American Journal of Respiratory and Critical Care Medicine

Evidence has accumulated that respiratory muscle dysfunction develops in critically ill patients and contributes to prolonged weaning from mechanical ventilation. Accordingly, it seems highly appropriate to monitor the respiratory muscles in these patients. Today, we are only at the beginning of routinely monitoring respiratory muscle function. Indeed, most clinicians do not evaluate respiratory muscle function in critically ill patients at all. In our opinion, however, practical issues and the absence of sound scientific data for clinical benefit should not discourage clinicians from having a closer look at respiratory muscle function in critically ill patients. This perspective discusses the latest developments in the field of respiratory muscle monitoring and possible implications of monitoring respiratory muscle function in critically ill patients.

The physiological status of critically ill patients is characterized by rapidly evolving and frequently life-threatening derangements as well as “silent” yet important alterations in organ function. The intensive care unit (ICU) environment is specifically equipped to monitor the critically ill patient. Intensivists monitor cardiac, pulmonary, and kidney function more or less continuously, and other organs or tissues, such as bone marrow and gastrointestinal tract, are closely monitored as well.

Despite growing evidence that respiratory muscle dysfunction develops in critically ill patients and contributes to weaning failure (13), the respiratory muscles are poorly monitored in the ICU. Therefore, diaphragm dysfunction is usually unrecognized in the ICU and only becomes apparent when a patient fails to wean from mechanical ventilation. This may be related to: (1) the limited knowledge of health care workers on the effects of critical illness on respiratory muscle function, (2) the limited availability and knowledge of tools to monitor respiratory muscle function in critically ill patients, or (3) the perception that monitoring respiratory muscle function has no clinical consequences.

In this perspective, we discuss the latest developments in the field of respiratory muscle monitoring (Table 1) and possible implications of monitoring respiratory muscle function in the critically ill. The effects of critical illness on respiratory muscle function will be described briefly.


Diagnostic ToolParameterComment
Pressure and flow recordings
 Airway pressure/flowInspiratory muscle strength (PImax)Easy to perform voluntary measurements of global respiratory muscle strength. High values exclude respiratory muscle weakness. Low values may reflect poor technique or effort rather than respiratory muscle weakness (23).
Expiratory muscle strength (PEmax)
Neural respiratory drive (P0.1)Available in most mechanical ventilators, but of limited value due to wide normal range (25).
 Transdiaphragmatic pressure*Diaphragm strength (Pdimax/ sniff Pdi)Voluntary measures of specific diaphragm strength. High values exclude respiratory muscle weakness. Low values may reflect poor technique or effort rather than respiratory muscle weakness (23).
Gilbert indexThese indices are frequently used for research purposes but without dedicated software are too complicated for routine clinical use.
Tension time index/pressure-time product
Neural respiratory drive (EAdi)Direct measure of respiratory output from the brainstem; no normal values available.
Patient–ventilator synchronyGold standard for detection of patient–ventilator asynchronies.
Neuroventilatory and neuromechanical efficiencyRelatively new indices still under evaluation; no normal values available.
Phrenic nerve stimulation
Diaphragm strength (Pditw / Pmotw)Nonvoluntary evaluation of diaphragm function, fairly invasive and technically difficult. Should be performed only in experienced centers in selected patients.
Phrenic nerve conduction time
 Chest X-rayDiaphragm positionAtelectasis, pneumonia, and diaphragmatic eventration complicate findings of hemidiaphragmatic elevation.
 FluoroscopyDiaphragm motionMisleading in patients with bilateral diaphragmatic paralysis and radiation exposure (44).
 Ultrasonography (B/M-mode)Diaphragm thickness/motionWell characterized, noninvasive, and easy to perform at bedside (47). M-mode difficult to perform for left hemidiaphragm. Technique of limited value during assisted breathing.
 CT/MRIDiaphragm position/motionApplicability for monitoring is very limited.
Circulatory biomarkersTroponin IThe relation between plasma troponin I levels and functional measures in critically ill patients has not yet been investigated.

Definition of abbreviations: CT = computed tomography; EAdi = electrical activity of the diaphragm; MRI = magnetic resonance imaging; P0.1 = mouth pressure generated in the first 100 milliseconds of inspiration; Pdi = transdiaphragmatic pressure; PEmax = maximal expiratory pressure; PImax = maximal inspiratory pressure; Pmo = mouth pressure.

*Requires placement of nasogastric tube.

The effects of critical illness on respiratory muscle function are often part of a more generalized phenomenon, known as “ICU-acquired weakness.” It should be recognized that ICU weakness may result from alteration in muscle or nerve function, and in fact both often migrate together. Factors such as systemic inflammation, drugs, electrolyte disturbances, and immobility have been identified in the pathogenesis of ICU-acquired weakness (4). The clinical relevance of ICU-acquired weakness is supported by the observations that prolonged mechanical ventilation is associated with decreased diaphragm strength (3) and that muscle weakness is among the most prominent long-term complications of survivors of acute respiratory distress syndrome (ARDS) (5).

