Comparative study of select biochemical markers in cerebrospinal fluid of healthy dogs before and after treatment with nutraceuticals.

BACKGROUND: Several studies indicate that changes in cerebrospinal fluid (CSF) composition depend on the disease stage and reflect modification of brain energy metabolism (BEM). Also, it has been reported that a decline in cognitive functions may be mitigated by incorporating nutraceuticals in the diet. OBJECTIVE: Assuming the beneficial effect of nutraceuticals on BEM and oxidative damage, the aim of this study was to determine if the administration of a nutraceutical compound results in changes of select CSF biomarkers in healthy adult Beagle dogs. METHODS: Two separate CSF and blood samples were obtained from 11 healthy adult Beagle dogs, before and after 50 days of treatment with a veterinary combined nutraceutical. CSF analysis included a total nucleated cell count, total protein, glucose, sodium, chloride, potassium, pyruvate, and lactate concentrations, and calculation of lactate/pyruvate ratio. CBC and serum biochemistry were also performed. The Wilcoxon test was used to analyze the significance of the changes after nutraceutical treatment. RESULTS: All studied variables remained within reference intervals, before and after treatment. A significant increase in CSF sodium and glucose concentration, and a decrease in lactate levels, was observed after treatment (P < .05), and the lactate/pyruvate ratio was decreased after treatment (P = .05). In serum, sodium and chloride concentrations were significantly increased (P < .05), and creatinine concentration was significantly decreased (P < .05) after treatment. CONCLUSIONS: After 50 days of treatment with a nutraceutical compound, CSF glucose, sodium, and lactate concentrations, and L/P ratio were significantly different, suggesting an influence of nutraceuticals' administration on CSF composition.

Lactate and pyruvate levels in blood and cerebrospinal fluid in patients with Menkes disease.

OBJECTIVE: To examine levels of lactate (LA) and pyruvate (PA) in both blood and cerebrospinal fluid (CSF) in patients with Menkes disease (MNK). STUDY DESIGN: A nationwide survey involving a retrospective review of medical records or medical record summaries of 42 male patients with MNK born between 1993 and 2008 were performed, and the genetic analysis of their ATP7A gene was reviewed. RESULTS: In these patients, LA and PA levels and the lactate vs pyruvate ratio (L/P ratio) at diagnosis in both blood and CSF were abnormally high. There were no significant differences in LA levels, PA levels, and the L/P ratio between blood and CSF at diagnosis (P > .05). There was also no correlation between LA levels, PA levels, and the L/P ratio, and age at measurement (P > .05). There was no or slight metabolic acidosis, as analyzed by blood gas analysis, in 7 patients. During treatment with subcutaneous injections of copper-histidine, LA and PA levels and the L/P ratio in both the blood and CSF decreased. CONCLUSION: Our findings suggest that LA and PA levels, and in particular, the L/P ratio, and blood gas analysis can be used to guide the diagnosis and management of MNK.

Intraparenchymal microdialysis after acute spinal cord injury reveals differential metabolic responses to contusive versus compressive mechanisms of injury.

In animal models, spinal cord injury (SCI) is typically imparted by contusion alone (e.g., weight drop) or by compression alone (e.g., clip compression). In humans, however, the cord is typically injured by a combination of violent contusion followed by varying degrees of ongoing mechanical compression. Understanding how the combination of contusion and compression influences the early pathophysiology of SCI is important for the pre-clinical development of neuroprotective therapies that are applicable to the human condition. Disturbances in the metabolism of energy-related substrates such as lactate, pyruvate, and glucose are important aspects of secondary damage. In this study, we used a porcine model of traumatic SCI to determine the extent to which these metabolites were influenced by contusion followed by sustained compression, using the microdialysis technique. Following contusion injury, lactate and pyruvate levels near the epicenter both increased, while glucose remained quite stable. When the contusion injury was followed by sustained compression, we observed a transient rise in lactate, while pyruvate and glucose levels dropped rapidly, which may reflect decreased regional spinal cord blood flow. Furthermore, contusion with sustained compression produced a prolonged and dramatic increase in the lactate-pyruvate (L/P) ratio as a marker of tissue hypoxia, whereas after contusion injury alone, a transient and less significant elevation of the L/P ratio was observed. In this study, we demonstrate that disturbances in energy metabolism within the injured spinal cord vary greatly depending upon the biomechanical nature of the injury. Such differences are likely to be relevant to the applicability of novel therapies targeting specific aspects of the early secondary injury cascade after acute human SCI.

