Biomedical subjects

A Marmarou

Publications and source records attributed to A Marmarou.

At least 19 recordsLinked to original sources

PubMed1999

Treatment of raised intracranial pressure following traumatic brain injury.

Appropriate treatment of raised intracranial pressure (ICP) after traumatic brain injury (TBI) remains a controversial topic in neurotraumatology. Several techniques are employed clinically, which include vasopressors, osmotically active substances, hyperventilation, and decompressive surgery. This article reviews six recent papers that have examined alternative methods of treating elevated ICP. The first two papers consider a new and controversial alternative to cerebral perfusion pressure (CPP) management, which involves mild hypotension coupled with pre-capillary vasoconstriction using dihydroergotamine. The authors claim success with this treatment, and although the patient numbers are small, there is no evidence that they fare any less well than patients treated with conventional techniques. The third and fourth papers consider hypertonic saline (HTS) as a possible osmotic treatment for raised ICP. The third examines HTS given as a 23.4% bolus and found beneficial effects. The fourth examines HTS as a 1.6% constant infusion for fluid replacement and found that patients fared less well. The reason for this difference between the results for the two administration methods is unknown, although it may relate to the triggering of body homeostatic mechanisms in the case of constant infusion. The fifth paper compares glycerol and mannitol as osmotic ICP agents and found no significant differences between them. The final study reports for the first time a series of patients treated for refractory elevations in ICP with bifrontal craniectomy. They report good results, and suggest that this therapy should be formalized as a treatment option for severely elevated ICP. The pathophysiological mechanisms underlying the generation of a raised ICP belie the use of one therapy to treat all cases. Analysis of these studies demonstrates how problematic heterogeneity in the injury population can be for the assessment of possible treatments. It is clear, therefore, that effective analysis of treatments for raised ICP requires appropriate subdivision of the injured population into common pathophysiological processes and, furthermore, that the future of clinical TBI management may well require a similar stratification in order to tailor treatments for the individual patient.

Journal Article↗

PubMed1999

Effects of the bradykinin antagonist Bradycor (deltibant, CP-1027) in severe traumatic brain injury: results of a multi-center, randomized, placebo-controlled trial. American Brain Injury Consortium Study Group.

A phase II prospective, randomized, double blind clinical trial of Bradycor, a bradykinin antagonist, was conducted at 31 centers within North America in severely brain injured patients. Patients of Glasgow Coma Score (GCS) 3-8 (n = 139) with at least one reactive pupil were randomized to receive either Bradycor, 3 microg/kg/min or placebo as a continuous intravenous infusion for 5 days, with the infusion beginning within 12 h of the injury. The primary objective was to assess the efficacy of a continuous infusion of Bradycor (3.0 mc/kg/min) in preventing elevation of intracranial pressure (ICP). Other efficacy measures included the effect of Bradycor on the Therapy Intensity Level (TIL), mortality, and functional outcome. A secondary objective was to evaluate the safety of Bradycor in patients with severe brain injury. Randomization was carried out according to a computer generated randomization list. Patients were followed for the first 14 days of hospitalization with long-term outcome assessed at 3 and 6 months after injury. During the infusion and while the ICP monitor was in place, ICP measurements were recorded hourly along with blood pressure and heart rate. A modified version of the TIL was used to record therapeutic interventions hourly, while the ICP was being monitored. Outcome was assessed at 3 and 6 months after injury using the Glasgow Outcome Score (GOS). Bradycor was well tolerated in this patient population, and no adverse events were attributable to the compound. Although positive trends were seen for both ICP and TIL in the Bradycor group, these differences analyzed on a daily basis were not significant. However, a mixed model of variance which included treatment, day, treatment by day interaction, age and GCS revealed that the percentage time ICP of >15 mm Hg on days 4 and 5 was significantly lower in the Bradycor group compared to placebo (p = 0.035). There were fewer deaths in the Bradycor group, which had a 28-day all cause mortality of 20% versus 27% on placebo. Patients treated with Bradycor showed a 10.3% improvement in favorable outcome at 3 months and a 12% improvement in dichotomized GOS at 6 months (p = 0.26). The consistent positive trends seen in ICP, TIL, neuropsychological tests, and, most importantly, 3- and 6-month GOS provide supportive evidence that a bradykinin antagonist may play a neuroprotective role in severe brain injury.

