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Daniel F. Kelly, Stefan M. Lee, Patty A. Pinanong, and David A. Hovda

✓ Acute ethanol intoxication is a frequent complicating factor in human head injury, yet its impact on neurological outcome remains poorly defined. This study was undertaken to assess the effect of varying levels of preinjury ethanol on early postinjury mortality, recovery of motor function, and degree of neural degeneration after cortical contusion injury in the rat. Adult rats were pretrained on a beam-walking task, then randomized to one of five groups: low-dose ethanol and injury (1 g/kg, 16 animals); moderate-dose ethanol and injury (2.5 g/kg, 11 animals); high-dose ethanol and injury (3 g/kg, 17 animals); no ethanol and injury (nine animals); or ethanol and sham injury (seven animals). Forty minutes after intraperitoneal injection of ethanol or saline, the rats received a pneumatic piston—induced contusion injury of the left primary motor cortex. Their beam-walking ability was assessed daily for the next 7 days. At 4 weeks postinjury, the brains were sectioned and the dimensions of the cortical lesions were determined.

Preinjury ethanol administration was associated with an acute postinjury mortality rate of 29.5% (p < 0.05); the highest mortality rate (47.1%) occurred in the high-dose ethanol group, whereas no deaths occurred in the animals in the no ethanol or sham-injured groups (p < 0.01). However, injured animals receiving low- and moderate-dose ethanol had significantly less severe beam-walking impairment initially, and a more rapid return to normal beam-walking ability, compared to the no and high-dose ethanol groups (p < 0.05). Additionally, the mean lesion volumes were significantly smaller in the low- and moderate-dose ethanol treatment groups compared to the no and high-dose ethanol groups (23.2 ± 8 mm3 and 29 ± 6.7 mm3 vs. 52 ± 8.8 mm3 and 53.7 ± 10.9 mm3, respectively, p < 0.01). In this cortical contusion model, the presence of ethanol before injury appears to exert a potent neuroprotective effect when administered in low or moderate doses. This action is postulated to result from ethanol-induced inhibition of N-methyl-d-aspartate receptor-mediated excitotoxicity. The loss of neuroprotection and increased mortality rates observed with high-dose ethanol may be related to ethanol-induced hemodynamic and respiratory depression.

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Yoichi Katayama, Donald P. Becker, Toru Tamura, and David A. Hovda

✓ An increase in extracellular K+ concentration ([K+]e) of the rat hippocampus following fluid-percussion concussive brain injury was demonstrated with microdialysis. The role of neuronal discharge was examined with in situ administration of 0.1 mM tetrodotoxin, a potent depressant of neuronal discharges, and of 0.5 to 20 mM cobalt, a blocker of Ca++ channels. While a small short-lasting [K+]e increase (1.40- to 2.15-fold) was observed after a mild insult, a more pronounced longer-lasting increase (4.28- to 5.90-fold) was induced without overt morphological damage as the severity of injury rose above a certain threshold (unconscious for 200 to 250 seconds). The small short-lasting increase was reduced with prior administration of tetrodotoxin but not with cobalt, indicating that neuronal discharges are the source of this increase. In contrast, the larger longer-lasting increase was resistant to tetrodotoxin and partially dependent on Ca++, suggesting that neurotransmitter release is involved. In order to test the hypothesis that the release of the excitatory amino acid neurotransmitter glutamate mediates this increase in [K+]e, the extracellular concentration of glutamate ([Glu]e) was measured along with [K+]e. The results indicate that a relatively specific increase in [Glu]e (as compared with other amino acids) was induced concomitantly with the increase in [K+]e. Furthermore, the in situ administration of 1 to 25 mM kynurenic acid, an excitatory amino acid antagonist, effectively attenuated the increase in [K+]e. A dose-response curve suggested that a maximum effect of kynurenic acid is obtained at a concentration that substantially blocks all receptor subtypes of excitatory amino acids. These data suggest that concussive brain injury causes a massive K+ flux which is likely to be related to an indiscriminate release of excitatory amino acids occurring immediately after brain injury.

