Persistently Low Extracellular Glucose Correlates With PoorOutcome 6 Months After Human Traumatic Brain Injury
Despite a Lack of Increased Lactate: A Microdialysis Study
Paul M. Vespa, David McArthur, Kristine O’Phelan, Thomas Glenn, Maria Etchepare,Daniel Kelly, Marvin Bergsneider, Neil A. Martin, and David A. Hovda
Division of Neurosurgery, David Geffen School of Medicine at University of California at Los Angeles, U.S.A.
Summary: Disturbed glucose brain metabolism after braintrauma is reflected by changes in extracellular glucose levels.The authors hypothesized that posttraumatic reductions in ex-tracellular glucose levels are not due to ischemia and are asso-ciated with poor outcome. Intracerebral microdialysis, electro-encephalography, and measurements of brain tissue oxygenlevels and jugular venous oxygen saturation were performed in30 patients with traumatic brain injury. Levels of glucose, lac-tate, pyruvate, glutamate, and urea were analyzed hourly. The6-month Glasgow Outcome Scale extended (GOSe6) score wasassessed for each patient. In regions of increased glucose uti-lization defined by positron emission tomography, the extra-cellular glucose concentration was less than 0.2 mmol/l. Extra-cellular glucose values were less than 0.2 mmol duringpostinjury days 0 to 7 in 19% to 30% of hourly samples on each
day. Transient decreases in glucose levels occurred with elec-trographic seizures and nonischemic reductions in cerebral per-fusion pressure and jugular venous oxygen saturation. Gluta-mate levels were elevated in the majority of low-glucosesamples, but the lactate/pyruvate ratio did not indicate focalischemia. Terminal herniation resulted in reductions in glucosewith increases in the lactate/pyruvate ratio but not in lactateconcentration alone. GOSe6 scores correlated with persistentlylow glucose levels, combined early low glucose levels and lowlactate/glucose ratio, and with the overall lactate/glucose ratio.These results suggest that the level of extracellular glucose istypically reduced after traumatic brain injury and associatedwith poor outcome, but is not associated with ischemia. KeyWords: Brain trauma—Microdialysis—Glucose—Lactate—Hyperglycolysis.
Traumatic brain injury results in primary cellulardeath in a limited region of the brain directly involved inthe insult while creating a more widespread state ofmetabolic dysfunction in remote areas of the brain (Fee-ney and Baron, 1986; Vink et al., 1988). This metabolicdysfunction is best characterized as a reduction in oxi-dative metabolism (Hovda et al., 1991; Vink et al.,1988). This deficit is in part compensated for by theactivation of glucose metabolism (Kawamata et al.,1992; Yoshino et al., 1991, 1992). As a result of in-creased glycolysis, lactate production increases, but lac-tic acid accumulation is in part mitigated by the ability ofneurons to use lactic acid as an alternative fuel (Pellerinand Magistretti, 1996).
Abnormalities of glucose metabolism have beenshown in multiple animal models of brain injury(Andersen and Maramarou, 1989; Hayes et al., 1988;Hovda et al., 1991; Yoshino et al., 1992) and in humanbrain trauma victims (Bergsneider et al., 1997, 2000,2001). These abnormalities occur during the acute peri-ods of increased energy demand and proceed through aphase of increased glucose metabolism followed by ametabolic depression. The rate of recovery from themetabolic depression matches the degree of recovery(Hovda, 1996; Moore et al., 2000). Despite the universaloccurrence of this phenomenon, the net impact of thisabnormality on clinical outcome remains controversial.
The extracellular glucose concentration that is mea-sured in cerebral microdialysis is a function of the avail-ability and utilization of glucose. Delivery of glucose israte limited via the glucose transporter. Thus, reductionsin extracellular glucose levels may reflect a limitation ofdelivery or increased utilization. After traumatic braininjury (TBI), the glucose transporter is upregulated(Cornford, et. al., 1996; Hamlin et al., 2001) and a
Received September 24, 2002; final revision received March 21,2003; accepted March 21, 2003.
This study was supported by the National Institutes of Health(NINDS) grants NS 02089 and NS 030308.
Address correspondence and reprint requests to Dr. Paul M. Vespa,10833 Le Conte Ave, CHS 18-218, Los Angeles, CA 90095, U.S.A.;e-mail: [email protected]
deficiency in glucose delivery under conditions otherthan ischemia is not likely, whereas availability may bereduced (Marklund et al. 1997; Nilsson et al. 1996).Measurement of brain metabolism has been performedindirectly using cerebral microdialysis, and the pattern oflow glucose and elevated glycerol levels has been cor-related with positron emission tomography (PET) find-ings showing increased glucose utilization (Vespa et al.,2002). Marked changes in the extracellular contents havebeen seen during terminal events, such as brain hernia-tion (Alessandri et al., 1999; Goodman et al., 1999;Landolt et al., 1994; Langemann et al., 2001; Stahl et al.,2001a; Valadka et al., 1998). These terminal events arethought to represent anaerobic hyperglycolysis, with re-ductions in extracellular glucose to undetectable levelsaccompanied by increases in lactate.
This article will outline the time course and nature ofchanges in extracellular glucose levels in traumatic braininjury, the incidence of low glucose levels, and the fac-tors that are related to low levels of glucose, and willevaluate the lactate response to low levels of glucose. Wedemonstrate that low levels of glucose are common andthat the total duration of low glucose levels negativelyaffects outcome.
MATERIALS AND METHODS
The University of California at Los Angeles (UCLA) insti-tutional review board for human research approved this study,which was conducted as an integral part of the UCLA BrainInjury Research Center in patients with severe traumatic braininjury with a Glasgow Coma Scale (GCS) score of 8 or less orwith evidence of traumatic mass lesion on a computerized to-mographic scan and GCS score of 12 or less. Subjects wereidentified in the emergency department, consented by proxy,and enrolled into the study as soon as possible. The manage-ment of these patients has been previously described (Kellyet al. 1997; Vespa et al., 1999). Acute-phase studies were car-ried out for up to 10 days after hospital admission, subject toconstraints including catheter removal, the patient’s graduationfrom intensive care, or death. Determination of the injury se-verity score was performed using the conventional assessmenttool (Baker et al., 1974).
Cerebral microdialysis was performed using the CMA70probe (10-cm flexible shaft, 10-mm membrane length, 20-kdcutoff; CMA, Stockholm, Sweden) inserted via a twist-drill burrhole adjacent to an existing ventriculostomy. The microdialysiscatheter was inserted to a depth of 1.5 to 2 cm below the skinat an angle 30 degrees lateral to the trajectory of the ventricu-lostomy, to place the catheter into the white matter. The probewas tunneled 3 cm under the skin and secured to the scalp witha flat profile, and then attached to the CMA103 perfusionpump. Normal saline was perfused through the catheter at a rateof 2 uL/min, and fluid was collected in 60-minute samples andplaced in dry ice or directly into the CMA600 instrument. Theinitial 60-minute sample was not used for analysis because thiswas the time allowed for stabilization of the probe. Microdi-alysis was not interrupted for transport or bedside testing. In thefive most recent patients, subcutaneous probes were placed inthe skin overlying the right lower abdominal quadrant in order
to control for hourly systemic changes in glucose, lactate,and urea.