Metabolomic analysis of cerebrospinal fluid indicates iron deficiency compromises cerebral energy metabolism in the infant monkey.

Iron deficiency anemia affects many pregnant women and young infants worldwide. The health impact is significant, given iron's known role in many body functions, including oxidative and lipid metabolism, protein synthesis and brain neurochemistry. The following research determined if (1)H NMR spectroscopy-based metabolomic analysis of cerebrospinal fluid (CSF) could detect the adverse influence of early life iron deficiency on the central nervous system. Using a controlled dietary model in 43 infant primates, distinct differences were found in spectra acquired at 600 MHz from the CSF of anemic monkeys. Three metabolite ratios, citrate/pyruvate, citrate/lactate and pyruvate/glutamine ratios, differed significantly in the iron deficient infant and then normalized following the consumption of dietary iron and improvement of clinical indices of anemia in the heme compartment. This distinctive metabolomic profile associated with anemia in the young infant indicates that CSF can be employed to track the neurological effects of iron deficiency and benefits of iron supplementation.

Cerebrospinal fluid lactate and pyruvate concentrations and their ratio.

OBJECTIVES: Determinations of cerebrospinal fluid (CSF) lactate and pyruvate concentrations and CSF lactate:pyruvate (L/P) ratios are important in several clinical settings, yet published normative data have significant limitations. We sought to determine a large dataset of stringently-defined normative data for CSF lactate and pyruvate concentrations and CSF L/P ratios. DESIGN AND METHODS: We evaluated data from 627 patients who had determinations of CSF lactate and/or CSF pyruvate from 2001 to 2011 at the Cleveland Clinic. Inclusion in the normal reference population required normal CSF cell counts, glucose and protein and routine serum chemistries and absence of progressive brain disorder, epilepsy, or seizure within 24h. Brain MRI, if done, showed no evidence of tumor, acute changes or basal ganglia abnormality. CSF cytology, CSF alanine and immunoglobulin levels, and oligoclonal band analysis were required to be normal, if done. Various inclusion/exclusion criteria were compared. RESULTS: 92 patients fulfilled inclusion/exclusion criteria for a reference population. The 95% central intervals (2.5%-97.5%) for CSF lactate and pyruvate levels were 1.01-2.09mM and 0.03-0.15mM, respectively, and 9.05-26.37 for CSF L/P. There were no significant gender-related differences of CSF lactate or pyruvate concentrations or of CSF L/P. Weak positive correlations between the concentration of CSF lactate or pyruvate and age were noted. CONCLUSIONS: Using stringent inclusion/exclusion criteria, we determined normative data for CSF lactate and pyruvate concentrations and CSF L/P ratios in a large, well-characterized reference population. Normalcy of routine CSF and blood analytes are the most important parameters in determining reference intervals for CSF lactate and pyruvate.

Beneficial effect of pyruvate therapy on Leigh syndrome due to a novel mutation in PDH E1α gene.

