Beruflich Dokumente
Kultur Dokumente
23:12391250 2003 The International Society for Cerebral Blood Flow and Metabolism
Published by Lippincott Williams & Wilkins, Inc., Baltimore
Although much is known regarding posttraumatic impairment of oxidative metabolism and its impact on outcome (Jaggi et al., 1990; Robertson et al., 1992; Tabaddor et al., 1972), less is understood about how alterations
in glucose and lactate metabolism impact recovery of
neurologic function. Cerebral oxidative metabolism generally remains markedly depressed for the first 2 weeks
after severe head injury, and the degree of depression has
been shown to correlate with poor long-term outcome
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DOI: 10.1097/01.WCB.0000089833.23606.7F
1240
T. C. GLENN ET AL.
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T. C. GLENN ET AL.
36 16
27% female
7 (range 3 to 14)
32 10
59.50%
6 Month GOS
20.40%
34.70%
26.50%
0.00%
18.40%
100%
10
17
13
0
9
49
Good Recovery
Moderate Disability
Severe Disability
Vegatative
Dead
Total
N 49
Statistical analysis
Mixed effects linear regression models were used throughout
to account for the uneven numbers of studies on patients at
different time points (Laird and Ware, 1982). To examine the
association of metabolism and 6-month GOS, the measurements of metabolic parameters were modeled as correlated outcomes within patients with different means for each level of the
GOS. A variety of covariance structures for the repeated measures were considered; we report results for models with random patient-level means and continuous time AR(1) correlation. For these statistical models, the estimated means by GOS
category can be thought of as a data-driven compromise between the means of the studies within each GOS category and
the mean of the patient means for each GOS category. We refer
to these quantities as the adjusted means in the results section;
they are adjusted for the unequal number of studies per patient
at different hours postinjury. Similar interpretation can be given
to the adjusted standard deviations for each GOS category.
Logarithmic transformations of the metabolic measurements
were used to obtain more accurate P values where appropriate;
however, adjusted means and standard deviations are reported
for the original scale data for clarity of interpretation. The
univariate mixed effect models were then augmented by controlling for a fixed set of clinical predictors including patient
age, ISS, pupillary findings, CT findings, mean ICP, mean
CPP, and best GCS. Comparisons of TBI patients to normal
volunteers were performed in a similar manner. In several instances, we consider repeated measures of a dichotomous indicator (e.g., lactate uptake above a certain threshold). Generalized Estimating Equations methods were used to analyze
these data (Liang and Zeger, 1986; Zeger and Liang, 1986).
Comparison of TBI patients with normal volunteers was performed in a similar manner. Statistical significance was defined
at P < 0.05, but in some instances, attention is drawn to suggestive results given the small sample sizes.
RESULTS
Head injury cohort
The 49 TBI patients were enrolled in the study between July 1998 and March 2002. The mean patient age
was 3616 years (range 16 to 81 years) and 13 (27%)
were female. (Table 1) The median postresuscitation
J Cereb Blood Flow Metab, Vol. 23, No. 10, 2003
Units
Trauma*
(n 49)
Normal
(n 31)
ml/100g/min
40.17 13.2 46.2 10.5
ml/100g/min
1.4 0.43 3.10 0.56
mg/100g/min
3.43 2.32 4.46 1.16
mg/100g/min 0.0355 0.41 0.18 0.21
ml/dl
3.76 1.37 6.89 1.35
mg/dl
8.94 6.57 9.89 2.92
mg/dl
0.0464 0.94 0.40 0.48
mg/dl
122.7 33.8 82.2 8.3
mg/dl
14.05 8.2
6.7 2.1
4.11 2.11 5.83 1.41
%
72.9 8.6
61.7 5.9
%
98.5 1.5
97.5 1.2
years
35.7
33.3 8.3
% Male
73%
74%
p
value
0.01
0.0001
0.0002
0.0001
0.0001
0.002
0.0002
0.0001
0.0001
0.0001
0.0001
0.0001
0.4
1
1243
Multivariate analysis
After controlling for injury characteristics, age, and
parameters of ICP and CPP, the associations between
GOS category and the following factors remained strong:
CMRO2 (P 0.002), arterial lactate (P 0.007), CSF
lactate (P 0.01), and arterial glucose (P 0.02)
Category
Metabolic
Acute
Injury
Char.
