546
Lactate and Glucose Concentrations in Brain Interstitial Fluid, Cerebrospinal Fluid, and Serum during Experimental Pneumococcal Meningitis Luis Guerra-Romero, Martin G. Tauber, Michael A. Fournier, and Jay H. Tureen
Microbial Pathogenesis Unit. San Francisco General Hospital. and Departments ofMedicine and Pediatrics, University ofCalifornia. San Francisco
Pathophysiologic changes in the central nervous system (CNS) in bacterial meningitis include metabolic disturbances, brain edema, intracranial hypertension, and reduction of cerebral blood flow [I, 2]. These alterations may directly or indirectly lead to neuronal dysfunction that can result in neurologic sequelae or death. Metabolic abnormalities within the CNS in bacterial meningitis, characterized by hypoglycorrhachia and cerebrospinal fluid (CSF) lactate accumulation, were identified in the I 920s [3-5]. The simultaneous occurrence of these changes has led some investigators to propose that anaerobic glycolysis with lactate production explains both, but the locus of the abnormal metabolism remains controversial [6]. It was initially hypothesized that metabolism by bacteria and leukocytes in the subarachnoid space resulted in glucose consumption with production of lactate [7]. Subsequently, alteration of glucose transport from blood to CSF has been documented [8, 9], raising the possibility that impaired diffusion across the blood-brain barrier (BBB) was responsible for hypoglycorrhachia; however, this did not address the coexisting CSF'lactic acidosis.
Received 7 February 1992; revised 24 April 1992. Presented in part: 31st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago. September 1991 (abstract 914). Grant support: Ministerio de Education i Licencia and Sociedad de Enfermedades Infectiosas i Microbiologia Clinica ofSpain (L.G.-R.). Roche Laboratory (M.G.T.). and National Institutes of Health (NS-27310 to J.H.T.). Reprints or correspondence: Dr. Jay H. Tureen. Microbial Pathogenesis Unit. Box 081 I, University of California San Francisco. 3rd and Parnassus Ave.. San Francisco. CA 94143.
The Journal of Infectious Diseases 1992;166:546-50 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6603-0013$01.00
Finally, recent data suggest that cerebral ischemia in meningitis could result in abnormal brain metabolism of glucose resulting in increased lactate production [10]. The changes oflactate and glucose concentrations in CSF are the net results of transfer into the subarachnoid space, local production (lactate) or utilization (glucose) in the CSF, and transfer across the BBB.To investigate these changes, we simultaneously and sequentially measured glucose and lactate in tissue, serum, and CSF. In vivo microdialysis was used, as it has been successful as a tool for sequentially studying brain interstitial fluid in other neurophysiologic and experimental models of CNS injury [11-13]. The purpose of the present study was to elucidate the mechanism and locus of metabolic changes within the CNS in bacterial meningitis during developing infection.
Materials and Methods Model ofexperimental meningitis. Meningitis was produced by intracisternal injection of 0.3 mL of saline containing an inoculum of 106-10 7 cfu of Streptococcus pneumoniae type 3 as described by Dacey and Sande [14]. New Zealand White rabbits (2.0-2.5 kg) were anesthetized by intravenous (iv) urethane (2.0 g/kg) for all procedures. Light general anesthesia was maintained by supplemental doses of urethane (0.5 g/kg iv). Local anesthesia for skin incisions was provided by lidocaine HCl. A polyethylene catheter (PE-90) was inserted into the femoral artery for measurement of blood pressure and blood sampling. A dental acrylic cap containing a turnbuckle was affixed to the outer table of cranial bone by steel screws. Rabbits were immobilized in a restraining frame, and cisternal puncture was done with a 25-gauge 8.9-cm spinal needle (Becton Dickinson. Franklin Lakes, NJ) for infection and sampling of CSF.
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on September 2, 2015
Metabolic abnormalities during bacterial meningitisinclude hypoglycorrhachiaand cerebrospinal fluid (CSF) lactate accumulation. The mechanisms by which these alterations occur within the central nervous system(CNS) are still incompletelydelineated. To determine the evolution of these changes and establish the locus of abnormal metabolism during meningitis, glucose and lactate concentrations in brain interstitial fluid, CSF, and serum were measured simultaneously and sequentially during experimental pneumococcal meningitis in rabbits. Interstitial fluid samples were obtained from the frontal cortex and hippocampus by using in situ brain microdialysis, and serum and CSF were directly sampled. There was an increase of CSF lactate concentration, accompanied by increased local production of lactate in the brain, and a decrease of CSF-toserum glucose ratio that was paralleled by a decrease in cortical glucose concentration. Brain microdialysate lactate concentration was not affected by either systemic lactic acidosis or artificially elevated CSF lactate concentration. These data support the hypothesis that the brain is a locus for anaerobic glycolysis during meningitis, resulting in increased lactate production and perhaps contributing to decreased tissue glucose concentration.
1ID 1992; 166 (September)
Lactate and Glucose in Experimental Meningitis
Table 1. Physiologicvariablesat 22 h in rabbits with pneumococcal meningitis and controls. Meningitis (n ~ 16) Blood pressure (mm Hg) Arterial pH HC0 3 (mmol/L) Pe02 (mm Hg)
Control ~ 13)
(n
81.1 ± 10.8
80.0 ± 15.9
7.36 ± 0.11* 16.0±4.4 28.1 ± 1O.0t
7.26 ± 0.08 18.8 ± 2.7 45.9 ± 10.6
* Significant difference from control t
(P < .05). Significant difference from control (P < .00 I).
gases were measured in a blood gas analyzer (Radiometer ABL 2; Radiometer, Copenhagen). Arterial pressure was measured with a water-filled pressure transducer (model P-23 XL; Gould, Santa Clara, CA) and recorded on a multichannel polygraph (5/6 H recorder; Gilson Medical Electronics, Middleton, WI). Statistical analysis. Data were expressed as mean ± SD and were analyzed by unpaired Student's t tests for comparison between groups, by paired Student's t test for comparison between paired samples ofthe same group, and by linear regression analysis for correlations between parameters.