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Jae Hong Lee, Neil A. Martin, George Alsina, David L. McArthur, Ken Zaucha, David A. Hovda, and Donald P. Becker

✓ The authors prospectively investigated cerebral hemodynamic changes in 152 patients with head injuries to clarify the relationship between cerebral vasospasm and outcome. They also sought to determine the most clinically meaningful criteria for diagnosing cerebral vasospasm. Patients with varying degrees of moderate-to-severe head injury were monitored using transcranial Doppler (TCD) ultrasonography and intravenous 133Xe—cerebral blood flow (CBF) measurements. Outcome was determined at 6 months. Using TCD ultrasonography, mean flow velocities were determined for the middle cerebral artery (VMCA, 149 patients) and basilar artery (VBA, 126 patients). Recordings of the mean extracranial internal carotid artery velocity (VEC-ICA) were also performed to determine the hemispheric ratio (VMCA/VEC-ICA, 147 patients). Cerebral blood flow measurements were obtained in 91 patients. Concurrent TCD and CBF data from 85 patients were used to calculate a “spasm index” (the VMCA or VBA, respectively, divided by the hemispheric or global CBF). The authors investigated the clinical significance of elevated flow velocity, hemispheric ratio, and spasm index. Patients diagnosed as having MCA or BA vasospasm on the basis of TCD-derived criteria alone had a significantly worse outcome than patients without vasospasm. When CBF was considered, hemodynamically significant vasospasm, as defined by an elevated spasm index, was even more strongly associated with poor outcome. Stepwise logistic regression analysis confirmed that hemodynamically significant vasospasm was a significant predictor of poor outcome, independent of the effects of admission Glasgow Coma Scale score and age. On the basis of the results of this study, the authors suggest that the important factor impacting on outcome is not vasospasm per se, but hemodynamically significant vasospasm with low CBF. These findings show that vasospasm is a pathophysiologically important posttraumatic secondary insult, which is best diagnosed by the combined use of TCD and CBF measurements.

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Neil A. Martin, Ravish V. Patwardhan, Michael J. Alexander, Cynthia Zane Africk, Jae Hong Lee, Ehud Shalmon, David A. Hovda, and Donald P. Becker

✓ The extent and timing of posttraumatic cerebral hemodynamic disturbances have significant implications for the monitoring and treatment of patients with head injury. This prospective study of cerebral blood flow (CBF) (measured using 133Xe clearance) and transcranial Doppler (TCD) measurements in 125 patients with severe head trauma has defined three distinct hemodynamic phases during the first 2 weeks after injury. The phases are further characterized by measurements of cerebral arteriovenous oxygen difference (AVDO2) and cerebral metabolic rate of oxygen (CMRO2). Phase I (hypoperfusion phase) occurs on the day of injury (Day 0) and is defined by a low CBF15 calculated from cerebral clearance curves integrated to 15 minutes (mean CBF15 32.3 ± 2 ml/100 g/minute), normal middle cerebral artery (MCA) velocity (mean VMCA 56.7 ± 2.9 cm/second), normal hemispheric index ([HI], mean HI 1.67 ± 0.11), and normal AVDO2 (mean AVDO2 5.4 ± 0.5 vol%). The CMRO2 is approximately 50% of normal (mean CMRO2 1.77 ± 0.18 ml/100 g/minute) during this phase and remains depressed during the second and third phases. In Phase II (hyperemia phase, Days 1–3), CBF increases (46.8 ± 3 ml/100 g/minute), AVDO2 falls (3.8 ± 0.1 vol%), VMCA rises (86 ± 3.7 cm/second), and the HI remains less than 3 (2.41 ± 0.1). In Phase III (vasospasm phase, Days 4–15), there is a fall in CBF (35.7 ± 3.8 ml/100 g/minute), a further increase in VMCA (96.7 ± 6.3 cm/second), and a pronounced rise in the HI (2.87 ± 0.22).

This is the first study in which CBF, metabolic, and TCD measurements are combined to define the characteristics and time courses of, and to suggest etiological factors for, the distinct cerebral hemodynamic phases that occur after severe craniocerebral trauma. This research is consistent with and builds on the findings of previous investigations and may provide a useful temporal framework for the organization of existing knowledge regarding posttraumatic cerebrovascular and metabolic pathophysiology.

