Daniel F. Kelly

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.

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.

Graded repair of cranial base defects and cerebrospinal fluid leaks in transsphenoidal surgery.

OBJECTIVE A graded approach to cerebrospinal fluid (CSF) leak repair after transsphenoidal surgery is presented. METHODS Patients undergoing endonasal tumor removal during an 8-year period were reviewed. Intraoperative CSF leaks were classified as Grade 0, no leak observed; Grade 1, small leak without obvious diaphragmatic defect; Grade 2, moderate leak; or Grade 3, large diaphragmatic/dural defect. Cranial base repair was tailored to the leak grade as Grade 0, collagen sponge; Grade 1, two-layered collagen sponge repair with intrasellar titanium mesh buttress; Grade 2, intrasellar and sphenoid sinus fat grafts with collagen sponge overlay and titanium buttress; and Grade 3, same as Grade 2 with CSF diversion in most cases. A provocative tilt test was performed before patient discharge to assess the integrity of the CSF leak repair. Protocol modifications adopted in 2003 included an intrasellar fat graft in Grade 1 leaks with a large intrasellar dead space, frequent use of BioGlue (CryoLife, Inc., Atlanta, GA) in Grade 1, 2, and 3 leaks, and CSF diversion for all Grade 3 leaks. RESULTS Among 668 cases in 620 patients (475 pituitary adenomas and 145 other lesions), an intraoperative CSF leak was observed in 57% of the cases: 32.5% Grade 1, 15% Grade 2, and 8.7% Grade 3. Postoperative repair failures occurred in 17 cases (2.5%), including 0.7, 3, 1, and 12% of Grade 0, 1, 2, and 3 CSF leaks, respectively. Bacterial meningitis occurred in three patients (0.45%). After protocol modifications in 2003, repair failures decreased from 4 to 1.2% (P = 0.02). CONCLUSION A graded repair approach to CSF leaks in transsphenoidal surgery avoids tissue grafts and CSF diversion in more than 60% of patients. Protocol modifications adopted in the last 340 cases have reduced the failure rate to 1% overall and 7% for Grade 3 leaks. Provocative tilt testing before patient discharge is helpful in the timely diagnosis of postoperative CSF leaks.

Endonasal versus supraorbital keyhole removal of craniopharyngiomas and tuberculum sellae meningiomas.

OBJECTIVE Endonasal and supraorbital “eyebrow” craniotomies are increasingly being used to remove craniopharyngiomas and tuberculum sellae meningiomas. Herein, we assess the relative advantages, disadvantages, and selection criteria of these 2 keyhole approaches. METHODS All consecutive patients who had endonasal or supraorbital removal of a craniopharyngioma or tuberculum sellae meningioma were analyzed. RESULTS Of 43 patients, 22 had a craniopharyngioma (18 endonasal, 4 supraorbital), and 21 had a meningioma (12 endonasal, 7 supraorbital, 2 both routes); 33% had prior surgery. Craniopharyngiomas were primarily retrochiasmal in location in 78% of endonasal cases versus 25% of supraorbital cases (P = 0.08). Meningiomas were larger when approached by the supraorbital route versus the endonasal route (33 ± 10 versus 25 ± 8 mm, respectively; P = 0.008). Endoscopy was used in 84% of endonasal approaches and in 31% of supraorbital approaches (P = 0.001). Of patients having first-time surgery for a craniopharyngioma (n = 14) or meningioma (n = 15), total/near total removal was achieved in 83% and 80% of patients by the endonasal route and in 50% and 80% of patients by the supraorbital route, respectively. Vision improved in 87% and 70% of patients who had surgery by an endonasal versus supraorbital route, respectively (P = 0.3). Visual deterioration occurred in 2 patients with meningiomas, 1 by endonasal (7%), and 1 by supraorbital (11%) removal. The endonasal approach was associated with a higher rate of postoperative cerebrospinal fluid leaks (16 versus 0%; P = 0.3), 4 of 5 of which occurred in patients with meningioma. CONCLUSION The endonasal route is preferred for removal of most retrochiasmal craniopharyngiomas, whereas the supraorbital route is recommended for meningiomas larger than 30 to 35 mm or with growth beyond the supraclinoid carotid arteries. For smaller midline tumors, either approach can be used, depending on surgeon experience and tumor anatomy. Compared with traditional craniotomies, the major limitation of both approaches is a narrow surgical corridor. The endonasal approach has the added challenges of restricted lateral suprasellar access, a greater need for endoscopy, and a more demanding cranial base repair.

