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Original Research: Critical Care |

Diaphragm Muscle Thinning in Patients Who Are Mechanically VentilatedDiaphragm Muscle Atrophy FREE TO VIEW

Horiana B. Grosu, MD; Young Im Lee, MD; Jarone Lee, MD; Edward Eden, MD, FCCP; Matthias Eikermann, MD; Keith M. Rose, MD
Author and Funding Information

From the Division of Pulmonary Critical Care and Sleep Medicine (Drs Grosu, Y. I. Lee, Eden, and Rose), St. Luke’s and Roosevelt Hospitals, Columbia University College of Physicians and Surgeons, New York, NY; and the Department of Anesthesia, Critical Care, and Pain Medicine (Drs J. Lee and Eikermann), Massachusetts General Hospital, Boston, MA.

Correspondence to: Keith M. Rose, MD, Division of Pulmonary and Critical Care, St. Luke’s-Roosevelt Hospital Center, 1000 Tenth Ave, New York, NY 10019; e-mail: KRose@chpnet.org


Funding/Support: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2012;142(6):1455-1460. doi:10.1378/chest.11-1638
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Published online

Background:  Approximately 40% of patients in medical ICUs require mechanical ventilation (MV). Approximately 20% to 25% of these patients will encounter difficulties in discontinuing MV. Multiple studies have suggested that MV has an unloading effect on the respiratory muscles that leads to diaphragmatic atrophy and dysfunction, a process called ventilator-induced diaphragmatic dysfunction (VIDD). VIDD may be an important factor affecting when and if MV can be discontinued. A sensitive and specific diagnostic test for VIDD could provide the physician with valuable information that might influence decisions regarding extubation or tracheostomy. The purpose of this study was to quantify, using daily sonographic assessments, the rate and degree of diaphragm thinning during MV.

Methods:  Seven intubated patients receiving MV during acute care were included. Using sonography, diaphragm muscle thickness was measured daily from the day of intubation until the patient underwent extubation or tracheostomy or died. We analyzed our data using standard descriptive statistics, linear regression, and mixed-model effects.

Results:  The overall rate of decrease in the diaphragm thickness of all seven patients over time averaged 6% per day of MV, which differed significantly from zero. Similarly, the diaphragm thickness decreased for each patient over time.

Conclusion:  Sonographic assessment of the diaphragm provides noninvasive measurement of diaphragmatic thickness and the degree of diaphragm thinning in patients receiving MV. Our data show that diaphragm muscle thinning starts within 48 h after initiation of MV. However, it is unclear if diaphragmatic thinning correlates with diaphragmatic atrophy or pulmonary function. The relationship between diaphragm thinning and diaphragm strength remains to be elucidated.

Figures in this Article

At any time, approximately 40% of patients in medical ICUs require mechanical ventilation (MV),1 making it one of the most frequently used critical care technologies. Difficulties in discontinuing MV are encountered in 20% to 25% of patients who receive MV,2 with a staggering 40% of the time spent in the ICU devoted to weaning from MV. Hence, techniques that expedite the weaning process should have a profound effect on the overall duration of MV.3

Animal and human studies have shown that critical illness and MV cause ventilator-induced diaphragmatic dysfunction (VIDD), which is defined as a loss of diaphragmatic force-generating capacity specifically related to the use of MV.47 The major clinical implication of VIDD is that even when used for relatively short periods, MV can lead to substantial diaphragmatic weakness and wasting that may impede its discontinuation. At this time, there is no clear definition of VIDD, and there are numerous other factors that can lead to diaphragmatic weakness and thinning, including critical illness polyneuropathy, ongoing multiorgan system failure, malnutrition, and cachexia.

