Pro-inflammatory and pro-apoptotic elements of the neuroinflammatory response are activated in traumatic brain injury.

BACKGROUND: The inflammatory response may contribute to cerebral edema, increased intracranial pressure and cellular loss in traumatic brain injury (TBI). Cytokines are biomarkers of this inflammatory response and new methods allow simultaneous measurement of multiple cytokines. METHODS: We examined the IL-1beta, IL-6, IL-8 and IL-12, TNFalpha, and IL-10 in arterial and jugular blood as well as cerebrospinal fluid in patients with severe traumatic brain injury. FINDINGS: Multiple cytokines, particularly pro-inflammatory cytokines, are up-regulated following TBI. Cerebrospinal fluid and arteriovenous differences of some of the cytokines suggest production within the central nervous system. Antiinflammatory cytokines are not up-regulated. CONCLUSIONS: Cytokine up-regulation may contribute to the neuroinflammatory reaction that follows traumatic brain injury and may contribute to secondary injury.

A new application for near-infrared spectroscopy: detection of delayed intracranial hematomas after head injury.

Clinical studies have documented the importance of secondary brain insults in determining neurologic outcome after head injury. Delayed intracranial hematomas are one of the most easily remediable causes of secondary injury if identified early, but can cause significant disability or death if not promptly recognized and treated. Early identification and treatment of these lesions that appear or enlarge after the initial CT scan may improve neurological outcome. Serial examinations using near-infrared spectroscopy (NIRS) to detect the development of delayed hematomas were obtained in 167 patients. The difference in absorbance of light (deltaOD) at 760 nm between the normal and the hematoma side was measured serially during the first 3 days after injury. Twenty-seven (16%) of the patients developed some type of late hematoma: an intracerebral hematoma in 8 patients, an extracerebral hematoma in 6 patients, and a postoperative hematoma in 13 patients. Eighteen of the delayed hematomas caused significant mass effect and required surgical evacuation. The hematomas appeared between 2 and 72 h after admission. In 24 of the 27 patients, a significant increase (>0.3) in the deltaOD occurred prior to an increase in intracranial pressure or a change in the neurological examination, or a change on CT scan. Early diagnosis using MRS may allow early treatment and reduce secondary injury caused by delayed hematomas.

Cerebral hemodynamic effects of pentobarbital coma in head-injured patients.

The purpose of this study was to examine the changes in cerebral hemodynamics of head-injured patients undergoing barbiturate treatment of refractory intracranial hypertension. Cerebral blood flow (CBF) and metabolism variables were measured in 67 severely head-injured patients at the following times: before the loading dose of pentobarbital; after the loading dose of pentobarbital (average pentobarbital level 28.1+/-8.3 microg/mL); and 3 days later, when the peak pentobarbital level averaged 42.5+/-17.2 microg/mL. Intracranial pressure (ICP) and mean arterial blood pressure (MAP) were decreased by the loading dose of pentobarbital by an average of 12 and 9 mm Hg, respectively. Cerebral perfusion pressure (CPP) was unchanged when the entire group was analyzed together. CBF, cerebral oxygen consumption (CMR(O)2), and arteriovenous oxygen difference (AVD(O)2) were significantly decreased after the loading dose of pentobarbital, by 20%, 31%, and 11%, respectively. The average cerebrovascular resistance (CVR) was increased by 20%. The change in CMR(O)2 with the loading dose of pentobarbital was closely related to the pretreatment value (n = 67, r2 = 0.65, p < .001). Thirty (45%) of the patients had a "good ICP response," with a reduction in ICP from 34+/-9 to 15+/-5 mm Hg after the initial loading dose of pentobarbital. Twenty-seven (40%) of the patients had a "partial ICP response," with ICP decreasing but still remaining above 20 mm Hg after the loading dose of pentobarbital. In the remaining 10 patients, ICP did not change or even increased after pentobarbital. In the 30 patients with a good ICP response, pretreatment CMR(O)2 and AVD(O)2 were greater before administration of pentobarbital, and CMR(O)2 and AVD(O)2 decreased more with the loading dose of pentobarbital, than in the patients with partial or no ICP response. The outcome was significantly better in the patients with a good or partial ICP response to pentobarbital, with 21% of these patients having a good recovery or moderate disability at 3 months after injury, compared with 100% persistent vegetative state or death in the nonresponders. In summary, barbiturate coma can be a useful treatment modality for acutely reducing ICP in selected patients. Patients with overwhelmingly severe injuries are not likely to benefit, partly because their CMR(O)2 is already markedly reduced by the injury and partly because their outcome is already predetermined by the injury. Patients with systemic hypotension are not likely to have a good response because hypotension limits the amount of barbiturates that can be given.

