Rationale: Diaphragm atrophy and dysfunction have been reported in humans during mechanical ventilation, but the prevalence, causes, and functional impact of changes in diaphragm thickness during routine mechanical ventilation for critically ill patients are unknown.
Objectives: To describe the evolution of diaphragm thickness over time during mechanical ventilation, its impact on diaphragm function, and the influence of inspiratory effort on this phenomenon.
Methods: In three academic intensive care units, 107 patients were enrolled shortly after initiating ventilation along with 10 nonventilated intensive care unit patients (control subjects). Diaphragm thickness and contractile activity (quantified by the inspiratory thickening fraction) were measured daily by ultrasound.
Measurements and Main Results: Over the first week of ventilation, diaphragm thickness decreased by more than 10% in 47 (44%), was unchanged in 47 (44%), and increased by more than 10% in 13 (12%). Thickness did not vary over time following extubation or in nonventilated patients. Low diaphragm contractile activity was associated with rapid decreases in diaphragm thickness, whereas high contractile activity was associated with increases in diaphragm thickness (P = 0.002). Contractile activity decreased with increasing ventilator driving pressure (P = 0.01) and controlled ventilator modes (P = 0.02). Maximal thickening fraction (a measure of diaphragm function) was lower in patients with decreased or increased diaphragm thickness (n = 10) compared with patients with unchanged thickness (n = 10; P = 0.05 for comparison).
Conclusions: Changes in diaphragm thickness are common during mechanical ventilation and may be associated with diaphragmatic weakness. Titrating ventilatory support to maintain normal levels of inspiratory effort may prevent changes in diaphragm configuration associated with mechanical ventilation.
Atrophy of the diaphragm has been observed in organ donors and in small series of mechanically ventilated patients, and laboratory data suggest that atrophy results from diaphragm inactivity. However, the prevalence, magnitude, and impact of diaphragm atrophy in mechanically ventilated patients are unknown, as is whether diaphragm inactivity is an important contributor to this process in the clinical setting.
Diaphragm thickness decreases rapidly during the first several days of mechanical ventilation in more than 40% of patients regardless of ventilator mode, and this is predicted by lower levels of inspiratory effort and higher levels of ventilatory support. Thickness increases in approximately 10% of patients in association with excess inspiratory effort and lower levels of ventilatory support. We propose that changes in diaphragm configuration associated with mechanical ventilation might be prevented by titrating ventilatory support to maintain normal levels of respiratory effort.
Many patients simply need liberation from the ventilator as they recover from an episode of acute respiratory failure, but a substantial proportion have difficult or prolonged weaning (1, 2). Diaphragm function is an important determinant of successful liberation from ventilation and recovery from critical illness (3–5). Both animal models and autopsy studies of brain-dead organ donors (6–11) suggest that mechanical ventilation can cause diaphragm myofiber atrophy, sarcomeric disruption, intracellular lipid accumulation, and mitochrondrial dysfunction (ventilator-induced diaphragm dysfunction [VIDD]).
The clinical significance of VIDD remains uncertain for several reasons. First, although diaphragm atrophy has been demonstrated in small studies of highly selected live mechanically ventilated patients (12–15), the prevalence and severity of changes in diaphragm thickness across the general population of mechanically ventilated patients are unknown. Second, it is unclear how the depth and duration of inactivity in living mechanically ventilated patients compares with the complete diaphragm inactivity seen following brain death. Third, given the widespread use of partially assisted modes of ventilation, which ameliorate diaphragm atrophy in animal models (16, 17), it is unknown whether disuse contributes significantly to diaphragm atrophy in the clinical setting (18). Finally, there are myriad mechanisms of muscle injury and dysfunction in critical illness and the specific contribution of mechanical ventilation is unknown in this context (19).
Diaphragm ultrasound is a promising new method for evaluating the diaphragm during mechanical ventilation, where loss of diaphragm thickness over time can indicate atrophy (20–22). The thickness of the right hemidiaphragm can be feasibly and reproducibly measured in the zone of apposition in mechanically ventilated patients (21). In addition, tidal diaphragm thickening during inspiration visualized by ultrasound provides a noninvasive means of quantifying inspiratory effort (diaphragm contractile activity) (21–24) and maximal diaphragm thickening (during a maximal inspiratory effort) can be used to assess diaphragm function (20, 25–27).