Besides generalized weakness, there is evidence that mechanical ventilation itself is an important cause of diaphragm dysfunction, which is collectively referred to as “ventilator-induced diaphragm dysfunction” (6). In a landmark paper, Levine and colleagues demonstrated that only a few days of controlled mechanical ventilation is associated with atrophy of the diaphragm but not the pectoralis major (7). In a recent study, Jaber and colleagues reported the functional consequences of critical illness on respiratory muscles (2). They found approximately 30% reduction in twitch airway pressure induced by magnetic phrenic nerve stimulation in the first 5 to 6 days of invasive mechanical ventilation, indicating the rapid development of diaphragm weakness.

In the last decade the understanding of the molecular and cellular mechanisms underlying respiratory muscle weakness in the critically ill has been the subject of intensive research (extensively reviewed in References 8 and 9). To summarize, an imbalance between proteolysis and protein synthesis results in a loss of contractile proteins (7, 10). In addition, function of remaining muscle proteins may be impaired by enhanced oxidation and dephosphorylation (1113). Inflammation and oxidative stress are the major drivers of these impairments (13). Figure 1 provides a graphic representation of conditions and their pathways contributing to acquired diaphragm weakness in critically ill patients.

History, Symptoms, and Signs

A patient’s past medical history can provide information on the patient’s premorbid functional status and, in particular, preexistent respiratory muscle dysfunction. Weakness of the respiratory muscles occurs in a variety of neuromuscular disorders (14) but also in nonmyopathic chronic diseases, such as chronic obstructive pulmonary disease and congestive heart failure (15, 16). Other conditions that may precipitate respiratory and peripheral muscle dysfunction include aging (sarcopenia) and cachexia (17, 18). A patient’s medication history should be reviewed, because respiratory muscle function can be negatively affected by drugs, including steroids, sedatives, and analgetics (1921).

Clinical examination may reveal evidence of respiratory muscle weakness. Accessory respiratory muscle recruitment, especially the sternocleidomastoid muscle, may be apparent by palpation in patients when inspiratory load exceeds the capacity of the diaphragm (22). When the diaphragm is very weak, a supine abdominal paradox can be observed. Conversely, care must be taken in assessing abdominal wall motion in patients actively exhaling. Contraction of the abdominal muscles during expiration and subsequent relaxation as an assistance to inspiration may give the appearance of outward motion of the anterior abdominal wall during inspiration. Thus, activation of the abdominal muscles during expiration could also be regarded as a sign of respiratory muscle dysfunction.

Pressure and Flow Recordings
Airway pressure and flow

Although routine assessment of respiratory muscle function using airway pressures is common in several diseases, such as chronic obstructive pulmonary disease, very few clinicians actually measure global respiratory muscle strength in the ICU. A maximal static inspiratory (Mueller maneuver) and expiratory maneuver can be obtained in intubated patients to evaluate global inspiratory (PImax) and expiratory (PEmax) muscle strength. Both can be measured either while the patient is connected to the ventilator or during brief disconnection using a handheld pressure monitoring device. Voluntary maneuvers require patient cooperation and are influenced by sedation level, anxiety, and pain. Therefore, high values exclude clinically significant weakness, but low values are common and may reflect poor technique or effort as well (23). To obtain more reliable measurements of PImax in ventilated and sedated patients, a 20-second end-expiratory occlusion period can be performed (24). A T-piece with one-way valves should be attached to the endotracheal tube to allow expiration but obstruct inspiration.

Airway pressure (Paw) generated in the first 100 milliseconds of inspiration (P0.1) has been used as an index of neural respiratory drive. Interpretation of P0.1 is limited by its wide normal range and dependency on lung volume and contractile properties of the diaphragm; nevertheless, the technique remains useful when its limitations are recognized (25).

Transdiaphragmatic pressure

In contrast to PImax, a specific measure of diaphragm muscle strength is transdiaphragmatic pressure (Pdi). Pdi is the difference between abdominal and pleural pressure. In practice, the difference between esophageal (Pes) and gastric pressure (Pga) is used to calculate Pdi. Voluntary measurements of maximum Pdi can be obtained by having the patients inspire as forcefully as possible against a closed airway (26) or by having the patient sniff forcefully (27). Sniff Pdi appears to be more reproducible than maximum inspiratory Pdi (27). The Gilbert index (ΔPga/ΔPdi) can be used to determine the relative contribution of the diaphragm to inspiration (28). The higher this index, the greater is the contribution of the diaphragm to total inspiratory effort. In case of a paralyzed diaphragm, the Gilbert index becomes negative. To estimate the energy expenditure of the diaphragm, the tension-time index and pressure-time product of the diaphragm can be calculated using Pdi (29, 30). These indices are frequently used for research purposes, but without dedicated software they are too complicated for routine clinical use.