Results CSF titers and leukocyte counts. The bacterial titer in the CSF for the infected animals was 8.76 ± 1.10 10glO cfu/ml. at 22 h of infection. At that time, the number of leukocytes in the CSF was 6.833 ± 3.850 X 103/mm '. Control animals had sterile cultures and a leukocyte count of 43 ± 79/mm 3 at 22 h. Physiologic variables. No significant difference in mean arterial blood pressure was observed at the end of the experiment between meningitis and control groups (table 1). Arterial blood gases at 22 h demonstrated a mild metabolic acidosis in both groups and a compensatory respiratory alkalosis in infected rabbits. As a consequence, serum pH was higher (7.36 ± 0.11 vs. 7.26 ± 0.08, P < .05) and Pco, was lower (28.1 ± 10 vs. 45.9 ± 10.6 mm Hg, P < .001) in the group with meningitis. Serum lactate and glucose. Serum lactate concentrations at 16 and 22 h in infected rabbits were significantly higher than in controls (2.33 ± 1.13 vs. 0.86 ± 0.58 mmol/L at 16 h and 3.66 ± 2.75 vs. 0.78 ± 0.51 mrnol/L at 22 h, P < .001). Although serum glucose concentrations at 22 h were not significantly different between the two groups, the infected animals (but not the controls) had significantly increased levels at the end of the infection compared with their baseline values (116.9 ± 32.4 and 183.8 ± 50.2 mg/dL at 0 and 22 h, respectively, P < .00 I; table 2). CSF lactate and glucose. CSF lactate concentration increased progressively in infected rabbits but did not change in controls (table 3). Lactate was significantly higher at 22 h
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on September 2, 2015
Microdialysis probes (2-mm membrane tip length; Bioanalytical Systems, West Lafayette, IN) were tested before implantation by perfusion with artificial CSF (0.75% NaCl, 0.02% KCl, 0.015% CaCI2 , and 0.019% MgCl2 diluted in filter-sterilized deionized distilled water) while suspended in a solution of known glucose and lactate concentrations. Glucose and lactate concentrations were measured in effluent to ensure that recovery was consistent (in vitro recovery test). Probes were used if they demonstrated recoveries in the range of 20%- 30% for lactate and 15%-20% for glucose. Probes were positioned with a micromanipulator in the left frontal cortex (4.0 mm anterior to the bregma, 4.0 mm lateral to the sagittal suture, 3.0 mm from the pial surface) and the right hippocampus (6.0 mm posterior to the bregma, 7.0 mm lateral to the sagittal suture, 6.0 mm from pial surface). After placement, the probes were fixed to the skull with dental cement. Throughout the study, probes were perfused with artificial CSF with a syringe pump (model 931; Harvard Apparatus, Millis, MA) at a rate of 1.36 pL/min. Fractions ofdialysate were periodically collected in polypropylene tubes for analysis. The perfusate from the first hour was discharged during stabilization following probe implantation. At the conclusion of the study, rabbits were killed with a lethal dose of pentobarbital (150 mg/kg iv), postmortem CSF and blood samples were collected to serve as an internal control, and Evans blue dye was pumped through the probe. After removal of the brain, correct anatomic placement of the probes was confirmed macroscopically. Study design. After probe implantation, animals were intracisternally infected with 0.3 mL of S. pneumoniae in 0.3 mL of sterile, non bacteriostatic saline without preservative; controls received saline alone. Blood samples for arterial lactate and glucose concentrations and blood gases were taken at 0, 6, 16, and 22 h; CSF was taken at 0, 16, and 22 h for measurement of lactate and glucose and at 22 h for measurement of bacterial titer and white blood cell count. Tissue microdialysate was sampled for glucose and lactate measurement during the following periods after implantation: 1-2,2-5,5-6,6-16, 16-17, 17-19, 19-21, and 21-22 h and postmortem. Blood pressure was measured at 22 h. To exclude the possibility that tissue lactate concentration could increase by diffusion from either CSF or serum, two additional groups were studied. In one group, CSF lactic acidosis was induced in uninfected animals by two intracisternal injections 30 min apart, of 3.75 mg of lactic acid in 0.25 mL of saline. Microdialysate, CSF, and blood were periodicallymeasured for 2 h. In a second group of infected rabbits, 0.5 g oflactic acid in 10 mL of distilled water was infused iv over 30 min early in the course of the infection (14 h) to produce severe systemic lactic acidosis, as described by Alexander et al. [15]. Microdialysate, CSF, and blood were sampled at 0, 30, and 60 min. Experimental parameters. Bacterial titers in CSF were determined by serial l O-fold dilution of CSF in saline after overnight incubation on blood agar plates at 37°C in 5% CO 2 and expressed as 10glO colony-forming units per milliliter. White blood cell counts in CSF were determined in a hemocytometer. CSF, blood, and microdialysate concentrations oflactate and glucose were measured immediately after sampling in a two-channel autoanalyzer (YSI 2300 G/L; Yellow Springs, OH). Arterial blood
547
Guerra-Romero et al.
548
Table 2. Serum concentrations of lactate and glucose in rabbits with pneumococcal meningitis and controls. Meningitis (n Time (h) 0 6 16 22
Lactate (mmol/L) 0.89 ± 1.09 ± 2.33 ± 3.66 ±
0.58 0.93 1.33* 2.75*
=
Control (n
16)
Glucose (mg/dL) 116.9 106.0 177.1 183.8
± ± ± ±
32.4 35.9 52.2 t 50.2 t
Lactate (mmol/L) 1.27 ± 0.71 1.11 ± 0.61 0.86 ± 0.58 0.78±0.51
=
13) Glucose (mg/dL)
117.6 121.1 135.8 145.1
± ± ± ±
28.6 25.3 60.0 69.4
* Significant difference from control (P < .00 I). t Significant difference from 0 h (P < .001).
Microdialysate concentration oflactate after induction ofartificial CSF and systemic lactic acidosis. To test whether in-
creased tissue lactate could be the result of diffusion from eSF to brain interstitial fluid, sodium lactate was administered intracisternally to 3 normal rabbits. eSF lactate concentration remained >2.8 mmoljL for at least 120 min after
infusion, with a peak of 25.2 mmol/L. Mean eSF l~ctate concentration over this period was 11.3 ± 8.2 mmol/L, which is similar to that observed during infection. The dialysate lactate concentrations from cortex and hippocampus samples did not change during the sampling period (pre- and postinfusion concentrations: 0.14 ± 0.05 and 0.13 ± 0.02 rnmol/L, respectively, for cortex; 0.15 ± 0.04 and 0.14 ± 0.03 for hippocampus). To test whether lactate could diffuse from blood to brain interstitial fluid in the presence of a damaged BBB during meningitis, sodium lactate was infused intravenously in 3 infected rabbits. Serum lactate pre- and postinfusion values were 1.3 ± 0.8 and 4.50 ± 1.13 mmoljL, respectively. Postinfusion serum lactate concentration was comparable to that in infected rabbits after 22 h of infection. The dialysate lactate concentrations were similar before and after the sodium lactate infusion (0.20 ± 0.10 mmol/L at 0 min, 0.20 ± 0.10 mrnol/L at 30 min, and 0.23 ± 0.12 mmoljL at 60 min).