We set out to determine whether the level of inspiratory effort during mechanical ventilation modifies diaphragm thickness and function over time in adult critically ill patients, accounting for the severity of illness, sepsis, and multiorgan failure. We hypothesized that there is a dose–response relationship between inspiratory effort and changes in diaphragm thickness over time during ventilation. We also aimed to ascertain the effect of changes in diaphragm thickness on diaphragm function in mechanically ventilated patients. Preliminary findings from this study were previously presented in the form of an abstract (28).
The study was conducted at three tertiary academic intensive care units (ICUs) in Toronto, Canada. The study was conducted in two separate epochs (epoch 1, May–August 2013, results previously presented in abstract form ; epoch 2, May 2014–January 2015). The Research Ethics Boards at the University Health Network and St. Michael’s Hospital approved the study protocol and informed consent was obtained from patients or their substitute decision makers prior to enrollment.
We identified eligible patients by regular screening (Monday–Thursday) in the ICU. Patients were eligible for enrollment if they had received invasive mechanical ventilation for acute respiratory failure for fewer than 72 hours, and after the first 53 subjects, enrollment was restricted to patients receiving mechanical ventilation for fewer than 36 hours. Patients were excluded if they were expected to be liberated from mechanical ventilation within 24 hours of screening or if they had received invasive mechanical ventilation for greater than 48 hours in the previous 6 months. We also enrolled a control group consisting of nonventilated patients admitted to the ICU for any reason. Patients were enrolled within 36 hours of ICU admission.
The thickness of the right hemidiaphragm at end-expiration (diaphragm thickness) was measured using techniques we have previously shown to be reliable (21). Measurement procedures are detailed in the Methods section of the online supplement. Briefly, we measured thickness using a high frequency (13 MHz) linear array transducer placed in the ninth or tenth intercostal space between the anterior and midaxillary lines in the zone of apposition (29). Diaphragm contractile activity (i.e., the level of inspiratory effort) was quantified by the percentage change in right hemidiaphragm thickness from end-expiration to peak inspiration during tidal breathing on ventilation (thickening fraction). These measurements were made daily from Monday to Friday until extubation or until Day 14 of ventilation, whichever came first.
In nonventilated control subjects, we measured diaphragm thickness measurements daily for up to 7 days. In a convenience sample of ventilated patients enrolled later in the study, we also collected thickness measurements over the first 4 days following extubation as an additional internal control.
At a later stage in the study, we assessed diaphragm function in study participants. Diaphragm function was assessed after 1 week of mechanical ventilation (once the patient was awake and breathing spontaneously) by measuring maximal diaphragm thickening fraction during coached maximal inspiratory efforts (20, 25, 26) and maximal inspiratory sniff maneuvers (5, 30) while in continuous positive airway pressure mode. The observer was masked to the change in diaphragm thickness over time. If the patient was extubated before 1 week of ventilation was completed, diaphragm function was assessed on the day of extubation (either before or immediately after extubation). In participants who were unable to follow instructions, the endotracheal tube was transiently occluded to stimulate maximal inspiratory efforts (31). The highest value obtained for thickening fraction during repeated inspiratory efforts was taken as the measurement of muscle function.
Demographic data, comorbidities, admission diagnosis, and severity of illness (Severe Acute Physiology Score II) were collected at baseline. Ventilator settings, arterial blood gas tensions, diagnosis of sepsis, and Severity of Organ Failure Assessment (SOFA) scores were ascertained on a daily basis for the duration of the study.
Data were expressed as mean (SD), median (interquartile range [IQR]), and absolute and relative frequencies, as indicated. Analysis of variance or Kruskal-Wallis tests were used to compare continuous variables and chi-square tests were used for categorical variables. Missing data for SOFA score (5% missing) were imputed from the median patient value. The amount of missing data was not significant for other variables (see Table E1 in the online supplement).
The study population was divided into three groups based on the overall change in diaphragm thickness from the baseline measurement to the last measurement obtained during the first week of mechanical ventilation using a 10% cutoff value selected a priori to define clinically relevant decreases or increases in diaphragm thickness. Cutoff selection was based on the measurement resolution of the ultrasound technique (21, 32) and in accordance with previous studies of myopathy in critical illness and respiratory disease (33–35). Clinical characteristics and changes in diaphragm function were compared among patients in these categories using analysis of variance or chi-square tests as appropriate.
We used linear mixed effects regression models to evaluate the effect of diaphragm contractile activity on changes in diaphragm thickness over time (primary analysis) and to identify key determinants of diaphragm contractile activity. This modeling strategy was selected for the primary analysis because it efficiently incorporates all repeated daily measurements from all patients. A series of secondary analyses were conducted to corroborate the primary analysis. The effect of theoretical mathematical coupling between diaphragm thickness and thickening fraction was explored using simulation (see the online supplement for details).
