Brain Tissue Oxygenation in Traumatic Brain Injury : Experimental and Clinical Studies

Traumatic brain injury (TBI) is a major cause of death and disability. TBI is frequently followed by cerebral ischemia which is a great contributor to secondary brain damage. The main causes of cerebral ischemia are pathophysiological changes in cerebral blood flow and metabolism. Treatment of TBI patients is currently based on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) targeted treatment protocols. However, ICP and CPP alone do not provide information of the oxygen availability in the brain. Monitoring of brain tissue oxygenation (BtipO2) may give additional and valuable information about the risk for development of ischemia in TBI patients. The aims of this thesis were to study BtipO2 monitoring devices in-vitro regarding accuracy and stability, to detect threshold level of cerebral ischemia in-vivo and finally to examine the cerebral oxygen levels and cerebral metabolism in TBI patients. The BtipO2 probes performed with high accuracy and stability at different clinically relevant oxygen concentrations. A pig TBI model was developed by step-wise intracranial volume/pressure increase. Volume increase resulted in a gradual increased ICP, decreased CPP, intracranial compliance and BtipO2, respectively. Brain death (BD) was confirmed by negative CPP and negligible amount of previously injected microspheres in the brain tissue. The model simulated the clinical development of BD in humans with a classical pressure-volume response and systemic cardiovascular reactions. The model should be suitable for studies of brain injury mechanisms. From the same in-vivo model it was also possible to detect the threshold level of cerebral ischemia in the pig, where BtipO2 below 10 mmHg and CPP below 30 mmHg was associated with an impaired cerebral metabolism (microdialysis lactate to pyruvate ratio >30). BtipO2 together with cerebral microdialysis were studied in 23 severe TBI patients. We observed different patterns of changes in BtipO2 and cerebral microdialysis biomarkers in focal and diffuse TBI.  Increased cerebral microdialysis levels of glutamate, glycerol or the lactate/pyruvate ratio were observed at BtipO2 < 5 mmHg, indicating increased vulnerability of the brain at this critical level of tissue oxygenation in TBI patients

Brain Tissue Oxygenation in Traumatic Brain Injury : Experimental and Clinical Studies

Traumatic brain injury (TBI) is a major cause of death and disability. TBI is frequently followed by cerebral ischemia which is a great contributor to secondary brain damage. The main causes of cerebral ischemia are pathophysiological changes in cerebral blood flow and metabolism. Treatment of TBI patients is currently based on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) targeted treatment protocols. However, ICP and CPP alone do not provide information of the oxygen availability in the brain. Monitoring of brain tissue oxygenation (BtipO2) may give additional and valuable information about the risk for development of ischemia in TBI patients. The aims of this thesis were to study BtipO2 monitoring devices in-vitro regarding accuracy and stability, to detect threshold level of cerebral ischemia in-vivo and finally to examine the cerebral oxygen levels and cerebral metabolism in TBI patients. The BtipO2 probes performed with high accuracy and stability at different clinically relevant oxygen concentrations. A pig TBI model was developed by step-wise intracranial volume/pressure increase. Volume increase resulted in a gradual increased ICP, decreased CPP, intracranial compliance and BtipO2, respectively. Brain death (BD) was confirmed by negative CPP and negligible amount of previously injected microspheres in the brain tissue. The model simulated the clinical development of BD in humans with a classical pressure-volume response and systemic cardiovascular reactions. The model should be suitable for studies of brain injury mechanisms. From the same in-vivo model it was also possible to detect the threshold level of cerebral ischemia in the pig, where BtipO2 below 10 mmHg and CPP below 30 mmHg was associated with an impaired cerebral metabolism (microdialysis lactate to pyruvate ratio >30). BtipO2 together with cerebral microdialysis were studied in 23 severe TBI patients. We observed different patterns of changes in BtipO2 and cerebral microdialysis biomarkers in focal and diffuse TBI.  Increased cerebral microdialysis levels of glutamate, glycerol or the lactate/pyruvate ratio were observed at BtipO2 < 5 mmHg, indicating increased vulnerability of the brain at this critical level of tissue oxygenation in TBI patients

Brain tissue oxygenation and cerebral metabolic patterns in focal and diffuse traumatic brain injury

Introduction: Neurointensive care of traumatic brain injury (TBI) patients is currently based on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) targeted protocols. There are reasons to believe that knowledge of brain tissue oxygenation (BtipO2) would add information with the potential of improving patient outcome. The aim of this study was to examine BtipO2 and cerebral metabolism using the Neurovent-PTO probe and cerebral microdialysis (MD) in TBI patients. Methods: Twenty-three severe TBI patients with monitoring of physiological parameters, ICP, CPP, BtipO2, and MD for biomarkers of energy metabolism (glucose, lactate, and pyruvate) and cellular distress (glutamate, glycerol) were included. Patients were grouped according to injury type (focal/diffuse) and placement of the Neurovent-PTO probe and MD catheter (injured/non-injured hemisphere). Results: We observed different patterns in BtipO2 and MD biomarkers in diffuse and focal injury where placement of the probe also influenced the results (ipsilateral/contralateral). In all groups, despite fairly normal levels of ICP and CPP, increased MD levels of glutamate, glycerol, or the L/P ratio were observed at BtipO2 <5 mmHg, indicating increased vulnerability of the brain at this level. Conclusion: Monitoring of BtipO2 adds important information in addition to traditional ICP and CPP surveillance. Because of the different metabolic responses to very low BtipO2 in the individual patient groups we submit that brain tissue oximetry is a complementary tool rather than an alternative to MD monitoring

Refined Microdialysis Method for Protein Biomarker Sampling in Acute Brain Injury in the Neurointensive Care Setting

There is growing interest in cerebral microdialysis (MD) for sampling of protein biomarkers in neurointensive care (NIC) patients. Published data point to inherent problems with this methodology including protein interaction and biofouling leading to unstable catheter performance. This study tested the in vivo performance of a refined MD method including catheter surface modification, for protein biomarker sampling in a clinically relevant porcine brain injury model. Seven pigs of both sexes (10–12 weeks old; 22.2–27.3 kg) were included. Mean arterial blood pressure, heart rate, intracranial pressure (ICP) and cerebral perfusion pressure was recorded during the stepwise elevation of intracranial pressure by inflation of an epidural balloon catheter with saline (1 mL/20 min) until brain death. One naïve MD catheter and one surface modified with Pluronic F-127 (10 mm membrane, 100 kDa molecular weight cutoff MD catheter) were inserted into the right frontal cortex and perfused with mock CSF with 3% Dextran 500 at a flow rate of 1.0 μL/min and 20 min sample collection. Naïve catheters showed unstable fluid recovery, sensitive to ICP changes, which was significantly stabilized by surface modification. Three of seven naïve catheters failed to deliver a stable fluid recovery. MD levels of glucose, lactate, pyruvate, glutamate, glycerol and urea measured enzymatically showed an expected gradual ischemic and cellular distress response to the intervention without differences between naïve and surface modified catheters. The 17 most common proteins quantified by iTRAQ and nanoflow LC-MS/MS were used as biomarker models. These proteins showed a significantly more homogeneous response to the ICP intervention in surface modified compared to naïve MD catheters with improved extraction efficiency for most of the proteins. The refined MD method appears to improve the accuracy and precision of protein biomarker sampling in the NIC setting