Discussion This study was designed to examine the development of metabolic abnormalities in the eNS during bacterial meningitis by using in situ brain microdialysis. Although it has been known for >60 years that increased eSF lactate concentration and hypoglycorrhachia are commonly present in human bacterial meningitis, the mechanisms for these abnormalities are not completely delineated. Metabolic abnormalities in the eNS were first noted in 1917 by Levinson [3], who suggested that low eSF pH was likely due to increased lactic acid concentration. In 1933, Kopetzky and Fishberg [16] suggested that "anemia of the brain" due to increased intracranial pressure and reduced blood oxygenation might induce anaerobic oxidation of carbohydrates with generation oflarge quantities oflactic acid. This hypothesis was further supported by Posner and Plum [17], who demonstrated that lactate concentration in the eSF was a reliable indicator of brain lactate content. The alternative hypothesis, linking eSF lactic acidosis with hy-
Table 3. Cerebrospinal fluid concentrations of lactate and glucosein rabbitswith pneumococcal meningitis and controls. Meningitis (n Time
=
16)
Control (n
=
13)
(h)
Lactate (mmoIjL)
Glucose (mg/dL)
Lactate (rnmol/L)
Glucose (mg/dL)
0 16 22
1.67 ± 0.38 13.85 ± 2.50 15.81 ± 3.70*
102.9 ± 23.4 111.3 ± 63.3 87.9 ± 46.6
1.69 ± 0.26
96.5 ± 10.6 ND 118.5 ± 58.7
NOTE.
ND
=
NO 1.83 ± 0.43
not determined.
* Significant difference from control
(P < .00 I).
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on September 2, 2015
in infected rabbits than in controls (15.81 ± 3.70 vs. 1.83 ± 0.43 mmolfL, P < .001). eSF glucose concentration was lower in infected animals than in controls, but the difference was not statistically significant. There was a significant difference in the eSF-to-blood glucose ratios at 22 h between infected and control animals, with a marked reduction in infected rabbits (0.47 ± 0.19 vs. 0.79 ± 0.19, P < .00 I). There were no significant correlations between eSF lactate or glucose concentrations and bacterial titer or eSF white blood cell counts. Microdialysate lactate and glucose. Microdialysate concentrations of lactate from frontal cortex and hippocampus of infected rabbits showed a progressive increase during the course of the infection, with similar rates of lactate accumulation in both tissues. Significant increases at both sites in infected rabbits were present at 16 h, and this trend continued for the rest of the study period (table 4, P < .001). No such changes were seen in control rabbits. There were no significant correlations between lactate concentrations and Pco, or other physiologic values in cortex or hippocampus at any time in the infected animals. Microdialysate concentrations of glucose from frontal cortex and hippocampus declined progressively in both infected and control rabbits; in infected rabbits, glucose concentration in cortex but not hippocampus was significantly reduced compared with baseline (3.27 ± 2.21 mg/dL at 1-2 h vs. 1.83 ± 1.48 mg/dL at 22 h, P < .05). Because tissue concentration of glucose can be affected by serum concentration ofglucose, we examined the microdialysate-to-serum ratio of concentration of glucose and found that there was a trend to a lower ratio in the cortex of infected rabbits compared with controls (0.109 ± 0.064 vs. 0.173 ± 0.088, P = .07) that was not present in hippocampal samples (table 5).
110 1992; 166 (September)
Lactate and Glucose in Experimental Meningitis
JID 1992; 166 (September)
549
Table 4.
Microdialysate concentration oflactate in frontal cortex and hippocampus in rabbits with pneumococcal meningitis and controls. Meningitis
Sampling period (h) 1-2 2-5 5-6 6-16 16-17 17-19 19-21 21-22
Cortex (n
0.14 0.19 0.19 0.21 0.26 0.28 0.34 0.35
Control Hippocampus
= 14) ± ± ± ± ± ± ± ±
(n
0.05 0.03 0.06 0.06 0.07* 0.16* 0.18* 0.18*
Cortex (n = 10)
= 14)
0.15 ± 0.08 0.18 ± 0.07 0.18 ± 0.07 0.21±0.10 0.31 ±0.14* 0.34 ± 0.17* 0.34 ± 0.12* 0.36 ± 0.16*
0.19 0.18 0.17 0.13 0.14 0.19 0.16 0.14
± ± ± ± ± ± ± ±
Hippocampus (n
0.09 0.07 0.06 0.05 0.08 0.07 0.05 0.05
0.17 0.21 0.18 0.20 0.18 0.16 0.16 0.16
= II) ± ± ± ± ± ± ± ±
0.13 0.11 0.11 O.IO 0.10 0.07 0.08 0.08
poglycorrhachia, was proposed by Petersdorf et al. [7], who suggested that lactate was produced and glucose consumed in the subarachnoid space by metabolism of bacteria and leukocytes [18]. Support of this by other investigators is based largely on the failure to demonstrate differences in brain lactate concentration between animals with meningitis and uninfected controls [19, 20]. However, each of these studies examined tissue and CSF lactate concentration at the conclusion of the study and the data may have been influenced by exclusion of the sickest animals, as 25%-58% of the rabbits either died prematurely or were excluded because of hypotension. In our study, sequential measurements of lactate in brain tissue documented a steady and progressive increase in lactate concentrations in interstitial fluid of two areas of the brain, the frontal cortex and the hippocampus, that were significantly elevated after 16 h of infection and continued to rise throughout the study period. That this was due to local production by brain is further supported by the lack of diffusion from either the CSF or the intravascular compartment and is in agreement with data reported by others [17]. The larger percentage increase of lactate in CSF than in intersti-
tial fluid may reflect either that lactate can be locally produced in the subarachnoid space or that clearance from the interstitium to the CSF is more effective than from the CSF to the blood, resulting in accumulation in CSF. Hypoglycorrhachia in bacterial meningitis was first observed in 1925 by Killian [5]. It has been speculated to.be due to increased use by bacteria or leukocytes in the subarachnoid space, altered transport from blood into CSF, or increased use of glucose by the brain during meningitis. Petersdorf et al. [7] observed in experimental pneumococcal meningitis that hypoglycorrhachia was associated with bacterial metabolism during replication, with little contribution from granulocytes. This was supported by Hochwald et al. [21], who observed hypoglycorrhachia with experimental Klebsiella pneumoniae and S. pneumoniae meningitis but not when meningeal inflammation was induced by intracisternal injection of heat-killed aliquots of these bacterial species. However, more recent investigations, with highly-purified, active components of bacterial cell membranes administered intracisternally, have documented that CSF glucose may be reduced in response to this stimulus in the absence of actively multiplying bacteria [22].
