Comunicación pulmón-cerebro durante la ventilación mecánica: estudio de la respueta inflamatoria y la activación neuronal en dos models experimentales

Student thesis: Doctoral thesis

Abstract

In the last decades, the increase in survival of patients admitted to intensive care units (ICU) has revealed a problem until now little known: the development of long-term neurocognitive impairment in many critical survivors. Clinical studies have also shown that the presence of these disorders is higher in some patient populations as survivors of acute respiratory distress syndrome (ARDS) or patients receiving mechanical ventilation (MV) during their stay in the ICU. These data suggest the existence of a possible crosstalk between the ventilated lung or signals derived from it and brain. In this context, MV although being a lifesaving procedure, can worsen lung injury and promoting the spread of inflammatory response to remote organs. Therefore, in the clinical setting numerous ventilation strategies have been implemented with the aim to reduce the deleterious effects of the VM. The so-called lung protective ventilation strategies are characterized by the use of use of low tidal volumes and positive end expiratory pressure (PEEP) and have been demonstrated to reduce mortality in ARDS patients, and likewise, to attenuate the inflammatory response associated to MV. Emerging clinical evidence suggests that patients undergoing critical VM are especially vulnerable to develop lung and neurocognitive impairment. It’s necessary to understand the molecular mechanisms involved in the mechanical ventilated lung and its potential effect on the central nervous system (CNS). The aim of this thesis is to investigate the complex lung-brain interactions in mechanical ventilated patients. To this purpose, we analyzed the influence of MV on the local and systemic inflammatory responses and neuronal activation, in an experimental model of MV. We also evaluated the effect of two protective ventilation strategies in the modulation of inflammation and the pattern of neuronal activation. In order to make a first approximation to the crosstalk between brain-lung during MV, we assessed the expression of c-Fos protein, a marker of neuronal activity, in some areas of the brain in a rat model of MV. Therefore, we compared rats ventilated with two different injurious ventilatory strategies, a high tidal volume (HVt) group vs. a low tidal volume (LVt) group. Our results showed that injurious MV might be associated with neuronal activation in discrete areas of the brain. The intensity of the response was higher in animals ventilated with high Vt, suggesting an iatrogenic effect of MV on the brain. In our second study, we aimed to determine the best level of PEEP to prevent lung inflammation and systemic dissemination and to explore the influence of PEEP level on neuronal activation. We investigated the effects of two levels of PEEP (2 cmH2O and 7 cmH2O) on local, systemic and brain responses in an experimental model of VM after intratracheal instillation of lipopolysaccharide. Our results showed that the use of a PEEP of 7 cmH2O prevented lung and systemic inflammation secondary to LPS instillation. Moreover, MV and PEEP level could modified neuronal activation pattern in some areas in the brain which are related to memory and learning processes. Our findings about regional brain activation during MV could help define particular areas susceptible to be activated by mechanoreceptors in the lung and areas which participate in the response to PEEP and LPS. Interestingly, some of these areas are involved in learning and memory processes. Characterizing the mechanisms underlying these CNS alterations could help improve strategies to prevent these pathologies. Ventilatory strategies that contribute to reducing lung and systemic inflammation might somehow help prevent future neurocognitive alterations in the intensive care survivors.
Date of Award1 Jun 2016
Original languageSpanish
Awarding Institution
  • Consorci Corporació Sanitària Parc Taulí de Sabadell
SupervisorFerran Segura Porta (Tutor) & Josefina López Aguilar (Director)

Keywords

  • Mechanical ventilation
  • Neuronal activation
  • Inflamatory response

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