History of cervical spine surgery: from nihilism to advanced reconstructive surgery.

STUDY DESIGN: Review of literature. OBJECTIVES: To review and analyze the evolution of cervical spine surgery from ancient times to current practice. The aim is to present an accessible overview, primarily intended for a broad readership. METHODS: Descriptive literature review and analysis of the development of cervical spine surgery from the prehistoric era until today. RESULTS: The first evidence for surgical treatment of spinal disorders dates back to approximately 1500 BC. Conservative approaches to treatment have been the hallmark for thousands of years, but over the past 50 years progress has been rapid. We illustrate how nations have added elements to this complex subject and how knowledge has surpassed borders and language barriers. Transferral of knowledge occurred from Babylon (Bagdad) to Old Egypt, to the Greek and Roman empires and finally via the Middle East (Bagdad and Damascus) back to Europe. Recent advances in the field of anesthesia, imaging and spinal instrumentation have changed long-standing nihilism in the treatment of cervical spine pathologies to the current practice of advanced reconstructive surgery of the cervical spine. A critical approach to the evaluation of benefits and complications of these advanced surgical techniques for treatment of cervical spine disorders is required. CONCLUSION: Advances in surgery now permit full mechanical reconstruction of the cervical spine. However, despite substantial experimental progress, spinal cord repair and restoration of lost functions remain a challenge. Modern surgeons are still looking for the best way to manage spine disorders.

Retrievable Gunther Tulip inferior vena cava filter: experience in 317 patients.

The aim of our study was to assess our experience with the retrievable Gunther Tulip (GT) inferior vena cava (IVC) filter, with regard to its insertion, efficacy, ease of placement and retrieval, and associated complications. Between November 2001 and October 2005, 322 GT filters were placed in 317 patients. Insertion indications included the following: pulmonary embolus (PE) prophylaxis in trauma patients (n = 232), PE prophylaxis in perioperative patients (n = 27), PE prophylaxis in moribund intensive care unit patients (n = 22), recent PE (n = 48), extensive deep venous thrombosis (n = 66), contraindication to anticoagulation (n = 63), anticoagulation complication (n = 8) and deep venous thrombosis with failed anticoagulation (n = 8). Some patients had more than one indication for caval filter placement. Two hundred and five attempted retrievals have been carried out, with 15 failures. Our successful retrieval rate is 92%. Nineteen filters were originally inserted permanently. There have been three minor complications associated with insertion and five with retrieval. The mean time from filter insertion to attempted retrieval was 76.95 days. The ideal filter implantation time gives the patient the benefit of PE protection, while avoiding the long-term risks associated with caval filters. Although GT retrieval times have lengthened considerably, our data suggest that this is at the expense of successful retrieval rates.

Prevalence of sleepiness in surviving drivers of motor vehicle collisions.

BACKGROUND: Although alcohol and recreational drugs are recognized as significant risk factors for motor vehicle collisions (MVC), the contribution of sleepiness alone is less clear. We therefore sought to identify the contribution of sleepiness to the risk of a MVC in injured drivers, independent of drugs and alcohol. METHODS: A prospective questionnaire and examination of sleep-related risk factors in drivers surviving MVC in a major hospital-based trauma centre was carried out. RESULTS: Forty of 112 injured drivers screened were interviewed, of whom approximately 50% had at least one sleep-related risk factor, 20% having two or more. Of the MVC deemed sleep-related by questionnaire, only 25% were identified by the Australian Transport Safety Bureau definitions. Shift work was the greatest sleep-related factor identified contributing to MVC. CONCLUSION: Sleepiness, particularly related to shift work, needs to be emphasized as a risk factor for MVC. Australian Transport Safety Bureau definitions of sleep-related MVC are too lenient.

Pleural decompression and drainage during trauma reception and resuscitation.