Adolescent↗

PubMed1999

Neuroprotective effect of hypothermia on neuronal injury in diffuse traumatic brain injury coupled with hypoxia and hypotension.

It is well established in mechanical head trauma that posttraumatic secondary insults, such as hypoxia and hypotension exacerbate neuronal injury and lead to worse outcome. In this study, the neuroprotective effect of hypothermia on the reduction of supraventricular subcortical neuronal damage was evaluated using an impact-acceleration model of diffuse traumatic brain injury coupled with both moderate and severe periods of hypoxia and hypotension. A total of 135 adult male Sprague-Dawley rats (340-375 g) were divided into three experimental studies: (I) physiological evaluation (n = 36); (II) quantitative analysis of the effect of trauma coupled with moderate and severe hypotension on neuronal damage assessed at 4 (n = 39) and 24 h (n = 24); and (III) the neuroprotective effect of hypothermia following moderate secondary insult (n = 36). Induction of hypothermia occurred at 15 min postinjury, to a level of 30 degrees C for 60 min. At the designated time points (4 and 24 h), the animals were sacrificed via standard transcardial perfusion techniques for histological processing. Quantitative assessment of neuronal damage using routine H&E staining at 4 hours showed neuronal damage which correlated with the severity of secondary insult. Animals exposed to trauma alone had a mean number of damaged neurons of 7.61 +/- 3.08/high powered field (hpf) compared with a mean of 1.21 +/- 0.30/hpf in the sham operated group (p = 0.015). Animals exposed to trauma with 10 min of hypoxia and hypotension (THH-10) showed a statistically significant number of damaged neurons compared to the sham-operated animals (7.50 +/- 2.15 damaged neurons/hpf, p = 0.013), whereas, neuronal damage in animals undergoing trauma with a 30-min secondary insult of hypoxia and hypotension (THH-30) was markedly increased (100 +/- 30.20/hpf, p = 0.002). Statistical analysis showed no significant difference in neuronal damage in animals subjected to secondary insult alone. At 24 h, the evolution of neuronal damage in the trauma alone group (5.08 +/- 1.63/hpf) was relatively static; however, there was a remarkable increase in the neuronal damage of the THH-10 group (29.88 50 +/- 8.20/hpf). However, hypothermia provided nearly complete protection against secondary insults, and neuronal damage was equal to that of the trauma alone group (p = 0.42). The results of this study confirm that hypothermia provides remarkable protection against the adverse effects of neuronal damage exacerbated by secondary injury. This study also presents a new model of secondary insult, which can be used experimentally to further define the mechanism of increased vulnerability of the injured brain.

Animals↗

PubMed1999

Use of magnetic resonance imaging for in vivo measurements of water content in human brain: method and normal values.

OBJECT: The authors present a quantitative in vivo magnetic resonance (MR) imaging method and propose its use for the accurate assessment of brain water in humans. METHODS: With this technique, a pure T1-weighted image of a selected brain slice in a patient is generated, and the image is subsequently converted to a pure water image by means of an equation derived from a tissue relaxation model. The image intensity in the resulting water map directly yields absolute measures of water expressed in grams of water per gram of tissue at a given anatomical location. The method has been validated previously in a series of phantom experiments and in an infusion model of brain edema in cats. In this report, the authors evaluate the method by using samples of tissue harvested from patients who underwent surgery for brain tumor removal and apply the technique to a series of normal volunteers, providing average regional brain water content (f(w)) values for a range of tissues. Application of the method in pathological conditions such as head trauma, tumor, and hydrocephalus allows quantification of regional or global increases in f(w) that result from edema. CONCLUSIONS: It is now possible to obtain accurate brain water measurements with the anatomical resolution of MR imaging. This permits monitoring of the development and resolution of edema in a variety of clinical circumstances, thus enhancing understanding of the underlying pathophysiological processes.

Adult↗

PubMed1998

The effect of human corticotrophin releasing factor on the formation of post-traumatic cerebral edema.

