A combined microdialysis and FDG-PET study of glucose metabolism in head injury

University of Cambridge Division of Anaesthesia, Department of Medicine Box 93 Addenbrooke’s Hospital, Hills Road Cambridge CB2 0QQ UK
Acta Neurochirurgica (Impact Factor: 1.77). 01/2008; 151(1):51-61. DOI: 10.1007/s00701-008-0169-1


Microdialysis continuously monitors the chemistry of a small focal volume of the cerebral extracellular space. Positron emission tomography (PET) establishes metabolism of the whole brain but only for the scan’s duration. This study’s objective was to apply these techniques together, in patients with traumatic brain injury, to assess the relationship between microdialysis (extracellular glucose, lactate, pyruvate, and the lactate/pyruvate (L/P) ratio as a marker of anaerobic metabolism) and PET parameters of glucose metabolism using the glucose analogue [18F]-fluorodeoxyglucose (FDG). In particular, we aimed to determine the fate of glucose in terms of differential metabolism to pyruvate and lactate.
Materials and methods
Microdialysis catheters (CMA70 or CMA71) were inserted into the cerebral cortex of 17 patients with major head injury. Microdialysis was performed during FDG-PET scans with regions of interest for PET analysis defined by the location of the gold-tipped microdialysis catheter. Microdialysate analysis was performed on a CMA600 analyser.
There was significant linear relationship between the PET-derived parameter of glucose metabolism (regional cerebral metabolic rate of glucose; CMRglc) and levels of lactate (r = 0.778, p < 0.0001) and pyruvate (r = 0.799, p < 0.0001), but not with the L/P ratio.
The results suggest that in this population of patients, glucose was metabolised to both lactate and pyruvate, but was not associated with an increase in the L/P ratio. This suggests an increase in glucose metabolism to both lactate and pyruvate, as opposed to a shift towards anaerobic metabolism.

