Corticosteroids in acute traumatic brain injury.
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Adrenal Cortex Hormones↗
Biomedical subjects
R Bullock
Publications and source records attributed to R Bullock.
Correlations between brain tissue oxygen tension, carbon dioxide tension, pH, and cerebral blood flow--a better way of monitoring the severely injured brain?
BACKGROUND: The ideal method for monitoring the acutely injured brain would measure substrate delivery and brain function continuously, quantitatively, and sensitively. We have tested the hypothesis that brain PO2, pCO2, and pH, which can now be measured continuously using a single sensor, are valid indicators of regional cerebral blood flow (CBF) and oxidative metabolism, by measuring its product, brain pCO2. METHODS: Twenty-five patients (Glasgow Coma Score < or = 8) were studied. A Clark electrode, combined with a fiber optic system (Paratrend 7, Biomedical Sensors, Malvern, PA) was used to measure intraparenchymal brain PO2, pCO2, and pH. Data were averaged over a 1-h period before and after CBF studies. Regional CBF was measured around the probe, using stable xenon computed tomography. Regression analyses and Spearman Rank tests were used for data analysis. RESULTS: Regional CBF and mean brain PO2 were strongly correlated (r=0.74, p=0.0001). CBF values < 18 mL/100 g/min were all accompanied by brain PO2 < or = 26 mm Hg. The four patients with a brain PO2 < 18 mm Hg died. Brain pCO2 and pH, however, were not correlated with CBF (r=0.36, p=0.24 and r=0.30, p=0.43, respectively). CONCLUSIONS: Until recently, substrate supply to the severely injured brain could only be intermittently estimated by measuring CBF. The excellent intra-regional correlation between CBF and brain pO2, suggests that this method does allow continuous monitoring of true substrate delivery, and offers the prospect that measures to increase O2 delivery (e.g., increasing CBF, CPP, perfluorocarbons etc.) can be reliably tested by brain PO2 monitoring.
Blood Flow Velocity↗
Extended neuromonitoring: new therapeutic opportunities?
In order to optimize therapy for the injured brain it is desirable to continuously monitor substrate delivery in the critically ill patient. Interruption of substrate delivery is a major factor of the great vulnerability to ischemic damage, which affects a majority of patients after severe head injury, stroke or subarachnoid hemorrhage. An approach to protecting the brain during ischemia is to increase the delivery of oxygen via residual blood flow through ischemic tissue. Hypothermia is also an important means of protecting brain cells from the deleterious effects of ischemia, after severe head injury, because it reduces metabolic demands. In this study we continuously measured brain oxygen, brain CO2, brain pH and brain temperature, as well as hourly brain glucose and lactate. A multiparameter sensor was inserted into brain tissue, via a three lumen bolt, along with a ventriculostomy catheter and a microdialysis probe in 60 severely head injured patients. Brain oxygen delivery was increased by stepwise increase of inspired oxygen (FiO2) from 30% to 60% to 100% over a period of 6 h, in order to test the effect of enhanced oxygen tension, on tissue oxygen. In most patients brain oxygen was initially low, and progressively increased, over the monitoring period, to a steady state level, around 30-40 mmHg. In those who died or remained vegetative, brain oxygen fell to anerobic levels. Episodes of increased ICP (n = 25), hypotension (n = 15), and respiratory difficulties (n = 9) caused an immediate increase in brain CO2. Multiple logistic regression analysis showed brain oxygen to be the strongest predictor for outcome in these patients. By increasing FiO2, an increase in oxygen delivery of more than 100%, and a simultaneous decline in lactate production was seen (p < 0.01). Brain temperature was closely related to rectal temperature, brain oxygen, and cerebral blood flow. Patients who were spontaneously hypothermic had a poor outcome (p < 0.01). A fuller understanding of dynamic factors affecting brain metabolism and substrate delivery may be obtained with extended neuromonitoring.
Adolescent↗
Increased free radical production due to subdural hematoma in the rat: effect of increased inspired oxygen fraction.