We planned to enroll 120 mechanically ventilated patients and 10 control patients (see online supplement for sample size considerations). All statistical analyses were conducted using R software, version 3.0.2 (www.r-project.org).
A total of 128 mechanically ventilated patients (54 in study epoch 1 and 74 in epoch 2) and 10 control patients were enrolled in the study (see enrollment flow diagram in Figure E1). Two patients withdrew consent and baseline measurements were not obtained in four patients. A further 15 patients were extubated or died before a second thickness measurement was obtained and were excluded from the study cohort, leaving 107 ventilated patients in whom changes in diaphragm thickness over time were ascertained. Of these, 23 (21%) were enrolled on Day 1 of mechanical ventilation, 72 (67%) on Day 2, and 12 (11%) on Day 3. Patients were enrolled in the study for a median of 7 days (IQR, 5–11). Diaphragm thickness measurements were obtained on a total of 527 patient-days during mechanical ventilation (median, four measurements per subject; IQR, 3–7).
Demographic and clinical characteristics of the study population are shown in Table 1. Most patients (71%) were initially ventilated in a controlled mode of mechanical ventilation. Clinical characteristics of control subjects are provided in Table E2.
|Overall Study Population (n = 107)||Change in Diaphragm Thickness during the First Week of Mechanical Ventilation|
|>10% Decrease (n = 47)||Within 10% of Baseline (n = 47)||>10% Increase (n = 13)||P Value|
|Age, yr, mean (SD)||59.6 (15.6)||60.7 (15.1)||56.7 (16.6)||66.8 (11.7)||0.10|
|Sex, % female*||39 (36%)||21 (45%)||15 (32%)||3 (23%)||0.25|
|Body mass index, kg/m2*||25.9 (21.5–28.7)||26.0 (21.5–28.6)||26.0 (22.1–28.9)||24.2 (20.7–26.8)||0.81|
|Severe Acute Physiology Score II||42 (33–56)||44 (33–55)||40 (32–56)||49 (35–61)||0.54|
|No. Failing Organs at Baseline, n (%)||0.20|
|1||31 (30%)||13 (28%)||17 (38%)||1 (8%)|
|2||40 (38%)||18 (38%)||13 (29%)||9 (69%)|
|3||18 (17%)||8 (17%)||9 (20%)||1 (8%)|
|≥4||16 (15%)||8 (17%)||6 (13%)||2 (15%)|
|Primary reason for ventilation, n (%)||0.38|
|Respiratory dysfunction||15 (14%)||7 (15%)||7 (15%)||1 (8%)|
|Cardiovascular dysfunction||10 (9%)||5 (11%)||3 (6%)||2 (15%)|
|Sepsis||30 (28%)||15 (32%)||12 (26%)||3 (23%)|
|Transplant||26 (24%)||13 (28%)||12 (26%)||1 (8%)|
|Other organ dysfunction||17 (16%)||5 (11%)||7 (15%)||5 (38%)|
|Postoperative||9 (8%)||2 (4%)||6 (13%)||1 (8%)|
|Baseline mode of mechanical ventilation, n (%)||0.18|
|Controlled mode (ACVC, PCV)||76 (71%)||37 (79%)||32 (68%)||7 (54%)|
|Partial assist mode (PSV)||31 (29%)||10 (21%)||15 (32%)||6 (46%)|
|Ventilator settings (average over first 3 d)|
|Tidal volume (ml/kg PBW)||6.4 (5.4–8.0)||6.1 (5.4–8.0)||6.6 (5.5–7.9)||6.2 (5.7–7.0)||0.92|
|Applied driving pressure, cm H2O, mean (SD)||11.0 (6.3)||12.2 (6.3)||10.4 (5.4)||8.5 (8.6)||0.04†|
|Frequency||21 (18–24)||21 (18–24)||20 (19–24)||23 (18–28)||0.56|
|Positive end-expiratory pressure, cm H2O||8 (5–10)||8 (5–10)||7 (5–9)||9 (6–10)||0.70|
|FiO2||0.45 (0.40–0.50)||0.45 (0.40–0.50)||0.45 (0.38–0.50)||0.45 (0.40–0.60)||0.84|
|Arterial blood gases (average over first 3 d)|
|pH||7.38 (7.34–7.42)||7.38 (7.34–7.43)||7.39 (7.33–7.42)||7.36 (7.31–7.41)||0.40|
|PaCO2, mm Hg||40 (34–47)||42 (35–48)||41 (35–47)||36 (32–46)||0.42|
|PaO2, mm Hg||97 (80–113)||98 (79–111)||99 (83–117)||82 (78–97)||0.45|
|Clinical management during first week of mechanical ventilation|
|Neuromuscular blockade administered by infusion at any time, n (%)||23 (21%)||10 (21%)||10 (21%)||3 (23%)||0.99|
|Corticosteroids administered at any time, n (%)||45 (42%)||23 (49%)||17 (36%)||5 (38%)||0.44|
|Days in controlled mode of ventilation||1 (0–2)||1 (0–2.5)||1 (0–2)||1 (0–3)||0.71|
|Days under heavy sedation (SAS 1-2)||1 (0–2)||1 (0–3)||1 (0–2)||1 (1–2)||0.48|
