Hemodynamic directed CPR improves cerebral perfusion pressure and brain tissue oxygenation

Aim

Advances in cardiopulmonary resuscitation (CPR) have focused on the generation and maintenance of adequate myocardial blood flow to optimize the return of spontaneous circulation and survival. Much of the morbidity associated with cardiac arrest survivors can be attributed to global brain hypoxic ischemic injury. The objective of this study was to compare cerebral physiological variables using a hemodynamic directed resuscitation strategy versus an absolute depth-guided approach in a porcine model of ventricular fibrillation (VF) cardiac arrest.

Methods

Intracranial pressure and brain tissue oxygen tension probes were placed in the frontal cortex prior to induction of VF in 21 female 3-month-old swine. After 7 min of VF, animals were randomized to receive one of three resuscitation strategies: (1) hemodynamic directed care (CPP-20): chest compressions (CCs) with depth titrated to a target systolic blood pressure of 100 mmHg and titration of vasopressors to maintain coronary perfusion pressure (CPP) >20 mmHg; (2) depth 33 mm (D33): target CC depth of 33 mm with standard American Heart Association (AHA) epinephrine dosing; or (3) depth 51 mm (D51): target CC depth of 51 mm with standard AHA epinephrine dosing.

Results

Cerebral perfusion pressures (CerePP) were significantly higher in the CPP-20 group compared to both D33 (p < 0.01) and D51 (p = 0.046), and higher in survivors compared to non-survivors irrespective of treatment group (p < 0.01). Brain tissue oxygen tension was also higher in the CPP-20 group compared to both D33 (p < 0.01) and D51 (p = 0.013), and higher in survivors compared to non-survivors irrespective of treatment group (p < 0.01). Subjects with a CPP >20 mmHg were 2.7 times more likely to have a CerePP >30 mmHg (p < 0.001).

Conclusions

Hemodynamic directed resuscitation strategy targeting coronary perfusion pressure >20 mmHg following VF arrest was associated with higher cerebral perfusion pressures and brain tissue oxygen tensions during CPR.     

Lack of consistent intracranial pressure pulse morphological changes during episodes of microdialysis lactate/pyruvate ratio increase

Lactate/pyruvate ratio (LPR) from microdialysis is a well-established marker of cerebral metabolic crisis. For brain injury patients, abnormally high LPR could indicate cerebral ischemia or failure of O(2) uptake. However, there is a debate on the primary factor responsible for LPR increase. Exploiting the potential of using the morphology of a high temporal resolution signal such as intracranial pulse (ICP) to characterize cerebrovascular changes, a data analysis experiment is taken to test whether consistent changes in ICP pulse morphological metrics accompany the LPR increase. We studied 3517 h of LPR and continuous ICP data from 19 severe traumatic brain injury patients. Our morphological clustering and analysis of intracranial pressure (MOCAIP) algorithm was applied to ICP pulses, which were matched in time to the LPR measurements, and 128 pulse morphological metrics were extracted. We automatically identified the episodes of LPR increases using a moving time window of 10-20 h. We then studied the trending patterns of each of the 128 ICP MOCAIP metrics within these identified periods and determined them to be one of the following three types: increasing, decreasing or no trend. A binomial test was employed to investigate whether any MOCAIP metrics show a consistent trend among all episodes of LPR increase per patient. Regardless of the selected values for different parameters of the proposed method, for the majority of the subjects in the study (78%), none of the ICP metrics show any consistent trend during the episodes of LPR increase. Even for the few subjects who have at least one ICP metric with a consistent trend during the LPR increase episodes, the number of such metrics is small and varies from subject to subject. Given the fact that ICP pulse morphology is influenced by the cerebral vasculature, our results suggest that a dominant cerebral vascular cause may be behind the changes in LPR when LPR trends correlate with ICP pulse morphological changes. However, the incidence of such correlation seems to be low.     