Wait et al8 first successfully used ultrasonography to measure diaphragm thickness in 1989. In 1997, Cohn et al9 used two-dimensional ultrasonography to measure diaphragm thickness. Comparing their ultrasound measurements with autopsy measurements, they demonstrated that their techniques were accurate and reproducible (degree of variability < 0.2 mm).8,9 Therefore, anatomic measurement of diaphragm muscle thickness can be achieved using ultrasonography, which has been shown to be cost efficient, noninvasive, painless, easy to perform, and safer than radiation.810 As a result, we elected to quantify, using daily sonographic assessments, the rate and degree of diaphragm thinning during MV.

Subjects

The St. Luke’s-Roosevelt Hospital Institutional Review Board approved this study and designated it study number 09-222. We randomly selected seven newly intubated patients (within 24 h) from the ED, ICU, or medical ward. Patients with tracheostomies were excluded. Informed consent was obtained from the patient or his/her health-care proxy. The patient’s chart was reviewed for demographic information and clinical data. Serial ultrasonographic measurements of diaphragm thickness were performed daily on each of the seven patients to evaluate the diaphragm thickness from day 1 of intubation until the day the patient underwent extubation or tracheostomy or died.

Measurement of Diaphragmatic Thickness

Diaphragm muscle thickness was measured using a standardized technique described previously by Cohn et al.9 Imaging was performed using the M-Turbo ultrasound system (SonoSite, Inc) with a 7.5- to 10.0-mHz transducer probe in two-dimensional B-mode. Subjects were seated upright in bed at a 90° angle. The probe was placed in the right midaxillary line, and, using sector mode, a two-dimensional coronal image of the zone of apposition was generated. The right diaphragm was identified as a three-layered structure just superficial to the liver, consisting of a relatively nonechogenic muscular layer bound by echogenic membranes of peritoneum and diaphragmatic pleura. The diaphragm was further identified dynamically as the most superficial structure that was obliterated by the leading edge of the lung upon inspiration. The diaphragm could also be identified by direct visualization of its contraction at the beginning of the respiratory cycle. Images were obtained at end-expiration, which correlates with functional residual capacity. We obtained three consecutive images to establish the reproducibility of our measurements. During ultrasound examination, we observed real-time graphics of airflow and airway pressure at the point of end-expiration.

Using this technique, we measured diaphragm thickness, defined as the distance from the middle of the diaphragmatic pleura to the middle of the peritoneal pleura, to the nearest 0.1 mm and recorded a digital image (Fig 1). Images were edited only for the removal of patient information and were interpreted by a separate, blinded interpreter. For standardization, the image with the greatest thickness was used as the final measurement.

Figure Jump LinkFigure 1. The diaphragm is a three-layered structure superficial to the liver, consisting of a relatively nonechogenic muscular layer bound by echogenic membranes of peritoneum and diaphragmatic pleura. Diaphragm thickness was defined as the distance from the middle of the diaphragmatic pleura to the middle of the peritoneal pleura.Grahic Jump Location

All of the patients were mechanically ventilated using pressure-regulated volume control. Additionally, all patients were receiving ventilation assistance at the time of measurement. The volumes of ventilation, respiratory rates, and extrinsic positive end-expiratory pressure (PEEP) levels were recorded upon inclusion and then daily. All patients were maintained on the same tidal volume (Vt) and PEEP levels during the study. Measuring the diaphragm thickness for each patient was done by observing real-time graphics of airflow and airway pressure at the point of end-expiration to assure that there was no change in ventilator parameters, such as intrinsic PEEP, which might affect lung volumes and hence transdiaphragmatic pressure and thickness.

Statistical Analysis

Statistical comparisons were made by using a linear mixed model (compound symmetry type).We used data from all patients and tested for an effect of the independent variable (day after onset of ventilation) on the dependent variable (diaphragmatic thickness).

Overall, the average diaphragm thickness in this group decreased significantly over time at a rate of 6% per day on MV. Similarly, the diaphragm thickness in each patient decreased over time (fig 2). Measurements of diaphragm thickness were taken successfully at end-expiration in all patients. In the group, initial diaphragmatic thickness correlates with weight in kilograms (Pearson correlation coefficient = 0.76, P = .046) (Fig 3).