Today, gastric and esophageal balloons are extensively used for research purpose but are not used routinely in clinical care. This is probably the result of the perceived invasiveness of the procedure and technical difficulties. It should be noted that techniques that are much more invasive and probably at least as complex (i.e., pulmonary artery catheter) are used to measure cardiac function in selected critically ill patients. Interestingly, in a recent study, esophageal pressure measurement was used to guide positive end-expiratory pressure setting, indicating the applicability in clinical care (31). In fact, some of the modern ventilators have auxiliary ports to measure esophageal pressure, which is a step forward to implement measurement of esophageal pressure in clinical care. However, one should keep in mind that Pdi is influenced by positive pressure of the mechanical ventilator and ideally should be measured during a trial of spontaneous breathing.

In conclusion, PImax and PEmax can be used as a global measure for respiratory muscle function and possibly to monitor the response of respiratory muscle training. We recommend the use of esophageal catheters only for monitoring diaphragm function in selected ICU patients, such as those with difficult weaning (32). In these patients, esophageal and gastric pressures could be used to closely monitor the role of the diaphragm in weaning failure (32).


Electromyography (EMG) comprises the temporal and spatial summation of neural impulses from the brain that are translated into muscle fiber action potentials. Diaphragm EMG can be recorded best using an esophageal catheter with multiple electrodes and has already proven its use as a powerful research tool (33). Today, the (processed) EMG signal can be obtained rather easily and continuously in ICU patients, which opens windows for using this tool in patient monitoring. The processed signal is referred to as the amplitude of the electrical activity of the diaphragm (EAdi). EAdi may be helpful in monitoring respiratory muscle loading, patient–ventilator synchrony, and efficiency of breathing in critically ill patients.

Respiratory muscle loading

An important goal of mechanical ventilation is to unload the respiratory muscles. The ratio of actual EAdi to maximum EAdi is a measure of the patient’s effort to breath, in which maximum EAdi can be defined as the peak activity observed during a 20-second inspiratory occlusion (24). A too-low ratio suggests a too-high level of support, whereas a high ratio strongly suggests inadequate unloading of the respiratory muscles. In controlled mechanical ventilation, disuse of the diaphragm results in atrophy within a few days (7). High levels of pressure support may also suppress output from the respiratory centers by overassistance resulting in respiratory muscle atrophy and contractile dysfunction (34, 35). In ARDS, extracorporeal membrane oxygenation (ECMO) improves oxygenation and carbon dioxide elimination. ECMO sweep gas flow can be adjusted to regulate carbon dioxide elimination. In patients recovering from ARDS, EAdi increases in response to decreasing ECMO sweep gas flow and vice versa (36). In selected cases, monitoring of EAdi during ECMO allows titration of sweep gas flow to prevent extreme unloading of the diaphragm. Besides an increase in EAdi, high inspiratory loading and/or low inspiratory muscle capacity is also characterized by recruitment of the accessory inspiratory muscles. Data show that with decreasing levels of support the accessory muscle are increasingly activated (37). Although clinical implications of this observation are still unclear, it seems reasonable to assume that an increase in accessory muscle recruitment is the result of inadequate unloading. In the future, activity of accessory muscle may play a role in determining optimal ventilator settings.

Patient–ventilator synchrony

To date, visual inspections of flow and pressure waveforms are used to detect patient–ventilator asynchronies. However, it has been shown that the ability of ICU physicians, even experts, to do so is overall quite low and decreases at higher prevalence of asynchronies (38). Because EAdi is a direct measure of neural respiratory drive, it can be used to detect the onset and duration of neural inspiration and expiration. Consequently, monitoring EAdi could be considered the gold standard for detection of patient–ventilator asynchronies, including trigger delays, early and late cycling off, auto triggering, double triggering, and wasted efforts (Figure 2).

Neuroventilatory and neuromechanical efficiency

Currently, new indices are evaluated for respiratory muscle function in ventilated patients. The ratio between Vt and EAdi represents neuroventilatory efficiency (NVE) of the diaphragm. An improved NVE indicates that a patient is able to generate the same Vt with lower levels of EAdi, whereas a higher EAdi suggests the opposite. NVE has been used to discriminate between extubation failure and success in patients weaning from mechanical ventilation (39). Evidently, NVE is sensitive to changes in diaphragm function (atrophy, fatigue, and hyperinflation) as well as a patient’s load of breathing (airway compliance and resistance). Monitoring the ratio between Pdi and EAdi, representing neuro-mechanical efficiency (NME), excludes the influence of a patient’s load of breathing. A gradual decrease in NME over days indicates the development of diaphragm weakness, whereas an increase suggests recovery.