血清丙酮酸水平和乳酸/丙酮酸比值在线粒体病筛查中的作用

目的分析线粒体病患者静息和进行最小运动量试验时血清乳酸和丙酮酸的浓度,探讨血清丙酮酸水平及乳酸/丙酮酸比值在线粒体病筛查中的临床意义。方法以线粒体病患者15例和其他肌病25例作为研究对象,30例健康体检者为正常对照。收集晨起空腹静息静脉血,采用气相色谱法定量测定血清乳酸、丙酮酸水平,以其中线粒体病组12例和其他肌病组12例做最小运动量试验,测定运动前、即刻、运动后5min和20min的血清乳酸、丙酮酸水平。结果静息时线粒体病组的血清乳酸(4.34±1.59)mmol/L、丙酮酸(0.21±0.05)mmol/L和其他肌病组血清乳酸(3.88±1.11)mmol/L均显著高于健康对照组的血清乳酸(1.24±0.55)mmol/L和丙酮酸(0.08±0.04)mmol/L(P0.01);在最小运动量试验,线粒体病组与其他肌病组相比较,血清丙酮酸水平在运动前、即刻、运动后5min和20min显著增高(P0.01),乳酸/丙酮酸的比值在运动前和运动后20min差异具有统计学意义(P0.05);与自身运动前比较,各组的乳酸、丙酮酸水平在运动后即刻和运动后5min均显著增高(P0.01),而乳酸/丙酮酸的比值差异无统计学意义(P0.05)。结论患者血清丙酮酸水平和乳酸/丙酮酸的比值可以作为筛查线粒体病的一种重要的生化指标。     

Intracranial pressure and cerebral perfusion pressure in patients developing brain death

PurposeWe investigated whether a critical rise of intracranial pressure (ICP) leading to a loss of cerebral perfusion pressure (CPP) could serve as a surrogate marker of brain death (BD).Materials and methodsWe retrospectively analyzed ICP and CPP of patients in whom BD was diagnosed (n = 32, 16-79 years). Intracranial pressure and CPP were recorded using parenchymal (n = 27) and ventricular probes (n = 5). Data were analyzed from admission until BD was diagnosed.ResultsIntracranial pressure was severely elevated (mean ± SD, 95.5 ± 9.8 mm Hg) in all patients when BD was diagnosed. In 28 patients, CPP was negative at the time of diagnosis (− 8.2 ± 6.5 mm Hg). In 4 patients (12.5%), CPP was reduced but not negative. In these patients, minimal CPP was 4 to 18 mm Hg. In 1 patient, loss of CPP occurred 4 hours before apnea completed the BD syndrome.ConclusionsBrain death was universally preceded by a severe reduction of CPP, supporting loss of cerebral perfusion as a critical step in BD development. Our data show that a negative CPP is neither sufficient nor a prerequisite to diagnose BD. In BD cases with positive CPP, we speculate that arterial blood pressure dropped below a critical closing pressure, thereby causing cessation of cerebral blood flow.     

Effect of alcohol on the lactate/pyruvate ratio of recently injured adults

OBJECTIVE: To compare the ability of plasma (lactate) and the plasma lactate/pyruvate (L/P) ratio to predict shock-related outcome after injury and also to examine the influence of plasma ethanol on any relationships found. DESIGN: Prospective observational study. SETTING: Emergency departments in the UK and the Republic of South Africa. PATIENTS: Blood samples were taken at presentation from 232 adult patients 1-23 hrs (median, 3.5 hrs) after sustaining an injury or injuries deemed sufficiently severe to require inpatient care. MEASUREMENTS: Plasma concentrations of lactate, pyruvate, and ethanol, anatomical severity of injury, development of multiple organ failure, and 30-day survival were determined. RESULTS: At 90% specificity for predicting subsequent mortality and/or multiple organ failure, plasma lactate >or=3.85 mmol/L was 23% (5% to 41%) more sensitive than an L/P ratio of >or=42.76. At 90% sensitivity for ruling out morbidity, plasma lactate <1.6 mmol/L is 6% (-1% to 13%) more specific than an L/P ratio of <14.08. High L/P ratios were noted to be associated with a detectable plasma alcohol level. A post hoc regression analysis showed that alcohol-positive/-negative status was a much stronger predictor of the L/P ratio than was anatomical severity of injury, shock, or time after injury. CONCLUSIONS: Plasma lactate alone is a better predictor than the L/P ratio of shock-related outcome after injury. The interpretation of L/P ratios after injury is confounded in the presence of elevated plasma ethanol.     

