**4. Conclusions**

Although mechanical ventilation is a life-saving procedure in the ICU, it has the potential to aggravate or even induce detrimental effects (Dreyfuss & Saumon, 1998; Slutsky, 1999). Our previous studies aimed at evaluating the mechanisms that may underlie the pathogenesis of VILI and MOF (figure 5). To summarize, we demonstrated that both LVT and HVTventilation increased pulmonary cytokine, chemokine and adhesion molecule expression accompanied by significant granulocyte infiltration (Hegeman et al, 2011b). We observed that 5 hours of either LVT or HVT-ventilation primarily induced caspase-independent pathways of cell death (figure 3). In addition, our findings strongly suggest that changes in the Ang-Tie2 system, together with elevated VEGF expression, are involved in the development of VILI (figure 4) (Hegeman et al, 2010). An intriguing clinical observation is that most critically ill ALI/ARDS patients do not succumb to acute lung failure but rather to progressive non-pulmonary organ dysfunction, so-called MOF (Ferring & Vincent, 1997; Montgomery et al, 1985; Valta et al, 1999). In this respect, we showed that mechanical ventilation with high pressures increased the pro-inflammatory state of the lung but also of the liver and kidney (figure 1) (Hegeman et al, 2009). Moreover, we observed that HVTventilation impairs functioning of peripheral lymphocytes (figure 2). Together, these data indicate that ventilator-induced alveolar (over)stretch may play a significant role in the pathogenesis of both VILI and MOF.

Based on the hypothesis that a ventilator-induced inflammatory response may precede lung injury, we evaluated the effects of different anti-inflammatory intervention strategies on various aspects considered to be important in the development of VILI. One of the most potent drugs to downregulate inflammatory responses are glucocorticoids (Brower et al, 2001; Luce, 2002). Despite the successful inhibitory effect on lung inflammation, we observed that glucocorticoid therapy did not prevent the elevation in BALf total protein levels, the increase in pulmonary wet-to-dry ratio and reduction of PaO2/FiO2 ratio during mechanical ventilation (Hegeman et al, 2011b). Similarly, the vessel protective factor Ang-1 did not protect ventilated mice against these more crude aspects of VILI even though granulocyte infiltration, inflammatory mediator and VEGF expression were markedly diminished (Hegeman et al, 2010). Thus, prevention of inflammation does not preclude loss of pulmonary function implying that lung inflammation and injury are two independent components of VILI.

In view of these most recent findings, we propose that anti-inflammatory therapy may not prevent the aspects of VILI driven by mechanosensitive alterations in barrier properties, like vascular leakage and impaired gas exchange, but will only regulate pulmonary inflammation. Therefore, future therapeutic intervention strategies in the ventilated, critically ill patient should aim at attacking the ventilator-induced impairment of alveolarcapillary barrier function. As Rho GTPases have been described to be important in the mechanosensitive regulation of endothelial barrier function (Birukov, 2009), ROCK or GEF-H1 inhibitors might be an attractive target to prevent the detrimental effects induced by the alveolar (over)stretch associated with mechanical ventilation. In addition, the attenuation of caspase-independent cell death – via calpain inhibitors or RIP-kinase inhibitors such as necrostatin – might also be a preventive strategy in maintaining alveolar-capillary barrier function. Moreover, restoring function of damaged tissue by autologous stem cell transplantation could become a beneficial approach to treat the critically ill patient as well. Nonetheless, preventing prolonged exposure to mechanical stretch by reducing tidal volumes remains of utmost importance.

Fig. 5. Possible mechanisms that may underlie the pathogenesis of ventilator-induced lung injury (VILI) and multiple-organ failure (MOF).

Part of illustration adapted with permission of H.A.E. Vreugdenhil (Thesis "Mechanical ventilation and immune function" by H.A.E. Vreugdenhil, 2003). Although life-saving, mechanical ventilation may cause harm by itself. Our previous studies investigated the mechanisms that may underlie the pathogenesis of VILI and MOF in healthy mice. We showed that mechanical ventilation provokes endothelial activation (including changes in the angiopoietin (Ang)-Tie2 system), inflammation and cell death (primarily via activation of the caspase-independent route) in pulmonary tissue. Besides these local effects of mechanical ventilation, we also demonstrated enhanced endothelial activation and inflammation in hepatic and renal tissue (enhanced pro-inflammatory milieu of distal organs). In addition, we observed reduced mitogen-induced splenocyte proliferation after mechanical ventilation with high tidal volumes (suppressed peripheral lymphocyte functioning). Alv = alveolar epithelial cell; Mϕ = macrophage.

#### **5. Acknowledgements**

340 Front Lines of Thoracic Surgery

Although mechanical ventilation is a life-saving procedure in the ICU, it has the potential to aggravate or even induce detrimental effects (Dreyfuss & Saumon, 1998; Slutsky, 1999). Our previous studies aimed at evaluating the mechanisms that may underlie the pathogenesis of VILI and MOF (figure 5). To summarize, we demonstrated that both LVT and HVTventilation increased pulmonary cytokine, chemokine and adhesion molecule expression accompanied by significant granulocyte infiltration (Hegeman et al, 2011b). We observed that 5 hours of either LVT or HVT-ventilation primarily induced caspase-independent pathways of cell death (figure 3). In addition, our findings strongly suggest that changes in the Ang-Tie2 system, together with elevated VEGF expression, are involved in the development of VILI (figure 4) (Hegeman et al, 2010). An intriguing clinical observation is that most critically ill ALI/ARDS patients do not succumb to acute lung failure but rather to progressive non-pulmonary organ dysfunction, so-called MOF (Ferring & Vincent, 1997; Montgomery et al, 1985; Valta et al, 1999). In this respect, we showed that mechanical ventilation with high pressures increased the pro-inflammatory state of the lung but also of the liver and kidney (figure 1) (Hegeman et al, 2009). Moreover, we observed that HVTventilation impairs functioning of peripheral lymphocytes (figure 2). Together, these data indicate that ventilator-induced alveolar (over)stretch may play a significant role in the