Diaphragm EMG is feasible in routine clinical care for monitoring respiratory muscle function. However, we still face several challenges. First, there is the need to identify the target level of EAdi or NVE that should be attained in the day-to-day management of mechanically ventilated patients. Second, it should be recognized that respiratory muscle activity is also suppressed by sedatives, in particular propofol and morphine-like analgetics (40). Third, insertion of an esophageal catheter carries a (low) risk for complications and may be an uncomfortable procedure in nonsedated patients. Nevertheless, most critically ill patients require nasogastric tubes for feeding, which are already commercially available with EMG electrodes (Maquet Critical Care, Solna, Sweden). Taken together, EAdi is a rational parameter to monitor respiratory muscle unloading and patient–ventilator synchrony from an early phase of critical illness. We expect that in the near future EAdi will become an important tool for respiratory muscle monitoring during mechanical ventilation and weaning (39, 41).

Phrenic Nerve Stimulation

Magnetic phrenic nerve stimulation allows nonvoluntary evaluation of diaphragm strength, measured as the magnitude of twitch transdiaphragmatic pressure (Pditw) or twitch airway pressure (Pawtw) (42). The integrity of the phrenic nerve, in response to stimulation, can be tested by recording the compound muscle action potential (CMAP) of the diaphragm (43). This allows calculation of phrenic nerve conduction time and subsequent detection of phrenic nerve injury. Phrenic nerve stimulation has been extensively used in research settings. The technique, however, is not applicable for routine bedside monitoring because of the fairly invasive nature, technical difficulties, and limitations concerning patients’ condition and tolerance. Therefore, this technique should be restricted for diagnostic purposes to a selection of patients (difficult weaning from mechanical ventilation) in centers that have sufficient experience with this technique.


Conventional radiography can be used for evaluating the position (chest X-ray) and motion (fluoroscopy) of the diaphragm. Elevation of the hemidiaphragm may be seen with hemidiaphragm paralysis. The clinical utility of this finding, however, is limited, as hemidiaphragmatic elevation can occur in the absence of paralysis, such as with atelectasis, pneumonia, and diaphragmatic eventration. Compared with chest X-ray, fluoroscopy provides more dynamic information and can be used to detect unilateral diaphragm paralysis. However, fluoroscopy is less helpful when the hemidiaphragm is weak but not completely paralyzed, and it can be particularly misleading in patients with bilateral diaphragmatic paralysis (44). Moreover, fluoroscopy is not suitable as a bedside monitoring tool.


Several recent studies have demonstrated the utility of ultrasonography for diaphragm muscle imaging. B-mode ultrasonography using a linear array transducer can be used to assess the diaphragm thickness in the zone of apposition (45, 46), an echogenic layer bordered by pleural and peritoneal membranes. Another promising method is the noninvasive evaluation of diaphragm motion with M-mode ultrasonography. With this mode, a phased array transducer is positioned subcostal or low intercostal between the midclavicular and midaxillary lines. Procedure, reproducibility, and normal values have been assessed recently in a large population of healthy subjects (47). In Figure 3, M-mode images are shown from a patient with normal diaphragm motion and diaphragm paralysis. Ultrasonography takes little time to perform, is noninvasive, and can be performed at the bedside. However, diaphragm ultrasonography will only provide useful information during unassisted breathing and is therefore of limited relevance in the very early course of critical illness.

More complex imaging techniques, such as magnetic resonance imaging and computed tomography, have been used to evaluate diaphragm function (48, 49) but are not suitable for monitoring, as these techniques are cumbersome in mechanically ventilated patients and should only be used for specific diagnostic purposes.

Circulatory Biomarkers

Studies in critically ill patients and ventilated animals revealed that respiratory muscle weakness is associated with muscle fiber damage and loss of contractile proteins (2, 7, 10, 12, 13). Considering the important role of plasma markers in the diagnosis of myocardial damage and rhabdomyolysis, it could be reasoned that the detection of muscle-specific proteins in plasma would be a valuable tool to monitor damage of the respiratory muscles. Although potential candidates include classical markers, such as creatine kinase and myoglobin, the clinical use of these markers is probably hampered by their large range in healthy individuals and nonspecificity for structural damage (50). Recent experimental findings indicate that measuring serum levels of skeletal muscle troponin I is more sensitive to detect structural injury of respiratory muscles (51). However, the relation between plasma troponin I levels and functional measures in critically ill patients has not yet been investigated. Of note, respiratory muscle weakness in the critically ill is often part of generalized muscle weakness. In those cases, evaluation of circulatory biomarkers of skeletal muscle damage may not specifically reflect the functioning of respiratory muscles but could rather represents overall skeletal muscle function.