Effect of decreased O2 supply to tissue on the lactate:pyruvate ratio in blood

Experiments were performed with trained conscious dogs with permanently implanted intravascular catheters. With the dogs in a basal resting state, the concentrations of lactate (L) and pyruvate (P) in arterial blood fluctuated widely from day to day, whereas their concentration ratio (L/P) remained relatively constant. By contrast, decrease in tissue O(2) supply induced by severe chronic anemia increased the arterial blood L/P, specifically, with only random accompanying changes in the lactate or pyruvate concentrations themselves.When systemic O(2) consumption was increased acutely by muscular exercise, cardiac output increased, and the changes in blood L/P were small and not consistent between different dogs. But when O(2) supply to the tissues was simultaneously limited by anemia, L/P increased during exercise, and the magnitude of the increase was proportional to the severity of the anemia. These results suggest that changes in blood L/P during exercise are related specifically to tissue O(2) supply.     

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

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

Relationship between brain perfusion computed tomography variables and cerebral perfusion pressure in severe head trauma patients

OBJECTIVE: To compare brain perfusion-computed tomography (CT) results with invasive cerebral perfusion pressure (CPP) monitoring in severe head trauma patients. DESIGN: Prospective cohort study. SETTING: Emergency room and surgical intensive care unit of our hospital. PATIENTS: Sixty-one severe head trauma patients. INTERVENTIONS: We prospectively collected 103 perfusion-CT examinations with simultaneous measurement of mean arterial pressure and intracranial pressure, affording calculation of CPP. The statistical relationship between perfusion-CT results and the corresponding CPP values was evaluated using Wilcoxon (Mann-Whitney) and generalized F-tests. The functional outcome of the 61 patients was evaluated 3 months after trauma on the basis of the Glasgow Outcome Scale score and compared between groups using Fisher's exact tests. MEASUREMENTS AND MAIN RESULTS: Perfusion-CT enabled us to distinguish between two groups of patients. Within each group, a significant correlation (p <.001) between the CPP values and the corresponding perfusion-CT results was demonstrated. There was also a significant correlation (p <.001) between the CPP values and the extent of the abnormal perfusion-CT areas (R up to.817).The first group was characterized by a weak dependence of perfusion-CT results on the corresponding CPP values (low slope) and the second group by a strong dependence (steep slope). These groups were interpreted as having preserved (or pseudo) and impaired cerebral vascular autoregulation, respectively. The functional outcome was better in the second group of patients. CONCLUSIONS: Intermittent perfusion-CT measurements plus continuous CPP measurement provide more information than continuous CPP alone. Perfusion-CT gives unique information regarding regional heterogeneity of brain perfusion. It might allow clinicians to distinguish between patients with preserved auto-regulation (or pseudoautoregulation) and those with impaired autoregulation and could therefore guide interpretation of CPP measurements and therapy.     

The impact of brain temperature and core temperature on intracranial pressure and cerebral perfusion pressure.