Based on the hypothesis that a ventilator-induced inflammatory response may precede lung injury, we evaluated the effects of different anti-inflammatory intervention strategies on various aspects considered to be important in the development of VILI. One of the most potent drugs to downregulate inflammatory responses are glucocorticoids (Brower et al, 2001; Luce, 2002). Despite the successful inhibitory effect on lung inflammation, we observed that glucocorticoid therapy did not prevent the elevation in BALf total protein levels, the increase in pulmonary wet-to-dry ratio and reduction of PaO2/FiO2 ratio during mechanical ventilation (Hegeman et al, 2011b). Similarly, the vessel protective factor Ang-1 did not protect ventilated mice against these more crude aspects of VILI even though granulocyte infiltration, inflammatory mediator and VEGF expression were markedly diminished (Hegeman et al, 2010). Thus, prevention of inflammation does not preclude loss of pulmonary function implying that lung inflammation and injury are two independent

In view of these most recent findings, we propose that anti-inflammatory therapy may not prevent the aspects of VILI driven by mechanosensitive alterations in barrier properties, like vascular leakage and impaired gas exchange, but will only regulate pulmonary inflammation. Therefore, future therapeutic intervention strategies in the ventilated, critically ill patient should aim at attacking the ventilator-induced impairment of alveolarcapillary barrier function. As Rho GTPases have been described to be important in the mechanosensitive regulation of endothelial barrier function (Birukov, 2009), ROCK or GEF-H1 inhibitors might be an attractive target to prevent the detrimental effects induced by the alveolar (over)stretch associated with mechanical ventilation. In addition, the attenuation of caspase-independent cell death – via calpain inhibitors or RIP-kinase inhibitors such as necrostatin – might also be a preventive strategy in maintaining alveolar-capillary barrier function. Moreover, restoring function of damaged tissue by autologous stem cell transplantation could become a beneficial approach to treat the critically ill patient as well. Nonetheless, preventing prolonged exposure to mechanical stretch by reducing tidal

**4. Conclusions** 

pathogenesis of both VILI and MOF.

volumes remains of utmost importance.

components of VILI.

The studies were financially supported by the Catharijne Foundation (University Medical Center Utrecht, Utrecht, the Netherlands). For their contribution to abovementioned studies, the authors thank: A. Kavelaars, E. Kooijman, I. den Hartog, J. Zijlstra, K. Amarouchi, M.P. Hennus, N.J.G. Jansen & P.M. Cobelens (University Medical Center Utrecht, Utrecht, the Netherlands); G. Molema, H. Moorlag, H. Morselt, J.A.A.M. Kamps, M. van Meurs & R. Jongman (University Medical Center Groningen, Groningen, the Netherlands); B. Lachmann & P.A.C. Specht (Erasmus Medical Center, Rotterdam, the Netherlands).

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**19** 

*Germany* 

**Optimizing Perioperative Ventilation** 

**Support with Adequate Settings of** 

**Positive End-Expiratory Pressure** 

Zhanqi Zhao1, Claudius Stahl2, Ullrich Müller-Lisse3,

*1Department of Biomedical Engineering, Furtwangen University, 2Department of Anesthesiology, University Medical Center of Freiburg,* 

Mechanical ventilation is often employed to replace spontaneous breathing of patients under general anesthesia. Even after operation, the patient still needs ventilation support until the respiratory muscles regain full function. A ventilator delivers a certain amount of air flow through a facial mask or tracheal tube to the patient whose respiratory system fails to function properly due to the effects of anesthetics or diseases. Based on the difference in breath initiation, mechanical ventilation can be divided into two categories: controlled ventilation and assisted ventilation. In this chapter, we focus on controlled mechanical ventilation, under which the patient is not able to trigger a valid breath and the ventilator overtakes all the workload of respiratory muscles. Respiratory parameters such as respiratory rate (RR), inspiratory–to-expiratory time ratio (I:E), tidal volume (Vt) (or minute

Traditionally, controlled mechanical ventilation can either be volume controlled (VCV) or pressure controlled (PCV). Ideal respiratory signals obtained in a healthy human during VCV and PCV are shown in Fig. 1. In the VCV mode, a patient receives constant flow from the ventilator until a preset Vt is reached. A severe drawback of VCV is missing control of the peak airway pressure. Airway pressure (Paw) depends on respiratory system compliance and resistance. In patients with certain lung diseases, such as acute lung injury (ALI), the same setting of Vt as in patients with healthy lungs may lead to a higher peak Paw with the potential to further injure the lung. Therefore, VCV is often applied with a pressure limitation. Once the peak Paw rises above this limit, the ventilator will stop delivering gas even if the preset Vt is not yet reached. In the PCV mode, a maximum airway pressure (Pmax) is defined. Inspiration ends when Pmax is reached i.e. the flow driven by the pressure difference decreases to zero. PCV may be superior to VCV in patients requiring one-lung

**1. Introduction** 

**1.1 Mechanical ventilation** 

volume) are controlled by the ventilator.

*4Department of Anesthesiology and Intensive Care Medicine, University Medical Center of Schleswig-Holstein Campus Kiel,* 

Inéz Frerichs4 and Knut Möller1

*3Department of Radiology, University of Munich,* 