The magnitude and rate of change in diaphragm thickness over time varied widely: over the first week of ventilation, diaphragm thickness remained unchanged in 47 subjects (44%), decreased by more than 10% in 47 subjects (44%), and increased by more than 10% in 13 subjects (12%) (Figure 1; see Figure E2). There were no significant differences in clinical, physiologic, or management characteristics among these three groups (Table 1). Changes in diaphragm thickness (increases and decreases) occurred predominantly during the early course of ventilation (see Figure E2) (P < 0.0001 for heterogeneity in rates of change between Week 1 and Week 2) and rapid early decreases in diaphragm thickness were observed during both controlled ventilation and partially assisted ventilation (see Figure E3).
Diaphragm thickness was comparatively stable over time in nonventilated control subjects (n = 10) (Figure 2A; see Table E3) and in patients following extubation (n = 29) (Figure 2B; see Table E3). In some patients, diaphragm thickness tended to return toward baseline following extubation (see Figure E4 and Table E3). Maximal diaphragm thickening fraction measurements obtained in 20 ventilated patients and 4 control subjects varied significantly according to the degree of change in diaphragm thickness over time (see online supplement for details).
The rate and direction of change in diaphragm thickness over time was significantly influenced by diaphragm contractile activity (Figure 3) (P = 0.002 for effect modification), even adjusting for age, sex, severity of illness, organ failures, and presence of sepsis (see Table E1). Lower contractile activity was associated with decreasing thickness over time, whereas higher contractile activity was associated with increasing diaphragm thickness over time (Figure 3; see Figure E5). The association between diaphragm contractile activity and changes in thickness over time was most pronounced during the first week of mechanical ventilation (adjusted interaction β = 0.063; 95% confidence interval, 0.012–0.114; P = 0.03 for heterogeneity between the first and second weeks of ventilation).
Higher daily SOFA scores were associated with increasing diaphragm thickness (adjusted interaction β = 0.002; 95% confidence interval, 0.001–0.002); diaphragm contractile activity and SOFA had additive effects on the rate of change in thickness (see Table E1, Figure E6). Sepsis did not significantly modify the rate of change in diaphragm thickness over time (adjusted interaction β = 0.001; 95% confidence interval, −0.006 to 0.008). The effect of diaphragm contractile activity on the rate and direction of change in diaphragm thickness was consistent across study epochs (P = 0.16 for heterogeneity). Model effects were robust to removal of two potentially influential observations.
In accordance with the results of the primary model, the change in diaphragm thickness over the first week of ventilation was correlated with diaphragm contractile activity as assessed by the average diaphragm thickening fraction during the first 3 days of ventilation (P < 0.01; R2 = 0.05) (see Figure E7). The change in diaphragm thickness over the first week of ventilation was inversely correlated with the average ventilator driving pressure over the first 72 hours of ventilation (Figure 4) (P = 0.04 after removal of a single highly influential outlier).
Diaphragm contractile activity varied widely between and within patients over the first week of ventilation and tended to increase over time from relatively low baseline levels (see Figure E8, median baseline thickening fraction 12%; IQR, 5–14%, reference range in healthy subjects during resting tidal breathing is 25–40% [21, 36]). The use of lower ventilator driving pressures and partially assisted modes of ventilation was associated with higher contractile activity (P = 0.01 and P = 0.02, respectively) (see Figure E9, Table E4), although there was considerable overlap in contractile activity across levels of exposure to controlled ventilation and across levels of ventilator driving pressure (see Figure E9). Contractile activity was only slightly higher when patients in controlled modes of ventilation were triggering the ventilator above the set rate (14% vs. 10%; P = 0.008). Contractile activity tended to be lower with higher SOFA scores (P = 0.01) (see Table E4) but arterial pH, PaCO2, sedation level (Sedation-Agitation Scale score), tidal volume, respiratory frequency, and positive end-expiratory pressure were not independently associated with contractile activity (see Table E4).
