Skip to main content

Strategies to optimize respiratory muscle function in ICU patients

Abstract

Respiratory muscle dysfunction may develop rapidly in critically ill ventilated patients and is associated with increased morbidity, length of intensive care unit stay, costs, and mortality. This review briefly discusses the pathophysiology of respiratory muscle dysfunction in intensive care unit patients and then focuses on strategies that prevent the development of muscle weakness or, if weakness has developed, how respiratory muscle function may be improved. We propose a simple strategy for how these can be implemented in clinical care.

Background

Respiratory muscle weakness may develop in ventilated critically ill patients [14]. For instance, Jaber and colleagues [1] demonstrated that after 5–6 days of controlled mechanical ventilation in intensive care unit (ICU) patients, force-generating capacity of the diaphragm was reduced by ±32 %. In ICU patients, impaired capacity of the respiratory muscles is accompanied by an increased load due to elevated elastic and resistive forces of the respiratory system. This imbalance in load and capacity plays an important role in the development of ventilatory failure, for instance during a weaning trial. Respiratory muscle weakness is associated with adverse clinical outcomes, including difficult weaning from mechanical ventilation, increased mortality, and increased risk of ICU/hospital readmission [5]. It is reasonable to propose that strategies that aim to restore respiratory muscle function in these patients improve outcome. The aim of this review is to discuss (future) strategies that prevent the development of respiratory muscle weakness or restore respiratory muscle function in weak ICU patients. We will mainly focus on interventions that are most likely to be of clinical importance in the near future.

Pathophysiology of respiratory muscle weakness in the critically ill

Reduced force output of the respiratory muscles in the critically ill may result from injury at any point between the central respiratory centers and the contractile proteins of diaphragm muscle fibers [6, 7]. In the absence of sedatives, reduced central respiratory drive is unlikely to explain reduced force output of the respiratory muscles in ICU patients [8]. Phrenic nerve neuropathy, as assessed by prolonged phrenic nerve conduction time, has been demonstrated in ICU patients, indicating that injury of the peripheral nerve may play a role in reduced force output [9].

Contractile dysfunction of the respiratory muscles in ICU patients may result from the loss of muscle mass (atrophy) and/or dysfunction of the remaining contractile proteins. In a landmark paper, Levine and colleagues [10] demonstrated the rapid development of diaphragm muscle atrophy in ventilated brain-dead patients. More recently, Hooijman and colleagues [11] performed in-depth functional and structural analysis of diaphragm biopsies in critically ill patients on the ventilator. In that study, muscle fiber cross-sectional area was reduced by ±25 % after an average of 7 days of mechanical ventilation. Muscle atrophy is the final result of an imbalance between protein synthesis and degradation. Upregulation of several proteolytic pathways has been demonstrated in the respiratory muscles of ICU patients [11]. For instance, key regulators of the ubiquitin-proteasome pathway are upregulated in the diaphragm of these patients [10, 11]. Other pathways such as lysosomal protein degradation and autophagy may play a role as well (Fig. 1) [12, 13]. In addition to enhanced proteolysis, decreased protein synthesis has been reported in the diaphragm of rodents subjected to controlled mechanical ventilation [14, 15]. Besides atrophy, diaphragm weakness may be the result of contractile protein dysfunction. Even when corrected for loss of protein, muscle fibers in ICU patients develop less force [4]. Furthermore, the sensitivity of the contractile proteins for calcium is reduced [4]. The pathophysiology of contractile protein dysfunction in these patients is incompletely understood, but animal models of mechanical ventilation and endotoxemia indicate that phosphorylation and oxidative modifications of the sarcomeric proteins and mitochondrial proteins play a role in dysfunction and injury [1619]. For an extensive background on the pathophysiology of muscle dysfunction in the critically ill, we refer to a recent excellent review on this subject [20].

Fig. 1
figure1

Proposed scheme of pathophysiologic pathways in the development of respiratory muscle weakness during critical illness. Oxidative stress [89], inflammation [71, 74], increased nuclear factor (NF)-κB activity [90], and mechanical unloading [10, 11] have been proposed to initiate respiratory muscle weakness. These initiators can result in contractile protein becoming dysfunctional [4], decreased synthesis [14, 15], or muscular autophagy [12]. Oxidative stress and inflammatory pathways can activate caspases and calpains [89, 91], thereby delivering substrates for the ubiquitin-proteasome [10, 11, 92], which further degrades contractile proteins

Evaluation of respiratory muscle function in ICU patients

We will briefly discuss the readily available techniques that are relevant and feasible in clinical practice. For a detailed overview we refer to other reviews [2123]. Maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) are used to evaluate global respiratory muscle strength and can be applied to selected ICU patients. MIP and MEP are measured using a handheld pressure device connected to the endotracheal tube or tracheostomy while the patient performs specific maneuvers. Although American Thoracic Society/European Respiratory Society guidelines advise a single inspiratory maneuver at residual volume in non-intubated patients [24], the reliability of MIP measurement in ICU patients is improved when using a unidirectional expiratory valve connected to the endotracheal tube or tracheostomy [25]. Alternatively, pressures can be assessed using the ventilator by performing an end-expiratory hold maneuver. A 20-s end-expiratory occlusion can be performed to obtain more reliable measurements in poorly cooperative patients [26]. It should be acknowledged that assessment of MIP and MEP requires a cooperative patient. Today, most ICU ventilators provide automatic functions to provide some useful parameters to evaluate the diaphragm function. High values for MIP and MEP exclude clinically significant weakness, but low values are common and may also reflect poor technique or effort [27].

