragm muscle fiber weakness and ubiquitin- P. Pandharipande, et al., Clinical practice guidelines for the prevention and
proteasome activation in critically ill patients, Am. J. Respir. Crit. Care Med. 191 management of pain, agitation/sedation, delirium, immobility, and sleep
(10) (2015) 1126–1138. disruption in adult patients in the ICU, Crit. Care Med. 46 (9) (2018) e825–e873.
[33] R.J. van der Pijl, H.L. Granzier, C.A.C. Ottenheijm, Diaphragm contractile [58] J.P. Belleville, D.S. Ward, B.C. Bloor, M. Maze, Effects of intravenous
weakness due to reduced mechanical loading: role of titin, Am. J. Physiol. Cell dexmedetomidine in humans. I. Sedation, ventilation, and metabolic rate,
Physiol. 317 (2) (2019). C167-c76. Anesthesiology 77 (6) (1992) 1125–1133.
[34] D. Cohn, J.O. Benditt, S. Eveloff, F.D. McCool, Diaphragm thickening during [59] S. Vorona, U. Sabatini, S. Al-Maqbali, M. Bertoni, M. Dres, B. Bissett, et al.,
inspiration, J. Appl. Physiol. 83 (1) (1997) 291–296, 1985. Inspiratory muscle rehabilitation in critically ill adults. A systematic review and
[35] E. Vivier, A. Mekontso Dessap, S. Dimassi, F. Vargas, A. Lyazidi, A.W. Thille, et al., meta-analysis, Ann Am Thorac Soc 15 (6) (2018) 735–744.
Diaphragm ultrasonography to estimate the work of breathing during non-invasive [60] R. Gosselink, J. De Vos, S.P. van den Heuvel, J. Segers, M. Decramer, G. Kwakkel,
ventilation, Intensive Care Med. 38 (5) (2012) 796–803. Impact of inspiratory muscle training in patients with COPD: what is the evidence?
[36] D. Matamis, E. Soilemezi, M. Tsagourias, E. Akoumianaki, S. Dimassi, F. Boroli, et Eur. Respir. J. 37 (2) (2011) 416–425.
al., Sonographic evaluation of the diaphragm in critically ill patients. Technique [61] I.S. Silva, G.A. Fregonezi, F.A. Dias, C.T. Ribeiro, R.O. Guerra, G.M. Ferreira,
and clinical applications, Intensive Care Med. 39 (5) (2013) 801–810. Inspiratory muscle training for asthma, Cochrane Database Syst. Rev. 2013 (9)
[37] F.D. McCool, P. Conomos, J.O. Benditt, D. Cohn, C.B. Sherman, F.G. Hoppin Jr., (2013) Cd003792.
Maximal inspiratory pressures and dimensions of the diaphragm, Am. J. Respir. [62] W.D. Reid, E.L. Geddes, K. O’Brien, D. Brooks, J. Crowe, Effects of inspiratory
Crit. Care Med. 155 (4) (1997) 1329–1334. muscle training in cystic fibrosis: a systematic review, Clin. Rehabil. 22 (10–11)
[38] E.C. Goligher, F. Laghi, M.E. Detsky, P. Farias, A. Murray, D. Brace, et al., (2008) 1003–1013.
Measuring diaphragm thickness with ultrasound in mechanically ventilated [63] D. Montemezzo, G.A. Fregonezi, D.A. Pereira, R.R. Britto, W.D. Reid, Influence of
patients: feasibility, reproducibility and validity, Intensive Care Med. 41 (4) (2015) inspiratory muscle weakness on inspiratory muscle training responses in chronic
642–649. heart failure patients: a systematic review and meta-analysis, Arch. Phys. Med.
[39] T. Schepens, S. Fard, E.C. Goligher, Assessing diaphragmatic function, Respir. Care Rehabil. 95 (7) (2014) 1398–1407.
65 (6) (2020) 807–819. [64] A.D. Martin, B.K. Smith, P.D. Davenport, E. Harman, R.J. Gonzalez-Rothi, M. Baz,
[40] A.C. Watson, P.D. Hughes, M. Louise Harris, N. Hart, R.J. Ware, J. Wendon, et al., et al., Inspiratory muscle strength training improves weaning outcome in failure to
Measurement of twitch transdiaphragmatic, esophageal, and endotracheal tube wean patients: a randomized trial, Crit. Care 15 (2) (2011) R84.
pressure with bilateral anterolateral magnetic phrenic nerve stimulation in patients [65] G. Le Bourdelles, N. Viires, J. Boczkowski, N. Seta, D. Pavlovic, M. Aubier, Effects
in the intensive care unit, Crit. Care Med. 29 (7) (2001) 1325–1331. of mechanical ventilation on diaphragmatic contractile properties in rats, Am. J.
[41] S.E. Cattapan, F. Laghi, M.J. Tobin, Can diaphragmatic contractility be assessed by Respir. Crit. Care Med. 149 (6) (1994) 1539–1544.
airway twitch pressure in mechanically ventilated patients? Thorax 58 (1) (2003) [66] H. Etienne, I.S. Morris, G. Hermans, L. Heunks, E.C. Goligher, S. Jaber, et al.,
58–62. Diaphragm neurostimulation assisted ventilation in critically ill patients, Am. J.
[42] P. Laveneziana, A. Albuquerque, A. Aliverti, T. Babb, E. Barreiro, M. Dres, et al., Respir. Crit. Care Med. 207 (10) (2023) 1275–1282.