Given the detrimental effects of critical illness, monitoring respiratory muscle function is a reasonable approach, even in the absence of evidence-based therapeutic implications. If monitoring indicates rapid loss of respiratory muscle function, then factors that negatively affect muscle function should be restricted as much as possible, including disuse by overassistance, patient–ventilator asynchrony, and drugs associated with side effects on muscle function. In fact, this is to a certain extent analogous to monitoring renal function in critically ill patients. There are no direct therapeutic implications in monitoring renal function, but clinicians will avoid certain nephrotoxic drugs when renal function is impaired.

Monitoring in the Early Phase

In the early phase of critical illness, monitoring of the respiratory muscles should focus on minimizing the negative effects of mechanical ventilation. During this phase, clinicians should avoid too-high (overassist) as well as too-low levels of pressure support. Although the width of this therapeutic margin is unknown, monitoring EAdi might prove helpful to detect suppressed output from the respiratory centers by overassistance as well as excessive respiratory drive during inadequate unloading. A considerable group of mechanically ventilated patients (25%) exhibit severe patient–ventilator asynchrony (52). Such a high incidence is associated with a prolonged duration of mechanical ventilation (52, 53). Hence, early detection of severe asynchrony by monitoring EAdi can be used to adjust ventilator settings to improve synchrony. For example, neurally adjusted ventilatory assist has been shown to reduce patient–ventilator asynchrony (54). In the early phase of ARDS, the use of neuromuscular blocking agents (NMBA) has been shown to improve outcome (55). Muscle paralysis prevents patient–ventilator asynchrony, thereby reducing the risk of barotrauma and volutrauma, providing an acceptable explanation for the beneficial effects observed in this latter study (56). If true, monitoring EAdi to detect patient–ventilator asynchrony, during brief interruption of NMBA, may help the clinician to decide when to stop further NMBA administration. Also, we use EAdi to titrate NMBA in selected patients with ARDS. A bolus is administered when EAdi is observed, thereby reducing the risk of overdose.

Monitoring during (Difficult) Weaning

During weaning from mechanical ventilation, short periods of unassisted breathing allow closer monitoring of respiratory muscle function using ultrasonography and respiratory pressure measurements. Using M-mode ultrasonography, diaphragm dysfunction was found in 29% of critically ill patients without history of diaphragm dysfunction (57). In a non-ICU population, it was shown that sequential measurements of diaphragm thickness using B-mode ultrasonography are useful not only in making the initial diagnosis of diaphragm weakness but also for determining subsequent recovery (58). Knowing whether or not the respiratory muscles are impaired is of major clinical importance. It allows development of an effective treatment plan (including mobilization and physiotherapy) and proper prognostic advice to the patient and relatives.

Therapeutic Strategies

Contrary to another vital muscle, the heart, there are currently limited strategies available to improve respiratory muscle function. However, data from recent preclinical studies offer hope for the near future (5961). Recently, we have shown that the calcium sensitizer levosimendan improves neuromechanical efficiency and contractile function of the human diaphragm in vivo. Our findings suggest a new therapeutic approach to improve respiratory muscle function in patients with respiratory failure (59). In mechanically ventilated rats, the antioxidant N-acetylcysteine prevented ventilation-induced diaphragmatic oxidative stress and proteolysis and abolished ventilation-induced diaphragmatic contractile dysfunction (60). Like any skeletal muscle, the diaphragm is responsive to training. In a randomized controlled trial, inspiratory muscle training has been shown to improve inspiratory muscle strength and weaning outcome in critically ill patients (61). Inspiratory muscle training should therefore be considered in difficult-to-wean patients with proven inspiratory muscle weakness.

Further studies are needed to establish the effects of these new pharmacological interventions and to develop specific training protocols for critically ill patients. Adequate monitoring of respiratory muscle function is indispensable to establish the effects of these interventions.

A large body of evidence shows the detrimental effects of critical illness on respiratory muscle structure and function, which is associated with prolonged weaning from mechanical ventilation. Although some factors related to impaired muscle function in the critically ill are unpreventable (e.g., sepsis), awareness of developing weakness may alter treatment (e.g., ventilator settings, training, drug prescription).

As outlined, different tools are available to assess respiratory muscle function. Some of these tools have limited value (chest X-ray, fluoroscopy) or are not suitable for routine clinical care monitoring (magnetic resonance imaging, computed tomography, phrenic nerve stimulation). However, more promising tools that can be used today or in the near future for monitoring of respiratory muscle function are (1) ultrasonography to evaluate diaphragm movement and thickness, (2) measurement of mouth and/or transdiaphragmatic pressure to monitor respiratory muscle strength, and (3) electromyography of the diaphragm to monitor respiratory muscle unloading and patient–ventilator asynchrony. Circulatory biomarkers for respiratory muscle injury are much needed, and it is hoped they will appear in the next few years.