Esophageal pressure (Pes) is an estimate of pleural pressure [28] and can be used to calculate the amount of work performed by the respiratory muscles. Simultaneous recording of Pes and gastric pressure (Pga) allows the calculation of transdiaphragmatic pressure (Pdi = Pga − Pes), a specific measure of diaphragm contractility. The latter is useful for close monitoring and evaluation of diaphragm function in difficult-to-wean patients [29]. However, acquisition, calculation, and interpretation of Pes, Pga, and their derived measures are rather complex and therefore not widely accepted in clinical practice.

Ultrasonography is an increasingly popular tool for assessment of diaphragm function in ICU patients [30]. In the subcostal view reduced caudal movement of the diaphragm during unassisted breathing is consistent with weakness and paradoxal movement indicates diaphragm paralysis [31, 32]. Diaphragm atrophy can be assessed by measuring diaphragm thickness in the midaxillary line at the level of the diaphragm dome [32, 33] and its thickening fraction during inspiration to asses contractile activity [30]. Diaphragm atrophy can also be evaluated more precisely with computed tomography, although this is more cumbersome than echography [34]. Using ultrasound, Goligher and colleagues [30] recently demonstrated in ICU patients that diaphragm atrophy is associated with diaphragm dysfunction and, in a minority of these patients, diaphragm thickness surprisingly increased while on the ventilator, which was associated with dysfunction as well. Diaphragm electromyography (EMG) reflects the electrical activity and is the gold standard to assess neural respiratory drive. Diaphragm EMG can be recorded best using an esophageal catheter with multiple electrodes. With the introduction of neurally adjusted ventilatory assist (NAVA; Maquet, Solna, Sweden) [35], the (processed) EMG signal can be obtained continuously in ICU patients. In these patients, diaphragm EMG may be used to monitor respiratory muscle unloading [36] and patient–ventilator interaction [37].

Modulation of contractile activity: disuse and inspiratory muscle training

Prevention of disuse atrophy

Like any other striated muscle, respiratory muscle mass is affected by contractile inactivity. In fact, the respiratory muscles appear more sensitive to the effects of disuse compared with other striated muscles [10, 11, 34]. In humans, relatively brief periods of diaphragm disuse (<3 days) due to controlled mechanical ventilation are associated with diaphragm muscle fiber atrophy [10].

Animal studies have demonstrated that mechanical ventilation-induced diaphragm atrophy and dysfunction is less severe in assisted modes of mechanical ventilation [38]. Recently, Goligher et al. [30] used ultrasound techniques to demonstrate that low levels of diaphragm activity, resulting from high levels of ventilator support, are associated with diaphragm atrophy and dysfunction in ICU patients. On the other hand, administration of muscle relaxants for 48 h in patients with early severe acute respiratory distress syndrome (ARDS) resulted in earlier withdrawal from mechanical ventilation and did not adversely affect peripheral muscle function [39]. Therefore, it appears that, under certain conditions (i.e., very severe ARDS), controlled mechanical ventilation is preferred to facilitate lung-protective ventilation and this beneficial effect outweighs the possible adverse effects on the respiratory muscles. Nevertheless, in general it is reasonable to limit the duration of controlled mechanical ventilation and prevent high levels of support under assisted ventilation in order to reduce the risk of disuse atrophy [10, 30, 40]. It is important to recognize that ventilator pressure and flow waveforms are unreliable to confirm the presence of respiratory muscle activity [21, 22, 41]. We recommend additional monitoring techniques as outlined above. Although the optimal level of activity for the respiratory muscles is unknown during mechanical ventilation, these monitoring techniques allow us to detect complete inactivity of the muscles due to over-assist.

Inspiratory muscle training

In general, training can be instituted to enhance muscle endurance or strength. These types of training require different strategies and have distinct physiological responses. In healthy subjects, respiratory muscle activity is characterized by development of low pressure during the entire life span of a subject. The pressure generated by the inspiratory muscles is only ±5 cmH2O (5 % of maximum inspiratory pressure) to generate a tidal volume of 500 ml, when respiratory compliance is 100 ml/cmH2O. At first sight, training of the respiratory muscle should, therefore, be designed to improve endurance. Indeed, in patients who are difficult to wean from the ventilator, progressive weaning trials (T-tube or low pressure support) are frequently instituted as training stimulus. Although reasonable from a physiological perspective, it has never been proven that this strategy indeed improves respiratory muscle endurance.

In very few circumstances is high inspiratory pressure required for prolonged periods of time and therefore strength training of the diaphragm seems of limited relevance. It has been demonstrated, however, that respiratory effort sensation depends on the maximal inspiratory pressure [42]. In healthy subjects, pharmacological induction of inspiratory muscle weakness increases respiratory effort sensation for the same workload [42], confirming the importance of adequate strength beyond that strictly required to generate tidal volume. It has been shown that inspiratory muscle strength training (IMST) improves whole body exercise performance, in particular in less fit subjects [43]. Also, in patients with chronic obstructive pulmonary disease (COPD), IMST improves inspiratory muscle strength and total body exercise and reduces dyspnea sensation [44]. Only three randomized studies have reported the effectiveness of IMST in ventilated ICU patients. In the trial by Cader et al. [45], 41 ventilated ICU patients with respiratory muscle weakness were randomized between inspiratory threshold loading and no training intervention. Training consisted of an inspiratory load of 30 % maximum inspiratory pressure for 5 minutes, twice a day, 7 days a week throughout the weaning period. Maximum inspiratory pressure was significantly increased in the training group (15 ± 3 to 25 ± 4 cmH2O) but not in the control group (15 ± 2 to 18 ± 2 cmH2O). The study was underpowered for clinically relevant endpoints, although weaning time was reduced in the training group. In another study, Martin and colleagues [46] randomized 69 ventilator-bound patients (mean duration of ventilation at inclusion ±44 days) to IMST or sham training added to endurance training. Strength training consisted of four sets of 6–10 breaths per day with 2 minutes rest between each set. Loading was individualized and set at a level that could just be tolerated by the patient. IMST significantly improved maximum inspiratory pressure (end of training 54 cmH2O in intervention group and 45 cmH2O in sham group, P < 0.05). Also, successful weaning at day 28 after inclusion was more likely in the intervention group compared with sham (71 versus 47 %, P < 0.05). No adverse events of IMST were reported in these two trials. Finally, Condessa et al. [47] randomized ventilated patients to inspiratory strength training on top of usual care versus usual care only. Each training session consisted of five sets of loaded breaths (40 % maximum inspiratory pressure), twice a day, 7 days a week. In this study, IMST significantly increased maximum inspiratory pressure but did not affect weaning time.