Acute subdural hematoma (ASDH) complicates about 15%-20% of severe head injury patients and is one of the major causes for bad outcome, yet the pathomechanisms involved are not well understood. This study has employed a recently developed technique to determine whether ASDH induces free radicals in the underlying brain. We also studied the effect of increased inspired oxygen fraction (FiO2) on free radical production, both in the normal rat brain and after ASDH induction. Twelve male Sprague Dawley rats were studied over 5 h (2 h of FiO2 = 30%, 3 h of FiO2 = 100%). Hydroxyl radical production was measured with microdialysis using the salicylate trapping technique by quantitating the 2,3 dihydroxy benzoic acid (2,3 DHBA) and 2,5 dihydroxy benzoic acid (2,5 DHBA), degradation products, in either noninjured brain (n = 6) or after ASDH (n = 6). Both 2,3 DHBA and 2,5 DHBA increased significantly by 39% and 108%, respectively, after the induction of the SDH (p < 0.05). By increasing the FiO2 to 100%, 2 h after ASDH induction, the 2,3 DHBA and 2,5 DHBA further increased only slightly (ns). After increasing the FiO2 to 100% in the noninjured group, the mean level of 2,3 DHBA increased by 56% (p = 0.06, ns). The level of 2,5 DHBA in the dialysate increased significantly by 56% (p < 0.05), when the FiO2 was increased to 100% ASDH results in a significant increase in free radical production. At the same time, prolonged increase in FiO2 does not lead to further increase in free radical production in the injured brain.
Acute Disease↗
The rationale for, and effects of oxygen delivery enhancement to ischemic brain in a feline model of human stroke.
Reduced brain tissue oxygenation is frequently seen in severe head injury and after subarachnoid hemorrhage, and this is considered a major cause of secondary ischemic brain injury. In fact, in a previous study, we found a tight correlation between low brain tissue oxygen tension and poor outcome. Therefore, we tested the hypothesis that an allosteric modifier of hemoglobin, which improves oxygen transport to tissue, could reduce the size of an acute infarct in a feline model of human stroke. This compound produces a shift in the hemoglobin dissociation curve to the right and therefore facilitates the unloading of oxygen during low oxygen tension. Seventeen adult cats were studied. Ischemic stroke was induced through a transorbital, permanent, middle cerebral artery occlusion. Seven animals received saline, and 10 received the allosteric Hb modifier RSR-13. Three different endpoints were used to determine the effect of the allosteric modifier. Delta p50 values were measured in the arterial blood; the intra-infarct oxygen tension was measured, and finally, the volume of the infarct was assessed using TTC staining. Mean delta p50 changes varied from 10.4 +/- 9.2 mmHg up to 15.0 +/- 6.8 mmHg. Mean intra-infarct oxygen tension was 27 +/- 6 mmHg for the control group and 33 +/- 7 mmHg for the drug-treated animals. The mean infarct size (measured as percentage of hemisphere volume) in the control group was 32 +/- 9% and for the RSR-13 animals 22 +/- 10% (p < 0.05). A definitive trend towards improvement in brain oxygen tension was seen, such that animals pretreated with RSR-13 showed a higher infarct oxygen tension. Infarct size was significantly reduced in the drug group. Therefore, RSR-13 is potentially beneficial in the treatment of brain ischemia. Since human studies with this compound are already completed, and other compounds which increase oxygen delivery, such as perfluorocarbons, are already being evaluated, it is likely that oxygen delivery enhancement will rapidly become the first 'neuroprotective' modality, employed in patients with severe brain injury, stroke and subarachnoid hemorrhage.
Adult↗
Clinical trials in traumatic brain injury. What can we learn from previous studies?
Many compounds have now been tested that were expected to ameliorate the secondary ischemic brain damage after severe head injury. Thus far, none of these have been clearly successful. This review is an attempt to identify factors that could be responsible for some of these failures. Recommendations are made that could help to avoid these pitfalls in the future. The usefulness and criteria for use of animal models for traumatic brain injury to depict human head injury are discussed. Clearly, it has now become widely accepted that mechanism-driven trials, in which individual pathophysiological mechanisms are targeted, are preferable in this heterogeneous patient population. Other factors, such as the effect of brain penetration, safety and tolerability of the compound, and the interface between the pharmaceutical industry and academics are a major influence in the success of these trials. Furthermore, different ways of analyzing trials such as sequential analysis and newer, alternative end points should be considered. Pharmacological agents will never be the "magic bullet" for a process as heterogenous in pathophysiological mechanisms as traumatic brain injury. This does not imply that the role of neuroprotective compounds will not be important in the future. New approaches in developing, conducting and analyzing these expensive clinical trials must be devised in the future.
Animals↗
Effects of mild hypothermia on cerebral blood flow-independent changes in cortical extracellular levels of amino acids following contusion trauma in the rat.