Controlled cortical impact is a well validated model of cortical contusion which is known to produce cerebral edema. Corticotrophin Releasing Factor (CRF) is a hypothalamic neuropeptide, which is known to inhibit transendothelial leakage of plasma derived fluid and tissue edema in response to injury. The aim of this study was to determine cerebral edema after controlled cortical impact and then compare the effect of high and low doses of CRF. We evaluated the effect of CRF in rats divided into groups of sham, trauma alone, and trauma treated with CRF at 50 micrograms/kg and 100 micrograms/kg. Animals were sacrificed at 24 hours and water content was determined. We found that CRF was effective in reducing cerebral edema associated with cortical contusion and propose that the action of CRF obviated barrier leakage.

Animals↗

PubMed1998

Relationship between excitatory amino acid release and outcome after severe human head injury.

In previous studies, Katayama and our group have documented a massive increase in excitatory amino acid release following traumatic brain injury, in both rat fluid percussion, and humans [2,5]. To test the hypothesis that the magnitude of this "Excitotoxic Surge" plays a significant role in determining 6-month patient outcome. We have studied 83 consecutive severely head injured patients at the Medical College of Virginia for inclusion into this study. A microdialysis probe was placed within the cortex to continuously measure dialysate excitatory amino acids (Glutamate and Aspartate), along with several other analytes for approximately 5 days after injury. ICP, CPP, and MABP measurements were also time linked with each analyte measurement to create a neurochemical, clinical, and physiological "profile" for each patient. Outcome was determined by follow up using the Glasgow 6-Month outcome scale. A very strong correlation existed between the release of the EAA's glutamate and aspartate after TBI (p < 0.0001). Patients with significantly elevated mean glutamate values for the entire monitoring period were most likely to exhibit elevated levels of ICP. The magnitude of glutamate released significantly correlates with 6-month patient outcome (p = 0.0234). When patients were subdivided by the CT diagnosis of lesion type, we found that those patients with contusions displayed the highest overall of EAA's.

Animals↗

PubMed1998

Hemodynamic monitoring prior to and at the time of death in status epilepticus.

Status epilepticus (SE) is a common neurological and medical emergency. Despite the significant mortality associated with SE, no human data have been available regarding cardiovascular changes prior to death in patients with this condition. This study was conducted to measure hemodynamic trends in the 24 h prior to death in a series of 24 prospectively evaluated SE patients. Two distinct cardiovascular patterns of mean arterial pressure (MAP) and heart rate (HR) were observed. Ten patients had a gradual decline in MAP and/or HR, and this group was designated as having gradual cardiac decompensation (GCD). The remaining 14 patients showed no significant changes in either MAP or HR up to the time of death. This group of patients was designated as having acute cardiac decompensation (ACD). The changes in MAP and HR over the last 24 h prior to death between the GCD and ACD groups were statistically significant. Ninety percent of the GCD patients had a history of multiple risk factors for arteriosclerotic cardiovascular disease (ASCVD), while only 30% of the ACD group had a history of multiple risk factors for ASCVD. The results provide the first human data of cardiovascular events immediately preceding death in SE patients. We propose that further investigation of the cardiovascular pathophysiology of SE may provide new therapeutic interventions which could decrease the significant mortality associated with SE.

Adult↗

PubMed1998

Primary end points in phase III clinical trials of severe head trauma: DRS versus GOS. The American Brain Injury Consortium Study Group.

The most commonly used primary end point in phase III clinical trials of severe head trauma is the Glasgow Outcome Scale (GOS), usually dichotomized to favorable (good) and unfavorable (poor) outcomes. The alternative endpoints include the Disability Rating Scale (DRS) with a 31-point scale. The purpose of this study was to compare DRS and GOS using the data collected from two completed clinical trials organized by the American Brain Injury Consortium and two pharmaceutical companies. The two outcome scales were examined and compared in terms of the correlation between the two scales, sensitivity, and p values between the differences between two arms of the trials. There was no indication that the DRS was more sensitive or advantageous relative to the dichotomized or four-category GOS. In addition, the highly significant correlation between the two outcome scales (r = 0.95; p < 0.0001) could not justify the DRS as an end point. The other problems with the DRS include the difficulty of determining the clinically meaningful difference in designing trials. The study suggested that the GOS is a better primary end point than DRS.