In conclusion, inspiratory muscle training is feasible and appears safe in patients with respiratory muscle weakness who are difficult to wean from the ventilator, which is supported by a recent systematic review [48]. Studies in other patient categories, including COPD, indicate that IMST improves outcome. In our opinion, it is reasonable to add IMST to endurance training in stable, difficult-to-wean patients with confirmed respiratory muscle weakness. Future studies are needed to determine the optimal training protocol and appropriate timing for initiation of IMST.

Antioxidants and nutrition

As outlined above, oxidative stress may play a role in the pathophysiology of ICU-acquired respiratory muscle weakness. Several experimental studies demonstrate that antioxidants attenuate the detrimental effects of controlled mechanical ventilation and/or systemic inflammation on respiratory muscle structure and function [18, 4951]. In healthy subjects, high dose N-acetylcysteine (150 mg/kg intravenously) attenuated diaphragm fatigue induced by an inspiratory resistive load [52]. Today, no study has specifically evaluated the effect of antioxidants on respiratory muscle function in ICU patients; however, some indirect evidence is available. In an open trial, 595 critically ill surgery or trauma patients were randomized between antioxidant supplementation (alpha-tocopherol and ascorbic acid) and standard care or standard care only [53]. Patients in the antioxidant group spent less time on the ventilator (3.7 versus 4.6 days, P < 0.05). It should be noted that patients in this study were young (38 ± 15 years) and total ventilation time was rather short. Therefore, it is questionable whether the beneficial effects of antioxidants were the result of improved respiratory muscle function. Heyland et al. [54] studied the effects of antioxidants and glutamine in a heterogeneous ICU population (N = 1223). Patients were divided into four groups: placebo, glutamine (0.35 g/kg/24 h of body weight intravenously), antioxidants (selenium, zinc, beta carotene, vitamin E, and vitamin C), or antioxidants plus glutamine. Again, respiratory muscle function was not specifically evaluated but no difference in duration of mechanical ventilation was observed among the four groups.

Today, only one study has evaluated the effects of two nutritional strategies on skeletal muscle structure and function in critically ill patients [55]. This study was a planned subanalysis of the EPaNIC trial that compared the effects of tolerating macronutrient deficiency versus early parenteral nutrition on skeletal muscle structure and function [56]. In that study, patients were randomized between early (within 2 days of ICU admission) versus late (<8 days after ICU admission) parenteral nutrition to prevent macronutrient deficiency. Skeletal muscle strength was assessed in 600 ICU patients using the Medical Research Council sum score. Weakness occurred less often in the late versus early parenteral nutrition group (34 versus 43 %, P = 0.030). Compared with healthy subjects, muscle fibers exhibited atrophy but were not significantly different between the early and late parenteral nutrition groups. However, markers for autophagosome formation were significantly higher in the late parenteral nutrition group. This indicates that autophagy plays an important role in protein turnover next to other effects to provide substrate for recycling. In conclusion, tolerating macronutrient deficiency in the first week after ICU admission is not associated with the development of muscle fiber atrophy but surprisingly appears to improve muscle contractility.

Although the effect of high-dose antioxidant administration on respiratory muscle structure and function is encouraging in animal models, no data support the routine administration of antioxidants or other specific feeding strategies on respiratory muscle function in the critically ill ventilated patient.

Improving respiratory muscle protein content: anabolics

Loss of muscle mass plays an important role in the development of ICU-acquired respiratory muscle weakness [10, 11]. Pharmacological interventions that restore protein balance seem a reasonable approach in these patients. First, inhibitors of proteolysis increase respiratory muscle mass in animal models with heart failure and under mechanical ventilation [57, 58] but toxicity limits the application of these agents for this specific indication in humans. Second, anabolic hormones have been used to enhance skeletal muscle mass under a variety of conditions (reviewed in [59]). We focus on the effects of endogenous and exogenous anabolic hormones on the respiratory muscles.

The most important endogenous anabolic hormones are growth hormone (GH), insulin-like growth factor-1 (IGF-1), insulin, and the anabolic steroid testosterone and its analogues. The effects of GH on skeletal muscle have been reviewed recently [60]. GH enhances production of IGF-1 in the liver but has direct anabolic effects on skeletal muscle as well. The effect of administration of GH/IGF-1 or its exogenous analogues on respiratory muscle function in critically ill patients has not been studied. However, Takala et al. [61] reported the effects of recombinant GH (Genotropin) administration in critically ill ICU patients relatively early during ICU stay in two placebo-controlled trials. Unexpectedly, both trials demonstrated significantly increased mortality in recombinant GH-treated patients (47 versus 25 % in the Finnish study and 61 versus 26 % in the multinational study). The mechanisms for increased mortality are incompletely understood, but modulation of immune function may play a role. Interestingly, Schols et al. [62] reported the effects of the exogenous anabolic steroid nadrolone in patients with stable COPD during an 8-week pulmonary rehabilitation program. Patients (N = 217) were randomized between placebo, placebo with high caloric feeding, and nandrolone with high caloric feeding. They found that nandrolone together with high caloric feeding significantly improved inspiratory muscle strength. These findings were more or less confirmed in a later trial by the same group [63]. Although case series report the use of anabolic steroids in difficult-to-wean patients [64], no randomized studies have evaluated the safety and efficacy of anabolic steroids in ICU patients with respiratory muscle weakness. Accordingly, anabolic hormones should not be used in the early stage of ICU admission but may have a role in more chronic and stable ICU patients with respiratory muscle weakness and who are difficult to wean from the ventilator.