This review examines pleural decompression and drainage during initial hospital adult trauma reception and resuscitation, when it is indicated for haemodynamically unstable patients with signs of pneumothorax or haemothorax. The relevant historical background, techniques, complications and current controversies are highlighted. Key findings of this review are that: 1. Needle thoracocentesis is an unreliable means of decompressing the chest of an unstable patient and should only be used as a technique of last resort. 2. Blunt dissection and digital decompression through the pleura is the essential first step for pleural decompression, as decompression of the pleural space is a primary goal during reception of the haemodynamically unstable patient with a haemothorax or pneumothorax. Drainage and insertion of a chest tube is a secondary priority. 3. Techniques to prevent tube thoracostomy (TT) complications include aseptic technique, avoidance of trocars, digital exploration of the insertion site and guidance of the tube posteriorly and superiorly during insertion. 4. Whenever possible, blunt thoracic trauma patients should undergo definitive CT imaging after TT to check for appropriate tube position.

Immunohistochemical characterization of Fas (CD95) and Fas Ligand (FasL/CD95L) expression in the injured brain: relationship with neuronal cell death and inflammatory mediators.

Traumatic brain injury causes progressive tissue atrophy and consequent neurological dysfunction, resulting from neuronal cell death in both animal models and patients. Fas (CD95) and Fas ligand (FasL/CD95L) are important mediators of apoptosis. However, little is known about the relationship between Fas and FasL and neuronal cell death in mice lacking the genes for inflammatory cytokines. In the present study, double tumor necrosis factor/lymphotoxin-alpha knockout (-/-) and interleukin-6-/- mice were subjected to closed head injury (CHI) and sacrificed at 24 hours or 7 days post-injury. Consecutive brain sections were evaluated for Fas and FasL expression, in situ DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling; TUNEL), morphologic characteristics of apoptotic cell death and leukocyte infiltration. A peak incidence of TUNEL positive cells was found in the injured cortex at 24 hours which remained slightly elevated at 7 days and coincided with maximum Fas expression. FasL was only moderately increased at 24 hours and showed maximum expression at 7 days. A few TUNEL positive cells were also found in the ipsilateral hippocampus at 24 hours. Apoptotic, TUNEL positive cells mostly co-localized with neurons and Fas and FasL immunoreactivity. The amount of accumulated polymorphonuclear leukocytes and CD11b positive cells was maximal in the injured hemispheres at 24 hours. We show strong evidence that Fas and FasL might be involved in neuronal apoptosis after CHI. Furthermore, Fas and FasL upregulation seems to be independent of neuroinflammation since no differences were found between cytokine-/- and wild-type mice.

[Experimental principles of the V.A.C.-therapy -- pressure values in superficial soft tissue and the applied foam]. / Experimentelle Grundlagen -- Druckwerte unter Vakuumtherapie-Schwämmen -- eine In-vitro- und In-vivo-Untersuchung.

OBJECT OF THE STUDY: Measurement of the pressure during V.A.C.(R)-therapy in superficial parts of the affected soft tissue as well as at the soft tissue/foam-interface, measurement of pressure values along bigger distances in the foam and the comparison of pressure transfer between polyurethane and polyvinyl-alcohol foams. MATERIAL AND METHODS: A multi-channel electronic transducer-tipped catheter system based on the piezo-resistant principle was used. Measurement was performed on a plain table surface, at a bovine muscle as well as in human tibial anterior muscle of a patient after fasciotomy. Applied pressure values by V.A.C.(R)-therapy-units were 50 to 200 mm Hg (continuous suction modus). RESULTS: 100 % pressure transition through vacuum-therapy-foams to wound surface, almost 100 % pressure transition even along 60 cm in very large polyurethane-foams using only one trac-pad connector. Pressure values > 125 mm Hg using polyvinyl-alcohol-foams showed a reduction of up to 25 % in distances > 15 cm from trac-pad-connector. On the surface of the affected soft tissue there are negative and positive pressure values (25 % quartile: - 25 mm Hg; 75 % quartile: + 15 mm Hg). DISCUSSION: Pore walls of the foam can produce positive pressure conditions resulting in soft tissue compression and consecutively hypoperfusion or ischemia. V.A.C.(R)-therapy seems to produce an heterogeneity of pressure distribution at the wound ground leading to pressure gradients and facilitating drainage of interstitial fluid. This mechanism could explain the anti-edema effects of V.A.C.(R)-therapy resulting indirectly in an increased nutritive perfusion.