Positron emission tomography was performed using a quan-titative method previously described (Bergsneider et al., 2001).Using an intensive care treatment model, a fluoro-deoxy-glucose (FGD)-PET scan was performed using a quantitativetechnique (10 mCi 2-deoxy-glucose, serial arterial sampling,three-dimensional acquisition) with calculation of regional glu-cose metabolic rates in a 2-cm3 region of the cerebral micro-dialysis probe. Coregistered magnetic resonance imaging wasusing to confirm probe location.
The bedside nurse and research team maintained a detailedpatient event log to identify important events and to recordtimes of vial sampling. In addition, automated computerizedcapture of all physiological monitoring data was conductedusing the UCLA-devised Brain Injury Research Program data-base. Using this program, sampling of the physiology occursevery 2 minutes and a 1-hour mean is generated. An experi-enced nurse then confirms the hourly mean values. The fol-lowing data was recorded hourly: intracranial pressure, meanarterial blood pressure (MAP), cerebral perfusion pressure(CPP), heart rate, arterial oxygen saturation, core temperature(jugular), jugular venous oxygen saturation (SjvO2), regionalbrain oxygen partial pressure (PTiO2), electroencephalography,and GCS score. In addition, serial measurements of dose ofsedatives, mannitol, and other neurologically active medica-tions were recorded hourly.
Intermittent (daily) testing was performed using the radioac-tive 133Xe Kety-Schmidt technique (Kety and Schmidt, 1945)for global measurement of cerebral blood flow, and glucose(CMRglc) and oxygen (CMRO2) metabolic rates, and theoxygen/glucose ratio (OGR) using previously defined methods(Lee et al., 2001). Matched samples of arterial and jugular bulbvenous blood samples were taken on a daily basis and matchedto the corresponding hourly microdialysis glucose sample.Blood glucose levels were determined using the glucose oxi-dase method. Intravenous injection of radioactive 133Xe wasperformed and the global CBF-15 was determined. Thereafter,global rates of glucose and oxidative metabolism were ob-tained. Determination of global glucose metabolism and cere-bral blood flow was performed for each patient and comparedwith a matched cerebral microdialysis sample taken during thehour of study.
Frozen samples were briefly centrifuged and then analyzedon the CMA600 in batch analysis. The standard CMA600 re-agents were used for analysis. The hourly samples were runtwice each for each analyte, and the mean final value was used.Quality control measurements using normal saline and waterblank samples, as well as standardized solutions across a rangeof concentrations (0.025 to 3.0 mmol/L) mimicking those of thehuman samples, were run weekly, with an additional internalcontrol sample for each subject. Acceptable values of coeffi-cient of variation (3% to 5%) and accuracy were obtained inorder to validate very low sample concentrations of selectedanalytes. Samples with extremely low glucose values (less than0.05 mmol/L) underwent repeat testing to confirm the extremevalue. The lowest confidence threshold of glucose values usingthis system was found to be those greater than or equal to 0.025mmol/L. Repeat testing on selected frozen samples was con-ducted across a 1-year time interval to determine that no sampledegradation occurred during the freezing or thawing process.High-performance liquid chromatography was performed onselected microdialysate samples to determine hypoxanthinelevels using the methods of Hillered and Persson (1999).Results are expressed as the absolute microdialysis values with-out correction.
P. M. VESPA ET AL.866
J Cereb Blood Flow Metab, Vol. 23, No. 7, 2003
Subjects were closely followed up with home and outpatientoffice visits to monitor recovery of function over the next 6months. At 6 months, patients underwent in-person follow-uptesting using the extended Glasgow Outcome Scale (GOSe)(Wilson et al., 1998) and the Disability Rating Scale (Rappa-port et al., 1982). The GOSe was deemed to be stable at 6months after injury and was used to assess the profile of mi-crodialysis based in each major category of GOSe.
Statistical analysisPearson product-moment correlations, analyses of propor-
tions, analyses of variance, computation of odds ratios with95% confidence intervals, and linear regression were per-formed to analyze the data. Data acquisition was handled inAccess 97 (Microsoft Corp., Redmond WA, U.S.A.), whereasstatistical procedures were conducted within Statistica 5.5(StatSoft, Inc., Tulsa, OK, U.S.A.).
RESULTS
Thirty consecutive subjects (23 men and 7 women)were enrolled into the microdialysis observational studyas part of the UCLA Brain Injury Program project. Thesubjects had a median GCS of 7, a mean age of34.4 ± 12.5 years, and mean injury severity score of32.7 ± 11.4. Microdialysis was started as soon as postin-jury hour 7 to 72, with a median of postinjury hour 10.The mean number of hourly samples for each patient was121, with a total of 2,708 samples. There were 13 con-tusion injuries (single or multiple), 8 subdural hemato-mas, 4 diffuse axonal injuries, 3 epidural hematomas,2 traumatic subarachnoid hemorrhages, and 2 intraven-tricular hemorrhages. The mean length of hospital staywas 19 ± 15 days. The median Glasgow Outcome Scalescore at discharge was 3. There was a 22% in-hospitalmortality rate. At 6 months, GOSe scores were 1 or 2 in5 patients (poor outcome), 5/30; 3 or 4 in 9 patients(moderate disability), and 5 to 8 in 14 patients (goodoutcome). There were no complications associated withmicrodialysis probe insertion or monitoring.
Probe locationThe microdialysis probes were located in the dorso-
lateral frontal white matter ipsilateral to the ventricularcatheter in all 30 cases. Location in white matter wasconfirmed using magnetic resonance imaging in 15 cases.
Probe recoveryThe in vitro recovery of analytes from a test solution
adjusted to mimic the extracellular concentrations usingthis system was as follows: glucose, 56% ± 1%; lactate,63% ± 2%; glutamate, 54% ± 1%; glycerol, 99% ± 1%;pyruvate, 66% ± 2%; and urea, 76% ± 2%. The coeffi-cients of variation for measurements of glucose werebetween 0.4% and 2.5% for values in the range from 0.05to 2.0 mmol. After removal of each brain microdialysiscatheter, this in vitro test was repeated and yielded simi-lar recovery rates (glucose, 55% ± 1%; lactate,63% ± 2%; glutamate, 55% ± 1%; glycerol, 98% ± 1%;
pyruvate, 66% ± 2%; and urea, 77% ± 2%). The stabilityof probe recovery over time was determined by examin-ing the changes in the concentration of urea over time(Ronne-Engstrom et al., 2001). Urea concentrations wereremarkably stable during 24-hour epochs, with a 10%coefficient of variation. When a change in urea concen-tration of greater than 10% occurred, glucose and lactatevalues taken during those time points were rejected. As aresult, 4% of all samples were discarded. Because similarin vitro recoveries were found using normal saline com-pared with artificial cerebrospinal fluid, the former wasused in vivo.