The mechanism of hypothermic cerebroprotection after traumatic brain injury (TBI) is unknown. The present study was conducted to investigate the effects of mild hypothermia on the changes in cortical extracellular amino acids and cerebral blood flow (CBF) caused by cerebral contusion created in the rat parietal cortex by a weight-drop method. CBF in both normothermia (37 degrees C) and hypothermia (32 degrees C) groups, which was monitored using the hydrogen clearance technique, decreased significantly after contusion, but never fell below the threshold for ischemia. Cortical levels of glutamate, aspartate, glycine and taurine, which were measured by intracerebral microdialysis, were significantly increased after contusion in each group. However, these increases were greater in the hypothermic than in the normothermic rats. Normal plasma amino acid levels were high, and autoradiography following intravenous injection of 14C-labeled glutamate revealed marked extravasation of [14C]glutamate at the site of cortical impact. These results suggest that the post-traumatic increase in extracellular amino acids occurs independently of CBF reduction, and that extravasation of amino acids from the vascular compartment partly contributes to this increase. Hypothermic cerebroprotection in TBI is thus likely to occur through a mechanism other than reduction in interstitial excitatory amino acids. In TBI, it is postulated that the postsynaptic effects of hypothermia may be more important than the presynaptic effects, when CBF is kept above the ischemic threshold.
Amino Acids↗
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↗
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↗
Multiparametric continuous monitoring of brain metabolism and substrate delivery in neurosurgical patients.
Brain function and tissue integrity are highly dependent on continuous oxygen supply and clearance of CO2. Aerobic metabolism is the major energy source to normal brain, however, during hypoxia and ischemia, lactate accumulation may sometimes be seen, indicating anaerobic glycolysis after severe head injury. Current monitoring techniques often fail to detect such events which can affect substrate delivery to the injured brain. We have recently adapted a method for continuous monitoring of brain tissue pO2, pCO2, pH and temperature, using a single sensor. The multiparameter sensor is inserted into brain tissue, via a new three lumen bolt, together with a standard ventriculostomy catheter and a microdialysis probe. The system has been left in place as long as needed, but never more than 7 days. All readings were compared to clinical parameters, and outcome. Stable measurements could be obtained in the first group of 20 patients, after calibration and rigid fixation, using the new bolt. Severely head injured patients had brain oxygen levels of less than 25-30 mmHg for the first hours after injury. Thereafter two patterns could be seen. Patients with favorable outcome had a slow increase in brain oxygen, and brain CO2 decreased to normal values, as long as the cerebral perfusion pressure (CPP) was kept above 70 mmHg. However, in those patients with secondary ischemic events, and bad outcome, a further decline in brain oxygen to anaerobic levels (< 20 mmHg) was seen. For these patients, both decreased and increased brain CO2 levels could be seen. Brain CO2 levels of 90-150 mmHg were consistently seen after brain death. Brain pH was inversely related to brain CO2 for all patients. Brain glucose and lactate in patients with poor outcome were 639 microM l-1 +/- 330, and 1642 microM l-1 +/- 788, whereas patients with good outcome had brain glucose levels of 808 microM l-1 +/- 321 and lactate levels of 1001 microM l-1 +/- 417. Extended neuromonitoring using a combined sensor for brain oxygen, CO2, pH and temperature measurements, as well as a microdialysis probe for glucose and lactate analysis may optimize the management of comatose neurosurgical patients in the future, by allowing a fuller understanding of dynamic factors affecting brain metabolism.
Acid-Base Equilibrium↗
The neuroprotective effect of the forebrain-selective NMDA antagonist CP101,606 upon focal ischemic brain damage caused by acute subdural hematoma in the rat.
The neuroprotective effects of drugs that act against excitotoxic damage, caused by glutamate, are well described in focal ischemia, but behavioral effects, and apparent failure in clinical trials of "first-generation" competitive N-methyl D-aspartate (NMDA) antagonists, such as Selfotel (CGS19755), has led to interest in evaluating newer NMDA antagonists with fewer behavioral effects. We have therefore evaluated the neuroprotective effect of a new forebrain-selective polyamine site NMDA antagonist, CP101,606 in a rat subdural hematoma (SDH) model. An SDH was produced by slow injection of 0.4 ml autologous blood into the parietal subdural space. Brain damage was assessed histologically at eight coronal planes, in animals sacrificed 4 h after induction of hematoma. The drug was infused 30 min after induction of SDH. The reductions of ischemic brain damage achieved by CP101,606, was 29% for the low dose and 37% for the high dose. This novel glutamate antagonist has shown a magnitude of neuroprotection which is comparable with that seen with "first-generation" NMDA antagonists such as MK801, D-CPP-ene and CGS19755, in this same model. This new agent is claimed to have fewer psychomotor and behavioral effects than MK801, D-CPP-ene, and CGS19755.
Animals↗
Clinical neuro-protection trials in severe traumatic brain injury: lessons from previous studies.
