Thomas C. Glenn

Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study

Brain trauma is accompanied by regional alterations of brain metabolism, reduction in metabolic rates and possible energy crisis. We hypothesize that microdialysis markers of energy crisis are present during the critical period of intensive care despite the absence of brain ischemia. In all, 19 brain injury patients (mean GCS 6) underwent combined positron emission tomography (PET) for metabolism of glucose (CMRglu) and oxygen (CMRO2) and cerebral microdialysis (MD) at a mean time of 36 h after injury. Microdialysis values were compared with the regional mean PET values adjacent to the probe. Longitudinal MD data revealed a 25% incidence rate of metabolic crisis (elevated lactate/pyruvate ratio (LPR)>40) but only a 2.4% incidence rate of ischemia. Positron emission tomography imaging revealed a 1% incidence of ischemia across all voxels as measured by oxygen extraction fraction (OEF) and cerebral venous oxygen content (CvO2). In the region of the MD probe, PET imaging revealed ischemia in a single patient despite increased LPR in other patients. Lactate/pyruvate ratio correlated negatively with CMRO2 (P<0.001), but not with OEF or CvO2. Traumatic brain injury leads to a state of persistent metabolic crisis as reflected by abnormal cerebral microdialysis LPR that is not related to ischemia.

Comparative Overview of Brain Perfusion Imaging Techniques

Background and Purpose— Numerous imaging techniques have been developed and applied to evaluate brain hemodynamics. Among these are positron emission tomography, single photon emission computed tomography, Xenon-enhanced computed tomography, dynamic perfusion computed tomography, MRI dynamic susceptibility contrast, arterial spin labeling, and Doppler ultrasound. These techniques give similar information about brain hemodynamics in the form of parameters such as cerebral blood flow or cerebral blood volume. All of them are used to characterize the same types of pathological conditions. However, each technique has its own advantages and drawbacks. Summary of Review— This article addresses the main imaging techniques dedicated to brain hemodynamics. It represents a comparative overview established by consensus among specialists of the various techniques. Conclusions— For clinicians, this article should offer a clearer picture of the pros and cons of currently available brain perfusion imaging techniques and assist them in choosing the proper method for every specific clinical setting.

Nonconvulsive electrographic seizures after traumatic brain injury result in a delayed, prolonged increase in intracranial pressure and metabolic crisis

Objective: To determine whether nonconvulsive electrographic post‐traumatic seizures result in increases in intracranial pressure and microdialysis lactate/pyruvate ratio. Design: Prospective monitoring with retrospective data analysis. Setting: Single center academic neurologic intensive care unit. Patients: Twenty moderate to severe traumatic brain injury patients (Glasgow Coma Score 3–13). Measurements and Main Results: Continuous electroencephalography and cerebral microdialysis were performed for 7 days after injury. Ten patients had seizures and were compared with a matched cohort of traumatic brain injury patients without seizures. The seizures were repetitive and constituted status epilepticus in seven of ten patients. Using a within‐subject design, post‐traumatic seizures resulted in episodic increases in intracranial pressure (22.4 ± 7 vs. 12.8 ± 4.3 mm Hg; p < .001) and an episodic increase in lactate/pyruvate ratio (49.4 ± 16 vs. 23.8 ± 7.6; p < .001) in the seizure group. Using a between‐subjects comparison, the seizure group demonstrated a higher mean intracranial pressure (17.6 ± 6.5 vs. 12.2 ± 4.2 mm Hg; p < .001), a higher mean lactate/pyruvate ratio (38.6 ± 18 vs. 27 ± 9; p < .001) compared with nonseizure patients. The intracranial pressure and lactate/pyruvate ratio remained elevated beyond postinjury hour 100 in the seizure group but not the nonseizure group (p < .02). Conclusion: Post‐traumatic seizures result in episodic as well as long‐lasting increases in intracranial pressure and microdialysis lactate/pyruvate ratio. These data suggest that post‐traumatic seizures represent a therapeutic target for patients with traumatic brain injury.