Leigh syndrome (LS) is a progressive untreatable degenerating mitochondrial disorder caused by either mitochondrial or nuclear DNA mutations. A patient was a second child of unconsanguineous parents. On the third day of birth, he was transferred to neonatal intensive care units because of severe lactic acidosis. Since he was showing continuous lactic acidosis, the oral supplementation of dichloroacetate (DCA) was introduced on 31st day of birth at initial dose of 50 mg/kg, followed by maintenance dose of 25 mg/kg/every 12 h. The patient was diagnosed with LS due to a point mutation of an A-C at nucleotide 599 in exon 6 in the pyruvate dehydrogenase E1α gene, resulting in the substitution of aspartate for threonine at position 200 (N200T). Although the concentrations of lactate and pyruvate in blood were slightly decreased, his clinical conditions were deteriorating progressively. In order to overcome the mitochondrial or cytosolic energy crisis indicated by lactic acidosis as well as clinical symptoms, we terminated the DCA and administered 0.5 g/kg/day TID of sodium pyruvate orally. We analyzed the therapeutic effects of DCA or sodium pyruvate in the patient, and found that pyruvate therapy significantly decreased lactate, pyruvate and alanine levels, showed no adverse effects such as severe neuropathy seen in DCA, and had better clinical response on development and epilepsy. Though the efficacy of pyruvate on LS will be evaluated by randomized double-blind placebo-controlled study design in future, pyruvate therapy is a possible candidate for therapeutic choice for currently incurable mitochondrial disorders such as LS.

Diagnostic accuracy of blood and CSF lactate in identifying children with mitochondrial diseases affecting the central nervous system.

OBJECTIVE: To determine the diagnostic accuracy of blood and cerebrospinal fluid (CSF) lactate and pyruvate concentrations in identifying children with mitochondrial diseases (MD) affecting the central nervous system (CNS). METHODS: We studied lactate and pyruvate concentrations in paired samples of blood and CSF collected concurrently from 17 patients with MD (Leigh encephalomyelopathy 10, MELAS 5, Pearson disease 1, PDH deficiency 1) and those from control patients (n=49). RESULTS: Although blood and CSF variables (lactate, pyruvate concentrations and lactate/pyruvate ratio) were significantly higher in the mitochondrial group than in the control group, there was considerable overlap of individual values between these two groups. The maximum value of the area under the receiver operating characteristic curve (AUC) was observed for the CSF lactate concentration (0.994, optimal cut-off value 19.9 mg/dl, sensitivity 0.941 and specificity 1.00), followed by the CSF pyruvate level (0.983). There was an inverse relationship between blood lactate and lactate CSF/blood ratio. For blood lactate concentrations between 20 and 40 mg/dl, a significant difference was also noted in the lactate CSF/blood ratio between the two groups (AUC 1.0, optimal cut-off value 0.91, sensitivity 1.0 and specificity 1.0). CONCLUSIONS: Our study suggests that that CSF lactate level>19.9 mg/dl is the most reliable variable for identifying patients with MD affecting the CNS. When blood lactate concentrations are marginally elevated (20-40 mg/dl), lactate CSF/blood ratio>0.91 may also provide diagnostic information.

Cerebrospinal fluid biochemistry reflects effects of therapeutic hypothermia after cardiac arrest in a porcine model.

BACKGROUND: Mild induced hypothermia (MIH) is recommended to treat neurologic injury after cardiac arrest (CA). However, clinical trials to assess MIH benefit after CA have been largely inconclusive. We investigated the subsequent changes in cerebrospinal fluid (CSF) biochemistry after MIH (33°C-34°C for 12 hours) and evaluated the importance of ongoing fever control. METHODS: Thirty-two male Wuzhishan inbred mini pigs (n = 16/group) underwent ventricular fibrillation followed by cardiopulmonary resuscitation and were randomized into 2 groups: hypothermic and control. Upon resumption of spontaneous circulation (ROSC) from CA, the hypothermic group was treated with MIH by endovascular cooling. The control group received no temperature intervention. Core temperatures were continually monitored. At various points throughout the procedure, CSF samples were obtained to measure glutamate, lactate, and pyruvate levels. RESULTS: The core temperature of the hypothermic group was found to have increased postrewarming and reached levels comparable with those of the control group at ROSC 72 hours. In both groups, glutamate increased significantly after ROSC, but the glutamate levels in the hypothermic group were lower than those in the control group, except at ROSC 1 hour. The lactate-pyruvate ratio increased in the control group at ROSC 1 hour and was significantly lower in the hypothermic group (P < .05). CONCLUSIONS: Mild induced hypothermia mitigated and delayed the CA-induced increase of CSF glutamate. Therefore, our results suggest that clinically inducing hypothermia as soon as possible after CA, or prolonging the time of MIH in combination with controlling ongoing fever, may enhance hypothermic protective effects.

