Effects of critical illness on diaphragm structure
Less than a decade ago, Levine et al. were the first to describe a rapid loss of diaphragm muscle mass in patients on controlled mechanical ventilation [
3]. Biopsies were obtained from 14 brain‐dead organ donors on controlled mechanical ventilation for 18 to 69 h before organ harvest. The cross‐sectional area (CSA) of diaphragm fibers was significantly lower (53 and 57% for fast‐ and slow‐twitch fibers respectively) compared to fibers obtained from patients referred for elective lung cancer surgery. Interestingly, the severity of atrophy was less pronounced in the pectoralis muscle, indicating that the diaphragm is much more sensitive to the effects of disuse. In subsequent studies, it was demonstrated that the decrease in diaphragm fiber CSA was proportional to the duration of mechanical ventilation (Pearson
r
2 = 0.28) [
4]. Diaphragm inactivity was associated with oxidative stress, active caspase‐3 expression and upregulation of mRNAs coding for ligands related to the proteolytic ubiquitin‐proteasome pathway (muscle atrophy F‐box [MAFBx] and muscle ring finger 1 [MuRF‐1]). In addition, activation of the lysosomal‐autophagy pathway was demonstrated in the diaphragm of these brain‐dead patients ventilated for ±60 h [
5]. Very recently, Matecki et al. demonstrated increased oxidation, nitrosylation and phosphorylation of the diaphragm sarcoplasmic reticulum ryanodine calcium release channel in ventilated brain‐dead patients [
6]. These molecular modifications were associated with enhanced calcium leak from the channel (increased open probability). Additional experiments in mice indicated that leaky ryanodine channels are associated with diaphragm weakness.
Collectively, these data demonstrate that inactivity of the diaphragm under controlled mechanical ventilation is associated with rapid posttranslational protein modifications, activation of proteolytic pathways and muscle fiber atrophy. However, these early studies used biopsies of the diaphragm of brain‐dead patients. This might be an excellent model for diaphragm disuse associated with mechanical ventilation, but differences in treatment and underlying pathophysiology in more representative ICU patients should be recognized. Hooijman et al. were the first to study structural, biochemical and functional modifications of biopsies obtained from the diaphragm of ventilated ICU patients (
n = 22, mean duration on the ventilator: 7 days, range 14 to 607 h) [
7]. These authors found that both fast‐ and slow‐twitch diaphragm fibers had a CSA that was approximately 25% smaller than that of fibers from the diaphragm of patients referred for elective surgery. Biochemical analysis revealed activation of the proteolytic ubiquitin‐proteasome pathway. Histological analysis demonstrated that the number of inflammatory cells, including neutrophils and macrophages, was significantly increased in the diaphragm of ICU patients; this supports a role for inflammatory mediators in the development of atrophy or injury. Interestingly, van Hees et al. demonstrated that plasma from septic shock patients, but not from healthy subjects, induced atrophy in (healthy) cultured skeletal muscle myotubes [
8]. This indicates that plasma from septic shock patients contains molecules with catabolic properties. Additional experiments presented in that paper suggest that interleukin (IL)‐6 plays a role in the development of muscle atrophy in sepsis.
Effect of critical illness on diaphragm function
Structural modifications of the respiratory muscles as described above may have functional implications. Single muscle fibers isolated from the diaphragm provide an excellent model to study contractile protein function. The force generated by single fibers from the diaphragm of ICU patients was significantly reduced compared to fibers from non‐ICU patients [
7]. Reduction in force resulted from loss of contractile proteins (atrophy) and contractile protein dysfunction.
The gold standard to evaluate in vivo diaphragm contractile function in ventilated patients is to assess the change in endotracheal tube pressure induced by magnetic stimulation of the phrenic nerves during airway occlusion (Ptr,magn). The major advantage of this technique is that it can be performed at the bedside and does not require patient cooperation. Demoule et al. measured Ptr,magn within 24 h of mechanical ventilation in a population of 85 critically ill patients [
9]. Of this group, 54 (64%) patients were diagnosed with diaphragm dysfunction defined as a Ptr,magn < 11 cmH
2O. More recently, the same investigators confirmed these earlier findings in 43 ventilated patients [
10]; 23 (53%) of these patients exhibited diaphragm dysfunction at ICU admission. These are important findings, as they indicate that other factors besides disuse play a role in the pathophysiology of respiratory muscle weakness in ICU patients. In fact, in their earlier study [
9], the authors reported that diaphragm dysfunction was independently associated with sepsis. Consistent with that study, Supinski et al. [
11] found that measures for in vivo contractile force were affected more in ventilated patients with infection than in ventilated patients without infection.
In a follow up study, Jaber et al. measured Ptr,magn every 24 to 36 h in ICU patients (
n = 6) ventilated for > 5 days [
4]. Ptr,magn rapidly declined by approximately 30% in the first 5 to 6 days of controlled mechanical ventilation. The recent study by Demoule et al. [
10] also assessed Ptr,magn during the ICU stay. In that study, 61% of patients fulfilling criteria for diaphragm dysfunction at admission had persistent respiratory muscle weakness while in the ICU. Of the patients with normal diaphragm function at ICU admission, 55% developed weakness while on the ventilator. This study demonstrates that 80% of all patients fulfilling their inclusion criteria (i. e., > 5 days on mechanical ventilation), develop respiratory muscle weakness at some time while on the ventilator.
Goligher et al. described the evolution of diaphragmatic thickness during mechanical ventilation and its impact on diaphragm function, assessed with ultrasound [
12]. Changes in diaphragm thickness were found in 56% of the study population (
n = 128). Both loss and gain of diaphragm thickness were observed during the first week of ventilation, in 44 and 12% of the patients, respectively. Contractile activity of the diaphragm was estimated as the diaphragm thickening fraction during maximal inspiratory effort. There was a significant correlation between the mean diaphragm thickening fraction during the first 3 days of ventilation and changes in diaphragm thickness (
p = 0.01): a loss of diaphragm muscle mass was associated with lower contractile activity, while higher contractile activity was found for patients exhibiting increases in diaphragm thickness. Both increased and decreased diaphragm thickness seemed to be modulated by the intensity of respiratory muscle work performed by the patient, because the change in diaphragm thickness was inversely correlated with the driving pressure applied by the ventilator over the first 72 h of ventilation (
p = 0.04, after removal of one outlier).
In conclusion, in the last decade our knowledge of the effects of critical illness and mechanical ventilation on respiratory muscle function has markedly improved. We have gained more insight into the pathophysiology, including molecular pathways, associated with dysfunction. In addition, it appears that the most important clinical risk factors for development of dysfunction include disuse and inflammation/sepsis.