Characterisation of orthopaedic trauma admitted to adult level 1 trauma centres.

BACKGROUND: Despite the vast number of traumatic injuries that are orthopaedic in nature, comprehensive epidemiological data that characterise orthopaedic trauma are limited. The aim of this study was to investigate the nature of orthopaedic trauma admitted to adult Level 1 Trauma Centres. METHODS: Data were obtained from the Victorian Orthopaedic Trauma Outcomes Registry (VOTOR), which includes all patients with orthopaedic trauma admitted to the two adult Level 1 Trauma Centres in Victoria (Australia). Information was collected from the medical record and hospital databases on patients' demographics and injury event, diagnoses and management. RESULTS: Data were analysed on 784 patients recruited between August 2003 and March 2004. Patients were mainly young (<65 years) (70.7%), male (59.1%) and injured in a transport collision (51.3%). Fractures of the femur (23.7%) and spine (23.5%) were the most common injuries and were predominately managed with operative (87.6%) and conservative (78.8%) methods, respectively. Differences in most parameters were evident between younger (<65 years) and older (> or =65 years) patients. CONCLUSIONS: This study presents epidemiological data on patients with orthopaedic trauma who were admitted to adult Level 1 Trauma Centres. This information is critical for the future monitoring and evaluation of the outcomes of orthopaedic trauma.

Risk factors for acquisition of methicillin-resistant Staphylococcus aureus (MRSA) by trauma patients in the intensive care unit.

In a previous study in the intensive care unit (ICU) of the Alfred Hospital, Melbourne, Australia, it was demonstrated that trauma patients were at particular risk of becoming colonized by methicillin-resistant Staphylococcus aureus (MRSA). We examined risk factors for MRSA acquisition in these patients using a cohort study comparing the 31 patients who acquired MRSA with 65 who did not. Data collected included ICU length of stay (LOS), mechanism of trauma, site of injury, type of surgery, trauma severity and antibiotic usage. Odds ratios (OR) were determined and adjusted for LOS. LOS in the ICU was a significant univariate predictor of MRSA acquisition (OR 13.7). When adjusted for LOS, mechanism of trauma (OR 10.4), laparotomy (OR 6.3) and administration of ticarcillin/clavulanic acid (OR 4.5) or glycopeptides (OR 5.9) remained significant. We confirmed our previous finding that LOS was associated with MRSA acquisition. Receipt of antibiotics correlated with reported literature. Novel associations were road trauma as a mechanism and laparotomy.

The use of a retractor system (SynFrame) for open, minimal invasive reconstruction of the anterior column of the thoracic and lumbar spine.

In 65 consecutive cases of trauma (n=55), pseudo-arthrosis (n=4) and metastasis (n=6), anterior reconstruction of the thoracic and lumbar spine was performed using a new minimal invasive but open access procedure. No operation had to be changed into an open procedure. The thoracolumbar junction was approached by a left-sided mini-thoracotomy (n=50), the thoracic spine by a right-sided mini-thoracotomy (n=8) and the lumbar spine by a left sided mini-retroperitoneal approach (n=7), using a new table-mounted retractor system called SynFrame (Stratec Medical, Switzerland). The anterior column was reconstructed using a variety of materials: autologous tricortical crest (n=11), autologous spongiosa (n=12), allografts (n=4) and cages (n=38). The mean overall operating time was 170 min (range 90-295 min); the time of surgery varied, depending on the spine pathology and the magnitude of the intervention in the anterior part of the spine. Mean overall blood loss was 912 ml, and only 7 out of the 65 patients needed blood transfusions. There were neither intra- nor postoperative complications related to the minimal access in particular, nor visceral/vascular complications. No intercostal neuralgia, no post-thoracotomy pain syndromes, no superficial or deep wound infections and no deep venous thromboses occurred. Four cases of pseudo-obstruction were treated conservatively. In this study, we describe the new minimal access technology to the anterior part of the thoracal and lumbar spine on the basis of 65 cases completed within 1 year. This open, but minimal invasive, access technology offers, in our view, additional advantages to the "pure" endoscopic procedures of spinal surgery.