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    • "Given this pre-existing data, perhaps the most unexpected finding was the lack of changes in lactate, pyruvate, and lactate:pyruvate (L:P) ratio. However, given the ambiguity in previously published work monitoring post-traumatic changes in these parameters, our result is perhaps not surprising (Nelson et al., 2004; Vespa et al., 2007a,b; Hutchinson et al., 2009; Zygun et al., 2009). This, to our knowledge, is one of the few studies to actually remove the injured region of the brain and quantify shifts in lactate and pyruvate and then calculate the ratio of the two. "
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    ABSTRACT: Traumatic brain injury (TBI) pathophysiology can be attributed to either the immediate, primary physical injury, or the delayed, secondary injury which begins minutes to hours after the initial injury and can persist for several months or longer. Because these secondary cascades are delayed and last for a significant time period post-TBI, they are primary research targets for new therapeutics. To investigate changes in mitochondrial function after a brain injury, both the cortical impact site and ipsilateral hippocampus of adult male rats 7 and 17 days after a controlled cortical impact (CCI) injury were examined. State 3, state 4, and uncoupler-stimulated rates of oxygen consumption, respiratory control ratios (RCRs) were measured and membrane potential quantified, and all were significantly decreased in 7 day post-TBI cortical mitochondria. By contrast, hippocampal mitochondria at 7 days showed only non-significant decreases in rates of oxygen consumption and membrane potential. NADH oxidase activities measured in disrupted mitochondria were normal in both injured cortex and hippocampus at 7 days post-CCI. Respiratory and phosphorylation capacities at 17 days post-CCI were comparable to naïve animals for both cortical and hippocampus mitochondria. However, unlike oxidative phosphorylation, membrane potential of mitochondria in the cortical lining of the impact site did not recover at 17 days, suggesting that while diminished cortical membrane potential at 17 days does not adversely affect mitochondrial capacity to synthesize ATP, it may negatively impact other membrane potential-sensitive mitochondrial functions. Memory status, as assessed by a passive avoidance paradigm, was not significantly impaired until 17 days after injury. These results indicate pronounced disturbances in cortical mitochondrial function 7 days after CCI which precede the behavioral impairment observed at 17 days.
    Full-text · Article · Jan 2013 · Frontiers in Neuroenergetics
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    • "In addition, irreversibly damaged (posthypoxic) but reperfused regions may also display extended periods with MD of ischemic and/or hypoxic character [35]. Alternative interpretations of lactate, pyruvate and LP ratios in TBI have therefore been postulated [11], and more complex supply-and-demand relations of these parameters under nonischemic conditions have also been identified [36]. Moreover, MD may also be influenced by static parameters such as catheter placement in gray or white matter [37], genetics [38] and patient sex [39]. "
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    ABSTRACT: Cerebral microdialysis (MD) is used to monitor local brain chemistry of patients with traumatic brain injury (TBI). Despite an extensive literature on cerebral MD in the clinical setting, it remains unclear how individual levels of real-time MD data are to be interpreted. Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) are important continuous brain monitors in neurointensive care. They are used as surrogate monitors of cerebral blood flow and have an established relation to outcome. The purpose of this study was to investigate the relations between MD parameters and ICP and/or CPP in patients with TBI. Cerebral MD, ICP and CPP were monitored in 90 patients with TBI. Data were extensively analyzed, using over 7,350 samples of complete (hourly) MD data sets (glucose, lactate, pyruvate and glycerol) to seek representations of ICP, CPP and MD that were best correlated. MD catheter positions were located on computed tomography scans as pericontusional or nonpericontusional. MD markers were analyzed for correlations to ICP and CPP using time series regression analysis, mixed effects models and nonlinear (artificial neural networks) computer-based pattern recognition methods. Despite much data indicating highly perturbed metabolism, MD shows weak correlations to ICP and CPP. In contrast, the autocorrelation of MD is high for all markers, even at up to 30 future hours. Consequently, subject identity alone explains 52% to 75% of MD marker variance. This indicates that the dominant metabolic processes monitored with MD are long-term, spanning days or longer. In comparison, short-term (differenced or Δ) changes of MD vs. CPP are significantly correlated in pericontusional locations, but with less than 1% explained variance. Moreover, CPP and ICP were significantly related to outcome based on Glasgow Outcome Scale scores, while no significant relations were found between outcome and MD. The multitude of highly perturbed local chemistry seen with MD in patients with TBI predominately represents long-term metabolic patterns and is weakly correlated to ICP and CPP. This suggests that disturbances other than pressure and/or flow have a dominant influence on MD levels in patients with TBI.
    Full-text · Article · Mar 2011 · BMC Medicine
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    • "To date, the optimal blood glucose range still remains elusive and requirements are discussed controversially as corroborated by the recently published results from the Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial, which showed a significant increase in mortality in patients subjected to the tight blood glucose range of 4.5 to 6.0 mmol/l compared with the conventional glucose control group with a blood glucose target of 10 mmol/l or less [15]. In patients with acute traumatic [16-18] and ischemic [19,20] brain damage microdialysis is used to gain detailed insight into otherwise occult metabolic alterations. In this context, glucose, lactate, pyruvate, and glutamate are routinely measured [6,16,21,22]. "
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    ABSTRACT: The optimal blood glucose target following severe traumatic brain injury (TBI) must be defined. Cerebral microdialysis was used to investigate the influence of arterial blood and brain glucose on cerebral glucose, lactate, pyruvate, glutamate, and calculated indices of downstream metabolism. In twenty TBI patients, microdialysis catheters inserted in the edematous frontal lobe were dialyzed at 1 microl/min, collecting samples at 60 minute intervals. Occult metabolic alterations were determined by calculating the lactate- pyruvate (L/P), lactate- glucose (L/Glc), and lactate- glutamate (L/Glu) ratios. Brain glucose was influenced by arterial blood glucose. Elevated L/P and L/Glc were significantly reduced at brain glucose above 1 mM, reaching lowest values at blood and brain glucose levels between 6-9 mM (P < 0.001). Lowest cerebral glutamate was measured at brain glucose 3-5 mM with a significant increase at brain glucose below 3 mM and above 6 mM. While L/Glu was significantly increased at low brain glucose levels, it was significantly decreased at brain glucose above 5 mM (P < 0.001). Insulin administration increased brain glutamate at low brain glucose, but prevented increase in L/Glu. Arterial blood glucose levels appear to be optimal at 6-9 mM. While low brain glucose levels below 1 mM are detrimental, elevated brain glucose are to be targeted despite increased brain glutamate at brain glucose >5 mM. Pathogenity of elevated glutamate appears to be relativized by L/Glu and suggests to exclude insulin- induced brain injury.
    Full-text · Article · Feb 2010 · Critical care (London, England)
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