David L. McArthur

Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study

Brain trauma is accompanied by regional alterations of brain metabolism, reduction in metabolic rates and possible energy crisis. We hypothesize that microdialysis markers of energy crisis are present during the critical period of intensive care despite the absence of brain ischemia. In all, 19 brain injury patients (mean GCS 6) underwent combined positron emission tomography (PET) for metabolism of glucose (CMRglu) and oxygen (CMRO2) and cerebral microdialysis (MD) at a mean time of 36 h after injury. Microdialysis values were compared with the regional mean PET values adjacent to the probe. Longitudinal MD data revealed a 25% incidence rate of metabolic crisis (elevated lactate/pyruvate ratio (LPR)>40) but only a 2.4% incidence rate of ischemia. Positron emission tomography imaging revealed a 1% incidence of ischemia across all voxels as measured by oxygen extraction fraction (OEF) and cerebral venous oxygen content (CvO2). In the region of the MD probe, PET imaging revealed ischemia in a single patient despite increased LPR in other patients. Lactate/pyruvate ratio correlated negatively with CMRO2 (P<0.001), but not with OEF or CvO2. Traumatic brain injury leads to a state of persistent metabolic crisis as reflected by abnormal cerebral microdialysis LPR that is not related to ischemia.

Nonconvulsive electrographic seizures after traumatic brain injury result in a delayed, prolonged increase in intracranial pressure and metabolic crisis

Objective: To determine whether nonconvulsive electrographic post‐traumatic seizures result in increases in intracranial pressure and microdialysis lactate/pyruvate ratio. Design: Prospective monitoring with retrospective data analysis. Setting: Single center academic neurologic intensive care unit. Patients: Twenty moderate to severe traumatic brain injury patients (Glasgow Coma Score 3–13). Measurements and Main Results: Continuous electroencephalography and cerebral microdialysis were performed for 7 days after injury. Ten patients had seizures and were compared with a matched cohort of traumatic brain injury patients without seizures. The seizures were repetitive and constituted status epilepticus in seven of ten patients. Using a within‐subject design, post‐traumatic seizures resulted in episodic increases in intracranial pressure (22.4 ± 7 vs. 12.8 ± 4.3 mm Hg; p < .001) and an episodic increase in lactate/pyruvate ratio (49.4 ± 16 vs. 23.8 ± 7.6; p < .001) in the seizure group. Using a between‐subjects comparison, the seizure group demonstrated a higher mean intracranial pressure (17.6 ± 6.5 vs. 12.2 ± 4.2 mm Hg; p < .001), a higher mean lactate/pyruvate ratio (38.6 ± 18 vs. 27 ± 9; p < .001) compared with nonseizure patients. The intracranial pressure and lactate/pyruvate ratio remained elevated beyond postinjury hour 100 in the seizure group but not the nonseizure group (p < .02). Conclusion: Post‐traumatic seizures result in episodic as well as long‐lasting increases in intracranial pressure and microdialysis lactate/pyruvate ratio. These data suggest that post‐traumatic seizures represent a therapeutic target for patients with traumatic brain injury.

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.

Persistently low extracellular glucose correlates with poor outcome 6 months after human traumatic brain injury despite a lack of increased lactate: a microdialysis study.

Disturbed glucose brain metabolism after brain trauma is reflected by changes in extracellular glucose levels. The authors hypothesized that posttraumatic reductions in extracellular glucose levels are not due to ischemia and are associated with poor outcome. Intracerebral microdialysis, electroencephalography, and measurements of brain tissue oxygen levels and jugular venous oxygen saturation were performed in 30 patients with traumatic brain injury. Levels of glucose, lactate, pyruvate, glutamate, and urea were analyzed hourly. The 6-month Glasgow Outcome Scale extended (GOSe6) score was assessed for each patient. In regions of increased glucose utilization defined by positron emission tomography, the extracellular glucose concentration was less than 0.2 mmol/l. Extracellular glucose values were less than 0.2 mmol during postinjury days 0 to 7 in 19% to 30% of hourly samples on each day. Transient decreases in glucose levels occurred with electrographic seizures and nonischemic reductions in cerebral perfusion pressure and jugular venous oxygen saturation. Glutamate levels were elevated in the majority of low-glucose samples, but the lactate/pyruvate ratio did not indicate focal ischemia. Terminal herniation resulted in reductions in glucose with increases in the lactate/pyruvate ratio but not in lactate concentration alone. GOSe6 scores correlated with persistently low glucose levels, combined early low glucose levels and low lactate/glucose ratio, and with the overall lactate/glucose ratio. These results suggest that the level of extracellular glucose is typically reduced after traumatic brain injury and associated with poor outcome, but is not associated with ischemia.

