Increased duration of mechanical ventilation is associated with decreased diaphragmatic force: a prospective observational study

ABSTRACT: INTRODUCTION: Respiratory muscle weakness is an important risk factor for delayed weaning. Animal data show that mechanical ventilation itself can cause atrophy and weakness of the diaphragm, called ventilator-induced diaphragmatic dysfunction (VIDD). Transdiaphragmatic pressure after magnetic stimulation (TwPdi BAMPS) allows evaluation of diaphragm strength. We aimed to evaluate the repeatability of TwPdi BAMPS in critically ill, mechanically ventilated patients and to describe the relation between TwPdi and the duration of mechanical ventilation. METHODS: This was a prospective observational study in critically ill and mechanically ventilated patients, admitted to the medical intensive care unit of a university hospital. Nineteen measurements were made in a total of 10 patients at various intervals after starting mechanical ventilation. In seven patients, measurements were made on two or more occasions, with a minimum interval of 24 hours. RESULTS: The TwPdi was 11.5 +/- 3.9 cm H2O (mean +/- SD), indicating severe respiratory muscle weakness. The between-occasion coefficient of variation of TwPdi was 9.7%, comparable with data from healthy volunteers. Increasing duration of mechanical ventilation was associated with a logarithmic decline in TwPdi (R = 0.69; P = 0.038). This association was also found for cumulative time on pressure control (R = 0.71; P = 0.03) and pressure-support ventilation (P = 0.05; R = 0.66) separately, as well as for cumulative dose of propofol (R = 0.66; P = 0.05) and piritramide (R = 0.79; P = 0.01). CONCLUSIONS: Duration of mechanical ventilation is associated with a logarithmic decline in diaphragmatic force, which is compatible with the concept of VIDD. The observed decline may also be due to other potentially contributing factors such as sedatives/analgesics, sepsis, or others.status: publishe