Positive inotropes

In addition to atrophy, dysfunction of the remaining muscle fibers has been demonstrated in critically ill patients [4]. Accordingly, optimizing contractility using positive inotropes seems a reasonable approach in these patients. ß-Adrenoreceptor agonists indeed exhibit a direct positive inotropic effect on the diaphragm muscle in vitro by increasing intracellular calcium influx. The effects of β2 adrenoreceptor agonists on respiratory muscle function in vivo are, however, controversial. Albuterol (oral) did not affect fatigability of the diaphragm in healthy subjects. However, fenoterol (oral) delayed the development of diaphragm fatigue in healthy volunteers subjected to inspiratory loading. In mechanically ventilated COPD patients with respiratory failure, respiratory muscle function significantly improved after dopamine infusion, probably by augmentation of diaphragm blood flow and improved cardiac output. Currently the administration of ß-adrenoreceptor agonists cannot be recommended to improve respiratory muscle function in ICU patients.

Muscle fibers isolated from the diaphragm of ICU patients display decreased maximal force-generating capacity, indicating intrinsic muscle weakness [11]. In fast-twitch diaphragm fibers the reduction of sub-maximal force generation even exceeds the loss of maximal force-generating capacity [4]. This implies that these fibers require more calcium to generate normal force levels, i.e., their sensitivity to calcium is reduced. Calcium sensitizers have been developed to treat similar pathology of cardiac muscle [65, 66]. Currently, levosimendan is the only calcium sensitizer approved for use in humans (>50 countries worldwide). Experimental studies have shown that levosimendan improves calcium sensitivity of diaphragm muscle fibers from patients with COPD [67]. Moreover, a recent double-blind, randomized, crossover study demonstrated that administration of levosimendan improved neuromechanical efficiency by >20 % and prevented contractile fatigue during a diaphragm-loading task in healthy subjects [68]. A randomized clinical trial (ClinicalTrials.gov identifier NCT01721434) is currently investigating whether levosimendan indeed facilitates liberation from the ventilator. In contrast to levosimendan, the effectiveness of other calcium sensitizers has so far only been studied in vitro. For example, exposure to EMD 57033 (a troponin activator) partially restored calcium sensitivity in diaphragm fibers isolated from piglets after 5 days of mechanical ventilation [69]. Furthermore, in diaphragm fibers from critically ill patients, CK-2066260 completely restores calcium sensitivity [4].

Taken together, calcium sensitizers might exert an energetically beneficial effect on diaphragm work [67]. When less calcium is needed to maintain force generation, muscle work becomes more efficient [68] and could improve respiratory muscle contractility in critically ill patients. However, further clinical trials are needed to prove the benefits of the calcium sensitizers in ICU patients with respiratory muscle weakness.

Future developments

Modulation of inflammation

Activation of pro-inflammatory pathways is associated with respiratory muscle weakness [7073]. Therefore, modulation of the inflammatory response to combat respiratory muscle dysfunction has been a focus of interest in recent experimental studies [71, 74, 75]. We demonstrated, for instance, that interleukin (IL)-6 plays an important role in the loss of contractile proteins in muscle fibers exposed to plasma from septic shock patients [71]. However, diaphragm fiber atrophy due to disuse in brain death patients was not associated with upregulation of IL-6 [10]. IL-10 is an interleukin with anti-inflammatory properties [76]. In a murine model of Pseudomonas aeruginosa pneumonia, diaphragm dysfunction was attenuated after experimental IL-10 administration [76]. During critical illness with subsequent inflammatory status, nuclear factor (NF)-κB is the key factor for transcription of several cytokines [77]. Recently, evidence was found that inhibition of NF-κB in endotoxemic mice protects against diaphragm muscle weakness, probably due to decreased generation of pro-inflammatory cytokines [75]. Proteolytic pathways can be activated through Toll-like receptor (TLR)-4, present in muscle plasma membrane [74]. TLRs are essential receptors in recognizing microbes and initiating an inflammatory immune response [78]. In TLR-4 knockout mice, loss of diaphragm contractile protein associated with controlled mechanical ventilation was attenuated compared with wild-type mice [74]. In a large clinical trial the TLR-4 antagonist eritoran did not, however, improve outcome in patients with severe sepsis or septic shock (±80 % on mechanical ventilation) [79]. Nevertheless, neither skeletal muscle function nor duration of mechanical ventilation was assessed in this trial.

Traditionally, steroids are associated with myopathy, atrophy, and dysfunction of the respiratory muscles [8082]. However, the final effects appear to be dose- and time-dependent, at least in experimental studies. For instance, Maes et al. [83] demonstrated that “low-dose” (5 mg/kg) methylprednisolone exacerbated ventilator-induced diaphragm dysfunction in rats, whereas a high dose (30 mg/kg) protected against the deleterious effects of controlled mechanical ventilation on diaphragm function. In ICU patients the effect of steroids on muscle function are conflicting [8486]. However, no study has prospectively evaluated the effects of corticosteroids on respiratory muscle function in ventilated ICU patients.

In conclusion, despite the encouraging data that modulation of inflammation improves respiratory muscle function in animals, data in humans are scarce and, where present, disappointing.