There is scarce literature that directly demonstrates improved outcome with close monitoring (and action) of the respiratory muscles. However, over the last years circumstantial evidence suggests that respiratory muscle monitoring can affect clinical care in the ICU.

Today, we are only at the beginning of routinely monitoring respiratory muscle function. In our opinion, however, practical issues and the absence of sound scientific data for clinical benefit should not discourage clinicians from having a closer look at respiratory muscle function in critically ill patients. In modern ICUs, monitoring the respiratory muscles should be as much part of the routine as monitoring any other organ function.

1. Laghi F, Cattapan SE, Jubran A, Parthasarathy S, Warshawsky P, Choi YS, Tobin MJ. Is weaning failure caused by low-frequency fatigue of the diaphragm? Am J Respir Crit Care Med 2003;167:120127.
2. Jaber S, Petrof BJ, Jung B, Chanques G, Berthet JP, Rabuel C, Bouyabrine H, Courouble P, Koechlin-Ramonatxo C, Sebbane M, et al.. Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans. Am J Respir Crit Care Med 2011;183:364371.
3. Hermans G, Agten A, Testelmans D, Decramer M, Gayan-Ramirez G. Increased duration of mechanical ventilation is associated with decreased diaphragmatic force: a prospective observational study. Crit Care 2010;14:R127.
4. Schweickert WD, Hall J. ICU-acquired weakness. Chest 2007;131:15411549.
5. Herridge MS, Tansey CM, Matte A, Tomlinson G, Diaz-Granados N, Cooper A, Guest CB, Mazer CD, Mehta S, Stewart TE, et al.. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011;364:12931304.
6. Vassilakopoulos T, Petrof BJ. Ventilator-induced diaphragmatic dysfunction. Am J Respir Crit Care Med 2004;169:336341.
7. Levine S, Nguyen T, Taylor N, Friscia ME, Budak MT, Rothenberg P, Zhu J, Sachdeva R, Sonnad S, Kaiser LR, et al.. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med 2008;358:13271335.
8. Bloch S, Polkey MI, Griffiths M, Kemp P. Molecular mechanisms of intensive care unit-acquired weakness. Eur Respir J 2012;39:10001011.
9. Jaber S, Jung B, Matecki S, Petrof BJ. Clinical review: ventilator-induced diaphragmatic dysfunction - human studies confirm animal model findings! Crit Care 2011;15:206.
10. Levine S, Biswas C, Dierov J, Barsotti R, Shrager JB, Nguyen T, Sonnad S, Kucharchzuk JC, Kaiser LR, Singhal S, et al.. Increased proteolysis, myosin depletion, and atrophic AKT-FOXO signaling in human diaphragm disuse. Am J Respir Crit Care Med 2011;183:483490.
11. Callahan LA, Nethery D, Stofan D, DiMarco A, Supinski G. Free radical-induced contractile protein dysfunction in endotoxin-induced sepsis. Am J Respir Cell Mol Biol 2001;24:210217.
12. van Hees HW, Schellekens WJ, Andrade Acuna GL, Linkels M, Hafmans T, Ottenheijm CA, Granzier HL, Scheffer GJ, van der Hoeven JG, Dekhuijzen PN, et al.. Titin and diaphragm dysfunction in mechanically ventilated rats. Intensive Care Med 2012;38:702709.
13. Shanely RA, Zergeroglu MA, Lennon SL, Sugiura T, Yimlamai T, Enns D, Belcastro A, Powers SK. Mechanical ventilation-induced diaphragmatic atrophy is associated with oxidative injury and increased proteolytic activity. Am J Respir Crit Care Med 2002;166:13691374.
14. McCool FD, Tzelepis GE. Dysfunction of the diaphragm. N Engl J Med 2012;366:932942.
15. Ottenheijm CA, Heunks LM, Sieck GC, Zhan WZ, Jansen SM, Degens H, de Boo T, Dekhuijzen PN. Diaphragm dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;172:200205.
16. Hughes PD, Polkey MI, Harrus ML, Coats AJ, Moxham J, Green M. Diaphragm strength in chronic heart failure. Am J Respir Crit Care Med 1999;160:529534.
17. Gea J, Casadevall C, Pascual S, Orozco-Levi M, Barreiro E. Respiratory diseases and muscle dysfunction. Expert Rev Respir Med 2012;6:7590.
18. Murciano D, Rigaud D, Pingleton S, Armengaud MH, Melchior JC, Aubier M. Diaphragmatic function in severely malnourished patients with anorexia nervosa. Effects of renutrition. Am J Respir Crit Care Med 1994;150:15691574.
19. Maes K, Agten A, Smuder A, Powers SK, Decramer M, Gayan-Ramirez G. Corticosteroid effects on ventilator-induced diaphragm dysfunction in anesthetized rats depend on the dose administered. Respir Res 2010;11:178.