Table 5. Microdialysate concentration and microdialysate-to-serum ratio of glucose in frontal cortex and hippocampus in rabbits with pneumococcal meningitis and controls. Meningitis Time (h)
Cortex
Control
Hippocampus (n= 16)
Cortex (n = 13)
Hippocampus (n = 13)
3.27 ± 2.21 1.83 ± 1.48*
4.79 ± 4.25 2.76 ± 2.41
3.38 ± 1.79 2.75 ± 1.67
5.19 ± 3.14 2.62 ± 1.62
0.109 ± 0.064
0.132 ± 0.059
0.173 ±0.088
0.161 ± 0.079
(n
= 16)
Microdialysate concentration (mg/dL) 1-2 21-22
Microdialysate-to-serum ratio 21-22
* Significant difference from 1-2 h (P < .05).
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on September 2, 2015
NOTE. Data are mmol/L. * Significant difference from control (P < .001).
550
Guerra-Romero et al.
References I. Saez-Llorens X, Ramilo O. Mustafa MM. Mertsola J. McCracken GH. Molecular pathophysiology of bacterial meningitis: current concepts and therapeutic implications. J Pediatr 1990;116;671-84. 2. Tunkel AR, Wispelwey B, Scheid WM. Bacterial meningitis: recent advances in pathophysiology and treatment. Ann Intern Med 1990;112:610-23. 3. Levinson A. The hydrogen-ion concentration of cerebrospinal fluid. Studies in meningitis. J Infect Dis 1917;21 :556-70. 4. Nishimura K. The lactic acid content of blood and spinal fluid. Proc Soc Exp Bioi Med 1924;22:323-4. 5. Killian J. Lactic acid of normal and pathological spinal fluids. Proc Soc Exp Bioi Med 1925;23:255-7.
6. Moxon ER, Smith AL, Averill DR. Brain carbohydrate metabolism during experimental Haemophilus influenzae meningitis. Pediatr Res 1979; 13:52-9. 7. Petersdorf R, Swarner D. Garcia M. Studies on the pathogenesis of meningitis. Relationship of phagocytosis to the fall in cerebrospinal fluid sugar in experimental pneumococcal meningitis. J Lab Clin Med 1963;61:745-54. 8. Prockop L. Fishman R. Pathophysiology of the cerebrospinal fluid changes in experimental pneumococcal meningitis. Trans Am Neurol Assoc 1966;91: 126-31. 9. Cooper A, Beaty H. Oppenheimer S, Goodner R, PetersdorfR. Studies on the pathogenesis ofmeningitis. Glucose transport and spinal fluid production in experimental pneumoccocal meningitis. J Lab Clin Med 1968;71:473-83. 10. Tureen JH, Tauber MG. Sande MA. Effect of hydration status on cerebral blood flow and cerebrospinal fluid lactic acidosis in rabbits with experimental meningitis. J Clin Invest 1992;89:947-53. II. Faden AI, Demediuk P, Panter SS. Vink R. The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 1989;244:798-800. 12. Benveniste H. Drejer J. Schousboe A, Diemer N. Elevation of extracellular concentration of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 1984;43: 1369-74. 13. Globus MYT, Busto R, Dietrich WD, Martinez E, Valdez I, Ginsberg MD. Effect ofischemia on in vivo release ofstriatal dopamine. glutamate and gamma-aminobutyric acid studied by intracerebral microdialysis. J Neurochem 1988;51:1455-64. 14. Dacey RG. Sande MA. Effect of probenecid on cerebrospinal fluid concentrations of penicillin and cephalosporin derivatives. Antimicrob Agents Chemother 1974;6:437-41. 15. Alexander Sc. Workman RD, Lambertsen CJ. Hyperthermia. lactic acid infusion. and the composition of arterial blood and cerebrospinal fluid. Am J Physiol 1962;202: 1049-54. 16. Kopetzky S, Fishberg E. Changes in distribution ratio of constituents of blood and spinal fluid in meningitis. J Lab Clin Med 1933; 18:796801. 17. Posner J. Plum F. Independence of blood and cerebrospinal fluid lactate. Arch Neurol 1967;16:492-6. 18. De Santis A, Killian J. Garcia T. Lactic acid of spinal fluid in meningitis. Am J Dis Child 1933;46:239-49. 19. Lindquist L. Wibom R. Lundberg P. Hultman E. Experimental meningitis in the rabbit. Cerebral energy metabolism in relation to increased cerebrospinal fluid concentrations of lactate. Acta Neurol Scand 1987;75:405-9. 20. Andersen N, Gyring J, Hansen A, Laursen H, Siesjo B. Brain acidosis in experimental pneumococcal meningitis. J Cereb Blood Flow Metab 1989;9:381-7. 21. Hochwald G, Nakamura S. Chase R, Gorelick J. Cerebrospinal fluid glucose and leukocyte responses in experimental meningitis. J Neurol Sci 1984;63:381-91. 22. Tuomanen E, Tomasz A, Hengstler B. Zak O. The relative role of bacterial cell wall and capsule in the induction of inflammation in pneumococcal meningitis. J Infect Dis 1985;151:535-45. 23. Fishman RA. Carrier transport of glucose between blood and cerebrospinal fluid. Am J Physiol 1964;206:836-44. 24. Brooke WR. Alterations in the glucose transport mechanism in patients with complications of bacterial meningitis. Pediatrics 1964;34:491502.
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on September 2, 2015
An alternative explanation for hypoglycorrhachia in meningitis was suggested by Fishman [23] and later extended by Prokop and Fishman [8], who demonstrated in experimental canine meningitis that low CSF glucose reflects the inhibition of carrier-mediated transport across the BBB. This was also shown in a single study involving children with bacterial meningitis, in which lack of elevation ofCSF glucose despite elevated serum glucose was associated with poor neurologic outcome [24]. As expected on the basis of these studies, we also found a reduction in concentration of glucose in brain interstitial fluid in the present study, even though the differences were less pronounced than for lactate and reached statistical significance only in the cortex. Our results do not permit a quantitative discrimination between a diffusion block at the level of the BBBand locally increased use ofglucose by the tissue as the cause of its reduced concentration. However, the increased tissue lactate concentration suggests that increased glucose consumption as a result of anaerobic glycolysis contributes to reduced tissue glucose concentration, while the reduced microdialysate-to-serum glucose ratio points to reduced diffusion across the BBB. It is therefore likely that both factors contribute to hypoglycorrhachia during meningitis. Our data support the hypothesis that anaerobic brain metabolism in bacterial meningitis contributes to the development of increased CSF lactate concentration and hypoglycorrhachia, rather than that these are changes occurring solely within the subarachnoid space. It seems likely that local changes in the brain, either as a result of ischemia or mediated by humoral factors, induce increased brain production of lactate, which contributes to increased CSF lactate concentration. Increased use ofglucose by the brain, in addition to the previously recognized disturbances of glucose transport across the BBB, may contribute to hypoglycorrhachia during bacterial meningitis.