Role of cerebral inflammation after traumatic brain injury: a revisited concept.

Neuroinflammation occuring after traumatic brain injury (TBI) is a complex phenomenon comprising distinct cellular and molecular events involving the injured as well as the healthy cerebral tissue. Although immunoactivation only represents a one of the many cascades initiated in the pathophysiology of TBI, the exact function of each mediator, activated cell types or pathophysiological mechanism, needs to be further elucidated. It is widely accepted that inflammatory events display dual and opposing roles promoting, on the one hand, the repair of the injured tissue and, on the other hand, causing additional brain damage mediated by the numerous neurotoxic substances released. Most of the data supporting these hypotheses derive from experimental work based on both animal models and cultured neuronal cells. More recently, evidence has been provided that a complete elimination of selected inflammatory mediators is rather detrimental as shown by the attenuation of neurological recovery. However, there are conflicting results reported on this issue which strongly depend on the experimental setting used. The history of immunoactivation in neurotrauma is the subject of this review article, giving particular emphasis to the comparison of clinical versus experimental studies performed over the last 10 years. These results also are evaluated with respect to other neuropathologies, which are years ahead as compared to the research in TBI. The possible reciprocal influence of peripheral and intrathecal activation of the immune system will also be discussed. To conclude, the future directions of research in the field of neurotrauma is considered.

Intrathecal levels of complement-derived soluble membrane attack complex (sC5b-9) correlate with blood-brain barrier dysfunction in patients with traumatic brain injury.

It has become evident in recent years that intracranial inflammation after traumatic brain injury (TBI) is, at least in part, mediated by activation of the complement system. However, most conclusions have been drawn from experimental studies, and the intrathecal activation of the complement cascade after TBI has not yet been demonstrated in humans. In the present study, we analyzed the levels of the soluble terminal complement complex sC5b-9 by ELISA in ventricular cerebrospinal fluid (CSF) of patients with severe TBI (n = 11) for up to 10 days after trauma. The mean sC5b-9 levels in CSF were significantly elevated in 10 of 11 TBI patients compared to control CSF from subjects without trauma or inflammatory neurological disease (n = 12; p < 0.001). In some patients, the maximal sC5b-9 concentrations were up to 1,800-fold higher than in control CSF. The analysis of the extent of posttraumatic blood-brain barrier (BBB) dysfunction, as determined by CSF/serum albumin quotient (Q(A)), revealed that patients with a moderate to severe BBB impairment (mean Q(A) > 0.01) had significantly higher intrathecal sC5b-9 levels as compared to patients with normal BBB function (mean Q(A) < 0.007; p < 0.0001). In addition, a significant correlation between the individual daily Q(A) values and the corresponding sC5b-9 CSF levels was detected in 8 of 11 patients (r = 0.72-0.998; p < 0.05). These data demonstrate for the first time that terminal pathway complement activation occurs after head injury and suggest a possible pathophysiological role of complement with regard to posttraumatic BBB dysfunction.

Regulation of chemokines and chemokine receptors after experimental closed head injury.