Major advances have been made in understanding the pathophysiological events after severe human traumatic brain injury, and consequently, many compounds have been tested in clinical trials. Thus far, no Phase III trials have been clearly successful, in human neurotrauma, although several Phase II studies have shown apparent benefit. This review is an attempt to identify factors that could be responsible for some of these failures. Recommendations are made that attempt to avoid these pitfalls in the future. Five criteria for future conduct of clinical trials are proposed. The usefulness of animal models for traumatic brain injury and their ability are discussed. Clearly, it is now becoming accepted that mechanism-driven trials, in which individual pathophysiological mechanisms are targeted, may be preferable in this heterogeneous patient population. The degree of brain penetration, the safety and tolerability of the compound, and end points used for outcome assessment are major influences upon the success of these trials. New approaches in developing, conducting, and analyzing these clinical trials should be considered in the future, if the costly failures of the past are not to be repeated, with the advent of newer "neuroprotective agents" and techniques.
Brain Injuries↗
Continuous monitoring of cerebral substrate delivery and clearance: initial experience in 24 patients with severe acute brain injuries.
OBJECTIVE: Current neuromonitoring techniques in severe human head injury often fail to detect the causes of clinical deterioration. A sensor is now available for continuous monitoring of brain oxygen tension, carbon dioxide tension, and pH values. In this study, brain tissue oxygen tension was used to differentiate patients at risk for brain ischemia and to predict outcome. METHODS: The multiparameter sensor was inserted into brain tissue, along with a standard ventriculostomy catheter and a microdialysis probe, in 24 patients. Lactate and glucose were measured by high-pressure liquid chromatography in hourly dialysate samples. RESULTS: Patients who experienced a good recovery (n = 8) sustained a mean brain partial oxygen pressure of 39 +/- 4 mm Hg, brain partial carbon dioxide pressure (PCO2) of 50 +/- 8 mm Hg, and a brain pH of 7.14 +/- 0.12. Patients with moderate to severe disability (n = 6) sustained a mean brain partial oxygen pressure of 31 +/- 5 mm Hg, brain PCO2 of 47 +/- 2 mm Hg, and a brain pH of 7.11 +/- 0.12. Ten patients who died or remained vegetative sustained a mean brain partial oxygen pressure of 19 +/- 8 mm Hg, a brain PCO2 of 64 +/- 21 mm Hg, and a brain pH of 6.85 +/- 0.41. Mean brain PCO2 levels of 90 to 150 mm Hg were consistently observed after cerebral circulatory arrest or brain death. Dialysate lactate and glucose were less clearly correlated to outcome than brain oxygen tension. Dialysate glucose was extremely low in all patients and zero in most patients who died. CONCLUSION: Brain oxygen pressure, brain carbon dioxide pressure, and brain pH measurements, as well as a microdialysis probe for glucose and lactate analysis, may optimize the management of comatose neurosurgical patients by allowing a fuller understanding of the dynamic factors affecting brain metabolism.
Acute Disease↗
Effect of CP101,606, a novel NR2B subunit antagonist of the N-methyl-D-aspartate receptor, on the volume of ischemic brain damage off cytotoxic brain edema after middle cerebral artery occlusion in the feline brain.
BACKGROUND AND PURPOSE: The purpose of this study was to test the hypothesis that the neuroprotective compound CP101,606 will ameliorate the increase in lactate, retard the development of cytotoxic edema, and decrease the infarct volume after ischemic stroke. METHODS: Seventeen adult cats were allocated to control (n = 7) and CP101,606-treated groups (n = 10). Transorbital middle cerebral artery occlusion was performed under anesthesia. Extracellular fluid lactate by microdialysis as well as infarct volume measurement by triphenyltetrazolium chloride (TTC)-stained section, with and without neuroprotective agents, was used to determine the value of these potential "surrogate markers" of ischemic damage. RESULTS: The control group showed an increased dialysate lactate (15.5% increase) at 30 minutes and a peak (332.0% increase) in dialysate lactate at 1 hour after middle cerebral artery occlusion compared with the drug-treated group. Significant differences between control and drug-treated groups were seen in the rate of fall of the apparent diffusion coefficient at both 1 and 5 hours. A close correlation was seen between the 1- and 5-hour apparent diffusion coefficient maps and the TTC-stained sections. There was a significantly smaller lesion in the CP101,606-treated group (62.9% reduction in infarct size compared with the control group; P < .001). CONCLUSIONS: CP101,606 ranks very highly among the current neuroprotection candidates for clinical trials, and its excellent safety record in both animals and phase II studies in conscious, moderate head injury patients suggests that it will be highly effective in human occlusive stroke.