Adult↗

PubMed1998

Factors affecting excitatory amino acid release following severe human head injury.

OBJECT: Recent animal studies demonstrate that excitatory amino acids (EAAs) play a major role in neuronal damage after brain trauma and ischemia. However, the role of EAAs in patients who have suffered severe head injury is not understood. Excess quantities of glutamate in the extracellular space may lead to uncontrolled shifts of sodium, potassium, and calcium, disrupting ionic homeostasis, which may lead to severe cell swelling and cell death. The authors evaluated the role of EEAs in human traumatic brain injury. METHODS: In 80 consecutive severely head injured patients, a microdialysis probe was placed into the gray matter along with a ventriculostomy catheter or an intracranial pressure (ICP) monitor for 4 days. Levels of EAAs and structural amino acids were analyzed using high-performance liquid chromatography. Multifactorial analysis of the amino acid pattern was performed and its correlations with clinical parameters and outcome were tested. The levels of EAAs were increased up to 50 times normal in 30% of the patients and were significantly correlated to levels of structural amino acids both in each patient and across the whole group (p < 0.01). Secondary ischemic brain injury and focal contusions were most strongly associated with high EAA levels (27+/-22 micromol/L). Sustained high ICP and poor outcome were significantly correlated to high levels of EAAs (glutamate > 20 micromol/L; p < 0.01). CONCLUSIONS: The release of EAAs is closely linked to the release of structural amino acids and may thus reflect nonspecific development of membrane micropores, rather than presynaptic neuronal vesicular exocytosis. The magnitude of EAA release in patients with focal contusions and ischemic events may be sufficient to exacerbate neuronal damage, and these patients may be the best candidates for treatment with glutamate antagonists in the future.

Amino Acids↗

PubMed1997

Traumatic brain swelling in head injured patients: brain edema or vascular engorgement?

Brain edema and vascular engorgement have been used interchangeably to describe brain swelling associated with severe brain trauma and their relative contribution of these compartments to the swelling process remains controversial. In this report, imaging techniques for measurement of brain water and blood volume have been used to study the relative contribution of blood volume and tissue water to the swelling process in severely brain injured patients. More specifically, magnetic resonance techniques for non-invasive tissue water measures founded on mathematical models and later substantiated in laboratory and clinical studies were used for measure of brain tissue water. These studies were combined with measures of cerebral blood volume utilizing indicator dilution methods. Studies indicated that brain water was increased while blood volume decreased. These studies provide compelling evidence that the major contributor to brain swelling is brain edema and not blood volume. Therapies should now be targeted toward preventing edema development and enhancing edema resolution.

Adolescent↗

PubMed1997

Evaluation of homeostatic changes in CSF circulation: in vivo analysis of the effect of neurotransmitter accumulation in the extracellular space following transient global ischemia.

Accumulation of potassium and excitatory amino acids (EAA) in the extracellular space (ECS) following ischemia has been well documented. Careful monitoring of these transients is crucial to gain a better understanding of CNS pathophysiology. This study was initiated to determine if CSF concentrations of EAAs reflect those measured in the ECS. Transient global ischemia, 20 minutes in duration, was produced by clamping the left subclavian and innominate arteries combined with hemorrhagic hypotension. The accumulation of glutamate and electrolytes were measured in CSF and the extracellular fluid (ECF) of cerebral cortex. Microdialysis (MD) was utilized to measure the extracellular concentrations while direct sampling of CSF was provided via cannulation of the cisterna magna. Hydrogen clearance and laser doppler methods were used to monitor regional cortical CBF. Our results show that extracellular concentrations of potassium ([K+]ECF) and glutamate significantly increased following the initiation of ischemia (p < 0.05). The extracellular concentration of these substances decreased with the restoration of CBF. In CSF, a similar trend was observed following re-circulation (p < 0.05). However, CSF glutamate levels did not return to pre-ischemic values.

Animals↗

PubMed1997

Detection of brain atrophy following traumatic brain injury using gravimetric techniques.