Predictor
JUGO2SAT
ARTO2SAT
ARTPO2
AVDO2
CMRO2
Art glucose
AVDglc
CMRglc
Metabolic Ratio
Art lactate
AVDlac
CMRlac
CBF
CSFglc
CSFlac
Pupils
Units
mm Hg
ml/dl
ml/100g/min
mg/dl
mg/dl
mg/100g/min
mg/dl
mg/dl
mg/100g/min
ml/100g/min
mg/dl
mg/dl
% any
abnormal
GCS
Hypot-Hypoxia % any
episode
CT Score
*CT Score BBB damage
ISS
Patient
Age
Characteristics
Gender
Intracranial
Physiology
years
P-values
Univariate
Multivariate
Univariate
Multivariate
GOS 1
(n 9)
GOS 3
(n 13)
GOS 4
(n 17)
GOS 5
(n 10)
linear
trend
linear
trend
good/
bad
good/
bad
75.8 8.0
98.4 1.6
155.1 85.1
3.4 1.3
1.2 0.4
143.8 46.3
9.0 5.7
3.2 1.8
3.45 1.7
21.9 12.0
0.4 1.3
0.18 0.59
36.5 14.9
91.5 41.7
32 10.4
70.4 7.6
98.1 1.8
132.8 49.3
3.9 1.28
1.3 0.3
123.8 33.9
8.8 6.0
3.1 1.7
4.1 2.1
14.6 7.8
0.04 0.76
0.19 0.27
36.2 11.9
83.0 26.2
25.9 10.9
71.9 9.2
98.7 1.3
144.0 42.4
3.9 1.4
1.4 0.4
113.9 30.4
9.6 8.0
3.7 3.0
4.1 2.3
11.5 7.1
0.02
0.02 0.42
40.3 12.2
76.1 26.4
20.7 8.5
75.4 8.8
98.8 1.1
156.2 48.0
3.5 1.3
1.6 0.5
110.4 23.1
7.9 5.3
3.6 2.2
4.7 2.1
10.7 5.8
0.13
0.04
48.6 11.9
76.6 21.2
19.3 7.1
0.9
0.04
0.8
0.8
0.0001
0.0008
0.4
0.1
0.05
0.0001
0.03
0.05
0.002
0.2
0.01
0.5
0.07
0.9
0.4
0.002
0.02
0.9
0.4
0.06
0.007
0.8
0.8
0.1
0.4
0.01
0.8
0.01
0.6
0.9
0.003
0.0008
0.7
0.1
0.2
0.0007
0.1
0.2
0.01
0.2
0.01
0.9
0.03
0.5
0.8
0.07
0.03
0.9
0.5
0.2
0.02
0.9
0.9
0.2
0.4
0.01
89%
62%
42%
30%
0.004
0.02
7.1 3.0
23%
6.9 1.9
29%
8.2 2.6
0%
0.003
0.5
0.03
0.7
2.4 1.0
1.6
1.3 0.9
1.3 1.3
35.7 14.8 32.7 7.3
1.4 1.0
0.8 0.6
32.9 9.3
1.3 1.3
0.8 0.6
26.0 6.1
0.03
0.1
0.2
0.08
0.03
0.2
0.2
0.08
5 1.9
22%
42.7 24.8
% Male
56%
85%
71%
80%
0.3
Mean CPP
mm Hg
73.7 9.4
82.1 6.8
85.8 7.4
78.5 4.8
0.5
0.2
% CPP < 60
Mean ICP
% ICP > 20
mm Hg
0.2
0.5
0.5
0.2
0.3
0.8
* CT score BBB (blood-brain-barrier) damage total number of following CT diagnoses - acute subdural hematomas, intracerebral hematomas or multiple contusions.