110 1992; 166 (September)
Lactate and Glucose Concentrations in Brain Interstitial Fluid, Cerebrospinal Fluid, and Serum during Experimental Pneumococcal Meningitis Luis Guerra-Romero, Martin G. Tauber, Michael A. Fournier, and Jay H. Tureen
Microbial Pathogenesis Unit. San Francisco General Hospital. and Departments ofMedicine and Pediatrics, University ofCalifornia. San Francisco
Pathophysiologic changes in the central nervous system (CNS) in bacterial meningitis include metabolic disturbances, brain edema, intracranial hypertension, and reduction of cerebral blood flow [I, 2]. These alterations may directly or indirectly lead to neuronal dysfunction that can result in neurologic sequelae or death. Metabolic abnormalities within the CNS in bacterial meningitis, characterized by hypoglycorrhachia and cerebrospinal fluid (CSF) lactate accumulation, were identified in the I 920s [3-5]. The simultaneous occurrence of these changes has led some investigators to propose that anaerobic glycolysis with lactate production explains both, but the locus of the abnormal metabolism remains controversial [6]. It was initially hypothesized that metabolism by bacteria and leukocytes in the subarachnoid space resulted in glucose consumption with production of lactate [7]. Subsequently, alteration of glucose transport from blood to CSF has been documented [8, 9], raising the possibility that impaired diffusion across the blood-brain barrier (BBB) was responsible for hypoglycorrhachia; however, this did not address the coexisting CSF'lactic acidosis.
Received 7 February 1992; revised 24 April 1992. Presented in part: 31st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago. September 1991 (abstract 914). Grant support: Ministerio de Education i Licencia and Sociedad de Enfermedades Infectiosas i Microbiologia Clinica ofSpain (L.G.-R.). Roche Laboratory (M.G.T.). and National Institutes of Health (NS-27310 to J.H.T.). Reprints or correspondence: Dr. Jay H. Tureen. Microbial Pathogenesis Unit. Box 081 I, University of California San Francisco. 3rd and Parnassus Ave.. San Francisco. CA 94143.
The Journal of Infectious Diseases 1992;166:546-50 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6603-0013$01.00
Finally, recent data suggest that cerebral ischemia in meningitis could result in abnormal brain metabolism of glucose resulting in increased lactate production [10]. The changes oflactate and glucose concentrations in CSF are the net results of transfer into the subarachnoid space, local production (lactate) or utilization (glucose) in the CSF, and transfer across the BBB.To investigate these changes, we simultaneously and sequentially measured glucose and lactate in tissue, serum, and CSF. In vivo microdialysis was used, as it has been successful as a tool for sequentially studying brain interstitial fluid in other neurophysiologic and experimental models of CNS injury [11-13]. The purpose of the present study was to elucidate the mechanism and locus of metabolic changes within the CNS in bacterial meningitis during developing infection.
Materials and Methods Model ofexperimental meningitis. Meningitis was produced by intracisternal injection of 0.3 mL of saline containing an inoculum of 106-10 7 cfu of Streptococcus pneumoniae type 3 as described by Dacey and Sande [14]. New Zealand White rabbits (2.0-2.5 kg) were anesthetized by intravenous (iv) urethane (2.0 g/kg) for all procedures. Light general anesthesia was maintained by supplemental doses of urethane (0.5 g/kg iv). Local anesthesia for skin incisions was provided by lidocaine HCl. A polyethylene catheter (PE-90) was inserted into the femoral artery for measurement of blood pressure and blood sampling. A dental acrylic cap containing a turnbuckle was affixed to the outer table of cranial bone by steel screws. Rabbits were immobilized in a restraining frame, and cisternal puncture was done with a 25-gauge 8.9-cm spinal needle (Becton Dickinson. Franklin Lakes, NJ) for infection and sampling of CSF.
Downloaded from http://jid.oxfordjournals.org/ at Cambridge University on September 2, 2015
Metabolic abnormalities during bacterial meningitisinclude hypoglycorrhachiaand cerebrospinal fluid (CSF) lactate accumulation. The mechanisms by which these alterations occur within the central nervous system(CNS) are still incompletelydelineated. To determine the evolution of these changes and establish the locus of abnormal metabolism during meningitis, glucose and lactate concentrations in brain interstitial fluid, CSF, and serum were measured simultaneously and sequentially during experimental pneumococcal meningitis in rabbits. Interstitial fluid samples were obtained from the frontal cortex and hippocampus by using in situ brain microdialysis, and serum and CSF were directly sampled. There was an increase of CSF lactate concentration, accompanied by increased local production of lactate in the brain, and a decrease of CSF-toserum glucose ratio that was paralleled by a decrease in cortical glucose concentration. Brain microdialysate lactate concentration was not affected by either systemic lactic acidosis or artificially elevated CSF lactate concentration. These data support the hypothesis that the brain is a locus for anaerobic glycolysis during meningitis, resulting in increased lactate production and perhaps contributing to decreased tissue glucose concentration.
1ID 1992; 166 (September)
Lactate and Glucose in Experimental Meningitis
Table 1. Physiologicvariablesat 22 h in rabbits with pneumococcal meningitis and controls. Meningitis (n ~ 16) Blood pressure (mm Hg) Arterial pH HC0 3 (mmol/L) Pe02 (mm Hg)
Control ~ 13)
(n
81.1 ± 10.8
80.0 ± 15.9
7.36 ± 0.11* 16.0±4.4 28.1 ± 1O.0t
7.26 ± 0.08 18.8 ± 2.7 45.9 ± 10.6
* Significant difference from control t
(P < .05). Significant difference from control (P < .00 I).
gases were measured in a blood gas analyzer (Radiometer ABL 2; Radiometer, Copenhagen). Arterial pressure was measured with a water-filled pressure transducer (model P-23 XL; Gould, Santa Clara, CA) and recorded on a multichannel polygraph (5/6 H recorder; Gilson Medical Electronics, Middleton, WI). Statistical analysis. Data were expressed as mean ± SD and were analyzed by unpaired Student's t tests for comparison between groups, by paired Student's t test for comparison between paired samples ofthe same group, and by linear regression analysis for correlations between parameters.