Intensive insulin therapy reduces microdialysis glucose values without altering glucose utilization or improving the lactate/pyruvate ratio after traumatic brain injury

Objective:To determine that intensive glycemic control does not reduce microdialysis glucose concentration brain metabolism of glucose. Design:Prospective monitoring followed by retrospective data analysis of cerebral microdialysis and global brain metabolism. Setting:Single center, academic neurointensive care unit. Patients:Forty-seven moderate to severe traumatic brain injury patients. Interventions:A nonrandomized, consecutive design was used for glycemic control with loose insulin (n = 33) for the initial 2 yrs or intensive insulin therapy (n = 14) for the last year. Measurements and Main Results:In 14 patients treated with intensive insulin therapy, there was a reduction in microdialysis glucose by 70% of baseline concentration compared with a 15% reduction in 33 patients treated with a loose insulin protocol. Despite this reduction in microdialysis glucose, the global metabolic rate of glucose did not change. However, intensive insulin therapy was associated with increased incidence of microdialysis markers of cellular distress, namely elevated glutamate (38 ± 37% vs. 10 ± 17%, p < .01), elevated lactate/pyruvate ratio (38 ± 37% vs. 19 ± 26%, p < .03) and low glucose (26 ± 17% vs. 11 ± 15%, p < .05, and increased global oxygen extraction fraction. Mortality was similar in the intensive and loose insulin treatment groups (14% vs. 15%, p = .9), as was 6-month clinical outcome (p = .3). Conclusions:Intensive insulin therapy results in a net reduction in microdialysis glucose and an increase in microdialysis glutamate and lactate/pyruvate without conveying a functional outcome advantage.

Persistently low extracellular glucose correlates with poor outcome 6 months after human traumatic brain injury despite a lack of increased lactate: a microdialysis study.

Disturbed glucose brain metabolism after brain trauma is reflected by changes in extracellular glucose levels. The authors hypothesized that posttraumatic reductions in extracellular glucose levels are not due to ischemia and are associated with poor outcome. Intracerebral microdialysis, electroencephalography, and measurements of brain tissue oxygen levels and jugular venous oxygen saturation were performed in 30 patients with traumatic brain injury. Levels of glucose, lactate, pyruvate, glutamate, and urea were analyzed hourly. The 6-month Glasgow Outcome Scale extended (GOSe6) score was assessed for each patient. In regions of increased glucose utilization defined by positron emission tomography, the extracellular glucose concentration was less than 0.2 mmol/l. Extracellular glucose values were less than 0.2 mmol during postinjury days 0 to 7 in 19% to 30% of hourly samples on each day. Transient decreases in glucose levels occurred with electrographic seizures and nonischemic reductions in cerebral perfusion pressure and jugular venous oxygen saturation. Glutamate levels were elevated in the majority of low-glucose samples, but the lactate/pyruvate ratio did not indicate focal ischemia. Terminal herniation resulted in reductions in glucose with increases in the lactate/pyruvate ratio but not in lactate concentration alone. GOSe6 scores correlated with persistently low glucose levels, combined early low glucose levels and low lactate/glucose ratio, and with the overall lactate/glucose ratio. These results suggest that the level of extracellular glucose is typically reduced after traumatic brain injury and associated with poor outcome, but is not associated with ischemia.

Energy dysfunction as a predictor of outcome after moderate or severe head injury: indices of oxygen, glucose, and lactate metabolism.