20. Zhang XJ, Yu G, Wen XH, Lin ZC, Yang FQ, Zheng ZG, Chen RC, Zhong NS. Effect of propofol on twitch diaphragmatic pressure evoked by cervical magnetic stimulation in patients. Br J Anaesth 2009;102:6164.
21. Testelmans D, Maes K, Wouters P, Gosselin N, Deruisseau K, Powers S, Sciot R, Decramer M, Gayan-Ramirez G. Rocuronium exacerbates mechanical ventilation-induced diaphragm dysfunction in rats. Crit Care Med 2006;34:30183023.
22. Parthasarathy S, Jubran A, Laghi F, Tobin MJ. Sternomastoid, rib cage, and expiratory muscle activity during weaning failure. J Appl Physiol 2007;103:140147.
23. Polkey MI, Green M, Moxham J. Measurement of respiratory muscle strength. Thorax 1995;50:11311135.
24. Truwit JD, Marini JJ. Validation of a technique to assess maximal inspiratory pressure in poorly cooperative patients. Chest 1992;102:12161219.
25. Whitelaw WA, Derenne JP. Airway occlusion pressure. J Appl Physiol 1993;74:14751483.
26. Rochester DF. Tests of respiratory muscle function. Clin Chest Med 1988;9:249261.
27. Miller JM, Moxham J, Green M. The maximal sniff in the assessment of diaphragm function in man. Clin Sci (Lond) 1985;69:9196.
28. Gilbert R, Auchincloss JH, Peppi D. Relationship of rib cage and abdomen motion to diaphragm function during quiet breathing. Chest 1981;80:607612.
29. Bellemare F, Grassino A. Effect of pressure and timing of contraction on human diaphragm fatigue. J Appl Physiol 1982;53:11901195.
30. Field S, Sanci S, Grassino A. Respiratory muscle oxygen consumption estimated by the diaphragm pressure-time index. J Appl Physiol 1984;57:4451.
31. Talmor D, Sarge T, Malhotra A, O’Donnell CR, Ritz R, Lisbon A, Novack V, Loring SH. Mechanical ventilation guided by esophageal pressure in acute lung injury. N Engl J Med 2008;359:20952104.
32. Heunks LM, van der Hoeven JG. Clinical review: the ABC of weaning failure - a structured approach. Crit Care 2010;14:245.
33. Luo YM, Moxham J, Polkey MI. Diaphragm electromyography using an oesophageal catheter: current concepts. Clin Sci (Lond) 2008;115:233244.
34. Colombo D, Cammarota G, Bergamaschi V, de Lucia M, Corte FD, Navalesi P. Physiologic response to varying levels of pressure support and neurally adjusted ventilatory assist in patients with acute respiratory failure. Intensive Care Med 2008;34:20102018.
35. Hudson MB, Smuder AJ, Nelson WB, Bruells CS, Levine S, Powers SK. Both high level pressure support ventilation and controlled mechanical ventilation induce diaphragm dysfunction and atrophy. Crit Care Med 2012;40:12541260.
36. Karagiannidis C, Lubnow M, Philipp A, Riegger GA, Schmid C, Pfeifer M, Mueller T. Autoregulation of ventilation with neurally adjusted ventilatory assist on extracorporeal lung support. Intensive Care Med 2010;36:20382044.
37. Schmidt M, Chiti L, Hug F, Demoule A, Similowski T. Surface electromyogram of inspiratory muscles: a possible routine monitoring tool in the intensive care unit. Br J Anaesth 2011;106:913914.
38. Colombo D, Cammarota G, Alemani M, Carenzo L, Barra F, Vaschetto R, Slutsky AS, Della CF, Navalesi P. Efficacy of ventilator waveforms observation in detecting patient-ventilator asynchrony. Crit Care Med 2011.
39. Liu L, Liu H, Yang Y, Huang Y, Liu S, Beck J, Slutsky AS, Sinderby C, Qiu H. Neuro-ventilatory efficiency and extubation readiness in critically ill patients. Crit Care 2012;16:R143.
40. Cammarota G, Longhini F, Colombo D, Giovanniello A, Della Corte F, Navalesi P. Effects of propofol infusion on patient-ventilator interaction during pressure support and neurally adjusted ventilatory assist in intubated patients with acute respiratory failure of varied etiology [abstract]. Intensive Care Med 2009;35:S21.
41. Roze H, Richard JC, Mercat A, Brochard L. Recording of possible diaphragm fatigue under neurally adjusted ventilatory assist. Am J Respir Crit Care Med 2011;184:12131214.
42. Cattapan SE, Laghi F, Tobin MJ. Can diaphragmatic contractility be assessed by airway twitch pressure in mechanically ventilated patients? Thorax 2003;58:5862.