ERS statement on respiratory muscle testing at rest and during exercise, Eur. [67] S. Reynolds, A. Ebner, T. Meffen, V. Thakkar, M. Gani, K. Taylor, et al., Diaphragm
Respir. J. 53 (6) (2019). activation in ventilated patients using a novel transvenous phrenic nerve pacing
[43] V. Karageorgos, A. Proklou, K. Vaporidi, Lung and diaphragm protective catheter, Crit. Care Med. 45 (7) (2017) e691–e694.
ventilation: a synthesis of recent data, Expet Rev. Respir. Med. 16 (4) (2022) [68] S.C. Reynolds, R. Meyyappan, V. Thakkar, B.D. Tran, M.A. Nolette, G. Sadarangani,
375–390. et al., Mitigation of ventilator-induced diaphragm atrophy by transvenous phrenic
[44] E.C. Goligher, M. Dres, B.K. Patel, S.K. Sahetya, J.R. Beitler, I. Telias, et al., Lung- nerve stimulation, Am. J. Respir. Crit. Care Med. 195 (3) (2017) 339–348.
and diaphragm-protective ventilation, Am. J. Respir. Crit. Care Med. 202 (7) [69] H. Masmoudi, C. Coirault, A. Demoule, J. Mayaux, M. Beuvin, N. Romero, et al.,
(2020) 950–961. Can phrenic stimulation protect the diaphragm from mechanical ventilation-
[45] T. Shimatani, N. Shime, T. Nakamura, S. Ohshimo, J. Hotz, R.G. Khemani, Neurally induced damage? Eur. Respir. J. 42 (1) (2013) 280–283.
adjusted ventilatory assist mitigates ventilator-induced diaphragm injury in [70] N.T. Ayas, F.D. McCool, R. Gore, S.L. Lieberman, R. Brown, Prevention of human
rabbits, Respir. Res. 20 (1) (2019) 293. diaphragm atrophy with short periods of electrical stimulation, Am. J. Respir. Crit.
[46] C.C.A. Morais, Y. Koyama, T. Yoshida, G.M. Plens, S. Gomes, C.A.S. Lima, et al., Care Med. 159 (6) (1999) 2018–2020.
High positive end-expiratory pressure renders spontaneous effort noninjurious, [71] A.D. Martin, A.M. Joseph, T.M. Beaver, B.K. Smith, T.D. Martin, K. Berg, et al.,
Am. J. Respir. Crit. Care Med. 197 (10) (2018) 1285–1296. Effect of intermittent phrenic nerve stimulation during cardiothoracic surgery on
[47] L.D. Pengelly, A.M. Alderson, J. Milic-Emili, Mechanics of the diaphragm, J. Appl. mitochondrial respiration in the human diaphragm, Crit. Care Med. 42 (2) (2014)
Physiol. 30 (6) (1971) 797–805. e152–e156.
[48] J. Lindqvist, M. van den Berg, R. van der Pijl, P.E. Hooijman, A. Beishuizen, [72] B. Ahn, T. Beaver, T. Martin, P. Hess, B.A. Brumback, S. Ahmed, et al., Phrenic
J. Elshof, et al., Positive end-expiratory pressure ventilation induces longitudinal nerve stimulation increases human diaphragm fiber force after cardiothoracic
atrophy in diaphragm fibers, Am. J. Respir. Crit. Care Med. 198 (4) (2018) surgery, Am. J. Respir. Crit. Care Med. 190 (7) (2014) 837–839.
472–485. [73] E. Keough-Delgado, L. López-Rodríguez, B. de Olaiz, A. Bertomeu-García,
[49] A.G. Horn, D.R. Baumfalk, K.M. Schulze, O.N. Kunkel, T.D. Colburn, R.E. Weber, et Ó. Peñuelas, M. Jiménez-Fernández, et al., Case Studies in Physiology:
al., Effects of elevated positive end-expiratory pressure on diaphragmatic blood physiological and clinical effects of temporary diaphragm pacing in two patients
flow and vascular resistance during mechanical ventilation, J. Appl. Physiol. 129 with ventilator-induced diaphragm dysfunction, J. Appl. Physiol. 130 (6) (2021)
(3) (2020) 626–635, 1985. 1736–1742, 1985.
[50] E.C. Goligher, A.H. Jonkman, J. Dianti, K. Vaporidi, J.R. Beitler, B.K. Patel, et al., [74] M. Dres, M.G. de Abreu, H. Merdji, H. Muller-Redetzky, D. Dellweg, W.
Clinical strategies for implementing lung and diaphragm-protective ventilation: J. Randerath, et al., Randomized clinical study of temporary transvenous phrenic
avoiding insufficient and excessive effort, Intensive Care Med. 46 (12) (2020) nerve stimulation in difficult-to-wean patients, Am. J. Respir. Crit. Care Med. 205
2314–2326. (10) (2022) 1169–1178.
[51] H.J. de Vries, A.H. Jonkman, H.J. de Grooth, J.W. Duitman, A.R.J. Girbes, C.A. [75] C. Keogh, F. Saavedra, S. Dubo, P. Aqueveque, P. Ortega, B. Gomez, et al., Non-
C. Ottenheijm, et al., Lung- and diaphragm-protective ventilation by titrating invasive phrenic nerve stimulation to avoid ventilator-induced diaphragm
dysfunction in critical care, Artif. Organs 46 (10) (2022) 1988–1997.