Results CSF titers and leukocyte counts. The bacterial titer in the CSF for the infected animals was 8.76 ± 1.10 10glO cfu/ml. at 22 h of infection. At that time, the number of leukocytes in the CSF was 6.833 ± 3.850 X 103/mm '. Control animals had sterile cultures and a leukocyte count of 43 ± 79/mm 3 at 22 h. Physiologic variables. No significant difference in mean arterial blood pressure was observed at the end of the experiment between meningitis and control groups (table 1). Arterial blood gases at 22 h demonstrated a mild metabolic acidosis in both groups and a compensatory respiratory alkalosis in infected rabbits. As a consequence, serum pH was higher (7.36 ± 0.11 vs. 7.26 ± 0.08, P < .05) and Pco, was lower (28.1 ± 10 vs. 45.9 ± 10.6 mm Hg, P < .001) in the group with meningitis. Serum lactate and glucose. Serum lactate concentrations at 16 and 22 h in infected rabbits were significantly higher than in controls (2.33 ± 1.13 vs. 0.86 ± 0.58 mmol/L at 16 h and 3.66 ± 2.75 vs. 0.78 ± 0.51 mrnol/L at 22 h, P < .001). Although serum glucose concentrations at 22 h were not significantly different between the two groups, the infected animals (but not the controls) had significantly increased levels at the end of the infection compared with their baseline values (116.9 ± 32.4 and 183.8 ± 50.2 mg/dL at 0 and 22 h, respectively, P < .00 I; table 2). CSF lactate and glucose. CSF lactate concentration increased progressively in infected rabbits but did not change in controls (table 3). Lactate was significantly higher at 22 h
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Microdialysis probes (2-mm membrane tip length; Bioanalytical Systems, West Lafayette, IN) were tested before implantation by perfusion with artificial CSF (0.75% NaCl, 0.02% KCl, 0.015% CaCI2 , and 0.019% MgCl2 diluted in filter-sterilized deionized distilled water) while suspended in a solution of known glucose and lactate concentrations. Glucose and lactate concentrations were measured in effluent to ensure that recovery was consistent (in vitro recovery test). Probes were used if they demonstrated recoveries in the range of 20%- 30% for lactate and 15%-20% for glucose. Probes were positioned with a micromanipulator in the left frontal cortex (4.0 mm anterior to the bregma, 4.0 mm lateral to the sagittal suture, 3.0 mm from the pial surface) and the right hippocampus (6.0 mm posterior to the bregma, 7.0 mm lateral to the sagittal suture, 6.0 mm from pial surface). After placement, the probes were fixed to the skull with dental cement. Throughout the study, probes were perfused with artificial CSF with a syringe pump (model 931; Harvard Apparatus, Millis, MA) at a rate of 1.36 pL/min. Fractions ofdialysate were periodically collected in polypropylene tubes for analysis. The perfusate from the first hour was discharged during stabilization following probe implantation. At the conclusion of the study, rabbits were killed with a lethal dose of pentobarbital (150 mg/kg iv), postmortem CSF and blood samples were collected to serve as an internal control, and Evans blue dye was pumped through the probe. After removal of the brain, correct anatomic placement of the probes was confirmed macroscopically. Study design. After probe implantation, animals were intracisternally infected with 0.3 mL of S. pneumoniae in 0.3 mL of sterile, non bacteriostatic saline without preservative; controls received saline alone. Blood samples for arterial lactate and glucose concentrations and blood gases were taken at 0, 6, 16, and 22 h; CSF was taken at 0, 16, and 22 h for measurement of lactate and glucose and at 22 h for measurement of bacterial titer and white blood cell count. Tissue microdialysate was sampled for glucose and lactate measurement during the following periods after implantation: 1-2,2-5,5-6,6-16, 16-17, 17-19, 19-21, and 21-22 h and postmortem. Blood pressure was measured at 22 h. To exclude the possibility that tissue lactate concentration could increase by diffusion from either CSF or serum, two additional groups were studied. In one group, CSF lactic acidosis was induced in uninfected animals by two intracisternal injections 30 min apart, of 3.75 mg of lactic acid in 0.25 mL of saline. Microdialysate, CSF, and blood were periodicallymeasured for 2 h. In a second group of infected rabbits, 0.5 g oflactic acid in 10 mL of distilled water was infused iv over 30 min early in the course of the infection (14 h) to produce severe systemic lactic acidosis, as described by Alexander et al. [15]. Microdialysate, CSF, and blood were sampled at 0, 30, and 60 min. Experimental parameters. Bacterial titers in CSF were determined by serial l O-fold dilution of CSF in saline after overnight incubation on blood agar plates at 37°C in 5% CO 2 and expressed as 10glO colony-forming units per milliliter. White blood cell counts in CSF were determined in a hemocytometer. CSF, blood, and microdialysate concentrations oflactate and glucose were measured immediately after sampling in a two-channel autoanalyzer (YSI 2300 G/L; Yellow Springs, OH). Arterial blood
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548
Table 2. Serum concentrations of lactate and glucose in rabbits with pneumococcal meningitis and controls. Meningitis (n Time (h) 0 6 16 22
Lactate (mmol/L) 0.89 ± 1.09 ± 2.33 ± 3.66 ±
0.58 0.93 1.33* 2.75*
=
Control (n
16)
Glucose (mg/dL) 116.9 106.0 177.1 183.8
± ± ± ±
32.4 35.9 52.2 t 50.2 t
Lactate (mmol/L) 1.27 ± 0.71 1.11 ± 0.61 0.86 ± 0.58 0.78±0.51
=
13) Glucose (mg/dL)
117.6 121.1 135.8 145.1
± ± ± ±
28.6 25.3 60.0 69.4
* Significant difference from control (P < .00 I). t Significant difference from 0 h (P < .001).
Microdialysate concentration oflactate after induction ofartificial CSF and systemic lactic acidosis. To test whether in-
creased tissue lactate could be the result of diffusion from eSF to brain interstitial fluid, sodium lactate was administered intracisternally to 3 normal rabbits. eSF lactate concentration remained >2.8 mmoljL for at least 120 min after
infusion, with a peak of 25.2 mmol/L. Mean eSF l~ctate concentration over this period was 11.3 ± 8.2 mmol/L, which is similar to that observed during infection. The dialysate lactate concentrations from cortex and hippocampus samples did not change during the sampling period (pre- and postinfusion concentrations: 0.14 ± 0.05 and 0.13 ± 0.02 rnmol/L, respectively, for cortex; 0.15 ± 0.04 and 0.14 ± 0.03 for hippocampus). To test whether lactate could diffuse from blood to brain interstitial fluid in the presence of a damaged BBB during meningitis, sodium lactate was infused intravenously in 3 infected rabbits. Serum lactate pre- and postinfusion values were 1.3 ± 0.8 and 4.50 ± 1.13 mmoljL, respectively. Postinfusion serum lactate concentration was comparable to that in infected rabbits after 22 h of infection. The dialysate lactate concentrations were similar before and after the sodium lactate infusion (0.20 ± 0.10 mmol/L at 0 min, 0.20 ± 0.10 mrnol/L at 30 min, and 0.23 ± 0.12 mmoljL at 60 min).
