Microdiálisis de alta resolución aplicada al estudio y tratamiento de trastornos metabólicos cerebrales

Resumen

In the past two decades, both clinicians and researchers have considered brain ischemic and non-ischemic cerebral hypoxia, the protagonist of most secondary lesions occurring in patients with severe traumatic brain injury (TBI). Both primary damage and cerebral ischemia trigger the release of neurotransmitters and an energy failure that causes massive ionic fluxes. Subsequent osmotic water movement across the cells is followed by brain edema. Brain edema is the major leading cause of death and disability in these patients. Better understanding of the complex ionic disturbances that cause edema would benefit the study and treatment of not only TBI patients but also patients with other acute neurological injuries, such as malignant middle cerebral artery infarct (MMCAI). Normobaric brain oxygen therapy (NBO) is one strategy already tested in experimental models of TBI and in pilot clinical trials. The main concern regarding NBO is the potential toxicity of using supranormal levels of partial pressure of arterial oxygen. High FiO2 could induce vasoconstriction, exacerbate oxidative stress (OxS), increase neuroinflammation, or induce excitotoxicity. Current multimodal neuromonitoring (MNM) techniques allow the study of the processes occurring after acute brain injury. Cerebral microdialysis (MD) is an advanced MNM technique that allows continuous sampling of the cerebral parenchyma. The main objectives of this thesis were: 1) to determine the ionic profile of brain extracellular space (ECS) in different brain areas in patients with acute brain injury, 2) to evaluate the metabolic response of TBI patients to 4 h of NBO and to determine whether hyperoxia increases OxS, and 3) to reproduce in vitro the abnormal brain metabolic profiles in one of the types of hypoxia described by Siggaar-Andersen in 1995 (low-extractivity hypoxia -LEH-). First, to analyze the ionic profile of brain ECS, microdialysate samples of 34 patients (TBI and MMCAI) were analyzed using inductively coupled plasma mass spectrometry (ICP-MS). The ionic profile was studied according to the position of the MD catheter. The results showed that the ionic composition of the brain ECS differs according to the severity of the tissue disturbance. Thus, the results should be interpreted according to the region of the brain sampled by the MD catheter. ICP-MS coupled to ionic assays creates a powerful tool for a better understanding of the complex ionic disturbances that occur after acute brain lesions. Secondly, 34 TBI patients were included to assess the metabolic response of the injured brain to NBO and to determine whether hyperoxia increases OxS. The results showed that NBO increased PtiO2 in both macroscopically normal injured brain and in traumatic regions at risk. NBO did not change energy metabolism in the entire group of patients. These results suggest that TBI patients would benefit from receiving NBO when they show indications of disturbed brain metabolism. The presence of OxS in MD samples was additionally measured using a robust indicator (8-iso-PGF2α). NBO maintained for 4 h did not induce OxS in patients without pre-existing OxS at baseline. However, for patients in whom OxS was detected at baseline, NBO induced a significant increase in 8-iso-PGF2α. Combined with the increasing evidence that metabolic crises are common in TBI without brain ischemia, these findings open new avenues for the use of this accessible therapeutic strategy in TBI patients. Finally, using an in vitro model of human cortical astrocytes, the energy metabolic profile and the changes in the glycolytic machinery of LEH were reproduced. This is a first step toward exploring the consequences of LEH in vitro for a better understating of the MD pattern found in neurocritical patients. Our aim was to acquire in-depth knowledge of more complex forms of brain hypoxia found in acute brain injuries.