The purpose of this study was to determine if the relationship between abnormalities in glucose, lactate, and oxygen metabolism were predictive of neurologic outcome after moderate or severe head injury, relative to other known prognostic factors. Serial assessments of the cerebral metabolic rates for glucose, lactate, and oxygen were performed using a modified Kety-Schmidt method. In total, 31 normal control subjects were studied once, and 49 TBI patients (mean age 36±16 years, median GCS 7) were studied five times median per patient from postinjury days 0 to 9. Univariate and multivariate analyses were performed. Univariate analysis showed that the 6-month postinjury Glasgow Outcome Scale (GOS) was most strongly associated with the mean cerebral metabolic rate of oxygen (CMRO2) (P = 0.0001), mean arterial lactate level (P = 0.0001), mean arterial glucose (P = 0.0008), mean cerebral blood flow (CBF), (P = 0.002), postresuscitation GCS (P = 0.003), and pupillary status (P = 0.004). Brain lactate uptake was observed in 44% of all metabolic studies, and 76% of patients had at least one episode of brain lactate uptake. By dichotomized GOS, patients achieving a favorable outcome (GOS 4-5) were distinguished from those with an unfavorable outcome (GOS1-3) by having a higher CMRO2 (P = 0.003), a higher rate of abnormal brain lactate uptake relative to arterial lactate levels (P = 0.04), and lesser degrees of blood-brain barrier damage based on CT findings (P = 0.03). Conclusions: During the first 6 days after moderate or severe TBI, CMRO2 and arterial lactate levels are the strongest predictors of neurologic outcome. However, the frequent occurrence of abnormal brain lactate uptake despite only moderate elevations in arterial lactate levels in the favorable outcome patients suggests the brains ability to use lactate as a fuel may be another key outcome predictor. Future studies are needed to determine to what degree nonglycolytic energy production from alternative fuels such as lactate occurs after TBI and whether alternative fuel administration is a viable therapy for TBI patients.

Pericontusional brain tissue exhibits persistent elevation of lactate/pyruvate ratio independent of cerebral perfusion pressure

Objective:To determine whether pericontusional tissue exhibits neurochemical responsiveness to changes in cerebral perfusion pressure as measured by microdialysis lactate/pyruvate ratio. Design:Prospective monitoring with retrospective data analysis. Setting:Single-center academic neurologic intensive care unit. Patients:Twenty-one patients with severe traumatic brain injury (Glasgow Coma Scale score 3–8). Interventions:None. Measurements and Main Results:Cerebral microdialysis was performed for the initial 7 days after traumatic brain injury. Thirteen patients had microdialysis probes in normal tissue and eight had two probes, one of which was located in pericontusional tissue. Retrospective analysis was performed to determine if microdialysis levels in pericontusional tissue demonstrates higher levels of lactate/pyruvate ratio than normal tissue and if lactate/pyruvate ratio increased with reductions in cerebral perfusion pressure. Univariate analysis revealed higher values for glutamate and lactate/pyruvate ratio in pericontusional tissue compared with normal tissue. However, based on the mixed-effects model analysis, the percent time of elevated lactate/pyruvate ratio was significantly higher in pericontusional tissue (40 ± 59% vs. 17 ± 37%, p < .05), and the mean lactate/pyruvate ratio values showed only a trend relationship (62 ± 134 vs. 34 ± 78, p < .06). When examined by cerebral perfusion pressure threshold, cerebral perfusion pressure <60 mm Hg was not associated with higher lactate/pyruvate ratio values in normal or pericontusional tissue. In addition, no single cerebral perfusion pressure threshold was associated with a significant reduction in lactate/pyruvate ratio in either pericontusional or normal tissue (p < .08). Conclusions:Sustained increases in lactate/pyruvate ratio occurred more frequently in pericontusional tissue compared with normal brain tissue. The lactate/pyruvate ratio was not related to cerebral perfusion pressure, nor was the percent time-burden of elevated lactate/pyruvate ratio related to any particular sustained cerebral perfusion pressure threshold. Lactate/pyruvate ratio values appear to be elevated despite cerebral perfusion pressure values customarily considered to be adequate.

Persistent metabolic crisis as measured by elevated cerebral microdialysis lactate-pyruvate ratio predicts chronic frontal lobe brain atrophy after traumatic brain injury.

