Ventilator-induced diaphragm dysfunction: towards a better understanding

Abstract

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