The expression of the chemokines macrophage inflammatory protein (MIP)-2 and MIP-1alpha and of their receptors CXCR2 and CCR5 was assessed in wild type (WT) and TNF/lymphotoxin-alpha knockout (TNF/LT-alpha-/-) mice subjected to closed head injury (CHI). At 4 h after trauma intracerebral MIP-2 and MIP-1alpha levels were increased in both groups with MIP-2 concentrations being significantly higher in WT than in TNF/LT-alpha-/- animals (p < 0.05). Thereafter, MIP-2 production declined rapidly, whereas MIP-1alpha remained elevated for 7 days. Expression of CXCR2 was confined to astrocytes and increased dramatically within 24 h in both mouse types. Contrarily, CCR5 expression remained constitutively low and was mainly localized to microglia. These results show that after CHI, chemokines and their receptors are regulated differentially and with independent kinetics.

Markers for cell-mediated immune response are elevated in cerebrospinal fluid and serum after severe traumatic brain injury in humans.

The brain is believed to be an immunologically privileged organ, sheltered from the systemic immunological defense by the blood-brain barrier (BBB). However, there is increasing evidence for a marked inflammatory response in the brain after traumatic brain injury (TBI). Markers for cellular immune activation, neopterin, beta2-microglobulin (beta2M), and soluble interleukin-2 receptor (sIL-2R), were measured for up to 3 weeks in cerebrospinal fluid (CSF) and serum of 41 patients with severe TBI in order to elucidate the time course and the origin of the cellular immune response following TBI. Neopterin gradually increased during the first posttraumatic week in both CSF and serum. Concentrations in CSF were generally higher than in serum, suggesting intrathecal release of this marker. beta2M showed similar kinetics but with higher serum than CSF concentrations. Nonetheless, intrathecal release as assessed by the beta2M index could be postulated for most of the patients. The mean levels of sIL-2R in both CSF and serum were elevated during the whole study period, serum concentrations being up to 2 x 10(4) times higher than in CSF. No significant intrathecal production of sIL-2R could be detected. The present data shows that severe TBI leads to a marked cell-mediated immune response within the brain and in the systemic circulation. In the intrathecal compartment the activated cells appear to be predominantly of the macrophage/microglia lineage, while the immune activation in the systemic circulation seems to involve mainly T-lymphocytes.

S-100 beta reflects the extent of injury and outcome, whereas neuronal specific enolase is a better indicator of neuroinflammation in patients with severe traumatic brain injury.

It has been hypothesized that immunoactivation may contribute to brain damage and affect outcome after traumatic brain injury (TBI). In order to determine the role of inflammation after TBI, we studied the interrelationship of the immune mediators sICAM-1 and IL-6 with the levels of S-100beta and neuronal specific enolase (NSE), both recognized markers of brain damage. In addition, the extent and type of cerebral injury and the neurological outcome were related to these measured markers of injury. An evident elevation of S-100beta (range of means: 2.7-81.4 ng/mL) and NSE (range of means: 2.0-81.3 ng/mL) was observed in CSF of all 13 patients during the first 3 posttraumatic days and decreased over 2 weeks. In parallel, the production of sICAM-1 (range of means: 0.7-11.9 ng/mL) and IL-6 (range of means: 0.1-8.2 ng/mL) was also markedly enhanced in CSF. The CSF means of S-100beta and NSE per patient correlated with IL-6 (r = 0.60, p < 0.05; and r = 0.64, p < 0.05, respectively), whereas the corresponding means in serum showed a significant correlation only between NSE and IL-6 (r = 0.56, p < 0.05). Maximal CSF values of NSE and sICAM-1 correlated with each other (r = 0.57, p < 0.05). The contusion sizes assessed on the CT scans correlated with the means of S-100beta (r = 0.63, p < 0.05) and NSE (r = 0.71, p < 0.05) in CSF and with the mean of S-100beta in serum, although not statistically significant (r = 0.52, p = 0.06), but not with serum NSE. Interestingly, linear regression analysis demonstrated that means of S-100beta in CSF (r = 0.78, p = 0.002) and serum (r = 0.82, p < 0.001) correlated with the GOS. These results indicate that the elevation of these parameters in CSF depends on the extent of injury and that S-100beta may be a predictor of outcome after TBI, whereas NSE reflects better the inflammatory response.