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T. C. GLENN ET AL.
arterial lactate levels overall had a strong inverse correlation with 6-month GOS (P 0.0001). As seen in Fig.
2, abnormal brain lactate production (CMRlac below the
2.5th percentile of normal, i.e., < 0.71 mg/100g/min)
was uncommon, occurring in only 4 (2%) of 179 measurements and in four (8%) patients, whereas abnormal
brain lactate uptake (CMRlaclac above the 97.5th percentile of normal, i.e., > 0.11 mg/100g/min) was observed in 51 (28%) of 179 measurements. Despite significantly lower levels of systemic arterial lactate in the
favorable outcome patients (GOS 4 or 5), abnormal brain
lactate uptake still occurred relatively frequently, being
observed in 26% and 33% of the measurements in these
patient groups, respectively (Fig. 3). Overall, a higher
rate of brain lactate uptake relative to the simultaneous
arterial lactate level was observed in the favorable outcome group (GOS 4 and 5) compared with the unfavorable outcome group (GOS 1 and 3) (P .04).
Glucose, hyperglycolysis, and outcome
High plasma glucose levels were associated with poor
outcome (Fig. 3). The mean plasma glucose was 23%
greater in patients who died compared with patients with
a GOS of 5. Relative hyperglycolysis (metabolic ratio <
FIG. 1. Boxplots of CMRO2, CMRglc, and CMRlac by 6-month Glasgow Outcome Scale. Summary of values in 49 patients collected from
postinjury days 0 to 5, stratified by 6-month GOS and compared with values of 31 normal control subjects. Lines within the box indicate
median, the box interquartile range, whiskers bracket 95% of the data, and straight bars outliers. Overall CMRO2 is higher in patients with
a good outcome but is depressed in all groups compared with control patients. CMRglc is also depressed after injury but to a lesser degree
than CMRO2. CMRlac was positive in almost half of all studies; note that the most positive values are in the patients who died (GOS 1).
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FIG. 2. Graph showing the percent of CMR measurements that were either below the 2.5th percentile, above the 97.5th percentile, or
within normal range of control subjects, stratified by 6-month GOS score. Note the relatively uncommon finding (2%) of abnormally
negative CMRlactate (C) values (cerebral lactate production). In contrast, abnormally positive CMRlactate values, indicating cerebral
uptake of lactate, were seen in 28% of studies. (A) CMRO2; (B) CMRglc; (C) CMRlac.
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T. C. GLENN ET AL.
FIG. 3. Mean arterial lactate and glucose levels. Mean arterial plasma glucose and lactate concentrations were lower in patients with
higher GOS (4 and 5), but both were abnormally elevated compared with control volunteers.
Glucose metabolism
Unlike the depression of oxidative metabolism, an increase in cerebral glucose use has been a consistent finding across animal brain-injury models, including concussive brain injury (Kawamata, 1992; Sunami et al., 1989;
Yoshino et al., 1991), cortical contusions (Sunami et al.,
1989), and experimental subdural hematoma (Inglis et
al., 1992). These studies have revealed that injured cells
are exposed to a massive ionic flux, in part because of the
release of excitatory amino acids (Katayama et al., 1989,
1990). This ionic imbalance transiently increases the use
of cerebral glucose, which activates Na+/K+ pumps in an
effort to restore ionic homeostasis (Hovda, 1996; Hovda
et al., 1992; Yoshino et al., 1991).
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measuring lactate that is diffusing into or being transported into the interstitial space from the extracranial
circulation (Chen et al., 2000b; Nemoto and Severinghaus, 1974; Rivers et al., 1991). Admittedly, the global
technique used in this study cannot detect areas of regional ischemia where high lactate production may occur.