Hyperthermia has been demonstrated to increase neuronal injury when present during or after an acute brain injury. The assumption that core temperature equals brain temperature exists. If the temperature of an injured brain is higher than core temperature, episodes of neural hyperthermia may go undetected. The objectives of this study were to (1) determine if differences exist between brain temperature and core temperature in subjects with acute neurological injuries in both normothermic and febrile states and (2) investigate the impact of brain and core temperatures on intracranial pressure (ICP) and cerebral perfusion pressure (CPP). The study was conducted through a retrospective chart audit of patients age 18 years or older admitted to a level I trauma center with a diagnosis of brain injury whose condition warranted placement of a pulmonary artery catheter (which measured core temperature) and an intraventricular catheter (which measured brain temperature). Thirty-one charts contained complete data; nine charts provided partial data. Mean brain temperature (100.8 degrees F, SD = 0.69) was found to be significantly higher than mean core temperature (100.2 degrees F, SD = 0.74; p = .00). Brain temperature means were hyperthermic (> or = 100.9 degrees F), while matching core temperatures were normothermic in almost one-third of the subjects. There was no significant difference found between hyperthermic ICP or CPP and normothermic ICP or CPP determined by brain or core temperature. No significant correlation was found between temperature and intracranial dynamics. Future research is needed with prospectively collected data of adequate sample size to continue to investigate the impact of core and brain temperature on the intracranial dynamics of ICP and CPP.     

体位对颅脑损伤患者颅内压、脑灌注压的影响

颅内压（ICP）增高是一个复杂的病理生理过程,是重型颅脑损伤的主要并发症。颅内高压如不能及早发现并解除,可引起脑代谢障碍、脑灌注压下降和脑疝形成等严重后果,难以控制的颅内高压病死率达到92％～100％［1-2］。目前脑室内放置 ICP 监测管是临床上常用的方法,被称为ICP 监测的“金标准”［3-4］。颅脑损伤后脑水肿早期,通过实时监测患者的颅内压（ICP）及脑灌注压（CPP）等重要指标,可保证脑组织有足够的血液供应,从而确保脑组织的氧供和糖分需要［5］。研究认为临床护理可影响这些指标的变化,其中患者的体位维持尤为重要［6］。本组选择了复旦大学附属华山医院神经外科急救中心2015年5月至12月期间收治的51例重型颅脑损伤行脑室内 ICP 监测的患者,分别观察其头轴位平卧、头偏位平卧、头轴位床头抬高30°、头偏位床头抬高30°对患者 ICP、CPP 的影响。现报道如下。     

动态脑灌注压监护在重型颅脑损伤患者治疗中的应用

目的探讨动态脑灌注压（CPP）监护在重型颅脑损伤患者治疗中的应用与意义。方法选择伤后72 h内首诊入院的重型颅脑损伤患者120例随机分为非监护组和监护组各60例。监护组其中伤后〈24 h内入院36例,伤后24～72 h入院24例,进行持续CPP和同步生理监护,以患者入院时的CPP值分为A组（CFP≥9.33 kPa）和B组（CPP〈9.33 kPa）,根据监测指标的变化给予早期临床干预。结果伤后24 h内入院的监护组中,B组患者平均动脉压（MABP）为8.33±1.08 kPa、血液PaO27.88±2.78 kPa,明显低于A组的MABP12.68±1.13 kPa和PaO212.22±2.33 kPa,经统计学比较差异有显著性意义（P〈0.05）;伤后24、72 h入院的监护组中,B组颅内压（ICP）为4.04±0.12 kPa,较A组2.55±0.09 kPa明显增高（P〈0.05）。结论重型颅脑损伤后的早期动态CPP监护,有助于病情变化的正确判断,可为疾病的正确治疗、护理及判断其预后提供依据。     

Time-pattern of lactate and lactate to pyruvate ratio in the first 24 hours of intensive care emergency admissions