43. Luo YM, Lyall RA, Lou HM, Rafferty GF, Polkey MI, Moxham J. Quantification of the esophageal diaphragm electromyogram with magnetic phrenic nerve stimulation. Am J Respir Crit Care Med 1999;160:16291634.
44. Newsom-Davis J. The diaphragm and neuromuscular disease. Am Rev Respir Dis 1979;119:115117.
45. Ueki J, De Bruin PF, Pride NB. In vivo assessment of diaphragm contraction by ultrasound in normal subjects. Thorax 1995;50:11571161.
46. McCool FD, Conomos P, Benditt JO, Cohn D, Sherman CB, Hoppin FG Maximal inspiratory pressures and dimensions of the diaphragm. Am J Respir Crit Care Med 1997;155:13291334.
47. Boussuges A, Gole Y, Blanc P. Diaphragmatic motion studied by m-mode ultrasonography: methods, reproducibility, and normal values. Chest 2009;135:391400.
48. Cluzel P, Similowski T, Chartrand-Lefebvre C, Zelter M, Derenne JP, Grenier PA. Diaphragm and chest wall: assessment of the inspiratory pump with MR imaging-preliminary observations. Radiology 2000;215:574583.
49. Pettiaux N, Cassart M, Paiva M, Estenne M. Three-dimensional reconstruction of human diaphragm with the use of spiral computed tomography. J Appl Physiol 1997;82:9981002.
50. Sorichter S, Puschendorf B, Mair J. Skeletal muscle injury induced by eccentric muscle action: muscle proteins as markers of muscle fiber injury. Exerc Immunol Rev 1999;5:521.
51. Foster GE, Nakano J, Sheel AW, Simpson JA, Road JD, Reid WD. Serum skeletal troponin I following inspiratory threshold loading in healthy young and middle-aged men. Eur J Appl Physiol 2012;112:35473558.
52. Thille AW, Rodriguez P, Cabello B, Lellouche F, Brochard L. Patient-ventilator asynchrony during assisted mechanical ventilation. Intensive Care Med 2006;32:15151522.
53. de Wit M, Miller KB, Green DA, Ostman HE, Gennings C, Epstein SK. Ineffective triggering predicts increased duration of mechanical ventilation. Crit Care Med 2009;37:27402745.
54. Spahija J, de Marchie M, Albert M, Bellemare P, Delisle S, Beck J, Sinderby C. Patient-ventilator interaction during pressure support ventilation and neurally adjusted ventilatory assist. Crit Care Med 2010;38:518526.
55. Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, et al.. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363:11071116.
56. Slutsky AS. Neuromuscular blocking agents in ARDS. N Engl J Med 2010;363:11761180.
57. Kim WY, Suh HJ, Hong SB, Koh Y, Lim CM. Diaphragm dysfunction assessed by ultrasonography: Influence on weaning from mechanical ventilation. Crit Care Med 2011;39:26272630.
58. Summerhill EM, El-Sameed YA, Glidden TJ, McCool FD. Monitoring recovery from diaphragm paralysis with ultrasound. Chest 2008;133:737743.
59. Doorduin J, Sinderby CA, Beck J, Stegeman DF, van Hees HW, van der Hoeven JG, Heunks LM. The calcium sensitizer levosimendan improves human diaphragm function. Am J Respir Crit Care Med 2012;185:9095.
60. Agten A, Maes K, Smuder A, Powers SK, Decramer M, Gayan-Ramirez G. N-acetylcysteine protects the rat diaphragm from the decreased contractility associated with controlled mechanical ventilation. Crit Care Med 2011;39:777782.
61. Martin AD, Smith BK, Davenport PD, Harman E, Gonzalez-Rothi RJ, Baz M, Layon AJ, Banner MJ, Caruso LJ, Deoghare H, et al.. Inspiratory muscle strength training improves weaning outcome in failure to wean patients: a randomized trial. Crit Care 2011;15:R84.
Correspondence and requests for reprints should be addressed to Leo Heunks, M.D., Ph.D., Radboud University Nijmegen Medical Centre, Department of Critical Care Medicine, Geert Grooteplein zuid 10, 6525 GA Nijmegen, The Netherlands. E-mail:

This manuscript was investigator initiated and financed by institutional resources.

Author Contributions: Drafting the article or revising it critically for important intellectual content: J.D., H.W.H.v.H., L.M.A.H.; final approval of the version to be published: J.G.v.d.H.

Originally Published in Press as DOI: 10.1164/rccm.201206-1117CP on October 26, 2012

Author disclosures are available with the text of this article at


No related items
American Journal of Respiratory and Critical Care Medicine

Click to see any corrections or updates and to confirm this is the authentic version of record