We hypothesized, that with atrophy, the correlation between water content and specific gravity of brain solids would break down signifying the onset of the atrophic process. The correlation between tissue water content, specific gravity of solids and ventricular size was studied in an impact acceleration model of closed head injury of the rat. Adult Sprague Dawley rats weighing 350 to 375 grams (n = 63) were separated into two groups: Group 1: Sham (n = 21), Group II: Trauma (n = 42). Water content was assessed using both gravimetric method and drying-weighing method at 1 hour, on days 1, 3, 7, 14, 28, and 42 in the trauma group as well as in the control group. Ventricular size was measured in cm2 on the MRI computer console in the coronal section at the coronal suture at the same time points. In the trauma group we found a significant increase (p < 0.01) in water content during the first week except on day 3 and there was a good correlation between the results of water content using both methods (p < 0.001). However, this relationship was poorly correlated after day 14 (p = 0.25). Although the ventricular size was the smallest at 1 hour post trauma, it significantly increased over the next 3 days (p < 0.001). On day 7 and 14 ventricular size decreased to normal size, yet gradually increased and then reached a significantly larger size on 42 days post trauma again (p < 0.01). We may consider, that brain edema following CHI begins immediately following trauma and resolves within 2 weeks. After 14 days degenerative change occurs in the cortex, as detected by specific gravity measurements which signifies the onset of the atrophic process and subsequent post traumatic ventricular dilatation.

Animals↗

PubMed1997

MRI diffusion-weighted spectroscopy of reversible and irreversible ischemic injury following closed head injury.

The objective of this study was to detect the threshold between reversible and irreversible secondary insult of hypoxia and hypotension following closed head injury as measured by MRI. Adult Sprague rats were separated into 3 groups: I: Sham (n = 6), II: Trauma and hypoxia coupled with mild hypotension of 40-50 mmHg (n = 6), III: Trauma and hypoxia coupled with severe hypotension of 30-40 mmHg (n = 6). The measurement of brain water content (BWC) was based on T1, whereas the differentiation between reversible and irreversible secondary insult on the measurement apparent diffusion coefficient (ADC). The ADCs in both trauma and secondary insult groups decreased rapidly from a control level of 0.68 +/- 0.5 x 10(-3) to significantly different minimum levels of 0.52 +/- 0.5 x 10(-3) in Group II and 0.42 +/- 0.5 x 10(-3) mm2/second in Group III at 30 minutes. In Group II rats there was a complete recovery in ADC as well as in their clinical conditions, whereas ADC in Group III rats remained at the minimum level and the animals were brain dead. The BWC was also significantly different at four hours post injury (Group II: 80.3 +/- 0.7%, Group III: 81.8 +/- 0.8%). The data lead the authors to suggest that the threshold between reversible and irreversible posttraumatic secondary insult is very narrow, and the measurement of ADC can provide information that will enable the clinician to identify critical threshold beyond which recovery is not possible.

Animals↗

PubMed1997

Biphasic pathophysiological response of vasogenic and cellular edema in traumatic brain swelling.

The objective of this study was to quantify the temporal water content changes and document the type of edema (cellular versus vasogenic) that is occurring during both the acute and the late stages of edema development following closed head injury. Adult Sprague rats (n = 50) were separated into two groups: Group I: Sham (n = 8), Group II: Trauma (n = 42). The measurement of brain water content (BWC) was based on T1, whereas the differentiation of edema on the measurement of the random, translational motion of water protons (apparent diffusion coefficients-ADC) by MRI. In trauma animals, we found a significant increase in ADC (105%) as well as in BWC (0.7 +/- 0.3%) during the first 60 minutes post injury indicating vasogenic edema formation. This transient increase; however, was followed by a continuing decrease in ADC beginning at 45 minutes post injury and reaching a minimum at days 7-14 (-103%). Since the BWC continued to increase during the next day (10.3%), it is suggested cellular edema formation started to develop soon after injury and became dominant between 1-2 weeks post injury. In conclusion we may consider, that there is a predominantly vasogenic edema formation immediately after injury and later a more widespread and slower edema formation due to a predominantly cellular swelling.