In this study we found that changes in diaphragm thickness are common in mechanically ventilated patients, occur early in the course of ventilation, and seem to be modulated by the intensity of respiratory muscle work done by the patient, even under partially assisted modes of ventilation. We also observed that diaphragm thickness increased in some patients and that both decreased and increased diaphragm thickness were associated with significant diaphragm dysfunction. Our findings raise the possibility that titrating ventilatory support to maintain adequate (but not excessive) levels of inspiratory effort might prevent changes in diaphragm configuration during mechanical ventilation.
Disuse atrophy of the diaphragm has been demonstrated repeatedly in animal models (9, 11, 37) but the significance of disuse atrophy in the clinical setting has been unclear because partially assisted modes of ventilation are commonly used (16, 38). Decreases in diaphragm thickness observed in this study likely correspond to diaphragm myofiber atrophy previously reported in various animal models (9, 11, 16, 38, 39), organ donors (6, 7), and a recently published series of living mechanically ventilated patients (12, 14). Our results suggest that decreases in diaphragm thickness are common during mechanical ventilation and are associated with impaired diaphragmatic function, consistent with previously documented in vitro contractile dysfunction (14).
This study provides strong evidence that mechanical ventilation injures the diaphragm in the clinical setting through its effects on inspiratory effort. Diaphragm thickness did not change following extubation or in nonventilated ICU patients (control subjects). Moreover, in both primary and secondary analyses there was a strong dose–response relationship between the level of diaphragm contractile activity and changes in diaphragm thickness over time. The level of contractile activity associated with stable diaphragm thickness corresponded to normal levels of inspiratory effort during resting breathing in healthy subjects (thickening fraction of 25–40%) (20, 21). Average ventilator driving pressure over the first 72 hours was also correlated with the change in diaphragm thickness during the first week of mechanical ventilation. Titrating ventilatory support to maintain some adequate level of diaphragm activity (“muscle-protective” mechanical ventilation) may therefore prevent changes in diaphragm configuration. Because diaphragm contractile activity varies considerably within modes of ventilation and levels of ventilator driving pressure, such titration strategies would require direct monitoring of diaphragm activity.
A minority of patients exhibited an increase in diaphragm thickness over time. Although increased diaphragm thickness following exercise training has been associated with increased strength (40, 41), function measurements obtained in three of these patients revealed marked weakness, suggesting that this increase in thickness may reflect structural injury rather than hypertrophy. Inferences related to this finding are significantly limited by the small size of this group. An early rapid increase in diaphragm thickness can occur following traumatic diaphragm injury (42, 43). Given that increases in thickness over time were associated with both higher thickening fraction and higher SOFA scores in our study, it is possible that an injurious increase in thickness may result from excess inspiratory loads during ventilation or from systemic inflammation. High inspiratory loads can cause myofibrillar and sarcolemmal injury (44–50). Systemic inflammation impairs diaphragm function apart from causing atrophy (51) and can sensitize the diaphragm to load-related injury (52). Further work is required to establish the structural basis of increases in diaphragm thickness in this setting.
In our study, thickening fraction was not significantly associated with sedation level, pH, or PaCO2 after adjusting for ventilator settings and SOFA score. This likely reflects the complex interplay between these variables in the clinical setting: low pH and high PaCO2 might be expected to increase thickening fraction in the absence of sedation, whereas in the presence of sedation, they may reflect a blunted respiratory drive associated with reduced diaphragm thickening. Alternatively, high thickening fraction might be expected to increase pH and lower PaCO2. The significance of the observed association between SOFA and thickening fraction is unclear; it is possible that residual confounding factors associated with greater severity of illness reduce inspiratory effort.
Our findings are subject to a number of limitations. First, although the reproducibility of end-expiratory right hemidiaphragm thickness measurement is adequate (repeatability coefficient of 0.2 mm), the reproducibility of the thickening fraction measurement is only moderately acceptable (repeatability coefficient of 16%) (21, 22). It is also unknown whether diaphragm contractile activity measured at a single point in time is representative of diaphragmatic activity over the whole course of the day. To minimize systematic bias, we obtained measurements at a similar time period on a daily basis (between 8 a.m. and 12 p.m.). Importantly, the “noise” resulting from measurement imprecision would be expected to obscure any observed associations and bias effects toward the null hypothesis. Consequently, the influence of inspiratory effort level on the rate and direction of changes in diaphragm thickness may in fact be underestimated in this study.
