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Studies of experimental cervical spinal cord transection

Part II: Plasma norepinephrine levels after acute cervical spinal cord transection

Phillip A. Tibbs, Byron Young, Michael G. Ziegler and R. G. McAllister Jr.

✓ Plasma concentrations of norepinephrine (NE) were measured by a radioenzymatic assay technique before and serially after laminectomy at the C-6 level in 14 anesthetized dogs. In half the animals, no further procedures were carried out (control group); in the other dogs, cervical cord transection was performed in addition to laminectomy (experimental group). Mean plasma NE levels were similar in both groups after laminectomy and before cord interruption. In the control group, NE levels increased gradually for 2 hours after the procedure. In the group with cord transection, however, NE rose immediately after transection to 267% of the baseline value, then fell to 25% of the plasma NE level in the control group at 30 minutes, 29% at 60 minutes, and 15% at 120 minutes. Cervical spinal cord transection, therefore, results in an abrupt but short-lived increase in plasma NE concentrations. These changes in plasma NE levels may explain, at least in part, the hemodynamic alterations and the acute central hemorrhagic necrosis that occur after high spinal cord trauma.

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Steven J. Goldstein, Charles Lee, A. Byron Young and George J. Guidry

✓ The authors describe the radiographic findings in a patient with Klippel-Trenaunay syndrome who also had aplasia of the left internal carotid artery and a very unusual malformation of the circle of Willis. This constellation of clinical and radiographic findings is unique and has not been previously reported in the medical literature.

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Mark W. Roy, Robert J. Dempsey, Kathleen L. Meyer, David L. Donaldson, Phillip A. Tibbs and A. Byron Young

✓ To test the effect of verapamil and diltiazem in acute stroke, three groups of mongrel cats of either sex underwent occlusion of the middle cerebral artery (MCA) via a transorbital approach under ketamine anesthesia. The first group served as controls, the second received an intravenous infusion of verapamil (0.1 µg/kg/min), and the third received an intravenous infusion of diltiazem (0.1 to 1.0 µg/kg/min). All drug infusions began 2 hours before MCA occlusion and continued for the remainder of the experiment. Before and for up to 24 hours after MCA occlusion, regional cerebral blood flow (rCBF), somatosensory evoked potentials (SSEP's), arterial blood gases, blood pressure, temperature, and hematocrit were measured at least every 2 hours. At the experiment's end, brains were perfused with India ink, removed, sliced, photographed for determination of nonperfused brain area, and weighed, dried, and reweighed for H2O content determination. In these studies, verapamil was associated with worsening of rCBF in ischemic regions and inappropriate increases in rCBF in nonischemic regions, indicating intracerebral steal. Diltiazem increased rCBF in marginally ischemic regions. Changes in SSEP's paralleled blood flow changes, with verapamil decreasing amplitude and conduction velocity while diltiazem slightly improved conduction in the ischemic brain. Verapamil increased the area of nonperfused brain and the content of cerebral H2O. Diltiazem-treated animals had decreased cerebral H2O content, but had a marked increase in the area of nonperfused brain, a finding associated with the high incidence of transtentorial herniation in the diltiazem-treated animals. These findings agree with in vitro studies demonstrating high sensitivity of cerebral blood vessels to calcium channel blockers. These studies further support the notion that calcium channel blockers probably affect several different classes of calcium channels, at different brain sites.

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Byron Young, Robert P. Rapp, J. A. Norton, Dennis Haack, Phillip A. Tibbs and James R. Bean

✓ This randomized double-blind placebo-controlled study was undertaken in a series of 179 patients to determine whether phenytoin administered soon after head injury lessens the incidence of late posttraumatic epilepsy. When delayed hypersensitivity to phenytoin developed, the patient was switched to phenobarbital. The patients were followed for 18 months to detect the occurrence of seizures and to serially measure plasma phenytoin concentrations. There was no significant difference in the percentage of patients having late seizures in the treated and placebo groups (p = 0.75). The time between injury and seizures did not significantly differ between the two groups. The results provide no support for the continued use of phenytoin in the low therapeutic range for prophylaxis against late posttraumatic seizures.