Figure Jump LinkFigure 2. Diaphragm thickness over time for each patient.Grahic Jump Location
Figure Jump LinkFigure 3. Correlation between diaphragm thickness on day 1 and weight in kilograms.Grahic Jump Location

Linear mixed models revealed that the duration of MV significantly predicted decreases in diaphragmatic thickness (F = 44, P < .001). In addition, a significant interaction effect between the days after onset of ventilation was found with the following variables: Vt, PEEP, and respiratory rate. In fact, linear-mixed-model variance analysis revealed a significant interaction between (high) Vt and progressive decrease in diaphragmatic thickness over time (F = 7.2, P = .004). In contrast, we observed a trend toward a protective effect of high PEEP and high respiratory rate on diaphragmatic thickness over time (F = 2.4, P = .08 and F = 2.0, P = .09 for the interaction effect, respectively). Although our sample size is too small to accept this as clinically meaningful, we believe this warrants further study. The following are descriptions of each patient and his/her outcome.

Patient 1

A 68-year-old man with a history of neck cancer was admitted for neutropenic fever complicated by septic shock. The patient was ventilated using pressure-regulated volume control (PRVC) as the mode of MV, with a Vt of 400 mL and a PEEP of 5 mm Hg, which did not vary during the period of measurements. The chest radiograph findings varied from a normal examination on day 1 of MV to increased opacity in the right lung concerning for pneumonia on day 4. The initial diaphragm thickness was 1.9 mm, which decreased to 1.6 mm at a rate of 0.15 mm/d over 3 days. The patient died on day 4 of MV.

Patient 2

A 74-year-old man with a history of COPD was intubated for hypercapnic respiratory failure. The patient was ventilated using PRVC as the mode of MV, with a Vt of 400 mL and a PEEP of 5 mm Hg, which did not vary during the period of measurements. The chest radiograph findings varied from underlying atelectasis and/or consolidation on day 1 to a retrocardiac density, obscuring the left hemidiaphragm, on day 8. The initial diaphragm thickness was 1.7 mm, which decreased to 1.0 mm at a rate of 0.10 mm/d over 8 days. The patient was extubated on day 9 of MV.

Patient 3

A 51-year-old man was admitted for multilobar pneumonia and respiratory failure. This patient was also ventilated using PRVC as the mode of MV, with a Vt of 400 mL and a PEEP of 5 mm Hg, which did not vary during the period of measurements. The chest radiograph findings varied from bilateral patchy airspace opacities on day 1 to better aeration of the lung fields on day 5. The initial diaphragm thickness was 2.9 mm, which decreased to 1.9 mm at a rate of 0.3 mm/d over 4 days. The patient was extubated on day 5 of MV.

Patient 4

A 68-year-old man was intubated for hypercapnic respiratory failure. This patient was ventilated using PRVC as the mode of MV, with a Vt of 400 mL and a PEEP of 5 mm Hg, which did not vary during the period of measurements. The chest radiograph findings varied from atelectasis of the left lower lobe and the right base on day 1 to an extensive opacity in the lower half of the right chest and a large left pleural effusion on day 4. The initial diaphragm thickness was 3.8 mm, which decreased to 2.8 mm at a rate of 0.3 mm/d over 4 days. The patient died on day 5 of MV.

Patient 5

A 74-year-old woman was intubated for status epilepticus. The patient was ventilated using PRVC as the mode of MV, with a Vt of 400 mL and a PEEP of 5 mm Hg, which did not vary during the period of measurements. The chest radiograph findings were normal on day 1 and progressed to poor inspiration with bilateral atelectasis on day 4. The initial diaphragm thickness was 1.2 mm, which decreased to 1.0 mm at a rate of 0.1 mm/d over 3 days. The patient was extubated on day 4 of MV.