Relevance of cerebral interleukin-6 after aneurysmal subarachnoid hemorrhage.

BACKGROUND: This study examines the inflammatory response via interleukin-6 (IL-6) in aneurysmal subarachnoid hemorrhage (aSAH) patients and its association with their clinical course (occurrence of acute focal neurological deficits, AFND; and delayed cerebral ischemia, DCI). METHODS: A total of 38 consecutive aSAH patients were studied prospectively within 14 days after admission and classified as asymptomatic (n = 9; WFNS grade 1 (1-2), median and quartiles) and symptomatic (n = 29; WFNS grade 4 (2-5)); the latter presenting with AFND (n = 13), DCI (n = 10) or both (n = 6). Levels of pro-inflammatory cytokine IL-6 were determined in cerebral extracellular fluid (ECF, using cerebral microdialysis), cerebrospinal fluid (CSF) and plasma for 10 days after aSAH. Additionally, C-reactive protein (CRP) levels were measured in plasma. RESULTS: High IL-6 levels in CSF, ECF and plasma were found in all patients, reflecting a pronounced local inflammatory response after aSAH, followed only in symptomatic patients by a delayed systemic inflammation (CRP P < 0.025, days 7-9 after aSAH). In all compartments, IL-6 levels appeared to be higher in symptomatic patients, accompanied also by a higher ECF lactate-pyruvate ratio (P = 0.04). Cerebral, but not plasma IL-6, levels were indicative of the development of DCI in symptomatic patients (ECF P = 0.003; CSF P = 0.001). CONCLUSIONS: A pronounced initial cerebral inflammatory state was observed in patients of all WFNS grades, suggesting that IL-6 elevations are not necessarily detrimental. Cerebral, but not plasma IL-6, levels were predictive of the development of delayed ischemic deficits in symptomatic patients, suggesting that CSF or ECF are the best sampling media for future studies.

Extended series of cardiac compressions during CPR in a swine model of perinatal asphyxia.

BACKGROUND: The rationale for a compression to ventilation ratio of 3:1 in neonates with primary hypoxic, hypercapnic cardiac arrest is to emphasize the importance of ventilation; however, there are no published studies testing this approach against alternative methods. An extended series of cardiac compressions offers the theoretical advantage of improving coronary perfusion pressures and hence, we aimed to explore the impact of compression cycles of two different durations. MATERIALS AND METHODS: Newborn swine (n = 32, age 12-36 h, weight 2.0-2.7 kg) were progressively asphyxiated until asystole occurred. Animals were randomized to receive compressions:ventilations 3:1 (n=16) or 9:3 (n=16). Return of spontaneous circulation (ROSC) was defined as a heart rate ≥ 100 beats min⁻¹. RESULTS: All animals except one in the 9:3 group achieved ROSC. One animal in the 3:1 group suffered bradycardia at baseline, and was excluded, leaving us with 15 animals in each group surviving to completion of protocol. Time to ROSC (median and interquartile range) was 150 s (115-180) vs. 148 s (116-195) for 3:1 and 9:3, respectively (P = 0.74). There were no differences in diastolic blood pressure during compression cycles or in markers of hypoxia and inflammation. The temporal changes in mean arterial blood pressure, heart rate, arterial blood gas parameters, and systemic and regional oxygen saturation were comparable between groups. CONCLUSION: Neonatal pigs with asphyxia-induced cardiac arrest did not respond to a compression:ventilation ratio of 9:3 better than to 3:1. Future research should address if alternative compression:ventilation ratios offer advantages over the current gold standard of 3:1.

High-resolution nuclear magnetic resonance spectroscopic study of metabolites in the cerebrospinal fluid of patients with cervical myelopathy and lumbar radiculopathy.