Ventilator-induced diaphragm dysfunction: towards a better understanding

Mechanical ventilation is a life-saving therapy for critically ill patients with respiratory failure. However, weaning difficulties are very often encountered and are time-consuming. Although weaning failure may be due to a variety of factors ventilator-induced diaphragm dysfunction may play an important role. Many animal models have consistently shown that controlled mechanical ventilation resulted in a decrease in force-generating capacity and atrophy of the diaphragm. In addition, several alterations such as increased oxidative stress, decreased protein synthesis and increased proteolysis were found in the diaphragm of mechanically ventilated animals. These findings were recently confirmed in human studies. Measurements of transdiaphragmatic pressure during bilateral anterior magnetic stimulation of the phrenic nerve showed that diaphragm force was decreased in mechanically ventilated patients. In addition, human studies have shown a great similarity in underlying mechanisms for ventilator-induced diaphragm dysfunction with animal models. Atrophy of diaphragm fibers was found in mechanically ventilated patients and is associated with increased oxidative stress and an increase in proteolysis biomarkers. Since mechanically ventilated patients are often treated with corticosteroids and a very high dose (80mg/kg) of corticosteroids seems to be protective against ventilator-induced diaphragm dysfunction, the first aim of this thesis was to examine whether lower doses of corticosteroids would also protect the diaphragm from the deleterious effects of controlled mechanical ventilation. On the other hand, the development of preventive strategies is an important clinical issue. Therefore, two different preventive strategies were developed. First we examined whether the administration of an anti-oxidant commonly used in the clinical practice, N-acetylcysteine, would protect the diaphragm against ventilator-induced disturbances in diaphragmatic redox-balance and thereby, prevent ventilator-induced diaphragmatic contractile dysfunction and proteolysis. The last aim of this thesis was to examine whether the administration of a proteasome inhibitor, bortezomib, would protect the diaphragm from atrophy and contractile dysfunction caused by controlled mechanical ventilation. The effects of corticosteroids on the diaphragm during controlled mechanical ventilation depended on the dose administered since decreased diaphragm force and atrophy were prevented with high dose (30mg/kg) corticosteroids and worsened with low dose (5mg/kg). Administration of N-acetylcysteine, an antioxidant, concomitantly with 24h of controlled mechanical ventilation prevented diaphragm contractile dysfunction caused by controlled mechanical ventilation and inhibited calpain, caspase-3 and 20S proteasome activity. Finally, the administration of bortezomib, a selective 20S proteasome inhibitor, resulted in a partial protection against ventilator-induced diaphragm dysfunction. Bortezomib had no effect on the calpain activity, while it partially inhibited caspase-3 activity. In conclusion, this doctoral thesis showed that the deleterious effects of controlled mechanical ventilation on the diaphragm can be prevented or minimized while using different strategies. In particular, the inhibition of the calpain and the caspase-3 system seems to be the most efficient strategy to achieve this goal as shown in the study with high dose corticosteroid administration or with N-acetylcysteine. Importantly, when this system is either not inhibited as was the case with a low dose corticosteroids or not fully inhibited as was the case with bortezomib treatment, only a partial prevention is obtained. The beneficial effect of high dose corticosteroids was associated with an inhibition of calpain activity and caspase-3 activity, but to a lesser extent. Interestingly, the beneficial role of N-acetylcysteine in this model was probably related to the ability of N-acetylcysteine to inhibit calpain and caspase-3 activity together with its anti-oxidant properties. This doctoral thesis clearly demonstrated the role of Ca2+-dependent proteases in ventilator-induced diaphragm dysfunction.Dankwoord vii List of abbreviations ix Chapter 1 General introduction and rationale 1 1.1 General Introduction 3 1.2 General aims 14 1.3 References 15 Chapter 2 Corticosteroid effects on ventilator-induced diaphragm dysfunction in anesthetized rats depend on the dose administered 23 2.1 Abstract 25 2.2 Introduction 26 2.3 Material and methods 27 2.4 Results 29 2.5 Discussion 34 2.6 References 38 Chapter 3 N-acetylcysteine protects the rat diaphragm from decreased contractility associated with controlled mechanical ventilation 43 3.1 Abstract 45 3.2 Introduction 46 3.3 Material and methods 47 3.4 Results 49 3.5 Discussion 54 3.6 References 58 3.7 Online data supplement 65 Chapter 4 Bortezomib partially protects the rat diaphragm from ventilator-induced diaphragm dysfunction 69 4.1 Abstract 71 4.2 Introduction 72 4.3 Material and methods 73 4.4 Results 75 4.5 Discussion 79 4.6 References 82 Chapter 5 General discussion, conclusions and future directions 87 5.1 General Discussion 89 5.2 Clinical implications 95 5.3 Conclusions and future directions 96 5.4 References 98 Summary 105 Samenvatting 109 Short curriculum vitae 115 List of publications 116nrpages: 124status: publishe

The Role of Skeletal Muscle Mitochondria in Colorectal Cancer Related Cachexia: Friends or Foes?

Up to 60% of colorectal cancer (CRC) patients develop cachexia. The presence of CRC related cachexia is associated with more adverse events during systemic therapy, leading to a high mortality rate. The main manifestation in CRC related cachexia is the loss of skeletal muscle mass, resulting from an imbalance between skeletal muscle protein synthesis and protein degradation. In CRC related cachexia, systemic inflammation, oxidative stress, and proteolytic systems lead to mitochondrial dysfunction, resulting in an imbalanced skeletal muscle metabolism. Mitochondria fulfill an important function in muscle maintenance. Thus, preservation of the skeletal muscle mitochondrial homeostasis may contribute to prevent the loss of muscle mass. However, it remains elusive whether mitochondria play a benign or malignant role in the development of cancer cachexia. This review summarizes current (mostly preclinical) evidence about the role of skeletal muscle mitochondria in the development of CRC related cachexia. Future human research is necessary to determine the physiological role of skeletal muscle mitochondria in the development of human CRC related cachexia