Modulation of proteolytic pathways

Since activation of proteolytic systems plays a key role in the development of respiratory muscle dysfunction during critical illness, several experimental studies have investigated the effect of specific inhibitors. For instance, in rats exposed to 24 h of mechanical ventilation, bortezomib treatment partially prevented the reduction of diaphragm force and atrophy [58]. These small positive effects were probably mediated by the ability of bortezomib to indirectly reduce caspase-3 activity [57]. Proteasomes are only able to process myofilaments that have been cleaved from the sarcomere by enzymes like caspases and calpains [87]. Accordingly, inhibition of the proteasome alone is not expected to have substantial effects on muscle function as this would leave the muscle cell with only unprocessed, but cleaved, myofilaments. Furthermore, considering the basic housekeeping cell functions of the proteasome, it is no surprise that the clinical application of bortezomib is accompanied by serious toxic adverse events, such as cytopenia and peripheral neuropathy [88]. Finally, although several compounds targeting proteolytic pathways upstream of the proteasome have a high potential to prevent the development of diaphragm weakness, this does not necessarily imply that these agents can also improve function of the weakened diaphragm. Nevertheless, modulation of the proteolytic system is a potentially interesting target to modulate loss of respiratory muscle function due to controlled mechanical ventilation.

Conclusion

Weakness of the respiratory muscles frequently develops in the ICU patient and is associated with adverse outcome, including prolonged mechanical ventilation. Despite the high incidence and clinical impact of ICU-acquired respiratory muscle dysfunction, no specific preventive or therapeutic interventions have been tested in large randomized controlled trials. Therefore, we should rely on interventions that seem reasonable from a physiological perspective or are supported by small clinical studies. As pointed out in Fig. 2, interventions could be subdivided into three categories: prevention of respiratory muscle dysfunction; therapeutic strategies that aim to improve respiratory muscle function; and so-called rescue interventions that should only be applied in exceptional cases and only after discussion with the patient or primary decision makers.

Fig. 2
figure2

Three groups of interventions to counteract respiratory muscle weakness during critical illness

Preventive strategies should limit development of disuse atrophy and muscle damage. We suggest using techniques that monitor diaphragm muscle function [21, 22] to confirm a physiologically acceptable level of diaphragm contractility and allow the clinician to optimize ventilator settings in order to improve patient–ventilator interaction. Drugs with potential side effects on skeletal muscle, in particular corticosteroids and muscle relaxants, should be avoided when appropriate.

Once ICU-acquired weakness has developed, a combined program of respiratory muscle endurance training and strength training should be considered. Endurance training can be instituted using progressive weaning trials and strength training by using a device for variable inspiratory threshold loading connected to the endotracheal tube [46]. Use of respiratory muscle positive inotropes, in particular levosimendan, is the subject of a current randomized controlled trial (NCT01721434) and not currently recommended for difficult-to-wean patients.

Abbreviations

ARDS:

acute respiratory distress syndrome

COPD:

chronic obstructive pulmonary disease

EMG:

electromyography

GH:

growth hormone

ICU:

intensive care unit

IGF-1:

insulin-like growth factor-1

IL:

interleukin

IMST:

inspiratory muscle strength training

MEP:

maximal expiratory pressure

MIP:

maximal inspiratory pressure

NF:

nuclear factor

Pdi:

transdiaphragmatic pressure

Pes:

esophageal pressure

Pga:

gastric pressure

TLR:

toll-like receptor

References

  1. 1.

    Jaber S, Petrof BJ, Jung B, Chanques G, Berthet J-P, Rabuel C, et al. Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans. Am J Respir Crit Care Med. 2011;183:364–71.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Demoule A, Jung B, Prodanovic H, Molinari N, Chanques G, Coirault C, et al. Diaphragm dysfunction on admission to ICU: prevalence, risk factors and prognostic impact—a prospective study. Am J Respir Crit Care Med. 2013;188:213–9.

    Article  PubMed  Google Scholar 

  3. 3.

    Supinski GS, Callahan LA. Diaphragm weakness in mechanically ventilated critically ill patients. Crit Care. 2013;17:R120.

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Hooijman PE, Beishuizen A, de Waard MC, de Man FS, Vermeijden JW, Steenvoorde P, et al. Diaphragm fiber strength is reduced in critically ill patients and restored by a troponin activator. Am J Respir Crit Care Med. 2014;189:863–5.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Adler D, Dupuis-Lozeron E, Richard JC, Janssens JP, Brochard L. Does inspiratory muscle dysfunction predict readmission after intensive care unit discharge? Am J Respir Crit Care Med. 2014;190:347–50.

    Article  PubMed  Google Scholar 

  6. 6.

    Petrof B, Jaber S, Matecki S. Ventilator-induced diaphragmatic dysfunction. Curr Opin Crit Care. 2009;16(1):19–25.

    Article  Google Scholar 

  7. 7.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Jubran A, Tobin MJ. Pathophysiologic basis of acute respiratory distress in patients who fail a trial of weaning from mechanical ventilation. Am J Respir Crit Care Med. 1997;155:906–15.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Demoule A, Morelot-Panzini C, Prodanovic H, Cracco C, Mayaux J, Duguet A, et al. Identification of prolonged phrenic nerve conduction time in the ICU: magnetic versus electrical stimulation. Intensive Care Med. 2011;37:1962–8.

    Article  PubMed  Google Scholar 

  10. 10.

    Levine S, Nguyen T, Taylor N, Friscia ME, Budak MT, Rothenberg P, et al. Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans. N Engl J Med. 2008;358:1327–35.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Hooijman PE, Beishuizen A, Witt CC, de Waard MC, Girbes AR, Spoelstra-de Man AM, et al. Diaphragm muscle fiber weakness and ubiquitin-proteasome activation in critically ill patients. Am J Respir Crit Care Med. 2015;191:1126–38.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Hussain SNA, Mofarrahi M, Sigala I, Kim HC, Vassilakopoulos T, Maltais F, et al. Mechanical ventilation-induced diaphragm disuse in humans triggers autophagy. Am J Respir Crit Care Med. 2010;182:1377–86.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Bloch S, Polkey MI, Griffiths M, Kemp P. Molecular mechanisms of intensive care unit-acquired weakness. Eur Respir J. 2012;39:1000–11.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Shanely RA, Van Gammeren D, Deruisseau KC, Zergeroglu AM, McKenzie MJ, Yarasheski KE, et al. Mechanical ventilation depresses protein synthesis in the rat diaphragm. Am J Respir Crit Care Med. 2004;170:994–9.