Patient 6

A 51-year-old man with a history of HIV, polysubstance abuse, and cardiomyopathy was admitted for hypoxemic respiratory failure due to Pneumocystis jiroveci pneumonia. The patient was ventilated using PRVC as the mode of MV, with a Vt of 480 mL and a PEEP of 12 mm Hg, which did not vary during the period of measurements. The chest radiograph findings varied from bilateral airspace opacities, right greater than left, concerning for multifocal pneumonia on day 1 to worsening multifocal pneumonia with ground-glass opacities on day 6. The initial diaphragm thickness was 2.3 mm, which decreased to 2.0 mm at a rate of 0.02 mm/d over 5 days. The patient died on day 6 of MV.

Patient 7

A 92-year-old man was intubated for pneumonia. The patient was ventilated using PRVC as the mode of MV, with a Vt of 400 mL and a PEEP of 5 mm Hg, which did not vary during the period of measurements. The chest radiograph findings varied from bilateral pleural effusions with atelectasis and opacities on day 1 to stable bilateral pleural effusions and atelectasis on day 4. The initial diaphragm thickness was 3.8 mm, which decreased to 2.2 mm at a rate of 0.8 mm/d over 3 days. The patient was extubated on day 4 of MV.

Diaphragm muscle strength has been demonstrated using functional, physiologic, and anatomic methods. Functional measurement includes inspiratory and expiratory pressure differences generated by patients breathing against a closed valve; however, this measurement is effort dependent and poorly reproducible, particularly in intubated, critically ill patients. Esophageal and gastric balloons with pressure transducers can also be used to calculate transdiaphragmatic pressures by subtracting the esophageal pressure from the gastric pressure correlating with diaphragmatic strength. Another method is the maximal sniff transdiaphragmatic pressure. This is used as the volitional indicator of diaphragm strength. These measurements, however, depend on effort and are poorly reproducible. As such, there is currently no simple and reproducible method to measure diaphragm muscle strength (force-generating capacity).

This longitudinal observational study using serial ultrasound measurements of the diaphragm showed that diaphragmatic thickness can be measured easily using ultrasonography shortly after endotracheal intubation. Furthermore, we observed that thinning begins within 48 h of the initiation of MV decrease, and occurs linearly over the subsequent time period. It remains unclear if this thinning correlates directly with diaphragmatic strength.

The methods commonly employed to diagnose diaphragmatic atrophy, such as esophageal and gastric balloons, phrenic nerve stimulation, and diaphragmatic biopsy, are either invasive or limited to nonintubated patients. In our study, two-dimensional B-mode ultrasound measurements provided a simple, noninvasive assessment of diaphragmatic thickness and the degree of thinning. Sitting up the patients was relatively easy, with no untoward effects. Additionally, by using two operators, the test could be done quickly, in approximately 4 to 5 min.

Our data agree with data from animal studies, in which diaphragm inactivity with controlled MV has been shown to produce myofibril damage that contributes to the reduction in diaphragmatic force over time. In these studies, the force reduction was measured and calculated using transdiaphragmatic pressure generation during phrenic nerve stimulation.11

Patients with asthma and COPD may have dynamic hyperinflation and auto-PEEP during MV. These effects can also occur in other circumstances, and if auto-PEEP or hyperinflation is present, the lungs do not have enough time to reach normal functional residual capacity. In patients with chronic hyperinflation states, diaphragm muscle length shortens by 30% to 40% from residual volume to total lung capacity.12 This is likely because of adaption (drop out) of sarcomeres in the chronic condition. The relationship between diaphragm length and thickness in response to acute hyperinflation is unknown.

Another variable that might have played a role in the diaphragmatic measurements is the interaction between diaphragm contour thickness, force generation, and coupling to abdominal and thoracic musculature. Complete relaxation of the abdominal and thoracic musculature would be expected to isolate diaphragm thickness measurements from the influences of abdominal and thoracic muscle tension and their effects on diaphragm curvature. Thickness measurements may not correlate well with length measurements in the acute situation.13,14

In these patients, there was no evidence that residual capacity changed significantly over the course of the study, and we were careful to measure thickness at end-expiration, minimizing hyperinflation as a confounding variable. We did not record auto-PEEP levels by performing an end-expiratory occlusion measurement; instead, we observed real-time graphics of airflow and airway pressure at end-expiration during the ultrasound measurements. None of the patients in this study had auto-PEEP at the time of the measurements.