There have been few reports describing substances related to oxidative and intermediary metabolism in the cerebrospinal fluid (CSF) in patients with spinal degenerative disorders. This study investigated whether the concentrations of metabolites in the CSF differed between patients with spinal degenerative disorders and controls, and whether the concentrations of these metabolites correlated with the severity of symptoms. CSF samples were obtained from 30 patients with cervical myelopathy (Group M), 30 patients with lumbar radiculopathy (Group R), and 10 volunteers (control). Metabolites in these CSF samples were measured by nuclear magnetic resonance spectroscopy. There were no differences in the concentrations of lactate, alanine, acetate, glutamate, pyruvate, or citrate between Groups M and R, between Group M and the control, or between Group R and the control. In Group M, neither symptom duration nor the Japanese Orthopaedic Association score correlated with the concentration of any metabolite. In Group R, the symptom duration positively correlated with the concentration of lactate, glutamate, and citrate in CSF. The duration of nerve root block showed a negative correlation with the concentrations of acetate in CSF of the patients in Group R. In patients with lumbar radiculopathy, there is a possibility of increased aerobic metabolic activity or decreased gluconeogenic activity in patients with shorter symptom duration, and increased aerobic metabolic activity in patients with severe inflammation around a nerve root.

Changes in cerebral blood flow, cerebral metabolites, and breathing movements in the sheep fetus following asphyxia produced by occlusion of the umbilical cord.

Severe global fetal asphyxia, if caused by a brief occlusion of the umbilical cord, results in prolonged cerebral hypoperfusion in fetal sheep. In this study, we sought evidence to support the hypothesis that cerebral hypoperfusion is a consequence of suppressed cerebral metabolism. In the 24 h following complete occlusion of the umbilical cord for 10 min, sagittal sinus blood flow velocity was significantly decreased for up to 12 h. Capillary blood flow, measured using microspheres, decreased at 1 and 5 h after cord occlusion in many brain regions, including cortical gray and white matter. Microdialysis probes implanted in the cerebral cortex revealed an increase in extracellular glucose concentrations in gray matter for 7-8 h postasphyxia, while lactate increased only briefly, suggesting decreased cerebral glucose utilization over this time. Although these data, as well as the concurrent suppression of breathing movements and electrocortical activity, support the concept of hypometabolic hypoperfusion, the significant increase of pyruvate and glycerol concentrations in dialysate fluid obtained from the cerebral cortex at 3-8 h after cord occlusion suggests an eventual loss of membrane integrity. The prolonged increase of breathing movements for many hours suggests loss of the pontine/thalamic control that produces the distinct pattern of fetal breathing movements.

Selective antegrade cerebral perfusion at two different temperatures compared to hypothermic circulatory arrest--an experimental study in the pig with microdialysis.

Hypothermic arrest and selective antegrade cerebral perfusion (SACP) is widely used during aortic arch surgery. The microdialysis technique monitors biomarkers of cellular metabolism and cellular integrity over time. In this study, the cerebral changes during hypothermic circulatory arrest (HCA) at 20 degrees C and HCA with SACP at two different temperatures, 20 and 28 degrees C, were monitored. Twenty-three pigs were divided into three groups. A microdialysis probe was fixated into the forebrain. Circulatory arrest started at a brain and body temperature of 20 degrees C or 28 degrees C. Arrest with/without cerebral perfusion (flow 10 ml/kg, max carotid artery pressure 70 mmHg) lasted for 80 min followed by reperfusion and rewarming during 40 min and an observation period of 120 min. The microdialysis markers were registered at six time-points. The lactate/pyruvate ratio (L/P ratio) and the lactate/glucose ratio (L/G ratio) increased significantly (P<0.05), during arrest, in the HCA group. The largest increase of glycerol was found in the group with tepid cerebral perfusion (28 degrees C) and the HCA group (P<0.05). This study supports the use of SACP over arrest. It also suggests that cerebral metabolism and cellular membrane integrity may be better preserved with SACP at 20 degrees C compared to 28 degrees C.

Ventriculostomy for control of raised ICP in acute traumatic brain injury.

