Traumatic Brain Injury

Challenges in the Development of Rodent Models of Mild Traumatic Brain Injury

Authors: Dewitt D, Perez-Polo JR Ph D, Hulsebosch C, Dash PK, Robertson CS.

Approximately 75% of traumatic brain injuries (TBI) are classified mild (mTBI). Despite the high frequency of mTBI, it is the least well studied. The prevalence of mTBI among service personnel returning from Operations Iraqi Freedom (OIF) and Enduring Freedom (OEF) and the recent reports of an association between repeated mTBI and the early onset of Alzheimer's and other types of dementias in retired athletes has focused much attention on mTBI. The study of mTBI requires the development and validation of experimental models of mTBI and one of the most basic requirements for an experimental model is that it replicates important features of the injury or disease in humans. mTBI in humans is associated with acute symptoms such as loss of consciousness and pre- and/or posttraumatic amnesia. In addition, although the majority of patients recover within a few months after mTBI, a small but significant number (2.5 - 26%) had Glasgow Outcome Scores in the "moderate disability" range. These mTBI patients experienced long-term effects of mTBI including deficits in speed of information processing, attention and concentration, memory acquisition, retention and retrieval and reasoning and decision-making. Although methods for the diagnosis and evaluation of the acute and chronic effects of mTBI in humans are well established, the same is not the case for rodents, the most widely used animal for TBI studies. Despite the magnitude of the difficulties associated with adapting these methods for experimental mTBI research, they must be surmounted. The identification and testing of treatments for mTBI depends of the development, characterization and validation of reproducible, clinically relevant models of mTBI.

Tissue vulnerability is increased following repetitive mild traumatic brain injury in the rat

Authors: Huang L, Coats JS, Mohd-Yusof A, Yin Y, Assaad S, Muellner MJ, Kamper JE, Hartman RE, Dulcich M, Donovan VM, Oyoyo U, Obenaus A.

Repetitive mild traumatic brain injury (rmTBI) is an important medical concern for active sports and military personnel. Multiple mild injuries may exacerbate tissue damage resulting in cumulative brain injury and poor functional recovery. In the present study, we investigated the time course of brain vulnerability to rmTBI in a rat model of mild cortical controlled impact. An initial mild injury was followed by a second injury unilaterally at an interval of 1, 3, or 7 days. RmTBI animals were compared to single mTBI and sham treated animals. Neuropathology was assessed using multi-modal magnetic resonance imaging (MRI), followed by ex vivo tissue immunohistochemistry. Neurological and behavioral outcomes were evaluated in a subset of animals receiving rmTBI 3 days apart and shams. RmTBI 1 or 3 days apart but not 7 days apart revealed significantly exacerbated MRI-definable lesion volumes compared to single mTBI and shams. Increases in cortical tissue damage, extravascular iron and glial activation assessed by histology/immunohistochemistry correlated with in vivo MRI findings where shorter intervals (1 or 3 days apart) resulted in increased tissue pathology. There were no neurological deficits associated with rmTBI 3 day animals. At 1 mo post-injury, animals with rmTBI 3 days apart showed reduced exploratory behaviors and subtle spatial learning memory impairments were observed. Collectively, our findings suggest that the mildly-impacted brain is more vulnerable to repetitive injury when delivered within 3 days following initial mTBI.

Novel Methods to Predict Increased Intracranial Pressure During Intensive Care and Long-Term Neurological Outcome After Traumatic Brain Injury: Development and Validation in a Multicenter Dataset.

Authors: Güiza F, Depreitere B, Piper I, Van den Berghe G, Meyfroidt G.

OBJECTIVE: Intracranial pressure monitoring is standard of care after severe traumatic brain injury. Episodes of increased intracranial pressure are secondary injuries associated with poor outcome. We developed a model to predict increased intracranial pressure episodes 30 mins in advance, by using the dynamic characteristics of continuous intracranial pressure and mean arterial pressure monitoring. In addition, we hypothesized that performance of current models to predict long-term neurologic outcome could be substantially improved by adding dynamic characteristics of continuous intracranial pressure and mean arterial pressure monitoring during the first 24 hrs in the ICU. DESIGN:: Prognostic modeling. Noninterventional, observational, retrospective study. SETTING AND PATIENTS:: The Brain Monitoring with Information Technology dataset consisted of 264 traumatic brain injury patients admitted to 22 neuro-ICUs from 11 European countries. INTERVENTIONS:: None. MEASUREMENTS:: Predictive models were built with multivariate logistic regression and Gaussian processes, a machine learning technique. Predictive attributes were Corticosteroid Randomisation After Significant Head Injury-basic and International Mission for Prognosis and Clinical Trial design in TBI-core predictors, together with time-series summary statistics of minute-by-minute mean arterial pressure and intracranial pressure. MAIN RESULTS:: Increased intracranial pressure episodes could be predicted 30 mins ahead with good calibration (Hosmer-Lemeshow p value 0.12, calibration slope 1.02, calibration-in-the-large -0.02) and discrimination (area under the receiver operating curve = 0.87) on an external validation dataset. Models for prediction of poor neurologic outcome at six months (Glasgow Outcome Score 1-2) based only on static admission data had 0.72 area under the receiver operating curve; adding dynamic information of intracranial pressure and mean arterial pressure during the first 24 hrs increased performance to 0.90. Similarly, prediction of Glasgow Outcome Score 1-3 was improved from 0.68 to 0.87 when including dynamic information. CONCLUSION:: The dynamic information in continuous mean arterial pressure and intracranial pressure monitoring allows to accurately predict increased intracranial pressure in the neuro-ICU. Adding information of the first 24 hrs of intracranial pressure and mean arterial pressure monitoring to known baseline risk factors allows very accurate prediction of long-term neurologic outcome at 6 months.