Animals↗
Assessment of health risks due to hazardous air pollutant emissions from electric utilities.
Hazardous air pollutant (HAP) emissions from electric utilities were evaluated. Cancer risks, as well as noncancer effects, due to inhalation exposure were assessed for 67 HAPs. Also, cancer risks due to multipathway exposure to radionuclide emissions were assessed. In addition, an assessment of the fate of mercury (Hg) through various environmental media was included. Results suggest arsenic, chromium, and nickel are the HAPs that present the highest cancer risk due to inhalation exposure. For noncancer effects due to inhalation exposure, hydrogen chloride appears to present the greatest potential concern. The risks due to multipathway exposure to radionuclides are estimated to be of similar magnitude to the risks posed by inhalation of arsenic and nickel. Mercury is of potential concern for multipathway exposures because it persists in the environmental and bioaccumulates in the aquatic food web. The study suggests there is a plausible link between Hg emissions from utilities and the Hg found in soil, water, and freshwater fish.
Air Pollutants↗
Intraoperative monitoring of substrate delivery during aneurysm and hematoma surgery: initial experience in 16 patients.
The effects of proximal occlusion of the parent artery during aneurysm surgery in humans are not fully understood, although this method is widely used. The reduction in substrate that can be tolerated by normal and subarachnoid hemorrhage (SAH)-affected brain is unknown. Therefore, the authors measured brain oxygen tension (brain PO2), carbon dioxide tension (brain PCO2), pH, and hemoglobin oxygen (HbO2) saturation before and after temporary occlusion in 12 patients with aneurysms. The effect of removal of a traumatic intracranial hematoma on cerebral oxygenation was also studied in four severely head injured patients. A multiparameter sensor was placed in the cortex of interest and locked by means of a specially designed skull bolt. The mean arterial blood pressure, inspired O2 fraction, and end-tidal PCO2 were analyzed. Brain PO2 and HbO2 saturation data were collected every 10 seconds. Descriptive and nonparametric analyses were used to analyze the data. A wide range in baseline PO2 was seen, although a decrease from baseline in brain PO2 was found in all patients. During temporary occlusion, brain PO2 in patients with unruptured aneurysm (seven patients) dropped significantly, from 60 +/- 31 to 27 +/- 17 mm Hg (p < 0.05). In the SAH group (five patients), the brain PO2 dropped from 106 +/- 74 to 87 +/- 73 mm Hg (not significant). Removal of intracranial hematomas in four severely head injured patients resulted in a significant increase in brain PO2, from 13 +/- 9 to 34 +/- 13 mm Hg (p < 0.05). The duration of safe temporary occlusion could not be determined from this group of patients, because none developed postoperative deterioration in their neurological status. However, the data indicate that this technique is useful to detect changes in substrate delivery during intraoperative maneuvers. This study also reemphasizes the need for emergency removal of intracranial hematomas to improve substrate delivery in severely head injured patients.
Adult↗
Glutamate release and cerebral blood flow after severe human head injury.
Elevations of extracellular glutamate have been found in patients with prolonged brain ischemia and focal cerebral contusions, following severe head injury. About 30% of severely head injured patients develop cerebral ischemia, defined as CBF < 18 ml/100g/min. Patients with both global and regional cerebral ischemia have the worst outcome. However, the relationship between CBF and EAA release is not well understood in head injured humans, and may differ from the findings in normal animals. To study the relationship between EAA release and CBF after severe head injury, we performed cerebral blood flow measurements using stable xenon enhanced computed tomography and correlated these with glutamate release in the extracellular fluid, measured by continuous microdialysis, in 25 severely head injured patients. Sustained cerebral blood flow reductions below the threshold for ischemic neuronal damage was closely related to massive excitatory amino acid release, as in previous animal studies. In patients without secondary ischemia, or focal contusions, delayed post-traumatic glutamate release appeared to be only transient or did not occur at all.
Cerebrovascular Circulation↗
Disappearance of antibodies to Cromer blood group system antigens during mid pregnancy.
The Cromer blood group system consists of 7 high incidence and 3 low incidence antigens that are carried on the complement regulatory glycoprotein called decay-accelerating factor (DAF; CD55). Despite laboratory results that would predict clinical significance, antibodies with specificities in the Cromer blood group system have not been reported to cause hemolytic disease of the newborn. It is possible that strong expression of DAF on the apical surface of antigen-positive fetally derived placental trophoblasts may absorb maternal antibodies that are directed to antigens in the Cromer blood group system. We studied two cases where strongly reactive anti-Cra and anti-Dra became undetectable during second and third trimesters of pregnancies.
Blood Group Antigens↗