    Article  PubMed  Google Scholar 

  15. 15.

    Thomas D, Maes K, Agten A, Heunks L, Dekhuijzen R, Decramer M, et al. Time course of diaphragm function recovery after controlled mechanical ventilation in rats. J Appl Physiol. 2013;115:775–84.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    van Hees HWH, Schellekens W-JM, Andrade Acuña GL, Linkels M, Hafmans T, Ottenheijm CAC, et al. Titin and diaphragm dysfunction in mechanically ventilated rats. Intensive Care Med. 2012;38:702–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    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;24:210–7.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Powers SK, Hudson MB, Nelson WB, Talbert EE, Min K, Szeto HH, et al. Mitochondria-targeted antioxidants protect against mechanical ventilation-induced diaphragm weakness. Crit Care Med. 2011;39:1749–59.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Supinski GS, Callahan LA. Hemin prevents cardiac and diaphragm mitochondrial dysfunction in sepsis. Free Radic Biol Med. 2006;40:127–37.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Friedrich O, Reid MB, Van den Berghe G, Vanhorebeek I, Hermans G, Rich MM, et al. The sick and the weak: neuropathies/myopathies in the critically ill. Physiol Rev. 2015;95:1025–109.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Doorduin J, van Hees HWH, van der Hoeven JG, Heunks LMA. Monitoring of the respiratory muscles in the critically ill. Am J Respir Crit Care Med. 2012;185:90–5.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Heunks LM, Doorduin J, van der Hoeven JG. Monitoring and preventing diaphragm injury. Curr Opin Crit Care. 2015;21:34–41.

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Laghi F, Tobin MJ. Disorders of the respiratory muscles. Am J Respir Crit Care Med. 2003;168:10–48.

    Article  PubMed  Google Scholar 

  24. 24.

    American Thoracic Society/European Respiratory Society. ATS/ERS Statement on respiratory muscle testing. Am J Respir Crit Care Med. 2002;166(4):518–624.

    Article  Google Scholar 

  25. 25.

    Caruso P, Friedrich C, Denari SD, Ruiz SA, Deheinzelin D. The unidirectional valve is the best method to determine maximal inspiratory pressure during weaning. Chest. 1999;115:1096–101.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Truwit JD, Marini JJ. Validation of a technique to assess maximal inspiratory pressure in poorly cooperative patients. Chest. 1992;102:1216–9.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Polkey MI, Green M, Moxham J. Measurement of respiratory muscle strength. Thorax. 1995;50:1131–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Akoumianaki E, Maggiore SM, Valenza F, Bellani G, Jubran A, Loring SH, et al. The application of esophageal pressure measurement in patients with respiratory failure. Am J Respir Crit Care Med. 2014;189:520–31.

    Article  PubMed  Google Scholar 

  29. 29.

    Heunks LM, van der Hoeven JG. Clinical review: The ABC of weaning failure—a structured approach. Crit Care. 2010;14:245.

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Goligher EC, Laghi F, Detsky ME, Farias P, Murray A, Brace D, et al. Measuring diaphragm thickness with ultrasound in mechanically ventilated patients: feasibility, reproducibility and validity. Intensive Care Med. 2015;41:642–9.

    Article  PubMed  Google Scholar 

  31. 31.

    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;39:2627–30.

    Article  PubMed  Google Scholar 

  32. 32.

    Matamis D, Soilemezi E, Tsagourias M, Akoumianaki E, Dimassi S, Boroli F, et al. Sonographic evaluation of the diaphragm in critically ill patients. Technique and clinical applications. Intensive Care Med. 2013;39:801–10.

    Article  PubMed  Google Scholar 

  33. 33.

    Grosu HB, Lee YI, Lee J, Eden E, Eikermann M, Rose K. Diaphragm muscle thinning in mechanically ventilated patients. Chest. 2012;142:1455–60.

    Article  PubMed  Google Scholar 

  34. 34.

    Jung B, Nougaret S, Conseil M, Coisel Y, Futier E, Chanques G, et al. Sepsis is associated with a preferential diaphragmatic atrophy: a critically ill patient study using tridimensional computed tomography. Anesthesiology. 2014;120(5):1182–91.

    Article  PubMed  Google Scholar 

  35. 35.

    Sinderby C, Navalesi P, Beck J, Skrobik Y, Comtois N, Friberg S, et al. Neural control of mechanical ventilation in respiratory failure. Nat Med. 1999;5:1433–6.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Liu L, Liu S, Xie J, Yang Y, Slutsky AS, Beck J, et al. Assessment of patient-ventilator breath contribution during neurally adjusted ventilatory assist in patients with acute respiratory failure. Crit Care. 2015;19:43.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Sinderby C, Liu S, Colombo D, Camarotta G, Slutsky AS, Navalesi P, et al. An automated and standardized neural index to quantify patient-ventilator interaction. Crit Care. 2013;17:R239.

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Sassoon CSH, Zhu E, Caiozzo VJ. Assist-control mechanical ventilation attenuates ventilator-induced diaphragmatic dysfunction. Am J Respir Crit Care Med. 2004;170:626–32.

    Article  PubMed  Google Scholar 

  39. 39.

    Papazian L, Forel J-M, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363:1107–16.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    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;40:1254–60.