Effects of the neurological wake-up test on clinical examination, intracranial pressure, brain metabolism and brain tissue oxygenation in severely brain-injured patients

Authors: Helbok R, Kurtz P, Schmidt MJ, Stuart MR, Fernandez L, Connolly SE, Lee K, Schmutzhard E, Mayer SA, Claassen J, Badjatia N.

INTRODUCTION: Daily interruption of sedation (IS) has been implemented in 30- 40% of intensive care units worldwide and may improve outcome in medical intensive care patients. Little is known about the benefit of IS in acutely brain-injured patients.
METHODS: This prospective observational study was performed in a neuroscience intensive care unit in a tertiary-care academic center. Twenty consecutive severely brain-injured patients with multimodal neuromonitoring were analyzed for levels of brain lactate, pyruvate and glucose, intracranial pressure (ICP), cerebral perfusion pressure (CPP) and brain tissue oxygen tension (PbtO2) during IS trials.
RESULTS: Of the 82 trial days, 54 IS-trials were performed as interruption of sedation and analgesics was not considered safe on 28 days (34%). An increase in the Four Score was observed in 50% of IS-trials by a median of 3 (2-4) points. Detection of a new neurologic deficit occurred in one trial (2%), and in one third the trial had to be stopped due to ICP-crisis (>20mmHg), agitation or systemic desaturation. In IS-trials that had to be aborted, a significant increase in ICP and decrease in PbtO2 (P<0.05), including 67% with critical values of PbtO2 <20mmHg, a tendency to brain metabolic distress (P<0.07) was observed.
CONCLUSIONS: Interruption of sedation revealed new relevant clinical information in only one trial and a large number of trials could not be performed or had to be stopped due to safety issues. Weighing pros and cons of IS-trials in patients with acute brain injury seems important as related side effects may overcome clinical benefit.

Albumin resuscitation for traumatic brain injury: is intracranial hypertension the cause of increased mortality?

Authors: Cooper DJ, Myburgh J, Finfer S, Heritier S, Bellomo R, Billot L, Murray L, Vallance S.

Mortality is higher in patients with traumatic brain injury (TBI) resuscitated with albumin compared to saline, but the mechanism for increased mortality is unknown. In patients from the Saline vs. Albumin Fluid Evaluation (SAFE) study with TBI who underwent ICP monitoring, interventional data were collected from randomization to day 14 to determine changes in ICP (primary outcome) and in therapies used to treat increased ICP. Pattern mixture modelling, designed to address informative dropouts, was used to compare temporal changes between the albumin and saline groups. 321 patients were identified, of whom 164 (51.1%) received albumin and 157 (48.9%) saline. There was a significant linear increase in mean ICP and significantly more deaths in the albumin group compared to saline when ICP monitoring was ceased during the first week (1.30±0.33 vs. -0.37±0.36, p=0.0006; and 34.4% vs. 17.4%; p=0.006 respectively), but not when monitoring ceased during the second week (-0.08±0.44 vs. -0.23±0.38, p=0.79; and 18.6% vs. 12.1%; p=0.36 respectively). There were statistically significant differences in the mean total daily doses of morphine (-0.42±0.07 vs. -0.66±0.0, p=0.0009), propofol (-0.45±0.11 vs. -0.76±0.11; p=0.034) and norepinephrine (-0.50±0.07 vs. -0.74±0.07) and in temperature (0.03 ± 0.03 vs. 0.16 ± 0.03; p=0.0014) between the albumin and saline groups when ICP monitoring ceased during the first week. The use of albumin for resuscitation in patients with severe TBI is associated with increased ICP during the first week. This is the most likely mechanism of increased mortality in these patients. Key words: traumatic brain injury, resuscitation, albumin, saline, intracranial pressure.

Exercise to enhance neurocognitive function after traumatic brain injury

Authors: Fogelman D, Zafonte R.

Vigorous exercise has long been associated with improved health in many domains. Results of clinical observation have suggested that neurocognitive performance also is improved by vigorous exercise. Data derived from animal model-based research have been emerging that show molecular and neuroanatomic mechanisms that may explain how exercise improves cognition, particularly after traumatic brain injury. This article will summarize the current state of the basic science and clinical literature regarding exercise as an intervention, both independently and in conjunction with other modalities, for brain injury rehabilitation. A key principle is the factor of timing of the initiation of exercise after mild traumatic brain injury, balancing potentially favorable and detrimental effects on recovery.
Copyright © 2012 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

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