Time course of diaphragm function recovery after mechanical ventilation in an animal model

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N-Acetylcysteine protects the rat diaphragm from the decreased contractility associated with controlled mechanical ventilation

OBJECTIVE:: Controlled mechanical ventilation results in diaphragmatic dysfunction, and oxidative stress has been shown to be an important contributor to ventilator-induced diaphragm dysfunction. We hypothesized that the administration of an antioxidant, N-acetylcysteine, would restore the redox balance in the diaphragm and prevent against the deleterious effects of controlled mechanical ventilation. DESIGN:: Randomized, controlled experiment. SETTINGS:: Basic science animal laboratory. SUBJECTS:: Male Wistar rats, 14 wks old. INTERVENTIONS:: Anesthetized rats were submitted for 24 hrs to either spontaneous breathing receiving 150 mg/kg N-acetylcysteine (SBNAC) or saline (SBSAL) or to controlled mechanical ventilation receiving 150 mg/kg N-acetylcysteine (MVNAC) or saline (MVSAL). MEASUREMENTS AND MAIN RESULTS:: After 24 hrs of controlled mechanical ventilation, diaphragmatic force production was significantly lower in MVSAL compared with all groups. Importantly, administration of N-acetylcysteine completely abolished this controlled mechanical ventilation-induced diaphragmatic contractile dysfunction. Diaphragmatic protein oxidation was significantly increased after 24 hrs of controlled mechanical ventilation (+53%, p < .01) in MVSAL animals, whereas administration of N-acetylcysteine prevented this controlled mechanical ventilation-induced oxidative stress. Diaphragmatic 20S proteasome activity was increased in MVSAL (+62%, p < .05). Further, compared with SBSAL, diaphragm caspase-3 activity was significantly increased in MVSAL (+279%, p < .001), and N-acetylcysteine treatment provided partial protection against caspase-3 activation (MVNAC = +158.5%, p < .01). Diaphragmatic calpain activity was significantly increased after controlled mechanical ventilation (+137%, p < .001) in MVSAL animals, but N-acetylcysteine treatment protected against this event. Finally, significant negative correlations existed between calpain activity and diaphragm force production (r from -0.56 to -0.49, p < .05). CONCLUSIONS:: These data show that the administration of N-acetylcysteine protects the diaphragm from the deleterious effects of controlled mechanical ventilation. Specifically, N-acetylcysteine prevents against controlled mechanical ventilation-induced diaphragmatic oxidative stress and proteolysis and abolishes controlled mechanical ventilation-induced diaphragmatic contractile dysfunction.status: publishe

Atrophy and hypertrophy signaling in the diaphragm of patients with COPD

We investigated whether atrophy and hypertrophy signaling was altered in the diaphragm of COPD patients.Diaphragm fiber dimensions and proportion, expression of markers of the ubiquitin-proteasome, the NF-kappaB pathways, the muscle regulatory factors and myostatin were studied in diaphragm biopsies from 19 patients with severe COPD and 13 patients without COPD.Type I proportion was significantly increased in the diaphragm of COPD patients while type II proportion was decreased. Cross-sectional area of all fiber types was reduced in the COPD patients. In addition, MAFbx mRNA was higher in the diaphragm of COPD patients while Nedd4 mRNA decreased. Cytoplasmatic levels of IkappaBalpha and IkappaBbeta were decreased in the COPD patients as was the nuclear NF-kappaB p50 DNA-binding activity. MyoD mRNA and its nuclear protein content were decreased in the diaphragm of COPD patients and myogenin mRNA and protein levels remained unchanged. Myostatin mRNA was decreased but its protein levels in the nuclear and cytoplasmic fraction were significantly increased in the COPD patients.These data showed that the ubiquitin-proteasome pathway, the NF-kappaB pathway and myostatin protein were upregulated in the diaphragm of COPD patients while MyoD expression was reduced. These alterations may contribute to diaphragm remodeling in COPD.status: publishe