To determine a comparison between our data and thatof groups in which a slower perfusion rate is used, theperfusion rate was set at 0.3 uL/min in one excludedsubject (patient no. 31). At this rate, the baseline meanglucose concentration was 2.5 mmol/l ± 0.7, which iscomparable with previous reports (Reinstrup et al.,2000). By comparison, the perfusion rate of 2 uL/minresulted in a 56% in vivo recovery and mean microdi-alysis concentration of 0.76 ± 0.5 mmol under conditionsof normal intracranial pressure, CPP, and SjvO2. Thus,an microdialysis glucose value less than 0.20 mmol/L ata perfusion rate of 2 uL/min is comparable to a level ofless than 0.66 mmol/L at a perfusion rate of 0.3 uL/min.
Arterial and subcutaneous monitoring of glucose andlactate concentrations was performed. Subcutaneous mi-crodialysis was used in five subjects to compare thechanges in systemic glucose to those in the brain extra-cellular space. A poor correlation (mean r � 0.07) wasfound between the subcutaneous extracellular glucosevalues and brain glucose values within subjects, suggest-ing that brain microdialysis glucose values are not re-flective of systemic changes in glucose. In 206 matchedsamples, arterial glucose ranged from 4.94 to 7.89mmol/L (89.2 to 142.3 mg/dL) compared with microdi-alysis glucose values between 0.08 to 3.8 mmol/L. Therewas a weak positive correlation between arterial andbrain extracellular glucose levels (r � 0.26, P<0.05),with no episode of arterial hypoglycemia (arterial glu-cose less than 5 mmol/L) occurring during episodes ofreduced brain extracellular glucose (microdialysis glu-cose less than 0.2 mmol/L). There was a similar weakcorrelation (r � 0.28) between cerebral microdialysisglucose and jugular venous glucose concentrations. Nocorrelations were found between levels of extracellularand arterial lactate (r � 0.03, n � 181 matchedsamples) or between levels of extracellular and jugularlactate (r � 0.02, n � 181 matched samples).
Extracellular glucose valuesThe range of hourly values of extracellular glucose
values across all subjects was 0.03 to 3.8 mmol/L.Within-subject hourly glucose values varied greatly, withthe coefficient of variation of ranging from 12% to 43%.
LOW EXTRACELLULAR GLUCOSE AFTER BRAIN TRAUMA 867
J Cereb Blood Flow Metab, Vol. 23, No. 7, 2003
Mean daily glucose values ranged from 0.05 to 3.2mmol/L, and the population mean of the daily mean val-ues ranged from 0.36 ± 0.36 to 0.86 ± 0.96 mmol/L. Fig-ure 1 outlines the mean daily glucose values for theentire population. The mean glucose values were withinthe normal range of 0.5 to 1.0 mmol/L on all days. In Fig.2, the daily mean values of each subject are plotted bypostinjury day. Three trajectories of the daily mean glu-cose values were found: initially low (n � 5), variable(n � 16), and initially normal-with-late-decline (n � 9).However, only the patients with good outcome (GOSescores of 5 or higher) demonstrated a uniform trajectorywith an initially normal-with- late-decline trajectory. Theinitially low-trajectory patients had glucose values lessthan 0.50 mmol/L for the initial 48 to 72 hours with laterincrease into the normal range (0.5 to 1.0 mmol/L). Somepatients with initially normal values demonstrated a de-cline below the normal range (i.e., less than 0.5 mmol/L)starting on the third postinjury day and continued todemonstrate low values after that time point.
A threshold of extracellular glucose less than 0.2mmol/L was selected based on the simultaneous mea-surement of extracellular glucose during an FDG-PET ina single patient with increased glucose utilization in theROI encompassing the microdialysis probe (see figure3). The corresponding regional CBF and oxygen extrac-tion fraction showed an absence of ischemia in the regionof the probe. Next, we used this threshold to determinethe frequency of low glucose values in all subjects. Fig-ure 4 shows the daily proportion of low (less than 0.2mmol/L), normal (0.2 to 1.0 mmol/L), and high (greaterthan 1.0 mmol/L) glucose values on each day after in-jury. The percentage of values falling below this criticalthreshold on each postinjury day ranged from 18% to30% during the initial 7 postinjury days. Normal andelevated levels of glucose accounted for 18% to 42% and20% to 50% of all values during the initial 7 days. After7 days, fewer subjects were studied (5 of 30), and thesamples are skewed towards extremely low values.
Etiology of low glucose levelsUsing a time-course analysis of matched hourly physi-
ologic values, the following factors coincided with lowglucose values: hypoglycemia (0%), jugular venous de-saturation (3%), brain tissue oxygen desaturation lessthan 10 mm Hg (0%), reduction in CPP to less than 60torr (3%), terminal herniation (with brain tissue oxygendesaturation) (6%), seizures (defined by EEG criteria)(10%), and unknown (72%) (Table 1). In addition, inter-mittent testing of a total of 185 samples of microdialysisglucose and lactate were compared with matched mea-sures of global CBF and glucose metabolism. Globalhyperglycolysis (Kety-Schmidt–derived metabolic rateof glucose greater than 5.8 mg · 100 g−1 · min−1) ac-counted for 2% of low microdialysis glucose values, allof which were less than 0.2 mmol/L. In contrast, globalischemia was present in 1.5% of global CBF measure-ments (less than 20 mL · 100 g−1 · min−1). These ischemicCBF events occurred during terminal events and were as-sociated with low levels of microdialysis-measured glucose(less than 0.10 mmol/L). Extremely low levels of glucose(less than 0.1 mmol/L) lasting for 4 or more hours oc-curred in the context of terminal herniation, and wereobserved in all six patients with terminal herniation.
Rare transient reductions in extracellular glucose con-centration occurred with reductions in CPP and seizures.When CPP was less than 70, there was a concomitantmean decrease in glucose of 0.2 ± 0.15 mmol/L thatlasted for a mean of 1 hour. Figure 5 outlines an event ofglucose reduction and modest lactate elevation with sei-zures. Six patients had terminal events in which brainherniation and global brain ischemia were documentedby SjvO2, xenon CBF testing, and brain tissue oxygenconcentration less than 10 mm Hg. An example of aterminal event is shown in Fig. 6. The hourly trendshows a marked reduction in glucose, and an increase inthe lactate/pyruvate ratio and glutamate during the final48 hours of monitoring. However, the lactate responsewas less well defined, with only a subtle increase duringthe terminal event. The lactate/pyruvate ratio progres-sively increased during the terminal event because of amarked reduction in pyruvate levels. Dramatic trendchanges were not seen in nonterminal cases.