Lactate and excitatory amino acids measured by microdialysis are decreased by pentobarbital coma in head-injured patients.

Primary traumatic brain injury and secondary ischemic/hypoxic injury are being increasingly characterized at the neurochemical level. Neurochemical monitoring using microdialysis has shown that these forms of tissue damage share many common features. In particular, anaerobic glycolysis with increased lactate production and release of excitatory amino acids into the extracellular space are seen in both conditions. Clinical microdialysis studies have heretofore focused on methodological issues, establishment of basal analyte values, and clinico-neurochemical correlation. Here we report the neurochemical consequences of therapeutic intervention in head injury. Specifically, induction of thiopental coma to manage severe increased intracranial pressure in seven patients was associated with a 37% reduction of lactate, 59% reduction of glutamate, and 66% reduction in aspartate in the extracellular space of the brain.

Comparison of brain tissue oxygen tension to microdialysis-based measures of cerebral ischemia in fatally head-injured humans.

This study investigated the relationship between brain tissue oxygen tension (PbtO2) and cerebral microdialysate concentrations of several compounds in five patients with refractory intracranial hypertension after severe head injury. The following substances were assayed: lactate and glucose; the excitatory amino acids glutamate and aspartate; and the cations potassium, calcium, and magnesium. Glucose concentrations did not correlate with PbtO2, but lactate increased as PbtO2 decreased. The lactate/glucose ratio exhibited a close relationship to PbtO2, increasing sharply only when oxygen tension reached zero. Although glucose and oxygen eventually reached very low levels and zero, respectively, in these fatally head-injured patients, the terminal decrease in PbtO2 slightly preceded that of glucose in four of the five patients. This time lag is the cause of the poor correlation between glucose and PbtO2. Glutamate and aspartate concentrations both demonstrated a close relationship to PbtO2, with sharp increases not occurring until PbtO2 was zero. Concentrations of these amino acids exhibited a similar pattern in response to decreasing glucose concentrations. Potassium concentrations began increasing at a PbtO2 of 35 mm Hg, which is not generally considered indicative of hypoxia. Sharper increases began occurring once PbtO2 dropped below 15 mm Hg, with a slight rise in the minimum potassium concentrations recorded at these low PbtO2 values. Calcium and magnesium concentrations did not vary in response to PbtO2. In summary, the most robust biochemical indicators of cerebral anoxia were elevations in the lactate/glucose ratio and in the concentrations of lactate and of the excitatory amino acids glutamate and aspartate. Furthermore, the fact that glucose concentrations continue to decrease for a short period after oxygen levels reach zero suggests that cells continue to utilize glucose anaerobically for such functions as maintenance of cellular integrity, with collapse of the cell membrane as evidenced by increases of extracellular glutamate and aspartate not occurring until both oxygen and glucose concentrations reach zero.

SjvO2 monitoring in head-injured patients.

