Journal of neurotrauma
-
Journal of neurotrauma · Jan 2006
Randomized Controlled TrialCyclosporin A disposition following acute traumatic brain injury.
Although the precise mechanism of action remains to be defined, Cyclosporin A (CsA) has demonstrated potential for neuroprotection in animal models. Predictive dosing strategies for CsA in acute traumatic brain injured (TBI) patients must account for the influence of the acute phase response on drug disposition. To characterize CsA pharmacokinetic parameters early following acute TBI, serial blood samples from patients enrolled into a Phase II dose-escalation trial were analyzed. ⋯ Whole blood clearance, steady state volume of distribution, and beta half-life were independent of dose and higher than published reports from other populations: 0.420 L/h/kg, 5.91 L/kg, and 17.3 h, respectively. These data show patients with acute severe TBI demonstrate a more rapid clearance and a larger distribution volume of CsA. Pharmacokinetic parameters derived from this study will guide dosing strategies for future prospective clinical trials evaluating CsA therapy following acute TBI.
-
Journal of neurotrauma · Dec 2005
Randomized Controlled Trial Multicenter StudyA single dose, three-arm, placebo-controlled, phase I study of the bradykinin B2 receptor antagonist Anatibant (LF16-0687Ms) in patients with severe traumatic brain injury.
Traumatic brain injury (TBI) mortality and morbidity remains a public health challenge. Because experimental studies support an important role of bradykinin (BK) in the neurological deterioration that follows TBI, a double-blind, randomized, placebo-controlled study of Anatibant (LF16- 0687Ms), a selective and potent antagonist of the BK B(2) receptor, was conducted in severe (Glasgow Coma Scale [GCS] < 8) TBI patients (n = 25) at six sites in the United States. At 8-12 h after injury (9.9 +/- 2.8 h), patients received a single subcutaneous injection of Anatibant (3.75 mg or 22.5 mg, n = 10 each) or placebo (n = 5). ⋯ Anatibant, administered as single subcutaneous injections of 3.75 g and 22.5 mg, was well tolerated in severe TBI patients with no unexpected clinical adverse events or biological abnormalities observed. Interestingly, plasma and CSF levels of BK1-5 were significantly and markedly increased after trauma (e.g., 34,700 +/- 35,300 fmol/mL in plasma vs. 34.9 +/- 5.6 fmol/mL previously reported for normal volunteers), supporting the use of Anatibant as a treatment of secondary brain damage. To address this issue, a dose-response trial that would investigate the effects of Anatibant on the incidence of raised ICP and on functional outcome in severe TBI patients is needed.
-
Journal of neurotrauma · Nov 2005
Randomized Controlled TrialHead position and impact direction in whiplash injuries: associations with MRI-verified lesions of ligaments and membranes in the upper cervical spine.
In the present study, we compared magnetic resonance imaging (MRI) findings of soft tissue structures in the upper cervical spine between whiplash-associated disorder (WAD) patients and population-based control persons, and examined whether MRI-verified abnormalities in WAD patients were related to accident-related factors hypothesized to be of importance for severity of injury. A total of 92 whiplash patients and 30 control persons, randomly drawn, were included. Information on the accident-related factors (i.e., head position and impact direction) was obtained by a questionnaire that was answered within 1 week after the accident. ⋯ Whiplash patients who had been sitting with their head/neck turned to one side at the moment of collision more often had high-grade lesions of the alar and transverse ligaments (p < 0.001, p = 0.040, respectively). Severe injuries to the transverse ligament and the posterior atlanto-occipital membrane were more common in front than in rear end collisions (p < 0.001, p = 0.001, respectively). In conclusion, the difference in MRI-verified lesions between WAD patients and control persons, and in particular the association with head position and impact direction at time of accident, indicate that these lesions are caused by the whiplash trauma.
-
Journal of neurotrauma · Jun 2005
Randomized Controlled Trial Multicenter Study Comparative Study Clinical TrialEfficacy of standard trauma craniectomy for refractory intracranial hypertension with severe traumatic brain injury: a multicenter, prospective, randomized controlled study.
To compare the effect of standard trauma craniectomy (STC) versus limited craniectomy (LC) on the outcome of severe traumatic brain injury (TBI) with refractory intracranial hypertension, we conducted a study at five medical centers of 486 patients with severe TBI (Glasgow Coma Scale score = 8) and refractory intracranial hypertension. In all 486 cases, refractory intracranial hypertension, caused by unilateral massive frontotemporoparietal contusion, intracerebral/subdural hematoma, and brain edema, was confirmed on a CT scan. The patients were randomly divided into two groups, one of which underwent STC (n = 241) with a unilateral frontotemporoparietal bone flap (12 x 15 cm), and the second of which underwent LC (n = 245) with a routine temporoparietal bone flap (6 x 8 cm). ⋯ In addition to these findings, the incidence of delayed intracranial hematoma, incisional hernia, and CSF fistula was lower in the STC group than in the LC group (p < 0.05), although the incidence of acute encephalomyelocele, traumatic seizure, and intracranial infection was not significantly different in the two groups (p > 0.05). The results of the study indicate that STC significantly improves outcome in severe TBI with refractory intracranial hypertension resulting from unilateral frontotemporoparietal contusion with or without intracerebral or subdural hematoma. This suggests that STC, rather than LC, be recommended for such patients.
-
Journal of neurotrauma · Feb 2004
Randomized Controlled Trial Clinical TrialRelationships between cerebrospinal fluid markers of excitotoxicity, ischemia, and oxidative damage after severe TBI: the impact of gender, age, and hypothermia.
Excitotoxicity and ischemia can result in oxidative stress after TBI. Female sex hormones are hypothesized to be neuroprotective after TBI by affecting multiple mechanisms of secondary injury, including oxidative damage, excitotoxicity and ischemia. Ca2+ mediated oxidative stress increases with age, and hypothermia is known to attenuate secondary injury. ⋯ These results indicate that females have smaller oxidative damage loads than males for a given excitotoxic or ischemic insult and female gonadal hormones may play a role in mediating this neuroprotective effect. These results also suggest that susceptibility to glutamate mediated oxidative damage increases with age and that hypothermia differentially attenuates CSF glutamate versus F2-isoprostane production. Gender and age differences in TBI pathophysiology should be considered when conducting clinical trials in TBI.