Distinct from global markers of ischemia, neuro-chemical markers of tissue metabolic crisis and ischemiacontained within the microdialysis fluid were evaluatedto determine the frequency of these markers during pe-riods of low extracellular glucose. Lactate/pyruvate ratioof more than 40 is considered the best microdialysismarker of microenvironment ischemia (Enblad et al.,1996). In a sample of 479 hourly samples in which theglucose level ranged between 0.03 and 0.20 mmol/L,31% of the lactate/pyruvate values were above the isch-emic threshold and indicated focal ischemia. Despite alack of markers of ischemia in most samples, glutamate
FIG. 1. The mean (SD) daily extracellular glucose concentra-tions for the entire cohort of 30 patients segregated by postinjuryday (PID). The total number of patients on each day appears asnumber inserts atop each histogram.
P. M. VESPA ET AL.868
J Cereb Blood Flow Metab, Vol. 23, No. 7, 2003
FIG. 2. (A) The mean daily extracellular glucose concentrationsof each subject are plotted as line graphs. These graphs are seg-regated according to the 6-month Glasgow Outcome Scale ex-tended (GOSe) score. The top graph shows the line curves forpatients with poor outcome (GOSe 1 or 2). The middle graphshows the line curves for patients with moderate disability (GOSe3 or 4), and the bottom graph corresponds to line curves for pa-tients with good outcome (GOSe 5 to 8). (B) The mean of meansfor glucose segregated by 6-month GOSe scores. Only the GOSe5+ group has a unique trajectory of initially normal glucose valueswith decline after postinjury day 5.
LOW EXTRACELLULAR GLUCOSE AFTER BRAIN TRAUMA 869
J Cereb Blood Flow Metab, Vol. 23, No. 7, 2003
levels were elevated (more than 5 umol/L) in 91% of thelow-glucose samples. Glutamate elevations were presentdespite the absence other markers of tissue ischemia (i.e.,reduction in CPP, SjvO2, PtiO2). In addition, elevatedextracellular glycerol levels were present in 39% of thelow-glucose samples. Thus, low extracellular glucoselevels occurred in the context of one or more microdi-alysis markers of metabolic crisis, but were not specificmarkers of ischemia.
Extracellular lactate valuesThe hourly values of extracellular lactate across all
patients ranged from 0.1 to 12.1 mmol/L. The distribu-tion of lactate values for each patient was assessed in amanner similar to that for glucose. Lactate levels weregreater than 1.2 mmol/L in 16% to 30% of samples dur-ing the initial 10 days after injury. Overall, there was nocorrelation between extracellular glucose and lactateconcentrations (r � −0.06). During periods of low glu-cose, mean lactate concentrations were lower than duringperiods of normal glucose (0.76 ± 0.51 versus 1.01 ± 1.1mmol/L, P<0.001). During periods of terminal herniationwith very low glucose (less than 0.10 mmol/L), the meanlactate concentration remained in the normal range(0.83 ± 0.51 mmol/L). By comparison, the meanlactate/pyruvate ratio during terminal herniation was el-evated but highly variable (400 ± 1000 umol/L).
Global measures of metabolismIntermittent testing of CBF and metabolism with si-
multaneous microdialysis was performed in 513 samples
from all 30 patients. As mentioned previously, the CBFwas in the ischemic range 1.5% of the time, and rangedfrom 13 to 88 mL·100 g−1·min−1. Table 2 outlines theglobal metabolic data. Pairwise correlations were run toassess the relationship between each microdialysis ana-lyte and global measures of CBF, CMRO2, CMRglc, andOGR. There was a poor correlation between each of thevariables, and the strongest correlation (0.32) was foundbetween CBF and glucose (Table 3). Next, the globalmetabolism measures obtained during a low-glucose pe-riod were compared with those in which the glucoselevel was in the normal or high range using analysisof variance (ANOVA). CBF was lower, but above theischemic range, in the context of low levels of microdi-alysis-measured glucose (P<0.001). There was no asso-ciation between microdialysis-measured glucose valuesand rates of oxidative or glucose metabolism. Table 4summarizes these results.
Association between microdialysis and6-month outcome
The mean hourly trends of glucose values over theinitial 10 days segregated by 6-month GOSe score areshown in Fig. 7. Initial ANOVA of differences in thetrend of glucose values over the entire time revealedstatistical differences between the three GOSe groups(P<0001), with the GOSe 1 or 2 group demonstrating thelowest overall mean value. Visual inspection of thetrends reveals a subtle difference in the trend of glucoseconcentration during the initial 50 postinjury hours. TheGOSe 5+ group demonstrated a plateau in glucose in thehigh-normal range in contrast to the GOSe1 or 2 group inwhom glucose was declining during postinjury hours0 to 50. Similar mean hourly trends of lactate andlactate/glucose ratio are shown in Figs. 8 and 9, respec-tively. Initial ANOVA of differences in lactate andlactate/glucose trends over time revealed statistical dif-ferences (P<0.0001). Visual inspection of the lactate/glu-
FIG. 4. Distribution of all microdialysis glucose values by postin-jury day. This graph shows the distribution of cerebral extracel-lular glucose values for the entire cohort segregated by thepostinjury day. Shaded bars indicate the percentage of all lowglucose values (less than 0.2 mmol), transparent bars indicatethe percentage of all normal glucose values, and hatched barsindicate the percentage of elevated glucose values on each day.
TABLE 1. Prevalence of selected causes of lowextracellular glucose levels
cose trends suggests that lactate/glucose values are lowerduring the initial 50 postinjury hours in the GOSe 1 or 2and GOSe 5+ groups compared with the GOSe 3 or 4group (P<0.001). However, the GOSe 1 or 2 group dem-onstrated a combined low glucose and lactate/glucoseratio during the initial 50 postinjury hours. There was norelationship between the overall time course or the early(50 postinjury hours) segment of the lactate levels.
When adjusted for a case-based analysis of these data,a regression analysis was conducted to determine theinfluence of levels of glucose and lactate and thelactate/glucose ratio on outcome. Using the case-basedapproach, analysis of the overall trends revealed thatonly the lactate/glucose ratio was higher in the GOSe 1or 2 group compared with the GOSe 3 or 4 and GOSe 5+group (P<0.01). If this trend analysis was restricted tothe initial 50 postinjury hours, only the lactate/glucoseratio was predictive of outcome (P<0.04). Subgroupanalysis excluding data from the terminal herniation pe-riods revealed similar relationships among levels of glu-cose and lactate and lactate/glucose ratio (Table 5).
The impact of cumulative exposure to low levels ofglucose were explored by comparing neurologic out-come for those patients with low glucose levels for pro-longed periods. The percentage of low glucose valuesacross all measured values was segregated by 6-monthGOSe score. Eleven patients demonstrated prolonged ex-posure to low glucose levels and 19 did not. The 6-monthGOSe score was lower in those patients with prolongedlow glucose exposure compared to those without thiscondition [odds ratio (OR): 2.6; 95% CI: 1.96–3.6;P<0.001). A similar relationship was found between du-
ration of low glucose and the Disability Rating Scalescore (OR: 3.25, 95% CI: 0.85 – 12.5; P<0.001.