Brain lactate uptake: two scenarios
The findings regarding lactate metabolism raise two
key questions. First, given that the majority of patients
are in a state of relative hyperglycolysis acutely after
injury in which CMRO2 is decreased to a greater degree
than CMRglc, why does abnormal uptake of lactate by
the brain occur so much more frequently than brain lactate production? Second, why is brain uptake of lactate
associated with both favorable and unfavorable clinical
outcomes? To answer these questions, we propose that
two very different clinical scenarios exist after TBI. In a
favorable outcome scenario (in patients who achieve a
GOS of 4 or 5), uptake of lactate by the brain occurs
primarily by facilitated transport through a largely intact
blood-brain barrier. Given a less depressed CMRO2 in
these patients, the lactate can be effectively used as a fuel
source. In an unfavorable outcome scenario (in patients
who achieve a GOS of 1 to 3), large amounts of lactate
passively enter the brain as a result of high systemic
arterial lactate levels and a damaged blood-brain barrier.
Given a severely depressed CMRO2 in these patients, the
abundant lactate cannot be effectively used.
Several findings in this study support this twoscenario concept of posttraumatic lactate metabolism.
Despite the fact that the favorable outcome patients had
lower arterial lactate levels than the poor outcome patients, these patients had a higher rate of abnormal brain
lactate uptake relative to arterial lactate levels. This finding of a high rate of brain lactate uptake despite lower
arterial lactate levels suggests the lactate was being actively taken into the brain. The favorable outcome group
was further distinguished from the unfavorable outcome
group by having higher values for CMRO2 and CMRglc
and lesser degrees of blood-brain barrier damage based
upon CT findings. The lesser degree of blood-brain barrier damage in the favorable outcome patients also argues against the possibility that the brain lactate uptake
in these patients was simply a result of diffusion into
the brain.
Previous studies confirm that under certain conditions,
the brain and other tissues, such as heart, kidney, liver,
and muscle, can use lactate through so-called lactate
shuttles and facilitated transport mechanisms (Amaral
et al., 1986; Brandt et al., 1984; Brooks, 2002; Rivers et
al., 1991). Others have shown brain uptake of lactate and
its conversion to pyruvate to enter the Krebs cycle for
ATP production (Chen et al., 2000a; Magistretti et al.,
1999; Ros et al., 2001). Lactate may also be used to
J Cereb Blood Flow Metab, Vol. 23, No. 10, 2003
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T. C. GLENN ET AL.
REFERENCES
Alessandri B, Doppenberg E, Zauner A, Woodward J, Choi S, Bullock
R (1999) Evidence for time-dependent glutamate-mediated glycolysis in head-injured patients: a microdialysis study. Acta Neurochir
Suppl 75:2528
Alessandri B, Rice AC, Levasseur J, DeFord M, Hamm RJ, Bullock
MR (2002) Cyclosporin-a improves brain tissue oxygen consumption and learning/memory performance after lateral fluid percussion injury in rats. J Neurotrauma 19:829841
Amaral JF, Shearer JD, Mastrofrancesco B, Gann DS, Caldwell MD
(1986) Can lactate be used as a fuel by wounded tissue? Surgery
100:252260
Barzo P, Marmarou A, Fatouros P, Corwin F, Dunbar J (1996) Magnetic resonance imaging-monitored acute blood-brain barrier
1249
RK, Wilberger JE, Povlishock JT, eds), New York, NY: McGrawHill, pp 14591478
Hovda DA, Becker DP, Katayama Y (1992) Secondary injury and
acidosis. J Neurotrauma 9 (Suppl): S47S60
Inao S, Marmarou A, Clarke GD, Andersen BJ, Fatouros PP, Young