UNLABELLED: The aim of this study was to evaluate the effect of ventriculostomy on intracranial pressure (ICP), and related parameters, including cerebrospinal compensation, cerebral oxygenation (PbtO2) and metabolism (microdialysis) in patients with traumatic brain injury (TBI). MATERIALS AND METHODS: Twenty-four patients with parenchymal ICP sensors were prospectively included in the study. Ventriculostomy was performed after failure to control ICP with initial measures. Monitoring parameters were digitally recorded before and after ventriculostomy and compared using appropriate tests. RESULTS: In all patients ventriculostomy led to rapid reduction in ICP. Pooled mean daily values of ICP remained < 20mmHg for 72h after ventriculostomy and were lower than before (p < 0.001). In 11 out of 24 patients during the initial 24-h period following ventriculostomy an increase in ICP to values exceeding 20mmHg was observed. In the remaining 13 patients ICP remained stable, allowing reduction in the intensity of treatment. In this group ventriculostomy led to significant improvement in craniospinal compensation (RAP index), cerebral perfusion pressure and PbtO2. Improvement in lactate/pyruvate ratio, a marker of energy metabolism, was correlated with the increase in PbtO2. CONCLUSION: Ventriculostomy is a useful ICP-lowering manoeuvre, with sustained ICP reduction and related physiological improvements achieved in > 50% of patients.

Impact of hyperglycemia on neurological deficits and extracellular glucose levels in aneurysmal subarachnoid hemorrhage patients.

OBJECTIVE: Hyperglycemia after aneurysmal subarachnoid hemorrhage (SAH) is associated with serious complications. Blood glucose may indicate a target for therapy to prevent delayed ischemic neurological deficits (DIND) and improve outcome. The objective of this study was to investigate energy metabolism in the extracellular/cerebrospinal fluid and blood in relation to outcome. METHODS: Prospective non-randomized study was carried out in the intensive care unit (ICU) of university hospital (n = 170 aneurysmal SAH patients, age: 51.0 +/- 12.6 years old). Following approval by the ethics committee, a microdialysis catheter was inserted into the vascular territory of the aneurysm after clipping. Patients were studied for 165 +/- 84 hours and classified according to the presence of neurological symptoms as asymptomatic (n = 66) and symptomatic (n = 104): acute focal neurological deficits (AFND, n = 61) and delayed ischemic neurological deficits (DIND, n = 43). The microdialysates were analysed hourly for energy metabolites. Daily morning blood glucose and cerebrospinal fluid (CSF) levels (glucose and lactate) were determined. Six-month Glasgow outcome scale (GOS) was assessed. RESULTS: Hyperglycemia on admission and high blood glucose levels on the following days were significantly related to the presence of symptoms, most pronounced in patients with poor outcome (p<0.05). In symptomatic patients (high blood glucose), the lowest extracellular fluid (ECF) glucose concentrations were found, most pronounced in the AFND group (1.0 +/- 1.2 mmol/l). The anaerobic metabolites lactate, lactate/pyruvate ratio (LPR) and lactate/glucose ratio (LGR) were higher in symptomatic patients (p<0.001) indicating cerebral metabolic distress. CSF concentrations of glucose and lactate were of no specific value. CONCLUSION: This study confirms the relevance of hyperglycemia to neurological outcome in SAH patients. Cerebral glucose was significantly lower in AFND patients despite hyperglycemic blood levels. More detailed works are necessary to select risk patients for optimized targeted therapy to avoid insulin-induced cerebral metabolic crisis.

Activin a release into cerebrospinal fluid in a subset of patients with severe traumatic brain injury.