Regression analysis was performed to determine iflow extracellular glucose is an independent predictor ofoutcome when traditional predictors of outcome wereassessed in the model. The traditional predictors thatwere considered were initial Glasgow Coma Scale score(best in 8 hours), initial computerized tomography scanscore (Marshall et al., 1992), pupil reactivity, initial hyp-oxemia, initial hypotension, age, and presence of el-evated intracranial pressure. No independent effect oflow glucose levels could be found using this model. Forcompleteness, mean values of major analytes segregatedby post-injury day are presented in Table 6.
DISCUSSION
This human microdialysis study reports several time-dependent observations of the behavior of extracellularglucose and lactate after traumatic brain injury. Between15% to 30% of all values of extracellular glucose arereduced below a critical threshold after TBI. The major-ity of low glucose values occur in the absence of iden-tifiable secondary ischemic insults, but persistent glucosevalues less than 0.1 mmol/L lasting over 4 hours occuronly with terminal events. Low glucose values are asso-ciated with markers of metabolic crisis as indicated byincreased extracellular glutamate. The mean lactate/glu-cose ratio over the entire course best predicted 6-monthoutcomes. Finally, reduction in glucose and lactate/glu-cose ratio during the initial 50 postinjury hours is asso-ciated with a poor outcome, indicating that there exists a
FIG. 5. A composite figureshowing a single patient whodisplayed a posttraumatic sei-zure-induced global hypergly-colysis in conjuction with low ex-tracellular glucose levels. (A)Global cerebral metabolic ratefor glucose (as determined bythe Kety-Schmidt technique)showing increased glucose utili-zation at postinjury hour 12. (B)Time-course plot of cerebral mi-crodialysis showing low levelsof glucose and elevated levelsof glutamate, lactate, lactate/py-ruvate ratio, and glycerol duringthe period of seizure-inducedhyperglycolysis. (C) Segment ofelectroencephalogram showingseizure activity.
LOW EXTRACELLULAR GLUCOSE AFTER BRAIN TRAUMA 871
J Cereb Blood Flow Metab, Vol. 23, No. 7, 2003
critical time window of unexpectedly low lactate levelsin poor-outcome patients.
Normal extracellular glucose concentrationsThe normal extracellular glucose concentration in hu-
man brain has not been well established. Normative data
are dependent on several technical factors, including theperfusion rate. Preliminary data from anesthetized neu-rosurgical patients in which the microdialysis probe isplaced in uninjured brain tissue with perfusion rate of2 uL/min have showed that glucose values of 0.5 to 1mmol/L and lactate values of 0.6 to 1.1 mmol/L areconsidered normal. Similarly designed microdialysismeasurements obtained in awake epilepsy patients withsampling of nonepileptic tissue and perfused at 2.5uL/min showed mean glucose values of 0.82 ± 0.27mmol/L and mean lactate levels of 1.3 ± 0.49 mmol/L(Abi-Saab et al., 2002).
In brain trauma patients in which microdialysis wasconducted in minimally injured brain at a rate of 2uL/min and under conditions of normal intracranial pres-sure and normal tissue oxygenation, reports of mean glu-cose values have ranged from 0.5 to 1.1 mmol/L (Ales-sanrdi et al., 2000; Goodman et al., 1999). Carefulassessment of the perfusion rate is required when com-paring various studies. With reduction in the perfusionrate to 0.3 uL/min, the in vivo recovery increases (Hill-ered and Persson, 1999; Hutchinson et al., 2000a; Rein-stup et al., 2000; Stahl et al., 2001b) with glucose andlactate values in the range of 2.5 and 3.5 mmol/L, re-spectively. In the current study, at a perfusion rate of 2uL/min, we obtained values similar to those found inprevious studies, and had a similar response of increasedbasal levels with reduction in perfusion rate to 0.3uL/min. Thus, at the perfusion rate of 2 uL/min used inthe current study, the probe in vivo recovery of 56%compares favorably with the previously reported 70%recovery at perfusion rates of 0.3 uL/min (Hutchinsonet al., 2000b). Thus, perfusion at 2 uL/min provides rea-sonable in vivo recovery so that relative changes in the
FIG. 6. A composite figure showing a single patient who dis-played a terminal herniation with a reduction in extracellular glu-cose levels in the context of global brain ischemia. (A) Time plotby postinjury hour of intracranial pressure (ICP), jugular venoussaturation (SjvO2), oxygen-to-glucose metabolism ratio (OGR),and 133Xe global cerebral blood flow (CBF) showing a terminalincrease in ICP an a reduction of CBF to ischemic levels. TheCBF and OGR measures indicate brain ischemia. (B) The coin-ciding time plots of cerebral microdialysis showing a terminalmarked reduction of glucose to very low levels (less than 0.05mmol) and increased lactate/pyruvate ratio (L/P), glutamate, andglycerol concentrations and modestly elevated lactate levels.
TABLE 2. Global measures of brain metabolism taken withmicrodialysis samples
* P <0.001.† P <0.05.OGR, oxygen/glucose ratio; L/P, lactate/pyruvate ratio.
P. M. VESPA ET AL.872
J Cereb Blood Flow Metab, Vol. 23, No. 7, 2003
extracellular glucose concentration can be tracked as re-liably as with a slower perfusion rate of 0.3 uL/min.
Etiology of low glucose levelsUsing a glucose threshold of less than 0.2 mmol, we
found that the majority of episodes of low glucose levelsoccur independent of overt secondary clinical insults andindependent of changes in systemic glucose levels. Per-sistent low extracellular glucose levels (less than 0.2mmol/L for greater than 20% of the time) correlatedindependently with a poor outcome at 6 months. Thisfinding suggests an effect of duration of low glucoselevels on eventual brain function and does not simplyindicate the severity of primary injury. Given the rela-tionship between regional glucose utilization and glucosevalues below the 0.2-mmol/L threshold, these data sug-
gest an increase in glucose utilization during the acutepostinjury period.
Measurement of regional and global CBF and brainoxygenation did not reveal frank ischemia or cerebraldeoxygenation. Our results mirror similar findings ofpoor correlation between ischemia and extracellular glu-cose (Alessandri et al., 2000; Valadka et al., 1998). Thisobservation is tempered by concurrent microdialysislactate/pyruvate data that suggest that 30% of the lowglucose concentrations are associated with very focalischemia, indicated only by the elevated lactate/pyruvateratio. A lactate/pyruvate ratio greater than 40 has beencorrelated with regional ischemia in PET studies (Enbladet al., 1996; Hutchinson et al., 2002), whereas an in-creased glutamate value has not been uniformly seenwith tissue ischemia. Increased extracellular glutamatelevels may occur with seizures and other nonischemicinsults (Vespa et al., 1998). The presence of elevatedglutamate concentrations ranging from 5 to 260 umol/Lsuggests that the low glucose concentrations are associ-ated with ongoing cellular injury or metabolic crisis,despite the absence of ischemia (defined by clinical in-dicators, CBF measurements, and increases in the lac-tate/pyruvate ratio). This begs the question of whetherthe definition of ischemia after TBI is really understood.Given the limitations in online detection of brain isch-emia and the poor correlation between brain tissue PO2
TABLE 4. Relationship between microdialysis-measuredglucose level and CBF, glucose metabolism, and
Data are mL�100 g−1�min−1 unless otherwise indicated.MDglc, glucose level (mmol) measured by microdialysis; OGR,
oxygen/glucose ratio; ANOVA, analysis of variance.