Jugular venous oxygen saturation (SjvO2) measures the balance between cerebral oxygen delivery and cerebral oxygen consumption. Abnormalities that increase oxygen consumption (e.g., fever or seizures) or that decrease oxygen delivery (e.g., increased ICP, hypotension, hypoxia, hypocapnia, or anemia) can decrease SjvO2. Measuring SjvO2 continuously in the ICU in 177 patients with severe head injury, jugular venous desaturation (SjvO2 < 50%) was identified at least once in 39% of the patients. Approximately half of the episodes of desaturation were due to intracranial hypertension and half were due to systemic causes. The occurrence of one or more episodes of desaturation was strongly associated with a poor outcome, suggesting that the reduction in oxygen delivery identified with the SjvO2 monitoring contributed to the neurological injury. In the operating room, jugular venous desaturation was identified in 6 of 8 patients who were monitored during emergency evacuation of a traumatic intracranial hematoma. The lowest SjvO2 observed was 28%. In all 8 cases, the SjvO2 increased, from 47 +/- 10% to 63 +/- 5% after evacuation of the hematoma. Additional data supporting the hypothesis that these secondary insults identified with the SjvO2 monitoring contribute to the patient's neurological injury come from measurement of the extracellular concentrations of lactate and excitatory amino acids in the brain using microdialysis. Lactate concentration increased from 0.9 +/- 0.3 to 2.4 +/- 0.5 mumol/L and glutamate increased from 11.5 +/- 8.5 to 55.0 +/- 10.4 mumol/L during 8 episodes of jugular venous desaturation in 7 of 22 patients monitored with microdialysis. SjvO2 identifies global reductions in cerebral oxygenation due to a variety of causes, and is useful as a monitor for secondary insults in patients with severe head injury.

Evaluation of a microsensor intracranial pressure transducer.

This report describes the results of a laboratory evaluation of a new device for monitoring intracranial pressure (ICP), consisting of a miniature pressure transducer mounted on a pressure sensing diaphragm. In in vitro tests, 6 microsensor transducers were monitored for drift at pressures of 10 mmHg and 20 mmHg. The maximal drift of any of the transducers was 1 mmHg over 9 days. In in vivo tests, the ICP measurement obtained with the microsensor transducer correlated well with pressures recorded from a catheter in the cisternal magna with a Statham transducer over a wide range of ICP values (n = 511, r = 0.998, P < 0.001). If these laboratory findings can be duplicated in clinical studies, this microsensor transducer may be a useful alternative to the ventriculostomy catheter and other currently used devices for monitoring ICP.

Intracranial pressure waveform indices in transient and refractory intracranial hypertension.

Analysis of data obtained by continuous computerized monitoring of intracranial pressure (ICP) in 109 adult patients with severe head trauma was performed to examine the pattern of change in indices of the ICP waveform. Indices derived from direct measurement of the ICP wave and obtained from a Fast Fourier Transform (FFT) were examined. Concurrent physiologic measurements were made. Two types of intracranial hypertension (ICH) were defined for comparison. 'Transient intracranial hypertension' occurred when an abrupt rise in ICP was followed by a return to below 25 mm Hg (n = 63). Increases in ICP that were progressive and led to neurologic deterioration and death were termed 'refractory intracranial hypertension' (n = 18). During transient ICH heart rate, arterial pressure, end-tidal carbon dioxide and jugular venous oxygen saturation all increased, while these measures either were unchanged or decreased during refractory ICH. The pulse amplitude of the ICP wave increased in both types of ICHtn. Other changes in the waveform indices were consistent with this change in pulse amplitude. HFC responded differently to the two types of changes, with an increase during the transient changes and a decrease during the refractory changes. The differences in changes in physiologic measurements as ICH occurred in the 2 groups suggest that in refractory ICH cerebral blood flow is maintained against the mounting ICP, while in transient ICH the hypertension is caused by an increase in cerebral blood flow. The waveform indices do not discriminate between the two types of changes.

Retrograde cerebral perfusion during profound hypothermia and circulatory arrest in pigs.