Upregulation of ICAM-1 and MCP-1 but not of MIP-2 and sensorimotor deficit in response to traumatic axonal injury in rats.

The pathophysiology of traumatic axonal injury (TAI) is only partially understood. In this study, we investigated the inflammatory response as well as the extent of neurological deficit in a rat model of traumatic brain injury (TBI). Forty-two adult rats were subjected to moderate impact-acceleration brain injury and their brains were analyzed immunohistochemically for ICAM-1 expression and neutrophil infiltration from 1 hr up to 14 days after trauma. In addition, the chemotactic factors MIP-2 and MCP-1 were measured in brain homogenates by ELISA. For evaluating the neurological deficit, three sensorimotor tests were applied for the first time in this model. In the first 24 hr after trauma, the number of ICAM-1 positive vessels increased up to 4-fold in cortical and subcortical regions compared with sham operated controls (P < 0.05). Maximal ICAM-1 expression (up to 8-fold increase) was detected after 4 days (P < 0.001 vs. 24 hr), returning to control levels in all brain regions by 7 days after trauma. MCP-1 was elevated between 4 hr and 16 hr post-injury as compared with controls. In contrast, neither neutrophil infiltration nor elevation of MIP-2, both events relevant in focal brain injury, could be detected. In all neurological tests, a significant deficit was observed in traumatized rats as compared with sham operated animals from Day 1 post-injury (grasping reflex of the hindpaws: P < 0.001, vibrissae-evoked forelimb placing: P = 0.002, lateral stepping: P = 0.037). In conclusion, after moderate impact acceleration brain injury ICAM-1 upregulation has been demonstrated in the absence of neutrophil infiltration and is paralleled by a selective induction of chemokines, pointing out that individual and distinct inflammatory events occur after diffuse vs. focal TBI.

Intracerebral complement C5a receptor (CD88) expression is regulated by TNF and lymphotoxin-alpha following closed head injury in mice.

The anaphylatoxin C5a is a potent mediator of inflammation in the CNS. We analyzed the intracerebral expression of the C5a receptor (C5aR) in a model of closed head injury (CHI) in mice. Up-regulation of C5aR mRNA and protein expression was observed mainly on neurons in sham-operated and head-injured wild-type mice at 24 h. In contrast, in TNF/lymphotoxin-alpha knockout mice, the intracerebral C5aR expression remained at low constitutive levels after sham operation, whereas it strongly increased in response to trauma between 24 and 72 h. Interestingly, by 7 days after CHI, the intrathecal C5aR expression was clearly attenuated in the knockout animals. These data show that the posttraumatic neuronal expression of the C5aR is, at least in part, regulated by TNF and lymphotoxin-alpha at 7 days after trauma.

[Instruments for quality control in management of severely injured patients]. / Instrumente zur Qualitätskontrolle bei der Versorgung schwerverletzter Patienten.

This article describes the most important scoring systems in trauma care and their application to quality control. Development and contents of the Glasgow Coma Scale (GCS), Abbreviated Injury Scale (AIS), Injury Severity Score (ISS), Trauma Score (TS), Revised Trauma Score (RTS) and of the TRISS-method are described. The advantages and the limitations of the mentioned scoring systems are discussed critically.

Cell activation and inflammatory response following traumatic axonal injury in the rat.