FIG. 7. Mean hourly glucose values segregated by 6-month out-come scores. A series of three line plots of hourly glucose values(SD) segregated by the 6-month Glasgow Outcome Scale ex-tended (GOSe) score. Normal glucose values during the initial50 hours after injury are associated with good outcome.
FIG. 8. Mean hourly lactate values segregated by 6-month out-come scores. Series of line plots showing the percentage of highlactate (more than 1.1 mmol) that occurs in each outcome group,segregated by the 6-month Glasgow Outcome Scale extended(GOSe) score. Poorer outcome is associated with a longer totalduration of high lactate concentration.
LOW EXTRACELLULAR GLUCOSE AFTER BRAIN TRAUMA 873
J Cereb Blood Flow Metab, Vol. 23, No. 7, 2003
and PET measures of ischemia (Gupta et al., 2002), onecannot entirely rule out that very focal ischemia waspresent. Therefore, the nature of ongoing cellular injuryis not entirely clear from the available data, but the ma-jority of occurrences of low glucose levels are not due toglobal, regional, or very focal brain ischemia.
Persistent very low levels of glucose (less than 0.1mmol/L) appear to be a function of limited glucose sup-ply caused by ischemia only in a few patients with ter-minal herniation events. Substrate (e.g., glucose) limita-
tion is well documented in animal and human studies(Landolt et al., 1994; Langemann et al., 2001). Substratelimitation occurs with terminal herniation events or withdevelopment of brain infarction during ischemia in pa-tients with brain trauma and subarachnoid hemorrhage(Abi-Saab et al., 2002; Hucthinson et al., 2002; Perssonet al., 1996; Unterberg et al., 2001). In this context, thereduction in brain tissue PO2 did correlate with low glu-cose levels, a finding in agreement with that reported byValadka and colleagues (1998). The occurrence of thisterminal herniation pattern (i.e., very low glucose leveland elevated lactate/pyruvate ratio) was infrequent in thepresent study and represents a distinct clinical entity thatis beyond the hope of treatment.
The majority of low glucose values appear to be due toreasons other than substrate limitation or ischemia. Wehave termed this etiology as occult, related primarily tothe brain trauma. Given that low levels of glucose areuniformly associated with increased glycolysis, that lowglucose values do occur in conjunction with all cases ofdocumented hyperglycolysis in this series of patients,and that low glucose is coassociated with increased glu-tamate in over 90% of the time, it is tempting to specu-late that continued hyperglycolysis is responsible for themajority of the low microdialysis-measured glucose val-ues reported herein. Regional and global hyperglycolysisduring the initial 5 postinjury days has been documented(Bergsneider et al., 1997). The initial intent of measuringextracellular glucose in a continuous fashion has beento use this as a surrogate marker for glucose utilization.However, this study lacks sufficient data to show thatall low microdialysis-measured glucose values are dueto hyperglycolysis, but the high concurrence of ele-vated glutamate with low glucose levels and the uniformreduction in oxidative metabolism are suggestive ofhyperglycolysis.
Alternative explanations for the low extracellular glu-cose values need to be considered. As previously men-tioned, the lack of global brain ischemia or limitation ofCBF may not reflect transient microenvironment isch-emia. The ischemia may be very focal and/or beyond thesensitivity range of current sensors (Valadka et al.,1998). However, no evidence of focal stroke lesions oc-curred in the area of the probe on follow-up neuroimag-ing. A second possibility is that the transfer of glucoseacross the blood–brain barrier occurs in the perivascularastrocytic foot processes without the direct transfer ofglucose into the extracellular space (Pellerin and Magis-tretti, 1994), resulting in a net reduction in the extracel-lular glucose level without a net increase in overall glu-cose utilization. A third possibility is that transientreduced probe efficiency due to brain edema results in anobserved reduction in the microdialysis-measured glu-cose level (Benveniste, 1989). Evidence against this lat-ter possibility is our measurements of steady probe re-
FIG. 9. Lactate/glucose trend segregated by outcome. A seriesof three line plots of hourly lactate values (SD) segregated by the6-month Glasgow Outcome Scale extended (GOSe) score. Nor-mal lactate values during the initial 50 hours after injury are as-sociated with good outcome.
TABLE 5. Means and significance tests of glucose, lactate,and lactate/glucose ratios
covery over time as reflected by stable urea values(Ronne-Engstrom et al., 2001) and preserved in vitrorecovery after probe removal.
Microdialysis indicators and outcomeThe present results indicate that several microdialysis
markers are related to outcome at 6 months. These resultsextend previous relationships between microdialysis andacute mortality (Bullock et al., 1998; Goodman et al.,1999) and offer a unique perspective about glucose andthe lactate/glucose ratio. Higher levels of lactate havebeen previously related to excess mortality (Goodmanet al., 1999); however, this relationship is related in partto measurement of terminal events. Our results are simi-lar to those of Cesarini et al. (2002), who demonstratedgood outcome with an initial higher glucose concentra-tion in subarachnoid hemorrhage patients. In the presentstudy, we found that when terminal events were ex-cluded, this relationship between lactate/glucose andoutcome is the only variable that predicts outcome at 6months. With higher mean lactate/glucose ratio, there isa greater likelihood that a poor outcome will occur. Incontrast, analysis of the time course of the levels of glu-cose and lactate and lactate/glucose ratio show thatwithin the initial 50 hours after injury, the lactate/glucoseratio is low in both the poor-outcome group (GOSe 1 or2) and the excellent-outcome group (GOSe 5+). Thisindicates that the lactate/glucose ratio changes over timeand that during a critical time window, the L/G ratio isnot indicative of eventual outcome. The significance of alow lactate/glucose ratio during this time window will bediscussed below.
Although it was not possible to perform repeated mea-sures of regional glucose utilization, this conclusion can-not be independently confirmed with the available data.However, experimentally induced stimulation leads toincreased glucose utilization after primary injury in therodent fluid-percussion model and is preliminarily asso-
ciated with increased cell loss (Ip et al., 2001). Thus, ourclinical findings are consistent with the concept that per-sistent increased glucose utilization occurs and may leadto worsened outcome.
Lactate paradoxThe expected response of increasing extracellular lac-
tate level during periods of reduced glucose was notuniformly seen during reversible adverse events or ter-minal herniation events. The lactate/pyruvate ratio doesincrease with reversible adverse events and terminal her-niation. After critical inspection of the available litera-ture, it seems that an increase in lactate level is not auniform finding. This paradox of a lack of increase inlactate concentration despite a reduction in glucose andthe positive correlation between extracellular glucoseand lactate levels were unexpected findings. Moreover,the lactate/glucose ratio is unexpectedly low in both thegood-outcome and poor-outcome groups during the ini-tial 50 postinjury hours, but later increases in the poor-outcome group. This early low lactate/glucose ratio issuggestive of lactate being consumed or not producedduring the early phase after injury. Given the correlationbetween low extracellular glucose levels and increasedglucose utilization, lactate consumption would be a morelikely possibility.