Depression, cognition, and functional correlates of recovery outcome after traumatic brain injury

The present study investigated the prevalence and magnitude of depressive symptomatology in a sample of patients who had sustained traumatic brain injury (TBI) six months earlier. Depression was examined as a function of recovery outcome status, and its association with neuropsychological functioning, personal competency, and employability was also explored. Subjects were 100 patients who had previously sustained moderate-to-severe TBI who were enrolled as research subjects in the UCLA Brain Injury Research Center, and 30 matched control subjects who had sustained traumatic injuries other than to the head six months prior to evaluation. The results showed a significant association between depression and recovery status as measured by the Glasgow Outcome Scale (GOS). A significant majority of depressed subjects were found in the poorer GOS outcome groups (severe and moderate disability), compared to TBI subjects who had good GOS outcomes, and control subjects. This association was also reflected in the magnitude of the mean depression scores on two self-report measures of depression. However, no association was found between depression status and performance on the neuropsychological measures. Effects of depression were found only on an examiner-rated Patient Competency scale, and a metacognition measure based on self-report. These results are discussed in terms of brain injury severity, recovery status, and metacognition issues in TBI and other disorders.

Interleukin-1β messenger ribonucleic acid and protein levels after fluid-percussion brain injury in rats: Importance of injury severity and brain temperature

OBJECTIVE Posttraumatic temperature manipulations have been reported to significantly influence the inflammatory response to traumatic brain injury (TBI). The purpose of this study was to determine the temporal and regional profiles of messenger ribonucleic acid (mRNA) expression and protein levels for the proinflammatory cytokine interleukin-1&bgr; (IL-1&bgr;), after moderate or severe TBI. The effects of posttraumatic hypothermia (33°C) or hyperthermia (39.5°C) on these consequences of TBI were then determined. METHODS Male Sprague-Dawley rats underwent fluid-percussion brain injury. In the first phase of the study, rats were killed 15 minutes or 1, 3, or 24 hours after moderate TBI (1.8–2.2 atmospheres), for reverse transcription-polymerase chain reaction analysis. Other groups of rats were killed 1, 3, 24, or 72 hours after moderate or severe TBI (2.4–2.7 atmospheres), for protein analysis. In the second phase, rats underwent moderate fluid-percussion brain injury, followed immediately by 3 hours of posttraumatic normothermia (37°C), hyperthermia (39.5°C), or hypothermia (33°C), and were then killed, for analyses of protein levels and mRNA expression. Brain samples, including cerebral cortex, hippocampus, thalamus, and cerebellum, were dissected and stored at −80°C until analyzed. RESULTS The findings indicated that mRNA levels were increased (P < 0.05) as early as 1 hour after TBI and remained elevated up to 3 hours after moderate TBI. Although both moderate and severe TBI induced increased levels of IL-1&bgr; (P < 0.05), increased protein levels were also noted in remote brain structures after severe TBI. Posttraumatic hypothermia attenuated IL-1&bgr; protein levels, compared with normothermia (P < 0.05), although the levels remained elevated in comparison with sham values. In contrast, hyperthermia had no significant effect on IL-1&bgr; levels, compared with normothermic values. Posttraumatic temperature manipulations had no significant effect on IL-1&bgr; mRNA levels. CONCLUSION Injury severity determines the degree of IL-1&bgr; protein level elevation after TBI. The effects of posttraumatic hypothermia on IL-1&bgr; protein levels (an important mediator of neurodegeneration after TBI) may partly explain the established effects of posttraumatic temperature manipulations on inflammatory processes after TBI.