The purpose of this study was to evaluate the use of retrograde cerebral perfusion via the superior vena cava during profound hypothermia and circulatory arrest (CA) in pigs. In three groups of 5 pigs each, group A (control) underwent cardiopulmonary bypass and normothermic CA for 1 hour, group B underwent cardiopulmonary bypass, profound hypothermia, and CA (15 degrees C nasopharyngeal) for 1 hour, and group C underwent the same procedure as group B plus retrograde cerebral perfusion. In group A none awoke. In group B, 2 of 5 did not awake and 3 of 5 awoke unable to stand, 2 with perceptive hind limb movement and 1 moving all extremities. In group C all awoke, 4 of 5 able to stand and 1 of 5 unable to stand but moving all limbs. In neurologic evaluation group B had significantly lower Tarlov scores than group C (p = 0.0090). Group B mean wake-up time, plus or minus standard error of the mean, was 124.6 +/- 4.6 minutes versus 29.2 +/- 5.1 in group C (p = 0.0090). In group B late phase CA cerebral blood flow dropped 30.9% +/- 4.8%, but in group C it rose 24.7% +/- 9.3% (p = 0.0007, pooled variance t test, two-tailed). In group B late phase CA brain oxygenation decreased 46.0% +/- 13.9% but it increased 26.1% +/- 5.4% in group C (p = 0.0013). This difference was reduced somewhat during rewarming (B, -21.2% +/- 14.9%; C, 16.4% +/- 4.7%; p = 0.043). Group B rewarming jugular venous O2 saturation was 30.8% +/- 2.5% versus 56.0% +/- 4.4% in group C (p = 0.0011). We conclude that in pigs retrograde cerebral perfusion combined with profound hypothermia during CA significantly reduces neurologic dysfunction, providing superior brain protection.

Clinical evaluation of a miniature strain-gauge transducer for monitoring intracranial pressure.

In 25 patients, we evaluated the accuracy of a new miniature strain-gauge transducer developed for the measurement of intracranial pressure (ICP). The ICP in each patient was measured with the intraventricular, miniature strain-gauge transducer, and that value was compared with the ICP measured with a ventriculostomy catheter coupled to an external strain-gauge transducer. From the two monitors, 2218 simultaneous measurements of ICP were obtained. The average ICP measured with the miniature strain-gauge transducer was 15.9 +/- 10.0 mm Hg (range, -3 to 104 mm Hg). The ICP measured with the ventriculostomy-catheter transducer averaged 15.4 +/- 10.1 mm Hg (range, -9 to 104 mm Hg). A highly significant correlation was found over the wide range of pressures observed (n = 2218, r = 0.97, P < 0.001). The average difference between the two measurements of the ICP was 0.5 +/- 2.6 mm Hg, and the differences were equally positive and negative, demonstrating no consistent bias. The two values for the ICP were within 2 mm Hg of each other on 63% of the measurements and within 4 mm Hg of each other on 89% of the measurements. The average zero drift of the miniature strain-gauge transducer, measured at ambient pressure after removal of the catheter, was 0.2 +/- 0.5 mm Hg. The results indicate that this miniature strain-gauge transducer is highly accurate and stable and that it is a reliable alternative to a ventriculostomy for monitoring the ICP.

Near-infrared spectroscopic localization of intracranial hematomas.

Near-infrared spectroscopy (NIRS) of the cerebral hemispheres, applied transcranially through the intact scalp and skull, was evaluated for its ability to detect the presence of an intracranial hematoma in 46 head-injured patients. In 40 patients intracranial hematomas (22 subdural, 10 epidural, eight intracerebral) were identified on computerized tomography (CT); in all 40 cases, NIRS demonstrated greater absorption of light at 760 nm on the side of the hematoma. The mean difference in optical density (OD) between the hemisphere with the hematoma and the normal hemisphere was 0.99 +/- 0.30 for epidural hematomas, 0.87 +/- 0.31 for subdural hematomas, but only 0.41 +/- 0.11 for intracerebral hematomas. In 36 patients, the asymmetry in OD resolved after surgical evacuation of the hematoma or with spontaneous resorption of the hematoma. Four patients who developed postoperative or delayed hematomas exhibited persistence of the asymmetry in OD. Six patients had only diffuse injuries and exhibited only minor differences in OD between the hemispheres, similar to 10 patients in the control group with no head injury. It appears that NIRS is useful in the initial examination of the head-injured patient, as an adjunct to CT, and in following patients postoperatively in the intensive care unit.