Animals↗

PubMed1997

Acute blood-brain barrier changes in experimental closed head injury as measured by MRI and Gd-DTPA.

The objective of this study was to determine the early time course of blood-brain barrier (BBB) changes in diffuse closed head injury (CHI) and to what extent BBB is affected by secondary insult. The BBB disruption was quantified using T1-weighted MRI following administration of Gd-DTPA. The maximal signal intensity (SI) enhancement was used to calculate BBB disruption. A new CHI model was used to induce injury. Adult SD rats were separated into four groups: Group I: Sham (n = 4), II: Hypoxia and Hypotension (HH, n = 4), III: Trauma alone (n = 23), and IV: Trauma coupled with HH (THH, n = 14). Following trauma, a 30 minute insult of hypoxia (PaO2 = 40 mmHg) and hypotension (MABP = 30 mmHg) were imposed. In trauma animals, SI increased dramatically immediately following impact. By 15 minutes, permeability decreased exponentially and by 30 minutes was equal to that of control. In THH animals, SI enhancement was lower after the trauma, consistent with reduced blood pressure and blood flow. However, the SI increased dramatically upon reperfusion and was equal to that of control after 60 minutes. In conclusion we may consider, that CHI is associated with a rapid and transient BBB opening which begins at the time of the trauma and lasts not more than 30 minutes. It has been also shown that addition of hypoxia and hypotension prolongs the time of BBB breakdown.

Animals↗

PubMed1997

A proposed relationship between increased intra-abdominal, intrathoracic, and intracranial pressure.

OBJECTIVES: To determine the effect of acutely increased intra-abdominal pressure on pleural pressure, intracranial pressure, and cerebral perfusion pressure, and to clarify the relationship between these parameters. DESIGN: Nonrandomized, controlled study. SETTING: Laboratory at a university medical center. SUBJECTS: Yorkshire swine, weighing 15 to 20 kg. INTERVENTIONS: Anesthetized, ventilated swine had a balloon inserted into the peritoneal cavity and catheters placed for measurement of intracranial pressure, pleural pressure, central venous pressure, pulmonary artery occlusion pressure, and mean arterial pressure. Following baseline measurements, intra-abdominal pressure was increased by incrementally inflating the intraperitoneal balloon. All parameters were remeasured 30 mins after each increase in intra-abdominal pressure. Two groups were studied: a) group 1 (n = 9) animals had intra-abdominal pressure increased to 25 mm Hg above baseline, then released; b) group 2 (n = 3) animals underwent sternotomy and pleuropericardotomy to prevent an increase in pleural pressure with increasing intra-abdominal pressure. MEASUREMENTS AND MAIN RESULTS: Increase of intra-abdominal pressure to 25 mm Hg above baseline caused significant (p < .05) increases in intracranial pressure (7.3 +/- 0.6 [SEM] to 16.4 +/- 1.9 mm Hg), pleural pressure (4.3 +/- 1.3 to 11.8 +/- 1.9 mm Hg), pulmonary artery occlusion pressure (9.0 +/- 0.6 to 14.3 +/- 0.8 mm Hg), and central venous pressure (6.6 +/- 0.7 to 10.7 +/- 0.9 mm Hg). The cardiac index (3.4 +/- 0.3 to 1.6 +/- 0.1 L/min/m2) and cerebral perfusion pressure (75.6 +/- 3.6 to 62.0 +/- 6.8 mm Hg) deceased significantly (p < .05), whereas mean arterial pressure (82.8 +/- 3.2 to 78.4 +/- 6.6 mm Hg) remained essentially constant. Sternotomy and pleuro-pericardotomy negated all effects of increased intra-abdominal pressure except the decreased cardiac index (1.6 +/- 0.1 to 2.5 +/- 0.2 L/min/m2). CONCLUSIONS: Acutely increased intra-abdominal pressure causes a significant increase in intracranial pressure and a decrease in cerebral perfusion pressure. Increased intra-abdominal pressure appears to produce this effect by augmenting pleural and other intrathoracic pressures and causing a functional obstruction to cerebral venous outflow via the jugular venous system. It is possible that the same phenomenon may be why persons with chronically increased intra-abdominal pressure, such as the morbidly obese, suffer from a high frequency rate of idiopathic intracranial hypertension.