It cannot be concluded that higher phenytoin plasma concentrations and higher compliance rates than obtained in this study would not have significantly decreased the occurrence of late posttraumatic epilepsy. The finding that no patient with a phenytoin plasma concentration of 12 µg/ml or higher had a seizure raises the question of whether phenytoin in blood concentrations in higher therapeutic ranges might lessen the occurrence of posttraumatic epilepsy, and should be studied further. Posttraumatic epilepsy is a major public health problem deserving a large cooperative trial to determine if phenytoin at higher blood levels than obtained in this study, or other currently available or newly developed drugs, can prevent the occurrence of posttraumatic epilepsy.

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A. Byron Young, Linda G. Ott, David Beard, Robert J. Dempsey, Phillip A. Tibbs and Craig J. McClain

✓ The acute response to injury and infection is manifested by increased synthesis of acute-phase proteins by the liver, an increased white blood cell count, fever, a negative nitrogen balance, and altered serum mineral levels (zinc, iron, and copper). This response is thought to be partially mediated by cytokines such as interleukin-1, but has not been well studied in head-injured patients. In this study, 25 patients were studied for evidence of the acute-phase response extending from hospital admission up to 21 days postinjury. The patients were divided into two groups to determine if severity of injury influenced the response. Group 1 consisted of nine patients with admission peak 24-hour Glasgow Coma Scale (GCS) scores of 4 or less; Group 2 consisted of 16 patients with admission peak 24-hour GCS scores of 8 or greater. All patients demonstrated some evidence of the acute-phase response. Serum alpha-1 acid glycoprotein, ceruloplasmin, and C-reactive protein levels were elevated on admission and throughout the study. Serum albumin and zinc levels were depressed on admission; zinc levels gradually normalized by Day 21 in both groups, but hypoalbuminemia was observed throughout the study period. Serum copper levels were normal on admission but increased to above normal in both groups by Day 11 postinjury. Urinary urea nitrogen excretion was elevated in both groups and peaked on Day 7 for Group 1 and Day 11 for Group 2 patients. The patients with admission GCS scores equal to or less than 4 had overall higher temperatures than were seen in those with GCS scores greater than or equal to 8 (p = 0.009). All patients but one had an elevated white blood cell count on admission. It is concluded that braininjured patients with admission GCS scores of 3 to 4 and 8 to 14 demonstrate an acute-phase response which lasts for at least 3 weeks postinjury. It is speculated that this response is at least partially mediated by increased intraventricular interleukin-1 activity.

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Byron Young, Robert P. Rapp, J. A. Norton, Dennis Haack, Phillip A. Tibbs and James R. Bean

✓ A randomized double-blind placebo-controlled study was carried out to determine whether phenytoin administered soon after injury lessens the incidence of epilepsy in the 1st week after severe head trauma. In this study, 244 patients were randomized into either a phenytoin or placebo group. The patients in the phenytoin group were administered phenytoin intravenously or intramuscularly within 24 hours of hospital admission. Patients in the placebo group received intravenous or intramuscular diluent. The patients were switched from parenterally administered phenytoin or placebo as soon as oral doses could be tolerated. Over 78% of the phenytoin patients had plasma concentrations of at least 10 µg/ml at 1, 3, and 7 days after injury. There was no significant difference in the percentage of patients having early seizures in the treated and placebo groups (p = 0.99). There was no significant difference in the interval from injury to first seizure between the treated and placebo groups (p = 0.41). The early administration of phenytoin did not lessen the occurrence of seizures in the 1st week after head injury. Since the effectiveness of seizure prophylaxis has not been established, the authors suggest that anticonvulsant drugs be administered only after an early seizure has occurred.

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Byron Young, Robert P. Rapp, J. A. Norton, Dennis Haack, Phillip A. Tibbs and James R. Bean

✓ The relationship between Glasgow Coma Scale (GCS) scores obtained during the 1st week after head injury and outcome at 1 year was analyzed in 170 patients. Seventy-two of 76 patients with initial GCS scores of higher than 7 had favorable outcomes. Only two of the 21 patients with initial GCS scores of 3 or 4 lived, and only one had a favorable outcome. Favorable and unfavorable outcomes were almost equally divided when the initial GCS scores were in the intermediate range of 5, 6, or 7. No patients with an initial GCS score in this intermediate range that subsequently worsened had a favorable outcome, while over 80% of those improving to a score higher than 7 had a favorable outcome. Only 12% of those persisting with a score of 5, 6, or 7 for 1 week had a favorable outcome.