By comparing our data with biopsy data presented by Levine et al,7 in which the cross-sectional area of slow-twitch fibers decreased by 57% and the fibers in the diaphragm biopsy specimens were appreciably smaller, we suggest that diaphragm thinning in our subjects was likely due to atrophy. Yet other factors, in addition to MV, are likely to contribute to diaphragm thinning.

The effect of nutritional status and lung disease progression on diaphragm performance is unclear. Looking at maximal inspiratory pressure and the dimensions of the diaphragm, McCool et al15 found that there was a strong correlation between maximal inspiratory pressure across the diaphragm and the weight of the subjects. The most direct measurement of diaphragm thickness is at autopsy. Arora and Rochester16 showed that diaphragm thickness correlates with muscularity and nutritional state when they evaluated a large number of malnourished, normally nourished, and especially muscular but nonobese persons who died suddenly. They concluded that there was a significant linear correlation between the weight of the diaphragm and body weight. Diaphragm muscle mass was 43% lower in patients who were underweight.16 In our study, the initial diaphragm thickness correlated with weight in kilograms. The decrease in diaphragm thickness may well have been associated with malnutrition. Our interpretation, however, is limited by lack of information on the markers of malnutrition.

There is little information about VIDD in humans, and we know that other factors, such as sepsis, the use of corticosteroids and neuromuscular blockers, and malnutrition can be other causes of diaphragmatic thinning. Nonetheless, our findings suggest that in the acute care setting, diaphragmatic thinning can be assessed easily using two-dimensional ultrasonography.

Our pilot study had several limitations. The study had a small sample size, lacked a control group, and did not show a correlation with the discontinuation of MV. Furthermore, we did not measure diaphragmatic strength and did not have long-term follow-up on the patients. Our sample size was also too small to analyze correlations among Vts, PEEP, and diaphragmatic thinning. Additionally, all these patients were ventilated using an assist control mode of MV, none of the patients were paralyzed, and we did not collect data on depth of sedation. Another weakness was that we did not examine diaphragm muscle activity because patients not assisting with the ventilator may be at greater risk of diaphragmatic atrophy. Our initial findings need to be evaluated by larger studies that relate diaphragm thinning to outcomes of MV.

We conclude from this study that measured thinning of the diaphragm occurs within 48 h after intubation and the initiation of MV, most consistent with MV-related atrophy. Ultrasound is an easily applied technology in this setting. Further studies are needed to evaluate if this uniform decrease in diaphragm thickness is indeed due to diaphragm atrophy, and if this has an impact on the discontinuation of MV. Larger studies are needed to clarify the relationship between diaphragmatic thinning and clinical outcomes.

Author contributions: Drs J. Lee and Rose had full access to the study data and can vouch for the study integrity and data analysis.

Dr Grosu: contributed to the identification of the purpose of the study, data collection and management, and the writing and revising of the manuscript.

Dr Y. I. Lee: contributed to the creation of the data collection instrument, data collection and management, the creation of the table, and the writing of the manuscript.

Dr J. Lee: contributed to the study design, data management and analysis, and manuscript preparation, revision, and approval.

Dr Eden: contributed to the writing and revising of the manuscript.

Dr. Eikermann: contributed to the review of data analysis and manuscript preparation, revision, and approval.

Dr Rose: contributed to the identification of the purpose of the study, study design, database management, data analysis, and the writing and revising of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: This work was performed at St. Luke’s-Roosevelt Hospital Center.