Adult respiratory distress syndrome: a complication of induced hypertension after severe head injury.

OBJECT: The factors involved in the development of adult respiratory distress syndrome (ARDS) after severe head injury were studied. The presence of ARDS complicates the treatment of patients with severe head injury, both because hypoxia causes additional injury to the brain and because therapies that are used to protect the lungs and improve oxygenation in patients with ARDS can reduce cerebral blood flow (CBF) and increase intracranial pressure (ICP). In a recent randomized trial of two head-injury management strategies (ICP-targeted and CBF-targeted), a fivefold increase in the incidence of ARDS was observed in the CBF-targeted group. METHODS: Injury severity, physiological data, and treatment data in 18 patients in whom ARDS had developed were compared with the remaining 171 patients in the randomized trial in whom it had not developed. Logistic regression analysis was used to study the interaction of the factors that were related to the development of ARDS. In the final exact logistic regression model, several factors were found to be significantly associated with an increased risk of ARDS: administration of epinephrine (5.7-fold increased risk), administration of dopamine in a larger than median dose (10.8-fold increased risk), and a history of drug abuse (3.1-fold increased risk). CONCLUSIONS: Although this clinical trial was not designed to study the association of management strategy and the occurrence of ARDS, the data strongly indicated that induced hypertension in this high-risk group of patients is associated with the development of symptomatic ARDS.

Early detection of delayed traumatic intracranial hematomas using near-infrared spectroscopy.

Delayed intracranial hematomas are an important treatable cause of secondary brain injury in patients with head trauma. Early identification and treatment of these lesions, which appear or enlarge after the initial computerized tomography (CT) scan, may improve neurological outcome. Serial examinations using near-infrared spectroscopy (NIRS) to detect the development of delayed hematomas were performed in 167 patients. The difference in absorbance of light (delta OD) at 760 nm between the normal and the hematoma side was measured serially during the first 3 days after injury. Twenty-seven (16%) of the patients developed a type of late hematoma: intracerebral hematoma in eight, extracerebral hematoma in six, and postoperative hematoma in 13 patients. Eighteen of the delayed hematomas caused significant mass effect and required surgical evacuation. The hematomas appeared between 2 and 72 hours after admission. In 24 of the 27 patients, a significant increase (> 0.3) in the delta OD occurred prior to an increase in intracranial pressure, a change in the neurological examination, or a change on CT scan. A favorable outcome occurred in 67% of the patients with delayed hematomas, which suggests that early diagnosis using NIRS may allow early treatment and reduce secondary injury caused by delayed hematomas.

Metabolic changes in the brain during transient ischemia measured with microdialysis.

Forty-four patients with severe head injury were monitored for episodes of cerebral ischemia using jugular venous oxygen saturation (sjvO2), brain tissue pO2 (ti-pO2), and a microdialysis probe. The concentration of lactate and glucose were measured in the microdialysate. A total of 10 episodes of global ischemia were observed. The characteristic pattern of a simultaneous decrease in sjvO2 and brain ti-pO2 with an increase in the concentration of lactate occurred in all 10 patients. In addition, 3 episodes of regional ischemia were observed. Although brain ti-pO2 decreased to very low values and the concentration of lactate increased in the microdialysate, sjvO2 remained unchanged. Brain ti-pO2 adds another dimension to our cerebral monitoring by allowing the detection of regional cerebral ischemia.

Positive end expiratory pressure reduces intracranial compliance in the rabbit.