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Colombo D, Cammarota G, Alemani M, Carenzo L, Barra FL, Vaschetto R, et al. Efficacy of ventilator waveforms observation in detecting patient-ventilator asynchrony. Crit Care Med. 2011;39:2452–7.

    Article  PubMed  Google Scholar 

  42. 42.

    Campbell EJ, Gandevia SC, Killian KJ, Mahutte CK, Rigg JR. Changes in the perception of inspiratory resistive loads during partial curarization. J Physiol. 1980;309:93–100.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Illi SK, Held U, Frank I, Spengler CM. Effect of respiratory muscle training on exercise performance in healthy individuals: a systematic review and meta-analysis. Sports Med. 2012;42:707–24.

    Article  PubMed  Google Scholar 

  44. 44.

    Hill K, Jenkins SC, Philippe DL, Cecins N, Shepherd KL, Green DJ, et al. High-intensity inspiratory muscle training in COPD. Eur Respir J. 2006;27:1119–28.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Cader SA, Vale RG, Castro JC, Bacelar SC, Biehl C, Gomes MC, et al. Inspiratory muscle training improves maximal inspiratory pressure and may assist weaning in older intubated patients: a randomised trial. J Physiother. 2010;56:171–7.

    Article  PubMed  Google Scholar 

  46. 46.

    Martin AD, Smith BK, Davenport PD, Harman E, Gonzalez-Rothi RJ, Baz M, et al. Inspiratory muscle strength training improves weaning outcome in failure to wean patients: a randomized trial. Crit Care. 2011;15:R84.

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Condessa RL, Brauner JS, Saul AL, Baptista M, Silva AC, Vieira SR. Inspiratory muscle training did not accelerate weaning from mechanical ventilation but did improve tidal volume and maximal respiratory pressures: a randomised trial. J Physiother. 2013;59:101–7.

    Article  PubMed  Google Scholar 

  48. 48.

    Elkins M, Dentice R. Inspiratory muscle training facilitates weaning from mechanical ventilation among patients in the intensive care unit: a systematic review. J Physiother. 2015;61:125–34.

    Article  PubMed  Google Scholar 

  49. 49.

    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;39:777–82.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Betters JL, Criswell DS, Shanely RA, Van Gammeren D, Falk D, Deruisseau KC, et al. Trolox attenuates mechanical ventilation-induced diaphragmatic dysfunction and proteolysis. Am J Respir Crit Care Med. 2004;170:1179–84.

    Article  PubMed  Google Scholar 

  51. 51.

    Supinski GS, Vanags J, Callahan LA. Eicosapentaenoic acid preserves diaphragm force generation following endotoxin administration. Crit Care. 2010;14:R35.

    Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Travaline JM, Sudarshan S, Roy BG, Cordova F, Leyenson V, Criner GJ. Effect of N-acetylcysteine on human diaphragm strength and fatigability. Am J Respir Crit Care Med. 1997;156:1567–71.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Nathens AB, Neff MJ, Jurkovich GJ, Klotz P, Farver K, Ruzinski JT, et al. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg. 2002;236:814–22.

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Heyland D, Muscedere J, Wischmeyer PE, Cook D, Jones G, Albert M, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013;368:1489–97.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Hermans G, Casaer MP, Clerckx B, Guiza F, Vanhullebusch T, Derde S, et al. Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial. Lancet Respir Med. 2013;1:621–9.

    Article  PubMed  Google Scholar 

  56. 56.

    Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011;365:506–17.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    van Hees HWH, Li Y-P, Ottenheijm CAC, Jin B, Pigmans CJC, Linkels M, et al. Proteasome inhibition improves diaphragm function in congestive heart failure rats. Am J Physiol Lung Cell Mol Physiol. 2008;294:L1260–8.

    Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Agten A, Maes K, Thomas D, Cielen N, van Hees HWH, Dekhuijzen RPN, et al. Bortezomib partially protects the rat diaphragm from ventilator-induced diaphragm dysfunction. Crit Care Med. 2012;40:2449–55.

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Balstad TR, Kaasa S, Solheim TS. Multimodal nutrition/anabolic therapy for wasting conditions. Curr Opin Clin Nutr Metab Care. 2014;17:226–35.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Chikani V, Ho KK. Action of GH on skeletal muscle function: molecular and metabolic mechanisms. J Mol Endocrinol. 2014;52:R107–23.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999;341:785–92.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Schols AM, Soeters PB, Mostert R, Pluymers RJ, Wouters EF. Physiologic effects of nutritional support and anabolic steroids in patients with chronic obstructive pulmonary disease. A placebo-controlled randomized trial. Am J Respir Crit Care Med. 1995;152:1268–74.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Creutzberg EC, Wouters EF, Mostert R, Pluymers RJ, Schols AM. A role for anabolic steroids in the rehabilitation of patients with COPD? A double-blind, placebo-controlled, randomized trial. Chest. 2003;124:1733–42.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Taylor BE, Buchman TG. Is there a role for growth hormone therapy in refractory critical illness? Curr Opin Crit Care. 2008;14:438–44.

    Article  PubMed  Google Scholar 

  65. 65.

    Follath F, Cleland JGF, Just H, Papp JGY, Scholz H, Peuhkurinen K, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet. 2002;360:196–202.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Kass DA, Solaro RJ. Mechanisms and use of calcium-sensitizing agents in the failing heart. Circulation. 2006;113:305–15.

    Article  PubMed  Google Scholar 

  67. 67.

    van Hees HWH, Dekhuijzen PNR, Heunks LMA. Levosimendan enhances force generation of diaphragm muscle from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;179:41–7.

    Article  PubMed  Google Scholar 

  68. 68.