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Neil A. Martin, Ravish V. Patwardhan, Michael J. Alexander, Cynthia Zane Africk, Jae Hong Lee, Ehud Shalmon, David A. Hovda, and Donald P. Becker

The extent and timing of posttraumatic cerebral hemodynamic disturbances have significant implications for the monitoring and treatment of patients with head injury. This prospective study of cerebral blood flow (CBF) (measured using 133Xe clearance) and transcranial Doppler (TCD) measurements in 125 patients with severe head trauma has defined three distinct hemodynamic phases during the first 2 weeks after injury. The phases are further characterized by measurements of cerebral arteriovenous oxygen difference (AVDO2) and cerebral metabolic rate of oxygen (CMRO2). Phase I (hypoperfusion phase) occurs on the day of injury (Day 0) and is defined by a low CBF15 calculated from cerebral clearance curves integrated to 15 minutes (mean CBF15 32.3 ± 2 ml/100 g/minute), normal middle cerebral artery (MCA) velocity (mean VMCA 56.7 ± 2.9 cm/second), normal hemispheric index (mean HI 1.67 ± 0.11), and normal AVDO2 (mean AVDO2 5.4 ± 0.5 vol%). The CMRO2 is approximately 50% of normal (mean CMRO2 1.77 ± 0.18 ml/100 g/minute) during this phase and remains depressed during the second and third phases. In Phase II (hyperemia phase, Days 1-3), CBF increases (46.8 ± 3 ml/100 g/minute), AVDO2 falls (3.8 ± 0.1 vol%), VMCA velocity rises (86 ± 3.7 cm/second), and the HI remains less than 3 (2.41 ± 0.1). In Phase III (vasospasm phase, Days 4-15), there is a fall in CBF (35.7 ± 3.8 ml/100 g/minute), a further increase in VMCA (96.7 ± 6.3 cm/second), and a pronounced rise in the HI (2.87 ± 0.22).

This is the first study in which CBF, metabolic, and TCD measurements are combined to define the characteristics and time courses of, and to suggest etiological factors for, the distinct cerebral hemodynamic phases that occur after severe craniocerebral trauma. This research is consistent with and builds on the findings of previous investigations and may provide a useful temporal framework for the organization of existing knowledge regarding posttraumatic cerebrovascular and metabolic pathophysiology.

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Paul Vespa, Mayumi Prins, Elizabeth Ronne-Engstrom, Michael Caron, Ehud Shalmon, David A. Hovda, Neil A. Martin, and Donald P. Becker

Object. To determine the extent and duration of change in extracellular glutamate levels after human traumatic brain injury (TBI), 17 severely brain injured adults underwent implantation of a cerebral microdialysis probe and systematic sampling was conducted for 1 to 9 days postinjury.

Methods. A total of 772 hourly microdialysis samples were obtained in 17 patients (median Glasgow Coma Scale score 5 ± 2.5, mean age 39.4 ± 20.4 years). The mean (± standard deviation) glutamate levels in the dialysate were evaluated for 9 days, during which the mean peak concentration reached 25.4 ± 13.7 (µM on postinjury Day 3. In each patient transient elevations in glutamate were seen each day. However, these elevations were most commonly seen on Day 3. In all patients there was a mean of 4.5 ± 2.5 transient elevations in glutamate lasting a mean duration of 4.4 ± 4.9 hours. These increases were seen in conjunction with seizure activity. However, in many seizure-free patients the increase in extracellular glutamate occurred when cerebral perfusion pressure was less than 70 mm Hg (p < 0.001). Given the potential injury-induced uncoupling of cerebral blood flow and metabolism after TBI, these increases in extracellular glutamate may reflect a degree of enhanced cellular crisis, which in severe head injury in humans appears to last up to 9 days.

Conclusions. Extracellular neurochemical measurements of excitatory amino acids may provide a marker for secondary insults that can compound human TBI.

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Matthias Oertel, Daniel F. Kelly, Jae Hong Lee, David L. McArthur, Thomas C. Glenn, Paul Vespa, W. John Boscardin, David A. Hovda, and Neil A. Martin

Object. Hyperventilation therapy, blood pressure augmentation, and metabolic suppression therapy are often used to reduce intracranial pressure (ICP) and improve cerebral perfusion pressure (CPP) in intubated head-injured patients. In this study, as part of routine vasoreactivity testing, these three therapies were assessed in their effectiveness in reducing ICP.