Blood lactate elevation in critically ill patients commonly is taken as a sign of impaired tissue perfusion. Simultaneous elevation of lactate to pyruvate ratio (L/P ratio) may be helpful in discriminating between different mechanisms of hyperlactatemia and thus in determining the relevance of the finding. We studied prospectively the prevalence and the time pattern of hyperlactatemia and simultaneous L/P ratio elevation in 98 consecutive emergency admission patients in a 23-bed surgical-medical University Hospital intensive care unit. Blood lactate, L/P ratio, and blood gases were measured at 2-h intervals during the initial 24 h of intensive care unit admission. Hyperlactatemia (blood lactate over 2 mmol/L) was found in 48 (49%) patients, and the median peak value of the non-survivors was higher than that of the survivors [5.3 (interquartile range 1.9-7.5) vs. 1.9 (1.3-2.9) mmol/L, respectively, p = 0.003]. Hyperlactatemia at admission (n = 31) was associated with a higher hospital mortality than hyperlactatemia developing later (n = 17) (29.0% vs. 5.9%, P = 0.003). Sustained admission hyperlactatemia (>6 h) was associated with higher mortality than short-lasting hyperlactatemia (36.8% vs. 0%, P = 0.008). Simultaneously elevated L/P ratio (L/P ratio > 18; n = 16) was associated with higher mortality than hyperlactatemia with normal L/P ratio (n = 32; 37.5% vs. 12.5%, respectively, P = 0.03) and was found mainly in patients who had severe circulatory failure. The hyperlactatemia of patients with sepsis was not associated with L/P ratio elevation. We conclude that hyperlactatemia is common in emergency admission patients. Hyperlactatemia with L/P ratio elevation and lactic acidosis is likely to be associated with inadequate tissue perfusion. Hyperlactatemia persisting more than 6 h and simultaneous elevation of L/P ratio are associated with increased mortality.     

Increased lactate/pyruvate ratio with normal b-hydroxybutyrate/acetoacetate ratio and lack of oxygen supply dependency in a patient with fatal septic shock

We report a case of fatal septic shock, with hyperlactatemia and blood cultures positive for Streptococcus pneumoniae, in a 70-year-old patient. On two occasions (5 days, and 2 days before the patient‘s death), the relationship between oxygen delivery (D˙O₂) and consumption (V˙O₂) was examined in conjunction with two presumed markers of tissue oxygenation: the lactate/pyruvate ratio (L/P), and the β-hydroxybutyrate acetoacetate ratio (βOHB/AcAc). Increasing D˙O₂ by about 30% (“oxygen flux test”) failed to increase V˙O₂. The βOHB/AcAc ratio remained within normal limits, thus suggesting uncompromised tissue oxygenation at the hepatic level. The L/P ratio remained persistently above normal limits, thus suggesting actual organ or regional hypoxia. This case shows that during an overwhelming septic shock, the “oxygen flux test” can be negative, despite the presence of hyperlactatemia and of an increased L/P ratio suggestive of impaired tissue oxygenation. Received: 7 December 1995 Accepted: 2 September 1996     

Influence of inspiration:expiration ratio on intracranial and cerebral perfusion pressure in acute stroke patients

OBJECTIVE: We undertook this study to evaluate the influence of the inspiration:expiration (I:E) ratio on intracranial pressure and cerebral perfusion in patients with acute stroke. DESIGN: Ventilated patients with acute stroke were examined under a protocol involving variations of I:E ratio from 1:2 to 1:1 to 1:2 under positive end-expiratory pressure (PEEP) of 5.3 and - subsequently - 10.6 cmH(2)O. Intracranial pressure was monitored with parenchymal or ventricular catheters. Mean arterial blood pressure, intracranial pressure (ICP), heart rate and peak mean flow velocity of the middle cerebral arteries were continuously recorded. SETTING: Neurological intensive care unit. PATIENTS: A total of 45 monitoring sessions were performed in 16 patients (subarachnoid haemorrhage 3, ischemic stroke 13). RESULTS: No significant changes in any of the parameters monitored were evident in association with the I:E ratio variations under either of the PEEP levels applied. It must be noted, though, that ICP exceeded 15 mmHg in only 5/45 monitoring sessions, and never exceeded 20 mmHg. CONCLUSIONS: Our preliminary results suggest that variations of the I:E ratio cause no significant changes in intracranial or cerebral perfusion pressure and, thus, can be safely used in patients with acute stroke without intracranial hypertension. The influence of I:E ratio variations on stroke patients with intracranial hypertension remains to be evaluated.     