HF (1988) Production and clearance of lactate from brain tissue,
cerebrospinal fluid, and serum following experimental brain injury. J Neurosurg 69:736744
Inglis F, Kuroda Y, Bullock R (1992) Glucose hypermetabolism after
acute subdural hematoma is ameliorated by a competitive NMDA
antagonist. J Neurotrauma 9:75
Jaggi JL, Obrist WD, Gennarelli TA, Langfitt TW (1990) Relationship
of early cerebral blood flow and metabolism to outcome in acute
head injury. J Neurosurg 72:176182
Jennett B, Bond M (1975) Assessment of outcome after severe brain
damage. A practical scale. Lancet 1:480484
Katayama Y, Becker DP, Tamura T, Hovda DA (1990) Massive increases in extracellular potassium and the indiscriminate release of
glutamate following concussive brain injury. J Neurosurg
73:889900
Katayama Y, Cheung MK, Alves A, et al. (1989) Ion fluxes and cell
swelling in experimental traumatic brain injury: The role of excitatory amino acids. In: Intracranial Pressure. (Hoff JT, Betz AL,
eds), Berlin, Springer-Verlag, pp 584588
Kawamata T, Katayama Y, Hovda DA, Yoshino A, Becker DP (1992)
Administration of excitatory amino acid antagonists via microdialysis attenuates the increase in glucose utilization seen following
concussive brain injury. J Cereb Blood Flow Metab 12:1224
Kawamata T, Katayama Y, Hovda DA, Yoshino A, Becker DP (1995)
Lactate accumulation following concussive brain injury: the role of
ionic fluxes induced by excitatory amino acids. Brain Res
674:196204
Kelly DF, Goodale DB, Williams J, Herr DL, Chappell ET, Rosner MJ,
Jacobson J, Levy ML, Croce MA, Maniker AH, Fulda GJ, Lovett
JV, Mohan O, Narayan RK (1999) Propofol in the treatment of
moderate and severe head injury: a randomized, prospective
double blinded pilot trial. J Neurosurg 90:10421052
Kelly DF, Martin NA, Kordestani R, Counelis G, Hovda DA, Bergsneider M, McBride DQ, Shalmon E, Herman D, Becker DP
(1997) Cerebral blood flow as a predictor of outcome following
traumatic brain injury. J Neurosurgery 86:633641
Kuroda Y, Inglis FM, Miller JD, McCulloch J, Graham DI, Bullock R
(1992) Transient glucose hypermetabolism after acute subdural
hematoma in the rat. J Neurosurg 76:471477
Laird NM, Ware JH (1982) Random-effects models for longitudinal
data. Biometrics 38:963974
Liang KY, Zeger SL (1986) Longitudinal data analysis using generalized linear models. Biometrika 73:1322
Madsen PL, Hasselbalch SG, Hagemann LP, Olsen KS, Bulow J, Holm
S, Wildschiodtz G, Paulson OB, Lassen NA (1995) Persistent resetting of the cerebral oxygen/glucose uptake ratio by brain activation: evidence obtained with the Kety-Schmidt technique. J
Cereb Blood Flow Metab 15:485491
Magistretti PJ, Pellerin L, Rothman DL, Shulman RG (1999) Energy on
demand. Science 283:496497
Marmarou A, Anderson RL, Ward JD, et al. (1991) Impact of ICP
instability and hypotension on outcome in patients with severe
head injury. J Neurosurg 75 (Suppl): S59S66
Marshall LF, Gautille T, Klauber MR, et al. (1991a) The outcome of
severe closed head injury. J Neurosurg 75 (Suppl):S2836
Marshall LF, Marshall SB, Klauber MR, et al. (1991b) A new classification of head injury based on computerized tomography. J Neurosurg 75 (Suppl):S14S20
Martin N, Patwardhan R, Zane C, Alexander M, Benalcazar H, Hovda
DA, Becker DP (1997) Characterization of the cerebral hemodynamic phases which follow severe head trauma: hyperperfusion,
hyperemia and vasospasm. J Neurosurg 87:919
Meixensberger J, Kunze E, Barcsay E, Vaeth A, Roosen K (2001)
Clinical cerebral microdialysis: brain metabolism and brain tissue
oxygenation after acute brain injury. Neurol Res 23:801806
Menzel M, Doppenberg EM, Zauner A, Soukup J, Reinert MM, Bullock R (1999) Increased inspired oxygen concentration as a factor