The ability of the brain to use lactate under conditionsof distress is well established (Pellerin and Magistretti,1994), with lactate utilization leading to a relativesparing of glucose utilization (Ros et al., 2001). Increasesin glucose may reflect a facultative response to this insultwith an increase in glucose levels (Jones et al., 2000)and may indicate an initial increase in CBF and glucosedelivery that then stabilizes. Thus, the current studyshows that extracellular glucose and lactate concentra-tions are dynamic and reflect changes in cellular metabo-lism during periods of transient and terminal tissuedistress.
TABLE 6. Mean (SD) concentrations of main metabolic analytes segregated by postinjury day
The main findings of this study are that the extracel-lular glucose concentration is low after TBI and is asso-ciated with microdialysis markers of tissue distress andwith poor outcome. In addition, combined low glucoselevels and increased lactate/glucose ratio rather than in-creased lactate levels alone are associated with a poor6-month outcome. The etiology of most occurrences oflow glucose is unknown, but low glucose levels can re-sult from posttraumatic hyperglycolysis and secondaryinsults, namely seizures and brain herniation that in-crease glucose utilization or reduce glucose supply.Combined low glucose and lactate levels within the ini-tial 50 hours after injury are seen in poor-outcome pa-tients, indicating that a metabolic crisis occurs in theabsence of ischemia in this group. This metabolic crisismay have clinical importance given the early postinjurytime window in which it occurs. This metabolic crisis ofcombined low glucose levels without a commensurateincrease in lactate levels suggests a fundamental depar-ture from standard hyperglycolysis. This relationship be-tween extracellular glucose and lactate after human TBIrequires additional study to determine the mechanism(e.g., lactate utilization) by which it can occur.
REFERENCES
Abi-Saab WM, Maggs DG, Jones T, Jacob R, Srihari V, Thompson J,Kerr D, Leone P, Krystal JH, Spencer DD, During MJ, Sherwin RS(2002) Striking differences in glucose and lactate levels betweenbrain extracellular fluid and plasma in conscious human subjects:effects of hyperglycemia and hypoglycemia. J Cereb Blood FlowMetab 22:271–279
Alessandri B, Doppenberg E, Bullock R, Woodward J, Choi S, KouraS, Young HF (1999) Glucose and lactate metabolism after severehuman head injury: influence of excitatory neurotransmitters andinjury type. Acta Neurochir (Suppl 1)75:21–24
Baker SP, O’Neill B, Haddon W Jr, Long WB (1974) The injuryseverity score: a method for describing patients with multiple in-juries and evaluating emergency care. J Trauma 14:187–196
Benveniste H (1989) Brain Microdialysis. J Neurochem 52:1667–1677Bergsneider MA, Hovda DA, Shalmon E, Kelly DF, Vespa PM, Martin
NA, Phelps ME, McArthur DL, Caron MJ, Kraus JF, Becker DP(1997) Cerebral Hyperglycolysis following severe human trau-matic brain injury: a positron emission tomography study. J Neu-rosurg 86:241–251
Bergsneider M, Hovda DA, Lee SM, Kelly DF, McArthur DL, VespaPM, Lee JH, Huang SC, Martin NA, Phelps ME, Becker DP (2000)Dissociation of cerebral glucose metabolism and level of con-sciousness during the period of metabolic depression followinghuman traumatic brain injury. J Neurotrauma 17:389–401
Bergsneider M, Hovda DA, McArthur DL, Etchepare M, Huang SC,Sehati N, Satz P, Phelps ME, Becker DP (2001) Metabolic recov-ery following human traumatic brain injury based on FDG-PET:time course and relationship to neurological disability. J HeadTrauma Rehabil 16:135–148
Bullock R, Zauner A, Woodward JJ, Myseros J, Choi SC, Ward JD,Marmarou A, Young HF (1998) Factors affecting excitatory aminoacid release following severe human head injury. J Neurosurg 89:507–518
Cesarini KG, Enblad P, Ronne-Engstrom E, Marklund N, Salci K,
Nilsson P, Hardemark HG, Hillered L, Persson L (2002) Earlycerebral hyperglycolysis after subarachnoid haemorrhage corre-lates with favourable outcome. Acta Neurochir (Wien) 144:1121–1131
Cornford EM, Hyman S, Cornford ME, Caron MJ (1996) Glut1 glucosetransporter activity in human brain injury. J Neurotrauma. 3:523–536
Enblad P, Valtysson J, Andersson J, Lilja A, Valind S, Antoni G,Langstrom B, Hillered L, Persson L (1996) Simultaneous intrace-rebral microdialysis and positron emission tomography in the de-tection of ischemia in patients with subarachnoid hemorrhage.J Cereb Blood Flow Metab 6:637–644
(1999) Extracellular lactate and glucose alterations in the brainafter head injury measured by microdialysis. Crit Care Med 27:1965–1973
Gupta AK, Hutchinson PJ, Fryer T, Al-Rawi PG, Parry DA, MinhasPS, Kett-White R, Kirkpatrick PJ, Mathews JC, Downey S, Aig-birhio F, Clark J, Pickard JD, Menon DK (2002) Measurement ofbrain tissue oxygenation performed using positron emission to-mography scanning to validate a novel monitoring method. J Neu-rosurg 96:263–268
Hamlin GP, Cernak I, Wixey JA, Vink R (2001) Increased expressionof neuronal glucose transporter 3 but not glial glucose transporter1 following severe diffuse traumatic brain injury in rats. J Neuro-trauma 18:1011–1018
Hayes RL, Katayama Y, Jenkins LW, Lyeth BG, Clifton GL, Gunter J,Povlishock JT, Young HF (1988) Regional rates of glucose utili-zation in the cat following concussive head injury. J Neurotrauma5:121–137
Hillered L, Persson L (1999) Neurochemical monitoring of the acutelyinjured human brain. Scand J Clin Lab Invest Suppl 229:9–18
Hovda DA, Yoshino A, Kawamata T, Katayama Y, Becker DP (1991)Diffuse prolonged depression of cerebral oxidative metabolismfollowing concussive brain injury in the rat: a cytochrome oxidasehistochemistry study. Brain Res 3:1–10
Hovda, DA (1996) Metabolic dysfunction. In: Neurotrauma (NarayanRK, et al., eds), New York: McGraw-Hill, Inc. pp 1459—1478
Ip, EY, Moore, AH, Lee, SM, Hovda, DA (2001) Response to motorcortex vibrissa respresentation stimulation after traumatic braininjury as measured by fluorodeoxyglucose. J Cereb Blood FlowMetab 21(Suppl 1):5187