Abdomen, Acute↗

PubMed1997

Contribution of vasogenic and cellular edema to traumatic brain swelling measured by diffusion-weighted imaging.

The contribution of brain edema to brain swelling in cases of traumatic brain injury remains a critical problem. The authors believe that cellular edema, the result of complex neurotoxic events, is the major contributor to brain swelling and that vasogenic edema, secondary to blood-brain barrier compromise, may be overemphasized. The objective of this study, therefore, was to quantify temporal water content changes and document the type of edema that forms during the acute and late stages of edema development following closed head injury (CHI). The measurement of brain water content was based on magnetic resonance imaging-determined values of tissue longitudinal relaxation time (T1-weighted imaging) and their subsequent conversion to percentage of water, whereas the differentiation of edema formation (cellular vs. vasogenic) was based on the measurement of the apparent diffusion coefficient (ADC) by diffusion-weighted imaging. A new impact-acceleration model was used to induce CHI. Thirty-six adult Sprague-Dawley rats were separated into two groups: Group I, control (six animals); and Group II, trauma (30 animals). Fast ADC measurements (localized, single-voxel) were obtained sequentially (every minute) up to 1 hour postinjury. The T1-weighted images, used for water content determination, and the diffusion-weighted images (ADC measurement with conventional diffusion-weighted imaging) were obtained at the end of the 1st hour postinjury and on Days 1, 3, 7, 14, 28, and 42 in animals from the trauma and control groups. In the animals subjected to trauma, the authors found a significant increase in ADC (10 +/- 5%) and brain water content (1.3 +/- 0.9%) during the first 60 minutes postinjury. This is consistent with an increase in the volume of extracellular fluid and vasogenic edema formation as a result of blood-brain barrier compromise. This transient increase, however, was followed by a continuing decrease in ADC that began 40 to 60 minutes postinjury and reached a minimum value on Days 7 to 14 (10 +/- 3% reduction). Because the water content of the brain continued to increase during the first 24 hours postinjury (1.9 +/- 0.9%), it is suggested that the decreased ADC indicated cellular edema formation, which started to develop soon after injury and became dominant between 1 and 2 weeks postinjury. The study provides supportive evidence that cellular edema is the major contributor to posttraumatic swelling in diffuse CHI and defines the onset and duration of the increase in cellular volume.

Acceleration↗

PubMed1997

Impact acceleration injury in the rat: evidence for focal axolemmal change and related neurofilament sidearm alteration.

Recently we reported that traumatic brain injury evokes local changes in the axolemma's permeability, in concert with local cytoskeletal changes involving neurofilament (NF) compaction and sidearm loss, all of which contribute to the genesis of reactive axonal change. Since it was of concern that these events may be either injury model- or species-specific, we sought to address these phenomena in a different but well-characterized animal model and species. Further, to provide more compelling insight into the potential for NF compaction and sidearm alteration, we also employed antibodies specific for the NF rod domains, which are readily visualized only when the NF sidearms are disturbed. Rats were subjected to impact acceleration injury. To assess the potential for altered axolemmal permeability, 5 animals received intrathecal horseradish peroxidase (HRP), normally excluded by the intact axolemma. To assess the potential for NF sidearm alteration, another 14 animals were processed for the visualization of antibodies targeting the NF rod domain at 5 minutes (min) to 24 hours (h) postinjury. All animals were evaluated at the LM and EM levels. Those animals receiving intrathecal HRP showed immediate focal alterations in the axolemma's permeability to the normally excluded tracer. Over a 2 h period, these axons demonstrated NF compaction. Antibodies targeted to the rod domains revealed focal intra-axonal immunoreactivity in sites closely correlated with those showing altered axolemmal permeability. These same sites also demonstrated evidence of NF compaction and sidearm loss/perturbation. Collectively, these findings suggest that occurrence of altered axolemmal permeability and concomitant cytoskeletal change are features common to traumatic brain injury in various animal models and species. Further, these studies underscore the utility of antibodies targeting the rod domain for the early detection of traumatically induced reactive change.

Animals↗