Effects of perfusion pressure on tissue perfusion in septic shock

OBJECTIVE: To measure the effects of increasing mean arterial pressure (MAP) on systemic oxygen metabolism and regional tissue perfusion in septic shock. DESIGN: Prospective study. SETTING: Medical and surgical intensive care units of a tertiary care teaching hospital. PATIENTS: Ten patients with the diagnosis of septic shock who required pressor agents to maintain a MAP > or = 60 mm Hg after fluid resuscitation to a pulmonary artery occlusion pressure (PAOP) > or = 12 mm Hg. INTERVENTIONS: Norepinephrine was titrated to MAPs of 65, 75, and 85 mm Hg in 10 patients with septic shock. MEASUREMENTS AND MAIN RESULTS: At each level of MAP, hemodynamic parameters (heart rate, PAOP, cardiac index, left ventricular stroke work index, and systemic vascular resistance index), metabolic parameters (oxygen delivery, oxygen consumption, arterial lactate), and regional perfusion parameters (gastric mucosal Pco2, skin capillary blood flow and red blood cell velocity, urine output) were measured. Increasing the MAP from 65 to 85 mm Hg with norepinephrine resulted in increases in cardiac index from 4.7+/-0.5 L/min/m2 to 5.5+/-0.6 L/min/m2 (p < 0.03). Arterial lactate was 3.1+/-0.9 mEq/L at a MAP of 65 mm Hg and 3.0+/-0.9 mEq/L at 85 mm Hg (NS). The gradient between arterial P(CO2) and gastric intramucosal Pco2 was 13+/-3 mm Hg (1.7+/-0.4 kPa) at a MAP of 65 mm Hg and 16+/-3 at 85 mm Hg (2.1+/-0.4 kPa) (NS). Urine output at 65 mm Hg was 49+/-18 mL/hr and was 43+/-13 mL/hr at 85 mm Hg (NS). As the MAP was raised, there were no significant changes in skin capillary blood flow or red blood cell velocity. CONCLUSIONS: Increasing the MAP from 65 mm Hg to 85 mm Hg with norepinephrine does not significantly affect systemic oxygen metabolism, skin microcirculatory blood flow, urine output, or splanchnic perfusion.     

Cerebral perfusion pressure and cerebral tissue oxygen tension in a patient during cardiopulmonary resuscitation

OBJECTIVE: To report on the effects of cardiopulmonary resuscitation (CPR) instituted immediately after a cardiac arrest on cerebral perfusion pressure (CPP) and cerebral tissue oxygen tension (PbrO(2)). DESIGN: Case report. SETTING: ICU of a university hospital. PATIENT: A head-injured 17-year-old man submitted to multimodal neurological monitoring underwent sudden cardiac arrest and successful CPR. INTERVENTIONS: External chest compression, 100% oxygen ventilation, volume expansion and standard ACLS protocols. MEASUREMENTS AND RESULTS: Heart rate, ECG, mean arterial blood pressure (MABP), ETCO(2), PaO(2), intracranial pressure (ICP), CPP and PbrO(2) were continuously monitored during CPR and data recorded at 15-s intervals by a dedicated personal computer. At the onset of the cardiac arrest, PbrO(2) decreased to zero. The institution of CPR resulted in a progressive increase of MABP, CPP and PbrO(2). Assuming, on the basis of previous experimental and clinical reports, 8 mmHg PbrO(2) as a possible ischaemic/hypoxic threshold value, during the first 6.5 min of CPR, PbrO(2) values were below this threshold (range 0-7 mmHg) and CPP values were <25 mmHg for 81.5% of the time. In the following 5.5 min, more efficient CPR generated CPP values >25 mmHg for 77.3% of the time. These values were associated with a PbrO(2) >8 mmHg (range 8-28 mmHg) at all times. CONCLUSIONS: In the clinical setting of a witnessed cardiac arrest, immediate institution of CPR can be effective in generating PbrO(2) values above a supposed ischaemic/hypoxic threshold when CPP is >25 mmHg. PbrO(2) monitoring by the Licox system is sensitive and reliable, even at low values, and can be suitable for evaluating cerebral oxygenation during experimental CPR.     

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.