MV

mechanical ventilation

PEEP

positive end-expiratory pressure

PRVC

pressure-regulated volume control

VIDD

ventilator-induced diaphragmatic dysfunction

Vt

tidal volume

Esteban A, Anzueto A, Alía I, et al. How is mechanical ventilation employed in the intensive care unit? An international utilization review. Am J Respir Crit Care Med. 2000;161(5):1450-1458. [PubMed]
 
Esteban A, Frutos F, Tobin MJ, et al; Spanish Lung Failure Collaborative Group Spanish Lung Failure Collaborative Group. A comparison of four methods of weaning patients from mechanical ventilation. N Engl J Med. 1995;332(6):345-350. [CrossRef] [PubMed]
 
Esteban A, Alía I, Ibañez J, Benito S, Tobin MJ The Spanish Lung Failure Collaborative Group The Spanish Lung Failure Collaborative Group. Modes of mechanical ventilation and weaning. A national survey of Spanish hospitals. Chest. 1994;106(4):1188-1193. [CrossRef] [PubMed]
 
Vassilakopoulos T, Petrof BJ. Ventilator-induced diaphragmatic dysfunction. Am J Respir Crit Care Med. 2004;169(3):336-341. [CrossRef] [PubMed]
 
Sassoon CS, Zhu E, Caiozzo VJ. Assist-control mechanical ventilation attenuates ventilator-induced diaphragmatic dysfunction. Am J Respir Crit Care Med. 2004;170(6):626-632. [CrossRef] [PubMed]
 
Betters JL, Criswell DS, Shanely RA, et al. Trolox attenuates mechanical ventilation-induced diaphragmatic dysfunction and proteolysis. Am J Respir Crit Care Med. 2004;170(11):1179-1184. [CrossRef] [PubMed]
 
Levine S, Nguyen T, Taylor N, et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. 2008;358(13):1327-1335. [CrossRef] [PubMed]
 
Wait JL, Nahormek PA, Yost WT, Rochester DP. Diaphragmatic thickness-lung volume relationship in vivo. J Appl Physiol. 1989;67(4):1560-1568. [PubMed]
 
Cohn D, Benditt JO, Eveloff S, McCool FD. Diaphragm thickening during inspiration J Appl Physiol. 1997;83(1):291-296. [PubMed]
 
McCool FD, Hoppin FG Jr. Ultrasonography of the diaphragm.. In:Roussos C., ed. The Thorax. New York, NY: M. Dekker; 1995:1295-1311.
 
Sassoon CS, Caiozzo VJ, Manka A, Sieck GC. Altered diaphragm contractile properties with controlled mechanical ventilation. J Appl Physiol. 2002;92(6):2585-2595. [PubMed]
 
De Troyer A. Effect of hyperinflation on the diaphragm. Eur Respir J. 1997;10(3):708-713. [PubMed]
 
Baldwin CE, Paratz JD, Bersten AD. Diaphragm and peripheral muscle thickness on ultrasound: intra-rater reliability and variability of a methodology using non-standard recumbent positions. Respirology. 2011;16(7):1136-1143. [CrossRef] [PubMed]
 
Boynton BR, Barnas GM, Dadmun JT, Fredberg JJ. Mechanical coupling of the rib cage, abdomen, and diaphragm through their area of apposition. J Appl Physiol. 1991;70(3):1235-1244. [CrossRef] [PubMed]
 
McCool FD, Benditt JO, Conomos P, Anderson L, Sherman CB, Hoppin FG Jr. Variability of diaphragm structure among healthy individuals. Am J Respir Crit Care Med. 1997;155(4):1323-1328. [PubMed]
 
Arora NS, Rochester DF. Effect of body weight and muscularity on human diaphragm muscle mass, thickness, and area. J Appl Physiol. 1982;52(1):64-70. [PubMed]
 