EPIDEMIOLOGIC ASPECTS OF BRAIN INJURY

Approximately 2 million head injuries occur each year in the United States, producing a brain injury rate of 175 to 200 per 100,000 population and causing as many as 56,000 deaths per year. The economic and emotional toll of this public health burden is staggering. By identifying risk factors, perhaps effective legislation and environmental and educational intervention strategies can be developed to prevent brain injury.

Energy dysfunction as a predictor of outcome after moderate or severe head injury: indices of oxygen, glucose, and lactate metabolism.

The purpose of this study was to determine if the relationship between abnormalities in glucose, lactate, and oxygen metabolism were predictive of neurologic outcome after moderate or severe head injury, relative to other known prognostic factors. Serial assessments of the cerebral metabolic rates for glucose, lactate, and oxygen were performed using a modified Kety-Schmidt method. In total, 31 normal control subjects were studied once, and 49 TBI patients (mean age 36±16 years, median GCS 7) were studied five times median per patient from postinjury days 0 to 9. Univariate and multivariate analyses were performed. Univariate analysis showed that the 6-month postinjury Glasgow Outcome Scale (GOS) was most strongly associated with the mean cerebral metabolic rate of oxygen (CMRO2) (P = 0.0001), mean arterial lactate level (P = 0.0001), mean arterial glucose (P = 0.0008), mean cerebral blood flow (CBF), (P = 0.002), postresuscitation GCS (P = 0.003), and pupillary status (P = 0.004). Brain lactate uptake was observed in 44% of all metabolic studies, and 76% of patients had at least one episode of brain lactate uptake. By dichotomized GOS, patients achieving a favorable outcome (GOS 4-5) were distinguished from those with an unfavorable outcome (GOS1-3) by having a higher CMRO2 (P = 0.003), a higher rate of abnormal brain lactate uptake relative to arterial lactate levels (P = 0.04), and lesser degrees of blood-brain barrier damage based on CT findings (P = 0.03). Conclusions: During the first 6 days after moderate or severe TBI, CMRO2 and arterial lactate levels are the strongest predictors of neurologic outcome. However, the frequent occurrence of abnormal brain lactate uptake despite only moderate elevations in arterial lactate levels in the favorable outcome patients suggests the brains ability to use lactate as a fuel may be another key outcome predictor. Future studies are needed to determine to what degree nonglycolytic energy production from alternative fuels such as lactate occurs after TBI and whether alternative fuel administration is a viable therapy for TBI patients.

Acute secondary adrenal insufficiency after traumatic brain injury: A prospective study

Objective:To determine the prevalence, time course, clinical characteristics, and effect of adrenal insufficiency (AI) after traumatic brain injury (TBI). Design:Prospective intensive care unit–based cohort study. Setting:Three level 1 trauma centers. Patients:A total of 80 patients with moderate or severe TBI (Glasgow Coma Scale score, 3–13) and 41 trauma patients without TBI (Injury Severity Score, >15) enrolled between June 2002 and November 2003. Measurements:Serum cortisol and adrenocorticotropic hormone levels were drawn twice daily for up to 9 days postinjury; AI was defined as two consecutive cortisols of ≤15 &mgr;g/dL (25th percentile for extracranial trauma patients) or one cortisol of <5 &mgr;g/dL. Principal outcome measures included: injury characteristics, hemodynamic data, usage of vasopressors, metabolic suppressive agents (high-dose pentobarbital and propofol), etomidate, and AI status. Main Results:AI occurred in 42 TBI patients (53%). Adrenocorticotropic hormone levels were lower at the time of AI (median, 18.9 vs. 36.1 pg/mL; p = .0001). Compared with patients without AI, those with AI were younger (p = .01), had higher injury severity (p = .02), had a higher frequency of early ischemic insults (hypotension, hypoxia, severe anemia) (p = .02), and were more likely to have received etomidate (p = .049). Over the acute postinjury period, patients with AI had lower trough mean arterial pressure (p = .001) and greater vasopressor use (p = .047). Mean arterial pressure was lower in the 8 hrs preceding a low (≤15 &mgr;g/dL) cortisol level (p = .003). There was an inverse relationship between cortisol levels and vasopressor use (p = .0005) and between cortisol levels within 24 hrs of injury and etomidate use (p = .002). Use of high-dose propofol and pentobarbital was strongly associated with lower cortisol levels (p < .0001). Conclusions:Approximately 50% of patients with moderate or severe TBI have at least transient AI. Younger age, greater injury severity, early ischemic insults, and the use of etomidate and metabolic suppressive agents are associated with AI. Because lower cortisol levels were associated with lower blood pressure and higher vasopressor use, consideration should be given to monitoring cortisol levels in intubated TBI patients, particularly those receiving high-dose pentobarbital or propofol. A randomized trial of stress-dose hydrocortisone in TBI patients with AI is underway.

Nonconvulsive seizures after traumatic brain injury are associated with hippocampal atrophy.