    Doorduin J, Sinderby CA, Beck J, Stegeman DF, Van Hees HW, van der Hoeven JG, et al. The calcium sensitizer levosimendan improves human diaphragm function. Am J Respir Crit Care Med. 2012;185:90–5.

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Ochala J, Radell PJ, Eriksson LI, Larsson L. EMD 57033 partially reverses ventilator-induced diaphragm muscle fibre calcium desensitisation. Pflugers Arch. 2010;459:475–83.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Schellekens W-JM, van Hees HW, Kox M, Linkels M, Acuña GL, Dekhuijzen PR, et al. Hypercapnia attenuates ventilator-induced diaphragm atrophy and modulates dysfunction. Crit Care. 2014;18:R28.

    Article  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Van Hees HW, Schellekens W-JM, Linkels M, Leenders F, Zoll J, Donders R, et al. Plasma from septic shock patients induces loss of muscle protein. Crit Care. 2011;15:R233.

    Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Reid MB, Lännergren J, Westerblad H. Respiratory and limb muscle weakness induced by tumor necrosis factor-alpha: involvement of muscle myofilaments. Am J Respir Crit Care Med. 2002;166:479–84.

    Article  PubMed  Google Scholar 

  73. 73.

    Maes K, Stamiris A, Thomas D, Cielen N, Smuder A, Powers SK, et al. Effects of controlled mechanical ventilation on sepsis-induced diaphragm dysfunction in rats. Crit Care Med. 2014;42:e772–82.

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Schellekens W-JM, van Hees HWH, Vaneker M, Linkels M, Dekhuijzen PNR, Scheffer GJ, et al. Toll-like receptor 4 signaling in ventilator-induced diaphragm atrophy. Anesthesiology. 2012;117:329–38.

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Okazaki T, Liang F, Li T, Lemaire C, Danialou G, Shoelson SE, et al. Muscle-specific inhibition of the classical nuclear factor-κb pathway is protective against diaphragmatic weakness in murine endotoxemia. Crit Care Med. 2014;42:e501–9.

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Divangahi M, Demoule A, Danialou G, Yahiaoui L, Bao W, Xing Z, et al. Impact of IL-10 on diaphragmatic cytokine expression and contractility during Pseudomonas infection. Am J Respir Cell Mol Biol. 2007;36:504–12.

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Sun Z, Andersson R. NF-kappaB activation and inhibition: a review. Shock. 2002;18:99–106.

    Article  PubMed  Google Scholar 

  78. 78.

    Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801.

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Opal SM, Laterre P-F, Francois B, LaRosa SP, Angus DC, Mira J-P, et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA. 2013;309:1154–62.

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Maes K, Testelmans D, Cadot P, Deruisseau K, Powers S, Decramer M, et al. Effects of acute administration of corticosteroids during mechanical ventilation on rat diaphragm. Am J Respir Crit Care Med. 2008;178:1219–26.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Dekhuijzen PN, Decramer M. Steroid-induced myopathy and its significance to respiratory disease: a known disease rediscovered. Eur Respir J. 1992;5:997–1003.

    CAS  PubMed  Google Scholar 

  82. 82.

    Sassoon CSH, Zhu E, Pham HT, Nelson RS, Fang L, Baker MJ, et al. Acute effects of high-dose methylprednisolone on diaphragm muscle function. Muscle Nerve. 2008;38:1161–72.

    CAS  Article  PubMed  Google Scholar 

  83. 83.

    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. Respiratory Res. 2010;11:178.

    CAS  Article  Google Scholar 

  84. 84.

    De Jonghe B, Sharshar T, Lefaucheur JP, Authier FJ, Durand-Zaleski I, Boussarsar M, et al. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA. 2002;288:2859–67.

    Article  PubMed  Google Scholar 

  85. 85.

    Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358:111–24.

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy R, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354:1671–84.

    CAS  Article  PubMed  Google Scholar 

  87. 87.

    Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev. 2002;82:373–428.

    CAS  Article  PubMed  Google Scholar 

  88. 88.

    Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609–17.

    CAS  Article  PubMed  Google Scholar 

  89. 89.

    Whidden MA, Smuder AJ, Wu M, Hudson MB, Nelson WB, Powers SK. Oxidative stress is required for mechanical ventilation-induced protease activation in the diaphragm. J Appl Physiol. 2010;108:1376–82.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Smuder AJ, Hudson MB, Nelson WB, Kavazis AN, Powers SK. Nuclear factor-kappaB signaling contributes to mechanical ventilation-induced diaphragm weakness. Crit Care Med. 2012;40:927–34.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Supinski GS, Wang W, Callahan LA. Caspase and calpain activation both contribute to sepsis-induced diaphragmatic weakness. J Appl Physiol. 2009;107:1389–96.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Supinski GS, Vanags J, Callahan LA. Effect of proteasome inhibitors on endotoxin-induced diaphragm dysfunction. Am J Physiol Lung Cell Mol Physiol. 2009;296:L994–L1001.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Leo M. A. Heunks.

Additional information

Competing interests

LMAH has received travel grants and speakers fees from Orion Pharma (Finland), Maquet Critical Care (Sweden), and Biomarin (USA). LMAH has received research grants paid to the institution from Bayer Pharma and Orion Pharma. The other authors declare that they have no competing interests.

Authors’ contributions

WJMS, HWHvH, JD, LHR, and LMAH contributed to writing the manuscript. GJS and JGvdH contributed to revising the manuscript. All authors read and approved the final manuscript for publication.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schellekens, W.M., van Hees, H.W.H., Doorduin, J. et al. Strategies to optimize respiratory muscle function in ICU patients. Crit Care 20, 103 (2016). https://doi.org/10.1186/s13054-016-1280-y

Download citation

Keywords

  • Intensive Care Unit Patient
  • Respiratory Muscle
  • Levosimendan
  • Control Mechanical Ventilation
  • Maximal Inspiratory Pressure