Figures

Figure Jump LinkFigure 1. The diaphragm is a three-layered structure superficial to the liver, consisting of a relatively nonechogenic muscular layer bound by echogenic membranes of peritoneum and diaphragmatic pleura. Diaphragm thickness was defined as the distance from the middle of the diaphragmatic pleura to the middle of the peritoneal pleura.Grahic Jump Location
Figure Jump LinkFigure 2. Diaphragm thickness over time for each patient.Grahic Jump Location
Figure Jump LinkFigure 3. Correlation between diaphragm thickness on day 1 and weight in kilograms.Grahic Jump Location

Tables

References

Esteban A, Anzueto A, Alía I, et al. How is mechanical ventilation employed in the intensive care unit? An international utilization review. Am J Respir Crit Care Med. 2000;161(5):1450-1458. [PubMed]
 
Esteban A, Frutos F, Tobin MJ, et al; Spanish Lung Failure Collaborative Group Spanish Lung Failure Collaborative Group. A comparison of four methods of weaning patients from mechanical ventilation. N Engl J Med. 1995;332(6):345-350. [CrossRef] [PubMed]
 
Esteban A, Alía I, Ibañez J, Benito S, Tobin MJ The Spanish Lung Failure Collaborative Group The Spanish Lung Failure Collaborative Group. Modes of mechanical ventilation and weaning. A national survey of Spanish hospitals. Chest. 1994;106(4):1188-1193. [CrossRef] [PubMed]
 
Vassilakopoulos T, Petrof BJ. Ventilator-induced diaphragmatic dysfunction. Am J Respir Crit Care Med. 2004;169(3):336-341. [CrossRef] [PubMed]
 
Sassoon CS, Zhu E, Caiozzo VJ. Assist-control mechanical ventilation attenuates ventilator-induced diaphragmatic dysfunction. Am J Respir Crit Care Med. 2004;170(6):626-632. [CrossRef] [PubMed]
 
Betters JL, Criswell DS, Shanely RA, et al. Trolox attenuates mechanical ventilation-induced diaphragmatic dysfunction and proteolysis. Am J Respir Crit Care Med. 2004;170(11):1179-1184. [CrossRef] [PubMed]
 
Levine S, Nguyen T, Taylor N, et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. 2008;358(13):1327-1335. [CrossRef] [PubMed]
 
Wait JL, Nahormek PA, Yost WT, Rochester DP. Diaphragmatic thickness-lung volume relationship in vivo. J Appl Physiol. 1989;67(4):1560-1568. [PubMed]
 
Cohn D, Benditt JO, Eveloff S, McCool FD. Diaphragm thickening during inspiration J Appl Physiol. 1997;83(1):291-296. [PubMed]
 
McCool FD, Hoppin FG Jr. Ultrasonography of the diaphragm.. In:Roussos C., ed. The Thorax. New York, NY: M. Dekker; 1995:1295-1311.
 
Sassoon CS, Caiozzo VJ, Manka A, Sieck GC. Altered diaphragm contractile properties with controlled mechanical ventilation. J Appl Physiol. 2002;92(6):2585-2595. [PubMed]
 
De Troyer A. Effect of hyperinflation on the diaphragm. Eur Respir J. 1997;10(3):708-713. [PubMed]
 
Baldwin CE, Paratz JD, Bersten AD. Diaphragm and peripheral muscle thickness on ultrasound: intra-rater reliability and variability of a methodology using non-standard recumbent positions. Respirology. 2011;16(7):1136-1143. [CrossRef] [PubMed]
 
Boynton BR, Barnas GM, Dadmun JT, Fredberg JJ. Mechanical coupling of the rib cage, abdomen, and diaphragm through their area of apposition. J Appl Physiol. 1991;70(3):1235-1244. [CrossRef] [PubMed]
 
McCool FD, Benditt JO, Conomos P, Anderson L, Sherman CB, Hoppin FG Jr. Variability of diaphragm structure among healthy individuals. Am J Respir Crit Care Med. 1997;155(4):1323-1328. [PubMed]
 
Arora NS, Rochester DF. Effect of body weight and muscularity on human diaphragm muscle mass, thickness, and area. J Appl Physiol. 1982;52(1):64-70. [PubMed]
 
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