Acute respiratory distress syndrome is commonly encountered in head-injured patients. Positive and expiratory pressure (PEEP) is useful in improving oxygenation. However, PEEP, by increasing intrathoracic pressure, decreases venous return, mean arterial pressure, and cardiac output and increases jugular vein pressure. There is conflicting evidence in the literature as to the potential effect of PEEP on intracranial pressure (ICP). The present study was undertaken to examine the effect of PEEP on ICP and intracranial compliance. Twelve male rabbits weighing 3.5-4.5 kg were used. The following parameters were monitored: arterial blood pressure, ICP (intraparenchymal Camino device), PaCO2, and PaO2. A space-occupying lesion was produced by inflation of a double lumen pediatric Swan-Ganz catheter placed over the right parietal dura. The amount of fluid required to reach the point of exponential increase of ICP was recorded at PEEP of 0 and 10 cm H2O. The mean volume needed to reach the deflection point of ICP was significantly lower when PEEP was 10 cm H2O compared to the value when PEEP was 0 cm H2O (685 +/- 48 vs. 883.3 +/- 46 microliters, respectively; p < 0.01). The results of the present study indicated that PEEP of 10 cm H2O decreases intracranial compensatory reserves for maintaining ICP at normal levels in the presence of an expanding intracranial mass.

Extracellular glutamate and aspartate in head injured patients.

Eighty-six patients in coma from a severe head injury underwent monitoring of extracellular concentrations of glutamate and aspartate by a microdialysis technique during the first few days after injury. The median value for glutamate was 7.4 microM (interquartile range 3.6-18.8 microM). The median value for aspartate was 2.4 microM (interquartile range 1.1-5.0 microM). Average values for the dialysate concentrations of glutamate and aspartate, were closely related to outcome (p < .001 and p = .002, respectively). Patients who died of their head injury had significantly higher dialysate glutamate and aspartate concentrations compared to patients who recovered to a Glasgow Outcome Score of good recovery or moderate disability. Dialysate glutamate and aspartate levels were also significantly related to type of injury (p = .008 and p = .004, respectively). The highest values were found in patients with gunshot wounds, followed by patients with evacuated and unevacuated mass lesions. Patients with diffuse injuries had the lowest values of glutamate and aspartate. These results suggest that excitatory amino acids may play a role in the evolution of injury to the brain after trauma.

Lactic acid and amino acid fluctuations measured using microdialysis reflect physiological derangements in head injury.

We examined the extracellular neurochemical milieu in 34 head injured patients using microdialysis while simultaneously monitoring intracranial pressure, cerebral perfusion pressure, and jugular venous oxygen saturation. Derangements of anaerobic metabolism reflected by increased lactate and lactate/pyruvate ratios, and release of amino acids were seen at the same time as physiological deterioration in the majority of instances. Clinical microdialysis may provide insights into the neurochemistry of head injury, and such information may lead to new methods of monitoring and treating head injured patients.

Simultaneous measurement of cortical potassium, calcium, and magnesium levels measured in head injured patients using microdialysis with ion chromatography.

Potassium, calcium and magnesium were measured in 3717 microdialysate samples in 43 patients with head injury experiencing refractory increased ICP, episodes of jugular venous oxygen desaturation and brain death. Cation analysis was performed with 'ion chromatography'. Potassium levels remained stable until severe physiological deterioration occurred, whereupon they increased 100-400%, usually associated with release of amino-acids including glutamate, aspartate, and taurine into the extracellular space. The magnesium and calcium levels remained unchanged, regardless of the severity of physiological deterioration.

Multiple myeloma presenting as solitary mass in the posterior fossa.

Intracranial plasma cell tumors are extremely rare and can either be solitary lesions or part of systemic multiple myeloma. We report a 42-year-old woman who presented with a posterior fossa mass and successfully underwent surgical resection, leading to the diagnosis of multiple myeloma. To our knowledge, this is the first reported case of multiple myeloma presenting as a posterior fossa mass lesion. This report highlights the importance of maintaining plasma cell tumor in the differential of intracranial mass with bony involvement. Furthermore, once the diagnosis is established, further work up is critical to evaluate for systemic disease.