Combined Intracerebral and Jugular Bulb Microdialysis

Study Overview
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Brief Summary
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The first aim of this study is to investigate the frequency and severity of a specific pathological metabolic pattern, mitochondrial dysfunction, of the brain in comatose patients under neurocritical care. This pattern is recognized as a complication after compromised blood flow to the brain and may be amenable to treatment. The other main aim of this study is to correlate patterns of metabolites between brain and jugular venous blood. It is probable but not proven that jugular venous microdialysis can mirror the global metabolic state of the brain.

Detailed Description
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Purpose To describe the incidence of cerebral mitochondrial dysfunction in comatose patients admitted to the Neurointensive Care Unit (NICU) at Odense University Hospital and to evaluate the possible correlations between cerebral and jugular bulb microdialysis in an effort to develop new, effective and less invasive diagnostical tools for relevant patient groups. Background The hallmark of several serious neurological and neurosurgical disorders including severe traumatic brain injury, intracranial haemorrhage, cerebral infection and global hypoxic injury after cardiac arrest, is that the primary insult is out of reach for therapeutic intervention. Secondary injuries however, ensuing in the days to weeks after the primary insult are amenable to prevention or treatment. Inflammation, transient ischemia, free radical formation, cellular Ca2+-influx and mitochondrial dysfunction are therefore all examples of current research topics in neurointensive care. The research group has a long history of experimental and clinical work in the area of cerebral metabolism in neurocritical disease. In recent years neuromonitoring with cerebral microdialysis has been a main focus, as well as mitochondrial dysfunction as a possible therapeutic target . In 2004 the investigators showed how monitoring SAH-patients with cerebral microdialysis could predict delayed neurological deterioration/vasospasm related complications, results that were corroborated by later external studies. In 2012 and 2014, results have been published showing how to diagnose mitochondrial dysfunction on the basis of the biochemical patterns of cerebral microdialysis experimentally as well as clinically. Briefly, a cerebrochemical pattern with elevated lactate/pyruvate-ratio with simultaneous normal or supranormal levels of pyruvate and glucose seen together with normal tissue oxygen monitoring indicates mitochondrial dysfunction. Mitochondrial dysfunction most likely plays a key role in the worsening of outcome in a variety cerebral pathological conditions, and might be amenable to pharmacologic intervention. The microdialysis technique is based on a thin probe with a semipermeable membrane being inserted in affected brain tissue, collecting interstitial fluid from a small area surrounding the probe. The fluid is analysed for metabolites, proteins or pharmacological substances and has earlier been shown to be of great value in guiding NICU care and prognostication. One problem with the technique is, however, that the measurements are regional and limited to the very small sampling volume of the probe. Another obstacle is that the technique is intracranial invasive. Aims In the current prospective cohort study, the investigators will describe the incidence of mitochondrial dysfunction in a patients admitted to the NICU with severe subarachnoid haemorrhage (SAH). As patients suffering from SAH often have a non-ischemic cerebral metabolic affliction, a global cerebral measurement would presumably be as useful or more so than a focal measurement from only a very small regional brain volume. The investigators wish to evaluate a new method of monitoring, namely microdialysis of cerebral venous blood drainage. The cerebral venous drainage passes almost without exception through the jugular bulbs, left or right sided majority depending on dominance. The investigators will compare results of regional cerebral and venous measurements in order to confirm the hypothesis that metabolic disturbances of the brain are mirrored in the venous blood drainage in the jugular bulb. A pilot study of patients undergoing open heart surgery has confirmed significant differences in lactate and pyruvate in arterial systemic vs jugular venous blood. Yet unpublished data from this groups porcine experimental model supports the possibility of global metabolic venous monitoring. Perspectives If jugular bulb microdialysis can be confirmed to give a reliable global estimate of cerebral metabolic state it might be possible to a implement a new, less invasive diagnostic tool for NICU-patients. Surrogate measures in use today as e.g. NIRS (Near Infrared Spectroscopy) correlate poorly to cerebral metabolic status.

Official Title
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Continuous Monitoring of Cerebral Metabolic State. Combined Intracerebral and Jugular Bulb Microdialysis in Neurocritical Care.

Conditions
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TBI, Subarachnoid Hemorrhage, Hypoxia Ischemia, Cerebral, Meningitis

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Glasgow coma score <8. Suspicion of intracranial pathology Exclusion Criteria: Suspected and/or Untreated coagulopathy Consent from closest of kin not given

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlations of lactate/pyruvate-ratio (LP-ratio) calculated by dividing lactate concentration in mM by pyruvate concentration in mikroM, in cerebral and venous microdialysis | Hourly samples of lactate (mM) and pyruvate (mikroM) are assessed using microdialysis measurements in brain and jugular bulb. The LP-ratio is calculated and compared at each timepoint. | Patients are monitored a mean of 5 days with hourly analysis. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlations of microdialysis values of glucose. | Cerebral and jugular bulb microdialysis measurements of glucose (mM)compared for co-variation. | Mean 5 day measurements | 
| Modified Rankin scale of outcome. | 6 month modified Rankin Scale (mRS) will be assessed at outpatient clinic. The mRS is the most widely used scale for measuring degree of disability in stroke trials, The scale ranges from 0 to 6, where 0 means no symptoms and 6 is dead. | 6 months | 
| Evaluation of mitochondrial dysfunction under study period. | Microdialysis results will be analysed for amount (hours) of mitochondrial dysfunction, defined as normal cerebral P02-measurements (mmHg), in combination with high LP-ratio (ratio) and simultaneous normal or high pyruvate concentration (mikroM). | calculations based on mean 5-day measurements per patient. |