Activin A is a member of the transforming growth factor-beta superfamily and has been demonstrated to be elevated during inflammation and to have neuroprotective properties following neural insults. In this study, we examined whether traumatic brain injury (TBI) induced a response in activin A or in the concentrations of its binding protein, follistatin. Thirty-nine patients with severe TBI had daily, matched cerebrospinal fluid (CSF) and serum samples collected post-TBI and these were assayed for activin A and follistatin using specific immunoassays. Concentrations of both molecules were assessed relative to a variety of clinical parameters, such as the Glasgow Coma Score, computer tomography classification of TBI, measurement of injury markers, cell metabolism and membrane breakdown products. In about half of the patients, there was a notable increase in CSF activin A concentrations in the first few days post-TBI. There were only minor perturbations in either serum activin or in either CSF or serum follistatin concentrations. The CSF activin A response was not related to any of the common TBI indices, but was strongly correlated with two common markers of brain damage, neuronal specific enolase and S100-beta. Further, activin A levels were also associated with indices of metabolism, such as lactate and pyruvate, excitotoxicity (glutamate) and membrane lipid breakdown products such as glycerol. In one of the two patients who developed a CSF infection, activin A concentrations in CSF became markedly elevated. Thus, some TBI patients have an early release of activin A into the CSF that may result from activation of inflammatory and/or neuroprotective pathways.

Severe cognitive impairment correlates with higher cerebrospinal fluid levels of lactate and pyruvate in a canine model of senile dementia.

Diagnosis of dementia of the Alzheimer's type depends on clinical criteria and exclusion of other disorders because, at this time, a validated biological marker, aside from histological brain examination, remains to be established. The canine counterpart of senile dementia of the Alzheimer type (ccSDAT) is considered a promising model for examining behavioral, cellular and molecular processes involved in early phases of human brain aging and Alzheimer disease (AD). In order to investigate the first events taking place in canine cognitive dysfunction, in this paper we established a new and rapid behavioral test that finely discriminates the degrees of cognitive impairment. Cerebrospinal fluid (CSF) analysis was performed to determine the relationship between each disease stage and modification of cerebral energy metabolism. Our results demonstrate a parallel increase of lactate, pyruvate and potassium concentrations in the severe cognitive deficit. These differences are discussed in view of the neuroprotective role presently given to lactate.

Gender associations with cerebrospinal fluid glutamate and lactate/pyruvate levels after severe traumatic brain injury.

OBJECTIVE: Female sex hormones appear to be neuroprotective after traumatic brain injury by attenuating multiple mechanisms of secondary insult, including excitotoxicity and ischemia. The purpose of this study was to evaluate associations between gender and cerebrospinal fluid glutamate and lactate/pyruvate production and the role of hypothermia with gender in attenuating these markers. DESIGN: Prospectively collected data were analyzed for adult patients with severe traumatic brain injury. Gender comparisons for cerebrospinal fluid glutamate and lactate/pyruvate production were determined using ventricular samples obtained over the first 48 hrs postinjury. SETTING: University-based level I trauma center. PATIENTS: There were 123 patients, male n = 93 and female n = 30 (n = 686 cerebrospinal fluid samples), with severe traumatic brain injury (Glasgow Coma Scale score < or =8). INTERVENTIONS: A portion of these patients were part of a randomized controlled trial evaluating the effect of (48 hrs) therapeutic hypothermia after severe traumatic brain injury. The remainder received hypothermia (24 hrs) if they met clinical care criteria. Patients were cooled to 32-33 degrees C (within approximately 8 hrs) for either 24 or 48 hrs and then were rewarmed or remained normothermic. MEASUREMENTS AND MAIN RESULTS: Regression analyses using generalized estimating equations for repeated measures showed significant increases in cerebrospinal fluid glutamate production for males compared with females (p = .0023) and a significant interaction between glutamate concentration, gender, and time (p = .0035) by 24 hrs postinjury. Females had lower lactate/pyruvate ratios than males (p = .0006), and there was a significant interaction between lactate/pyruvate, gender, and time (p = .0045) throughout the first 48 hrs postinjury. Hypothermia attenuated glutamate levels, particularly for males, over the time course studied. CONCLUSIONS: These data suggest significant gender differences with glutamate and lactate/pyruvate production after severe traumatic brain injury. Gender- and hormone-mediated differences in central nervous system pathophysiology should be considered with clinical trials in traumatic brain injury.