Objective: To determine if posttraumatic nonconvulsive electrographic seizures result in long-term brain atrophy. Methods: Prospective continuous EEG (cEEG) monitoring was done in 140 patients with moderate to severe traumatic brain injury (TBI) and in-depth study of 16 selected patients was done using serial volumetric MRI acutely and at 6 months after TBI. Fluorodeoxyglucose PET was done in the acute stage in 14/16 patients. These data were retrospectively analyzed after collection of data for 7 years. Results: cEEG detected seizures in 32/140 (23%) of the entire cohort. In the selected imaging subgroup, 6 patients with seizures were compared with a cohort of 10 age- and GCS-matched patients with TBI without seizures. In this subgroup, the seizures were repetitive and constituted status epilepticus in 4/6 patients. Patients with seizures had greater hippocampal atrophy as compared to those without seizures (21 ± 9 vs 12 ± 6%, p = 0.017). Hippocampi ipsilateral to the electrographic seizure focus demonstrated a greater degree of volumetric atrophy as compared with nonseizure hippocampi (28 ± 5 vs 13 ± 9%, p = 0.007). A single patient had an ictal PET scan which demonstrated increased hippocampal glucose uptake. Conclusion: Acute posttraumatic nonconvulsive seizures occur frequently after TBI and, in a selected subgroup, appear to be associated with disproportionate long-term hippocampal atrophy. These data suggest anatomic damage is potentially elicited by nonconvulsive seizures in the acute postinjury setting.

Metabolic recovery following human traumatic brain injury based on FDG-PET: time course and relationship to neurological disability.

Objective:Utilizing [18F]fluorodeoxyglucose positron emission tomography (FDG-PET), we assessed the temporal pattern and the correlation of functional and metabolic recovery following human traumatic brain injury. Design and Subjects:Fifty-four patients with injury severity ranging from mild to severe were studied. Thirteen of these patients underwent both an acute and delayed FDG-PET study. Results:Analysis of the pooled global cerebral metabolic rate of glucose (CMRglc) values revealed that the intermediate metabolic reduction phase begins to resolve approximately one month following injury, regardless of injury severity. The correlation, in the 13 patients studied twice, between the extent of change in neurologic disability, assessed by the Disability Rating Scale (DRS), and the change in CMRglc from the early to late period was modest (r = −0.42). Potential explanations for this rather poor correlation are discussed. A review of the pertinent literature regarding the use of PET and related imaging modalities, including single photon emission tomography (SPECT) for the assessment of patients following traumatic brain injury is given. Conclusion:The dynamic profile of CMRglc that changes following traumatic brain injury is seemingly stereotypic across a broad range and severity of injury types. Quantitative FDG-PET cannot be used as a surrogate technique for estimating degree of global functional recovery following traumatic brain injury.

Pericontusional brain tissue exhibits persistent elevation of lactate/pyruvate ratio independent of cerebral perfusion pressure

Objective:To determine whether pericontusional tissue exhibits neurochemical responsiveness to changes in cerebral perfusion pressure as measured by microdialysis lactate/pyruvate ratio. Design:Prospective monitoring with retrospective data analysis. Setting:Single-center academic neurologic intensive care unit. Patients:Twenty-one patients with severe traumatic brain injury (Glasgow Coma Scale score 3–8). Interventions:None. Measurements and Main Results:Cerebral microdialysis was performed for the initial 7 days after traumatic brain injury. Thirteen patients had microdialysis probes in normal tissue and eight had two probes, one of which was located in pericontusional tissue. Retrospective analysis was performed to determine if microdialysis levels in pericontusional tissue demonstrates higher levels of lactate/pyruvate ratio than normal tissue and if lactate/pyruvate ratio increased with reductions in cerebral perfusion pressure. Univariate analysis revealed higher values for glutamate and lactate/pyruvate ratio in pericontusional tissue compared with normal tissue. However, based on the mixed-effects model analysis, the percent time of elevated lactate/pyruvate ratio was significantly higher in pericontusional tissue (40 ± 59% vs. 17 ± 37%, p < .05), and the mean lactate/pyruvate ratio values showed only a trend relationship (62 ± 134 vs. 34 ± 78, p < .06). When examined by cerebral perfusion pressure threshold, cerebral perfusion pressure <60 mm Hg was not associated with higher lactate/pyruvate ratio values in normal or pericontusional tissue. In addition, no single cerebral perfusion pressure threshold was associated with a significant reduction in lactate/pyruvate ratio in either pericontusional or normal tissue (p < .08). Conclusions:Sustained increases in lactate/pyruvate ratio occurred more frequently in pericontusional tissue compared with normal brain tissue. The lactate/pyruvate ratio was not related to cerebral perfusion pressure, nor was the percent time-burden of elevated lactate/pyruvate ratio related to any particular sustained cerebral perfusion pressure threshold. Lactate/pyruvate ratio values appear to be elevated despite cerebral perfusion pressure values customarily considered to be adequate.