Outcome predictions using the multiple logistic model were made for this intermediate group of patients based on GCS scores and data on midline shift derived from computerized tomography (CT). The patients with initial scores of 5, 6, or 7 with midline shifts of less than 4.1 mm on initial CT scanning had a significantly higher favorable outcome rate compared with patients with a larger shift. However, outcome predictions made by combining shift data and initial GCS scores are not significantly more accurate than predictions based solely on initial GCS scores. Combining 48-hour GCS scores and shift data significantly improves predictive accuracy based only on coma scores. The data obtained by combining GCS scores at 72 hours and 1 week and shift data is marginally significant for improving accuracy of outcome predictions. It is concluded that GCS scores and shift data are highly accurate indicators of outcome in head-injured patients.

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William F. Regine, Roy A. Patchell, James M. Strottmann, Ali Meigooni, Michael Sanders and Byron Young

Object. This investigation was performed to determine the tolerance and toxicities of split-course fractionated gamma knife radiosurgery (FSRS) given in combination with conventional external-beam radiation therapy (CEBRT).

Methods. Eighteen patients with previously unirradiated, gliomas treated between March 1995 and January 2000 form the substrate of this report. These included 11 patients with malignant gliomas, six with low-grade gliomas, and one with a recurrent glioma. They were stratified into three groups according to tumor volume (TV). Fifteen were treated using the initial FSRS dose schedule and form the subject of this report. Group A (four patients), had TV of 5 cm3 or less (7 Gy twice pre- and twice post-CEBRT); Group B (six patients), TV greater than 5 cm3 but less than or equal to 15 cm3 (7 Gy twice pre-CEBRT and once post-CEBRT); and Group C (five patients), TV greater than 15 cm3 but less than or equal to 30 cm3 (7 Gy once pre- and once post-CEBRT). All patients received CEBRT to 59.4 Gy in 1.8-Gy fractions. Dose escalation was planned, provided the level of toxicity was acceptable. All patients were able to complete CEBRT without interruption or experiencing disease progression. Unacceptable toxicity was observed in two Grade 4/Group B patients and two Grade 4/Group C patients. Eight patients required reoperation. In three (38%) there was necrosis without evidence of tumor. Neuroimaging studies were available for evaluation in 14 patients. Two had a partial (≥ 50%) reduction in volume and nine had a minor (> 20%) reduction in size. The median follow-up period was 15 months (range 9–60 months). Six patients remained alive for 3 to 60 months.

Conclusions. The imaging responses and the ability of these patients with intracranial gliomas to complete therapy without interruption or experiencing disease progression is encouraging. Excessive toxicity derived from combined FSRS and CEBRT treatment, as evaluated thus far in this study, was seen in patients with Group B and C lesions at the 7-Gy dose level. Evaluation of this novel treatment strategy with dose modification is ongoing.

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Studies of experimental cervical spinal cord transection

Part I: Hemodynamic changes after acute cervical spinal cord transection

Phillip A. Tibbs, Byron Young, R. G. McAllister Jr., William H. Brooks and Laddie Tackett

✓ Two distinct and sequential patterns of hemodynamic alteration were observed after acute cervical spinal cord transection in anesthetized dogs. Interruption of the cord initially caused a 45% increase in mean arterial pressure (p < 0.01), a 34% increase in systemic vascular resistance (p < 0.05), and a 92% increase in left ventricular dp/dt (p < 0.01), reflecting a generalized sympathetic response to trauma. Concomitant bradycardia and escape arrhythmias suggested relative parasympathetic hyperactivity. Resolution of the brief pressor response was followed by a second, more prolonged, period characterized by a fall in arterial pressure to 71% of control levels (p < 0.05), a 16% decrease in systemic vascular resistance, and a 58.5% decrease in left ventricular dp/dt (p < 0.01). These latter hemodynamic changes are consistent with sympathetic denervation and failure of regulatory mechanisms mediated by both alpha- and beta-adrenergic peripheral vascular and myocardial receptors.