Discussion This study was designed to examine the development of metabolic abnormalities in the eNS during bacterial meningitis by using in situ brain microdialysis. Although it has been known for >60 years that increased eSF lactate concentration and hypoglycorrhachia are commonly present in human bacterial meningitis, the mechanisms for these abnormalities are not completely delineated. Metabolic abnormalities in the eNS were first noted in 1917 by Levinson [3], who suggested that low eSF pH was likely due to increased lactic acid concentration. In 1933, Kopetzky and Fishberg [16] suggested that "anemia of the brain" due to increased intracranial pressure and reduced blood oxygenation might induce anaerobic oxidation of carbohydrates with generation oflarge quantities oflactic acid. This hypothesis was further supported by Posner and Plum [17], who demonstrated that lactate concentration in the eSF was a reliable indicator of brain lactate content. The alternative hypothesis, linking eSF lactic acidosis with hy-
Table 3. Cerebrospinal fluid concentrations of lactate and glucosein rabbitswith pneumococcal meningitis and controls. Meningitis (n Time
=
16)
Control (n
=
13)
(h)
Lactate (mmoIjL)
Glucose (mg/dL)
Lactate (rnmol/L)
Glucose (mg/dL)
0 16 22
1.67 ± 0.38 13.85 ± 2.50 15.81 ± 3.70*
102.9 ± 23.4 111.3 ± 63.3 87.9 ± 46.6
1.69 ± 0.26
96.5 ± 10.6 ND 118.5 ± 58.7
NOTE.
ND
=
NO 1.83 ± 0.43
not determined.
* Significant difference from control
(P < .00 I).
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in infected rabbits than in controls (15.81 ± 3.70 vs. 1.83 ± 0.43 mmolfL, P < .001). eSF glucose concentration was lower in infected animals than in controls, but the difference was not statistically significant. There was a significant difference in the eSF-to-blood glucose ratios at 22 h between infected and control animals, with a marked reduction in infected rabbits (0.47 ± 0.19 vs. 0.79 ± 0.19, P < .00 I). There were no significant correlations between eSF lactate or glucose concentrations and bacterial titer or eSF white blood cell counts. Microdialysate lactate and glucose. Microdialysate concentrations of lactate from frontal cortex and hippocampus of infected rabbits showed a progressive increase during the course of the infection, with similar rates of lactate accumulation in both tissues. Significant increases at both sites in infected rabbits were present at 16 h, and this trend continued for the rest of the study period (table 4, P < .001). No such changes were seen in control rabbits. There were no significant correlations between lactate concentrations and Pco, or other physiologic values in cortex or hippocampus at any time in the infected animals. Microdialysate concentrations of glucose from frontal cortex and hippocampus declined progressively in both infected and control rabbits; in infected rabbits, glucose concentration in cortex but not hippocampus was significantly reduced compared with baseline (3.27 ± 2.21 mg/dL at 1-2 h vs. 1.83 ± 1.48 mg/dL at 22 h, P < .05). Because tissue concentration of glucose can be affected by serum concentration ofglucose, we examined the microdialysate-to-serum ratio of concentration of glucose and found that there was a trend to a lower ratio in the cortex of infected rabbits compared with controls (0.109 ± 0.064 vs. 0.173 ± 0.088, P = .07) that was not present in hippocampal samples (table 5).
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Table 4.
Microdialysate concentration oflactate in frontal cortex and hippocampus in rabbits with pneumococcal meningitis and controls. Meningitis
Sampling period (h) 1-2 2-5 5-6 6-16 16-17 17-19 19-21 21-22
Cortex (n
0.14 0.19 0.19 0.21 0.26 0.28 0.34 0.35
Control Hippocampus
= 14) ± ± ± ± ± ± ± ±
(n
0.05 0.03 0.06 0.06 0.07* 0.16* 0.18* 0.18*
Cortex (n = 10)
= 14)
0.15 ± 0.08 0.18 ± 0.07 0.18 ± 0.07 0.21±0.10 0.31 ±0.14* 0.34 ± 0.17* 0.34 ± 0.12* 0.36 ± 0.16*
0.19 0.18 0.17 0.13 0.14 0.19 0.16 0.14
± ± ± ± ± ± ± ±
Hippocampus (n
0.09 0.07 0.06 0.05 0.08 0.07 0.05 0.05
0.17 0.21 0.18 0.20 0.18 0.16 0.16 0.16
= II) ± ± ± ± ± ± ± ±
0.13 0.11 0.11 O.IO 0.10 0.07 0.08 0.08
poglycorrhachia, was proposed by Petersdorf et al. [7], who suggested that lactate was produced and glucose consumed in the subarachnoid space by metabolism of bacteria and leukocytes [18]. Support of this by other investigators is based largely on the failure to demonstrate differences in brain lactate concentration between animals with meningitis and uninfected controls [19, 20]. However, each of these studies examined tissue and CSF lactate concentration at the conclusion of the study and the data may have been influenced by exclusion of the sickest animals, as 25%-58% of the rabbits either died prematurely or were excluded because of hypotension. In our study, sequential measurements of lactate in brain tissue documented a steady and progressive increase in lactate concentrations in interstitial fluid of two areas of the brain, the frontal cortex and the hippocampus, that were significantly elevated after 16 h of infection and continued to rise throughout the study period. That this was due to local production by brain is further supported by the lack of diffusion from either the CSF or the intravascular compartment and is in agreement with data reported by others [17]. The larger percentage increase of lactate in CSF than in intersti-
tial fluid may reflect either that lactate can be locally produced in the subarachnoid space or that clearance from the interstitium to the CSF is more effective than from the CSF to the blood, resulting in accumulation in CSF. Hypoglycorrhachia in bacterial meningitis was first observed in 1925 by Killian [5]. It has been speculated to.be due to increased use by bacteria or leukocytes in the subarachnoid space, altered transport from blood into CSF, or increased use of glucose by the brain during meningitis. Petersdorf et al. [7] observed in experimental pneumococcal meningitis that hypoglycorrhachia was associated with bacterial metabolism during replication, with little contribution from granulocytes. This was supported by Hochwald et al. [21], who observed hypoglycorrhachia with experimental Klebsiella pneumoniae and S. pneumoniae meningitis but not when meningeal inflammation was induced by intracisternal injection of heat-killed aliquots of these bacterial species. However, more recent investigations, with highly-purified, active components of bacterial cell membranes administered intracisternally, have documented that CSF glucose may be reduced in response to this stimulus in the absence of actively multiplying bacteria [22].