1250
T. C. GLENN ET AL.
Rockswold SB, Rockswold GL, Vargo JM, Erickson CA, Sutton RL,
Bergman TA, Biros MH (2001) Effects of hyperbaric oxygenation
therapy on cerebral metabolism and intracranial pressure in severely brain injured patients. J Neurosurg 94:40311
Ros J, Pecinska N, Alessandri B, Landolt H, Fillenz M (2001) Lactate
reduces glutamate-induced neurotoxicity in rat cortex. J Neurosci
Res 66:790794
Rosenthal RE, Williams R, Bogaert YE, Getson PR, Fiskum G (1992)
Prevention of postischemic canine neurological injury through potentiation of brain energy metabolism by acetyl-L-carnitine. Stroke
23:13121317
Sheline CT, Behrens MM, Choi DW (2000) Zinc-induced cortical neuronal death: contribution of energy failure attributable to loss of
NAD(+) and inhibition of glycolysis. J Neurosci 20:31393146
Simonsen L, Bulow J, Madsen J (1994) Adipose tissue metabolism in
man determined by vein catheterization and microdialysis techniques. Am J Physiol 266:E357E365
Sunami K, Nakamura T, Ozawa Y, Kubota M, Namba H, Yamaura A
(1989) Hypermetabolic state following experimental head injury.
Neurosurg Rev 12:400-411
Suzuki M, Suzuki M, Sato K, Dohi S, Sato T, Matsuura A, Hiraide A
(2001) Effect of beta-hydroxybutyrate, a cerebral function improving agent, on cerebral hypoxia, anoxia and ischemia in mice and
rats. Jpn J Pharmacol 87:14350
Tabaddor K, Bhushan C, Pevsner PH, Walker AE (1972) Prognostic
value of cerebral blood flow (CBF) and cerebral metabolic rate of
oxygen (CMRO2) in acute head trauma. J Trauma 12:10531055
Tenjin H, Ueda S, Nizukawa N, Inahori Y, Hino A, Yamaki T,
Kuboyama T, Ebisu T, Hirakawa K, Yamashita M, Makahashi H
(1990) Positron emission tomographic studies on cerebral hemodynamics in patients with cerebral contusion. Neurosurgery
26:971979
Verweij BH, Muizelaar JP, Vinas FC, Peterson PL, Xiong Y, Lee CP
(2000) Impaired cerebral mitochondrial function after traumatic
brain injury in humans. J Neurosurg 93:815820
Vespa P, Prins M, Ronne-Engstrom E, Caron M, Shalmon E, Hovda
DA, Martin NA, Becker DP (1998) Increase in extracellular glutamate caused by reduced cerebral perfusion pressure and seizures
after human traumatic brain injury: a microdialysis study. J Neurosurg 89:971982
Vollmer DG, Torner JC, Jane JA (1991) Age and outcome following
traumatic coma: why do older patients fare worse? J Neurosurg
75:S37S49
Xi G, Hua Y, Bhasin RR, Ennis SR, Keep RF, Hoff JT (2001) Mechanisms of edema formation after intracerebral hemorrhage: effects
of extravasated red blood cells on blood flow and blood-brain
barrier integrity. Stroke 32:29322938
Yamaki T, Imahori Y, Ohmori Y, Yoshino E, Hohri T, Ebisu T, Ueda
S (1996) Cerebral hemodynamics and metabolism of severe diffuse
brain injury measured by PET. J Nucl Med 37:11661170
Ying W, Chen Y, Alano CC, Swanson RA (2002) Tricarboxylic Acid
Cycle Substrates Prevent PARP-Mediated Death of Neurons and
Astrocytes. J Cereb Blood Flow Metab 22:774779
Yoshino A, Hovda DA, Katayama Y, Kawamata T, Becker DP (1992)
Hippocampal CA3 lesion prevents postconcussive metabolic dysfunction in CA1. J Cereb Blood Flow Metab 12:9961006
Yoshino A, Hovda DA, Kawamata T, Katayama Y, Becker DP (1991)
Dynamic changes in local cerebral glucose utilization following
cerebral concussion in rats: evidence of a hyper- and subsequent
hypometabolic state. Brain Res 561:106119
Zeger SL, Liang K (1986) Longitudinal data analysis for discrete and
continuous outcomes. Biometrics 42:121130