Objective:To determine whether persistent metabolic dysfunction in normal-appearing frontal lobe tissue is correlated with long-term tissue atrophy. Design:Prospective monitoring with retrospective data analysis. Setting:Single-center academic neurointensive care unit. Patients:Fifteen patients with moderate to severe traumatic brain injury (Glasgow Coma Scale score 3–12). Interventions:None. Measurements and Main Results:Hourly cerebral microdialysis was performed for the initial 96 hrs after trauma to determine extracellular levels of glucose, glutamate, glycerol, lactate, and pyruvate in normal appearing frontal lobes. Six months after injury, the anatomical outcome was assessed by measures of global and regional cerebral atrophy using volumetric brain magnetic resonance imaging. The lactate/pyruvate ratio was elevated >40 after traumatic brain injury in most patients, with a mean percent time of 32 ± 29% of hours monitored. At 6 months after traumatic brain injury, there was a mean frontal lobe atrophy of 12 ± 11% and global brain atrophy of 8.5 ± 4.5%. The percentage of time of elevated lactate/pyruvate ratio correlated with the extent of frontal lobe brain atrophy (r = −.56, p < 0.01), but not global brain atrophy (r = −.31, p = 0.20). The predictive effect of lactate/pyruvate ratio was independent of patient age, Glasgow Coma Scale score, and volume of frontal lobe contusion. Conclusion:Persistent metabolic crisis, as reflected by an elevated lactate/pyruvate ratio, in normal appearing posttraumatic frontal lobe, is predictive of the degree of tissue atrophy at 6 months.

Comparative overview of brain perfusion imaging techniques

Numerous imaging techniques have been developed and applied to evaluate brain hemodynamics. Among these are: Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), Xenon-enhanced Computed Tomography (XeCT), Dynamic Perfusion-computed Tomography (PCT), Magnetic Resonance Imaging Dynamic Susceptibility Contrast (DSC), Arterial Spin-Labeling (ASL), and Doppler Ultrasound. These techniques give similar information about brain hemodynamics in the form of parameters such as cerebral blood flow (CBF) or volume (CBV). All of them are used to characterize the same types of pathological conditions. However, each technique has its own advantages and drawbacks. This article addresses the main imaging techniques dedicated to brain hemodynamics. It represents a comparative overview, established by consensus among specialists of the various techniques. For clinicians, this paper should offers a clearer picture of the pros and cons of currently available brain perfusion imaging techniques, and assist them in choosing the proper method in every specific clinical setting.

Increased pentose phosphate pathway flux after clinical traumatic brain injury : a [1,2.13C2]glucose labeling study in humans

Patients with traumatic brain injury (TBI) routinely exhibit cerebral glucose uptake in excess of that expected by the low levels of oxygen consumption and lactate production. This brings into question the metabolic fate of glucose. Prior studies have shown increased flux through the pentose phosphate cycle (PPC) during cellular stress. This study assessed the PPC after TBI in humans. [1,2-13C2]glucose was infused for 60 mins in six consented, severe-TBI patients (GCS < 9) and six control subjects. Arterial and jugular bulb blood sampled during infusion was analyzed for 13C-labeled isotopomers of lactate by gas chromatography/mass spectroscopy. The product of lactate concentration and fractional abundance of isotopomers was used to determine blood concentration of each isotopomer. The difference of jugular and arterial concentrations determined cerebral contribution. The formula PPC = (m1/m2)/(3 + (m1/m2)) was used to calculate PPC flux relative to glycolysis. There was enrichment of [1,2-13C2]glucose in arterial-venous blood (enrichment averaged 16.6% in TBI subjects and 28.2% in controls) and incorporation of 13C-label into lactate, showing metabolism of labeled substrate. The PPC was increased in TBI patients relative to controls (19.6 versus 6.9%, respectively; P = 0.002) and was excellent for distinguishing the groups (AUC = 0.944, P < 0.0001). No correlations were found between PPC and other clinical parameters, although PPC was highest in patients studied within 48 h of injury (averaging 33% versus 13% in others; P = 0.0006). This elevation in the PPC in the acute period after severe TBI likely represents a shunting of substrate into alternative biochemical pathways that may be critical for preventing secondary injury and initiating recovery.