Methods. Thirty-three patients with a mean age of 33 ± 13 years and a median Glasgow Coma Scale (GCS) score of 7 underwent a total of 70 vasoreactivity testing sessions from postinjury Days 0 to 13. After an initial 133Xe cerebral blood flow (CBF) assessment, transcranial Doppler ultrasonography recordings of the middle cerebral arteries were obtained to assess blood flow velocity changes resulting from transient hyperventilation (57 studies in 27 patients), phenylephrine-induced hypertension (55 studies in 26 patients), and propofol-induced metabolic suppression (43 studies in 21 patients). Changes in ICP, mean arterial blood pressure (MABP), CPP, PaCO2, and jugular venous oxygen saturation (SjvO2) were recorded. With hyperventilation therapy, patients experienced a mean decrease in PaCO2 from 35 ± 5 to 27 ± 5 mm Hg and in ICP from 20 ± 11 to 13 ± 8 mm Hg (p < 0.001). In no patient who underwent hyperventilation therapy did SjvO2 fall below 55%. With induced hypertension, MABP in patients increased by 14 ± 5 mm Hg and ICP increased from 16 ± 9 to 19 ± 9 mm Hg (p = 0.001). With the aid of metabolic suppression, MABP remained stable and ICP decreased from 20 ± 10 to 16 ± 11 mm Hg (p < 0.001). A decrease in ICP of more than 20% below the baseline value was observed in 77.2, 5.5, and 48.8% of hyperventilation, induced-hypertension, and metabolic suppression tests, respectively (p < 0.001 for all comparisons). Predictors of an effective reduction in ICP included a high PaCO2 for hyperventilation, a high study GCS score for induced hypertension, and a high PaCO2 and a high CBF for metabolic suppression.

Conclusions Of the three modalities tested to reduce ICP, hyperventilation therapy was the most consistently effective, metabolic suppression therapy was variably effective, and induced hypertension was generally ineffective and in some instances significantly raised ICP. The results of this study suggest that hyperventilation may be used more aggressively to control ICP in head-injured patients, provided it is performed in conjunction with monitoring of SjvO2.

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Daniel F. Kelly, Rouzbeh K. Kordestani, Neil A. Martin, Tien Nguyen, David A. Hovda, Marvin Bergsneider, David L. McArthur, and Donald P. Becker

✓ The role of posttraumatic hyperemia in the development of raised intracranial pressure (ICP) has important pathophysiological and therapeutic implications. To determine the relationship between hyperemia (cerebral blood flow (CBF) > 55 ml/100 g/minute), intracranial hypertension (ICP > 20 mm Hg), and neurological outcome, 193 simultaneous measurements of ICP and CBF (xenon-133 method) were obtained in 59 patients with moderate and severe head injury.

Hyperemia was associated with an increased incidence of simultaneous intracranial hypertension compared to nonhyperemic CBF measurements (32.2% vs. 21.6%, respectively; p < 0.059). However, in 78% of blood flow studies in which ICP was greater than 20 mm Hg, CBF was less than or equal to 55 ml/100 g/minute. At least one episode of hyperemia was documented in 34% of patients, all of whom had a Glasgow Coma Scale (GCS) score of 9 or below. In 12 individuals with hyperemia without simultaneous intracranial hypertension, ICP was greater than 20 mm Hg for an average of 11 ± 16 hours and favorable outcomes were seen in 75% of patients. In contrast, in eight individuals with hyperemia and at least one episode of hyperemia-associated intracranial hypertension, ICP was greater than 20 mm Hg for an average of 148 ± 84 hours (p < 0.001), and a favorable outcome was seen in only one patient (p < 0.001). Compared to the remainder of the cohort, patients with hyperemia-associated intracranial hypertension were distinctive in being the youngest, exhibiting the lowest GCS scores (all ≤ 6), and having the highest incidence of effaced basilar cisterns and intractable intracranial hypertension.

In the majority of individuals with hyperemia-associated intracranial hypertension, their clinical profile suggests the occurrence of a severe initial insult with resultant gross impairment of metabolic vasoreactivity and pressure autoregulation. In a minority of these patients, however, high CBF may be coupled to a hypermetabolic state, given their responsiveness to metabolic suppressive therapy. In patients with hyperemia but without intracranial hypertension, elevated CBF is also likely to be a manifestation of appropriate coupling to increased metabolic demand consistent with a generally favorable outcome. This study supports the concept that there are multiple etiologies of both elevated blood flow and intracranial hypertension after head injury.