In a rat model of traumatic brain injury cell activation was characterized immunohistochemically from 2 h up to 2 weeks. Reactive astrocytosis became apparent perivascularly and in the grey matter within 4h after trauma. Increased OX42 immunoreactivity indicated microglial activation in cortex and hippocampus as early as 4 h, whereas up-regulation of MHC class II (OX6) was evident in white matter tracts at 24 h. Although macrophage (ED1) numbers increased in the meninges and perivascularly, brain infiltration appeared marginal. Accumulation of lymphocytes and granulocytes was not observed. Our results show that traumatic axonal injury induces a rapid and sustained glial activation in the absence of leukocyte infiltration. Thus, cell activation following diffuse trauma strongly differs from that found after focal brain damage, awaiting further functional characterization.

[Traumatic paraplegia: surgical measures]. / Traumatische Querschnittlähmung: operative Massnahmen.

Reduction and fixation of unstable spine injuries in patients with neurological deficit are the prerequisites for early rehabilitation. Diagnostic procedures and surgery in patients with para-/tetraplegia must be performed urgently to avoid further neurological damage and ensure recovery. In parallel administration, high-dose steroids are initiated immediately after admission. In general, unstable spine fractures are reduced in a closed or open manner and stabilised. Bony fragments occluding the spinal channel are removed and, if necessary, the anterior column is reconstructed. Unstable fractures of the cervical spine are operated on either from the back and/or anteriorly, although the techniques used in the upper cervical spine are quite different from those used in the lower cervical spine. Instabilities of the thoraco-lumbar junction are reduced and stabilised via a dorsal and/or anterior-lateral approach (transthoracic or retroperitoneal). Exact preoperative planning is necessary due to the proximity of large vessels and organs, as well as the narrow space for positioning of the implants. With early operative stabilisation of the spine paretic/paralysed patients can be mobilised immediately and personal care is facilitated. In this article the operative techniques are described on the basis of examples chosen from 606 patients treated at the Division of Trauma Surgery, University Hospital of Zurich from 1992 to 1997. 119 patients (19%) were diagnosed with incomplete/complete para-/tetraplegia and 51 with various degrees of neurological deficit.

sICAM-1 and TNF-alpha induce MIP-2 with distinct kinetics in astrocytes and brain microvascular endothelial cells.

The dysfunction of the blood-brain barrier (BBB) occurring after traumatic brain injury (TBI) is mediated by intracerebral neutrophil accumulation, chemokine release (e.g., interleukin (IL)-8) and upregulation of adhesion molecules (e.g., intercellular adhesion molecule (ICAM)-1). In patients with severe TBI, we previously found that elevated cerebrospinal fluid (CSF) IL-8 and soluble (s)ICAM-1 correlate with BBB dysfunction, and this prompted us to concomitantly monitor IL-8, sICAM-1 and their stimulator tumor necrosis factor (TNF)-alpha in CSF. Potential mechanisms for upregulation of the IL-8 analogue, murine macrophage inflammatory protein (MIP)-2, and sICAM-1 at the BBB were studied using cultured mouse astrocytes and brain microvascular endothelial cells (MVEC). In CSF of seven patients, IL-8 and sICAM-1 were elevated for 19 days after severe TBI, whereas TNF-alpha exceeded normal values on 9 days. Stimulation of MVEC and astrocytes with TNF-alpha simultaneously induced the release of MIP-2 reaching saturation by 4-8 hr and of sICAM-1 increasing continuously from 2-4 hr to 12 hr. Augmented sICAM-1 production correlated with enhanced membrane-bound (m)ICAM-1 expression in both cell types (r(s) = 0.96 and 0.90, P < 0.0001), but was markedly higher in astrocytes. The release of sICAM-1 was not influenced by IL-8 or MIP-2, although astrocytes and MVEC expressed the IL-8/MIP-2 receptor (CXCR-2) as determined by FACS analysis. Instead, we found that sICAM-1 strongly induced MIP-2 secretion by both cell types with kinetics differing from those evoked by TNF-alpha. If added together, sICAM-1 and TNF-alpha synergistically induced MIP-2 production suggesting the involvement of two different pathways for MIP-2 regulation.