CHRONIC HYPOPITUITARISM AFTER TRAUMATIC BRAIN INJURY: RISK ASSESSMENT AND RELATIONSHIP TO OUTCOME

OBJECTIVE Chronic pituitary dysfunction is increasingly recognized as a sequela of traumatic brain injury. We sought to define the incidence, risk factors, and neurobehavioral consequences of chronic hormonal deficiencies after complicated mild, moderate, or severe traumatic brain injury. METHODS Patients aged 14 to 80 years were prospectively enrolled at the time of injury and assessed at 3 and 6 to 9 months after injury for hormonal function and neurobehavioral consequences. Major and minor (subclinical) hormonal deficiencies, including growth hormone deficiency (GHD) and growth hormone insufficiency (GHI), were identified. Acute injury characteristics, neurobehavioral, and quality of life measures were compared in patients with and without major hormonal deficits by the use of multivariate analysis. RESULTS Out of 70 patients (mean age, 32 yr; median Glasgow Coma Scale score, 7; 19% women) tested at 6 to 9 months after injury, 15 (21%) had at least one major hormonal deficiency, 20 (29%) had minor deficiencies, and 30 (43%) had major and/or minor deficiencies. Patients with major deficiencies included 16% with GHD or GHI, 10.5% with hypogonadism, and 1.4% with diabetes insipidus. None of the patients required adrenal or thyroid replacement. At 6 to 9 months after injury, patients with major hormonal deficits had more abnormal acute computed tomographic findings (P = 0.014), greater acute and chronic body mass index (P < 0.01), and a worse Disability Rating Scale score (multivariate P = 0.04). Compared with the 59 growth hormone-sufficient patients, the 11 patients with GHD or GHI had worse Disability Rating Scale scores (multivariate P = 0.04), greater rates of depression, (90 versus 53%; multivariate P = 0.06), and worse quality of life in the Short Form-36 domains of energy and fatigue (multivariate P = 0.03), emotional well-being (multivariate P = 0.02), and general health (multivariate P = 0.07). CONCLUSION Chronic hypopituitarism warranting hormone replacement occurs in approximately 20% of patients after complicated mild, moderate, or severe traumatic brain injury and is associated with more severe brain injuries and increased disability. GHD and GHI are also associated with increased disability, poor quality of life, and a greater likelihood of depression. The clinical significance of minor hormonal deficits, which occur in almost 30% of patients, warrants further study. Given that major deficiencies are readily treatable, routine pituitary hormonal testing within 6 months of injury is indicated for this patient population.

Avoidance of carotid artery injuries in transsphenoidal surgery with the Doppler probe and micro-hook blades.

OBJECTIVE Internal carotid artery (ICA) injury during sellar dural opening is a potentially catastrophic complication of transsphenoidal surgery. We describe two ICA injuries that occurred early in our endonasal transsphenoidal experience. We then describe our subsequent protocol to prevent this complication in which we use the Doppler probe for carotid localization and micro-hook blades for lateral dural opening. METHODS All patients undergoing endonasal tumor removal were analyzed since beginning this approach in 1998. Of 631 procedures (585 patients), three patients sustained an ICA injury. RESULTS In the first 114 procedures (105 patients) in which the Doppler probe was not used and hook blades were used infrequently, two (1.8%) ICA injuries occurred. In both cases, a right nostril approach was used and the left ICA was punctured on dural opening with a straight scalpel; both patients recovered without neurological sequelae. In the subsequent 517 procedures in which the Doppler probe and hook blades were used in all cases, one (0.19%) probable ICA injury occurred during an attempted removal of a cavernous sinus schwannoma, although there was no angiographic evidence of vascular injury. There were no ICA or other intracranial vascular injuries in the last 510 procedures for tumors not solely confined to the cavernous sinus. CONCLUSION Cavernous carotid localization with the Doppler probe before dural opening and angled hook blades for lateral dural opening can help minimize the risk of ICA injury and are recommended for all transsphenoidal operations. Because of the wider contralateral exposure provided by the endonasal approach, the ICA contralateral to the nostril of approach is at higher risk of injury on dural opening.

Endonasal Transsphenoidal Removal of Tuberculum Sellae Meningiomas: Technical Note

OBJECTIVE:Tuberculum sellae meningiomas traditionally have been removed through a transcranial approach. More recently, the sublabial transsphenoidal approach has been used to remove such tumors. Here, we describe use of the direct endonasal transsphenoidal approach for removal of suprasellar meningiomas. METHODS:Three women, aged 32, 34, and 55 years, each sought treatment for visual loss and headaches. In each patient, magnetic resonance imaging (MRI) showed a suprasellar mass causing optic chiasmal and optic nerve compression (average size, 2 × 2 cm). All three patients underwent tumor removal via an endonasal approach with the operating microscope. Suprasellar exposure was facilitated by removal of the posterior planum sphenoidale. Ultrasound was used to help define tumor location before dural opening. The extent of tumor removal was verified with angled endoscopes in all patients, and with intraoperative MRI in one patient. The surgical dural and bony defects were repaired in all patients with abdominal fat, titanium mesh, and 2 to 3 days of cerebrospinal fluid lumbar drainage. Nasal packing was not used. RESULTS:There were no postoperative cerebrospinal fluid leaks or meningitis. One patient required a reoperation 2 weeks after surgery to reduce the size of her fat graft, which was causing optic nerve compression; within 24 hours, her vision rapidly improved. At 3 months after surgery, all three patients had normal vision, no new endocrinopathy, and no residual tumor on MRI. At 10 months after surgery, one patient had a small asymptomatic tumor regrowth seen on MRI. CONCLUSION:The endonasal approach with the operating microscope appears to be an effective minimally invasive method for removing relatively small midline tuberculum sellae meningiomas. Intraoperative ultrasound, the micro-Doppler probe, and angled endoscopes are useful adjuncts for safely and completely removing such tumors. Longer follow-up is needed to monitor for tumor recurrence in these patients.