Table 5. Microdialysate concentration and microdialysate-to-serum ratio of glucose in frontal cortex and hippocampus in rabbits with pneumococcal meningitis and controls. Meningitis Time (h)
Cortex
Control
Hippocampus (n= 16)
Cortex (n = 13)
Hippocampus (n = 13)
3.27 ± 2.21 1.83 ± 1.48*
4.79 ± 4.25 2.76 ± 2.41
3.38 ± 1.79 2.75 ± 1.67
5.19 ± 3.14 2.62 ± 1.62
0.109 ± 0.064
0.132 ± 0.059
0.173 ±0.088
0.161 ± 0.079
(n
= 16)
Microdialysate concentration (mg/dL) 1-2 21-22
Microdialysate-to-serum ratio 21-22
* Significant difference from 1-2 h (P < .05).
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NOTE. Data are mmol/L. * Significant difference from control (P < .001).
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References I. Saez-Llorens X, Ramilo O. Mustafa MM. Mertsola J. McCracken GH. Molecular pathophysiology of bacterial meningitis: current concepts and therapeutic implications. J Pediatr 1990;116;671-84. 2. Tunkel AR, Wispelwey B, Scheid WM. Bacterial meningitis: recent advances in pathophysiology and treatment. Ann Intern Med 1990;112:610-23. 3. Levinson A. The hydrogen-ion concentration of cerebrospinal fluid. Studies in meningitis. J Infect Dis 1917;21 :556-70. 4. Nishimura K. The lactic acid content of blood and spinal fluid. Proc Soc Exp Bioi Med 1924;22:323-4. 5. Killian J. Lactic acid of normal and pathological spinal fluids. Proc Soc Exp Bioi Med 1925;23:255-7.
6. Moxon ER, Smith AL, Averill DR. Brain carbohydrate metabolism during experimental Haemophilus influenzae meningitis. Pediatr Res 1979; 13:52-9. 7. Petersdorf R, Swarner D. Garcia M. Studies on the pathogenesis of meningitis. Relationship of phagocytosis to the fall in cerebrospinal fluid sugar in experimental pneumococcal meningitis. J Lab Clin Med 1963;61:745-54. 8. Prockop L. Fishman R. Pathophysiology of the cerebrospinal fluid changes in experimental pneumococcal meningitis. Trans Am Neurol Assoc 1966;91: 126-31. 9. Cooper A, Beaty H. Oppenheimer S, Goodner R, PetersdorfR. Studies on the pathogenesis ofmeningitis. Glucose transport and spinal fluid production in experimental pneumoccocal meningitis. J Lab Clin Med 1968;71:473-83. 10. Tureen JH, Tauber MG. Sande MA. Effect of hydration status on cerebral blood flow and cerebrospinal fluid lactic acidosis in rabbits with experimental meningitis. J Clin Invest 1992;89:947-53. II. Faden AI, Demediuk P, Panter SS. Vink R. The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 1989;244:798-800. 12. Benveniste H. Drejer J. Schousboe A, Diemer N. Elevation of extracellular concentration of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 1984;43: 1369-74. 13. Globus MYT, Busto R, Dietrich WD, Martinez E, Valdez I, Ginsberg MD. Effect ofischemia on in vivo release ofstriatal dopamine. glutamate and gamma-aminobutyric acid studied by intracerebral microdialysis. J Neurochem 1988;51:1455-64. 14. Dacey RG. Sande MA. Effect of probenecid on cerebrospinal fluid concentrations of penicillin and cephalosporin derivatives. Antimicrob Agents Chemother 1974;6:437-41. 15. Alexander Sc. Workman RD, Lambertsen CJ. Hyperthermia. lactic acid infusion. and the composition of arterial blood and cerebrospinal fluid. Am J Physiol 1962;202: 1049-54. 16. Kopetzky S, Fishberg E. Changes in distribution ratio of constituents of blood and spinal fluid in meningitis. J Lab Clin Med 1933; 18:796801. 17. Posner J. Plum F. Independence of blood and cerebrospinal fluid lactate. Arch Neurol 1967;16:492-6. 18. De Santis A, Killian J. Garcia T. Lactic acid of spinal fluid in meningitis. Am J Dis Child 1933;46:239-49. 19. Lindquist L. Wibom R. Lundberg P. Hultman E. Experimental meningitis in the rabbit. Cerebral energy metabolism in relation to increased cerebrospinal fluid concentrations of lactate. Acta Neurol Scand 1987;75:405-9. 20. Andersen N, Gyring J, Hansen A, Laursen H, Siesjo B. Brain acidosis in experimental pneumococcal meningitis. J Cereb Blood Flow Metab 1989;9:381-7. 21. Hochwald G, Nakamura S. Chase R, Gorelick J. Cerebrospinal fluid glucose and leukocyte responses in experimental meningitis. J Neurol Sci 1984;63:381-91. 22. Tuomanen E, Tomasz A, Hengstler B. Zak O. The relative role of bacterial cell wall and capsule in the induction of inflammation in pneumococcal meningitis. J Infect Dis 1985;151:535-45. 23. Fishman RA. Carrier transport of glucose between blood and cerebrospinal fluid. Am J Physiol 1964;206:836-44. 24. Brooke WR. Alterations in the glucose transport mechanism in patients with complications of bacterial meningitis. Pediatrics 1964;34:491502.
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An alternative explanation for hypoglycorrhachia in meningitis was suggested by Fishman [23] and later extended by Prokop and Fishman [8], who demonstrated in experimental canine meningitis that low CSF glucose reflects the inhibition of carrier-mediated transport across the BBB. This was also shown in a single study involving children with bacterial meningitis, in which lack of elevation ofCSF glucose despite elevated serum glucose was associated with poor neurologic outcome [24]. As expected on the basis of these studies, we also found a reduction in concentration of glucose in brain interstitial fluid in the present study, even though the differences were less pronounced than for lactate and reached statistical significance only in the cortex. Our results do not permit a quantitative discrimination between a diffusion block at the level of the BBBand locally increased use ofglucose by the tissue as the cause of its reduced concentration. However, the increased tissue lactate concentration suggests that increased glucose consumption as a result of anaerobic glycolysis contributes to reduced tissue glucose concentration, while the reduced microdialysate-to-serum glucose ratio points to reduced diffusion across the BBB. It is therefore likely that both factors contribute to hypoglycorrhachia during meningitis. Our data support the hypothesis that anaerobic brain metabolism in bacterial meningitis contributes to the development of increased CSF lactate concentration and hypoglycorrhachia, rather than that these are changes occurring solely within the subarachnoid space. It seems likely that local changes in the brain, either as a result of ischemia or mediated by humoral factors, induce increased brain production of lactate, which contributes to increased CSF lactate concentration. Increased use ofglucose by the brain, in addition to the previously recognized disturbances of glucose transport across the BBB, may contribute to hypoglycorrhachia during bacterial meningitis.
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