Second, we ascertained diaphragm function by measuring diaphragm thickening fraction during a maximal inspiratory effort. Although diaphragm thickening fraction does not actually “measure” pressure generation by the diaphragm, this measurement provides a valid method of estimating diaphragmatic contractile force in ventilated patients (21, 22, 24). Maximum inspiratory efforts can be challenging to obtain in ventilated patients (31) and our technique has not yet been validated against the current gold standard, magnetic twitch transdiaphragmatic pressure (53, 54). Maximal thickening fraction was measured under isometric conditions with the airway occluded in some subjects and this may reduce the degree of thickening observed at a given level of inspiratory effort (55), although isometric maximal thickening fraction is generally above 50% in healthy subjects (26, 27). Further studies are required to confirm that changes in diaphragm thickness are associated with true contractile weakness.
Nevertheless, previous studies suggest that maximal diaphragm thickening fraction is strongly associated with maximal inspiratory pressure in outpatients (26, 56) and ventilated patients (57) and was recently shown to predict extubation success when measured during a spontaneous breathing trial in two separate studies (25, 57). Maximal thickening fraction measurements therefore likely reflect true diaphragm function. We took great care to obtain the most reliable measurements (21) but the number of patients is limited and future studies are required to confirm that changes in diaphragm thickness are associated with contractile weakness.
Third, we did not obtain serial diaphragm tissue specimens for histologic analysis to correlate with the changes in diaphragm thickness observed on ultrasound. The structural changes accounting for the observed variation in diaphragm thickness over time are therefore uncertain. Aside from changes in myofibrillar structure, tissue edema or tonic diaphragm activity might account for variation in diaphragm thickness. However, these phenomena would be expected to increase muscle thickness; they are unlikely to account for early rapid decreases in diaphragm thickness. Decreases in diaphragm thickness on ultrasound were recently found to be correlated with reduced myocyte cross-sectional area in a porcine model of VIDD (58).
Fourth, the interpretation of the primary regression model is subject to a number of limitations. We cannot exclude the possibility that atrophy causes weakness and consequently reduces contractile activity (reverse causation of association). However, contractile activity levels were lowest at baseline before significant changes in diaphragm thickness occurred and contractile activity increased over time (whereas diaphragm thickness decreased), arguing against such reverse causation. Furthermore, inspiratory effort was documented to be normal or even above normal in ventilated patients with diaphragm dysfunction (59).
The observed association between inspiratory effort and changes in thickness over time may have arisen from residual confounding unaccounted for in our model. For example, a considerable subset of patients enrolled in the study received large doses of corticosteroids following transplantation. However, significant changes in diaphragm thickness were observed across all admission categories.
Finally, we cannot draw inferences about the impact of changes in diaphragm thickness on clinical outcomes. Although diaphragm dysfunction is associated with prolonged mechanical ventilation (4, 60), it remains unclear whether preventing diaphragm atrophy would accelerate liberation from mechanical ventilation. Our findings do not provide definitive evidence of causality; it therefore remains unknown whether optimizing inspiratory effort level would protect against deleterious changes in diaphragm structure and function during mechanical ventilation.
In summary, we describe important changes in diaphragm muscle thickness that may be caused by excessive or inadequate ventilatory support that may impair muscle function (VIDD). These changes in diaphragm configuration might be prevented by muscle-protective ventilation strategies titrated to optimize patient inspiratory effort.
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Supported by salary support grants from the Canadian Institutes for Health Research in the form of a Post-Doctoral Fellowship (E.C.G.) and New Investigator Award (N.D.F.).
Author Contributions: E.C.G. and N.D.F. conceived and designed the study. E.F., M.S.H., L.J.B., G.T., G.D.R., B.P.K., S.-S.B., and J.M.S. made substantial contributions to the design and analysis plan of the study. A.M., S.V., D.B., N.R., A.L., and E.C.G. collected the data. E.C.G. and G.T. conducted the data analysis. E.C.G., E.F., G.T., G.D.R., B.P.K., S.-S.B., J.M.S., M.S.H., L.J.B., and N.D.F. contributed to the interpretation of the analysis results. E.C.G. prepared the first draft of the manuscript, and all authors revised the draft critically for important intellectual content. All authors gave final approval of the manuscript version to be published.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201503-0620OC on July 13, 2015