Jones DA, Ros J, Landolt H, Fillenz M, Boutelle MG (2000) Dynamicchanges in glucose and lactate in the cortex of the freely moving ratmonitored using microdialysis. J Neurochem 75:1703–1708
Kawamata T, Katayama Y, Hovda DA, Yoshino A, Becker DP (1992)Administration of excitatory amino acid antagonists via microdi-alysis attenuates the increase in glucose utilization seen followingconcussive brain injury. J Cereb Blood Flow Metab J 12:12–24
Kelly DF, Martin NA, Kordestani R, Counelis G, Hovda DA, Bergs-neider M, McBride DQ, Shalmon E, Herman D, Becker DP (1997)Cerebral blood flow as a predictor of outcome following traumaticbrain injury. J Neurosurg 86:633–641
Kety SS, Schmidt CF (1945) The determination of cerebral blood flow
P. M. VESPA ET AL.876
J Cereb Blood Flow Metab, Vol. 23, No. 7, 2003
in man by the use of nitrous oxide in low concentrations. AmerJ Physiol 143:53–66
Landolt H, Langemann H, Mendelowitsch A, Gratzl O (1994) Neuro-chemical monitoring and on-line pH measurements using brainmicrodialysis in patients in intensive care. Acta Neurochir 60:475–478
Langemann H, Alessandri B, Mendelowitsch A, Feuerstein T, LandoltH, Gratzl O (2001) Extracellular levels of glucose and lactatemeasured by quantitative microdialysis in the human brain. NeurolRes 23:531–536
Lee JH, Kelly DF, Oertel M, McArthur DL, Glenn TC, Vespa P,Boscardin WJ, Martin NA (2001) Carbon dioxide reactivity, pres-sure autoregulation, and metabolic suppression reactivity afterhead injury: a transcranial Doppler study. J Neurosurg 95:222–232
Marklund, N, Salci K, Lewen A, Hillered L (1997) Glycerol as amarker for post-traumatic membrane phospholipid degradation inrat brain. Neuroreport 8:1457–1461
Marshall LF, Marshall SB, Klauber MR, Van Berkum Clark M,Eisenberg H, Jane JA, Luerssen TG, Marmarou A, Foulkes MA(1992) The diagnosis of head injury requires a classification basedon computed axial tomography. J Neurotrauma 9(Suppl 1):S287–S292
Moore, AH, Osteen, TL, Chatziioannou, TF, Hovda, DA, Cherry, TR(2000) Quantitative assessment of longitudinal metabolic changesin vivo after traumatic brain injury in the adult rat using FDG-microPET. J Cereb Blood Flow Metab 20:1492–1501
Nilsson P, Gazelius B, Carlson H, Hillered L (1996) Continuous mea-surement of changes in regional cerebral blood flow followingcortical compression contusion trauma in the rat. J Neurotrauma13:201–207
Pellerin L, Magistretti PJ (1994) Glutamate uptake into astrocytesstimulates aerobic glycolysis: a mechanism coupling neuronal ac-tivity to glucose utilization. Proc Natl Acad Sci U S A 91:10625–10629
Pellerin L, Magistretti PJ (1996) Excitatory amino acids stimulate aero-bic glycolysis in astrocytes via an activation of the Na+/K+ATPase. Dev Neurosci 18:336–342
Persson L, Valtysson J, Enblad P, Warme PE, Cesarini K, Lewen A,Hillered L (1996) Neurochemical monitoring using intracerebralmicrodialysis in patients with subarachnoid hemorrhage. J Neuro-surg 84:606–616
Rappaport M, Hall KM, Hopkins K, Belleza T, Cope DN Disabilityrating scale for severe head trauma: coma to community (1982)Arch Phys Med Rehabil 63:118–123
Reinstrup P, Stahl N, Mellergard P, Uski T, Ungerstedt U, NordstromCH (2000) Intracerebral microdialysis in clinical practice: baselinevalues for chemical markers during wakefulness, anesthesia, andneurosurgery. Neurosurgery 47:701–709
Ronne-Engstrom, E, Cesarini KG, Enblad P, Hesselager G, MarklundN, Nilsson P, Salci K, Persson L, Hillered L (2001) Intracerebralmicrodialysis in neurointensive care: the use of urea as an endog-enous reference compound. J Neurosurg 94:397–402
Ros, J, Pecinska, N, Alessandri, B, Landolt, H, Fillenz, M (2001)Lactate reduced glutamate-induced neurotoxicity in rat cortex.J Neurosci Res 66:790–794
Stahl N, Mellergard P, Hallstrom A, Ungerstedt U, Nordstrom CH(2001a) Intracerebral microdialysis and bedside biochemicalanalysis in patients with fatal traumatic brain lesions. Acta Anes-thesiol Scand 45:977–985
Stahl N, Ungerstedt U, Nordstrom CH (2001b) Brain energy metabo-lism during controlled reduction of cerebral perfusion pressure insevere head injuries. Intensive Care Med 27:1215–1223
Unterberg AW, Sakowitz OW, Sarrafzadeh AS, Benndorf G, LankschWR (2001) Role of bedside microdialysis in the diagnosis of ce-rebral vasospasm following aneurysmal subarachnoid hemorrhage.J Neurosurg 94:740–749
Valadka AB, Goodman JC, Gopinath SP, Uzura M, Robertson CS(1998) Comparison of brain tissue oxygen tension to microdialy-sis-based measures of cerebral ischemia in fatally head-injuredhumans. J Neurotrauma 15:509–519
Vespa P, Prins M, Ronne-Engstrom E, Caron M, Shalmon E, HovdaDA, Martin NA, Becker DP (1998) Increase in extracellular glu-tamate caused by reduced cerebral perfusion pressure and seizuresafter human traumatic brain injury: a microdialysis study. J Neu-rosurg 89:971–982
Vespa P, Martin NA, Nenov V, Glenn T, Bergsneider M, Kelly D,Becker DP, Hovda DA (2002) Delayed increase in extracellularglycerol with post-traumatic electrographic epileptic activity: sup-port for the theory that seizures induce secondary injury Acta Neu-rochir (Suppl) 81:355–357
Vink R, Faden AI, McIntosh TK (1988) Changes in cellular bioener-getic state following graded traumatic brain injury in rats: deter-mination by phosphorus 31 magnetic resonance spectroscopy.J Neurotrauma 5:315–330
Wilson JT, Pettigrew LE, Teasdale GM (1998) Structured interviewsfor the Glasgow Outcome Scale and the extended Glasgow Out-come Scale: guidelines for their use. J Neurotrauma 15:573–585
Yoshino A, Hovda DA, Kawamata T, Katayama Y, Becker DP (1991)Dynamic changes in local cerebral glucose utilization followingcerebral conclusion in rats: evidence of a hyper- and subsequenthypometabolic state. Brain Res 4:106–119
Yoshino A, Hovda DA, Katayama Y, Kawamata T, Becker DP (1992)Hippocampal CA3 lesion prevents postconcussive metabolic dys-function in CA1. J Cereb Blood Flow Metab 12:996–1006
