Decompressive craniectomy in diffuse traumatic brain injury.

BACKGROUND: It is unclear whether decompressive craniectomy improves the functional outcome in patients with severe traumatic brain injury and refractory raised intracranial pressure. METHODS: From December 2002 through April 2010, we randomly assigned 155 adults with severe diffuse traumatic brain injury and intracranial hypertension that was refractory to first-tier therapies to undergo either bifrontotemporoparietal decompressive craniectomy or standard care. The original primary outcome was an unfavorable outcome (a composite of death, vegetative state, or severe disability), as evaluated on the Extended Glasgow Outcome Scale 6 months after the injury. The final primary outcome was the score on the Extended Glasgow Outcome Scale at 6 months. RESULTS: Patients in the craniectomy group, as compared with those in the standard-care group, had less time with intracranial pressures above the treatment threshold (P<0.001), fewer interventions for increased intracranial pressure (P<0.02 for all comparisons), and fewer days in the intensive care unit (ICU) (P<0.001). However, patients undergoing craniectomy had worse scores on the Extended Glasgow Outcome Scale than those receiving standard care (odds ratio for a worse score in the craniectomy group, 1.84; 95% confidence interval [CI], 1.05 to 3.24; P=0.03) and a greater risk of an unfavorable outcome (odds ratio, 2.21; 95% CI, 1.14 to 4.26; P=0.02). Rates of death at 6 months were similar in the craniectomy group (19%) and the standard-care group (18%). CONCLUSIONS: In adults with severe diffuse traumatic brain injury and refractory intracranial hypertension, early bifrontotemporoparietal decompressive craniectomy decreased intracranial pressure and the length of stay in the ICU but was associated with more unfavorable outcomes. (Funded by the National Health and Medical Research Council of Australia and others; DECRA Australian Clinical Trials Registry number, ACTRN012605000009617.).

Endogenous melatonin increases in cerebrospinal fluid of patients after severe traumatic brain injury and correlates with oxidative stress and metabolic disarray.

Oxidative stress plays a significant role in secondary damage after severe traumatic brain injury (TBI); and melatonin exhibits both direct and indirect antioxidant effects. Melatonin deficiency is deleterious in TBI animal models, and its administration confers neuroprotection, reducing cerebral oedema, and improving neurobehavioural outcome. This study aimed to measure the endogenous cerebrospinal fluid (CSF) and serum melatonin levels post-TBI in humans and to identify relationships with markers of oxidative stress via 8-isoprostaglandin-F2alpha (isoprostane), brain metabolism and neurologic outcome. Cerebrospinal fluid and serum samples of 39 TBI patients were assessed for melatonin, isoprostane, and various metabolites. Cerebrospinal fluid but not serum melatonin levels were markedly elevated (7.28+/-0.92 versus 1.47+/-0.35 pg/mL, P<0.0005). Isoprostane levels also increased in both CSF (127.62+/-16.85 versus 18.28+/-4.88 pg/mL, P<0.0005) and serum (562.46+/-50.78 versus 126.15+/-40.08 pg/mL (P<0.0005). A strong correlation between CSF melatonin and CSF isoprostane on day 1 after injury (r=0.563, P=0.002) suggests that melatonin production increases in conjunction with lipid peroxidation in TBI. Relationships between CSF melatonin and pyruvate (r=0.369, P=0.049) and glutamate (r=0.373, P=0.046) indicate that melatonin production increases with metabolic disarray. In conclusion, endogenous CSF melatonin levels increase after TBI, whereas serum levels do not. This elevation is likely to represent a response to oxidative stress and metabolic disarray, although further studies are required to elucidate these relationships.

Functional measures at discharge: are they useful predictors of longer term outcomes for trauma registries?

OBJECTIVE: Trauma registries are integral to trauma systems, but reliance on mortality as the primary outcome measure remains a limitation. Some registries have included measures of discharge function, usually the modified Functional Independence Measure (FIM) or the Glasgow Outcome Scale (GOS), with the potential benefit being the ability to identify patients at risk for poor outcome. This study investigates the ability of these measures to predict longer term outcomes. METHODS: Two hundred forty-three blunt major trauma patients participated. Data were captured from the trauma registry and discharge function was assessed using the modified FIM, FIM, and GOS. At 6 months postinjury, the GOS, FIM, modified FIM, return to work/study, and other outcome measures were collected by telephone interview. Multivariate analyses were used to assess the performance of discharge functional measures as predictors of 6-month outcomes. RESULTS: Two hundred thirty-six (97.1%) participants were followed at 6 months postinjury. Disability was prevalent at 6 months; 42% had not returned to work/study, and only 32% were categorized as a "good recovery" by the GOS. Neither the GOS nor modified FIM at discharge were independent predictors of 6-month outcomes, whereas the FIM score and the FIM motor score were independent predictors of functional recovery (adjusted odds ratios 0.97; 95% confidence intervals: 0.96-0.99) and return to work/study (adjusted odds ratios 1.03, 95% confidence intervals: 1.01-1.04), respectively. CONCLUSIONS: For trauma registries to compare outcomes between regions and improvements over time, it is important that survivors with poor long-term outcomes are identified. Present measurement of discharge outcomes for trauma patients is inadequate for this purpose.

General health status and functional disability following injury in traffic crashes.

OBJECTIVE: With increasing rates of survival associated with traffic crashes, a shift to understand the consequences of injury has risen to prominence. This prospective cohort study set out to examine general health status and functional disability at 2 months and 6-8 months post-crash. METHODS: Participants were otherwise healthy adults aged 18-59 years admitted to hospitals, excluding those with moderate-severe head injury and spinal cord injury. Sixty-two adults completed interviews prior to discharge and at 2 months and 8 months post-discharge. RESULTS: By 8 months post-crash, 89 percent had resumed employment and or study, two thirds rated the resolution of their medical problems to be excellent (14.5 percent) or good (53 percent), and 82 percent were considered to be fully self-sufficient with respect to activities of daily living. Despite this, results from the SF-36 indicated significant reductions in health status at 2 and 8 months post-crash relative to pre-crash health, with domain scores up to 26 percent lower than pre-crash scores, while assessment of activities of daily living indicated residual functional disability at both follow-up times. Self-reported pain was higher for both males and females at both follow-up times compared with pre-crash self-reported pain. CONCLUSION: This study demonstrated significant, ongoing loss of health-related quality of life and impairment associated with injuries sustained in road crashes, highlighting the need for continuing care post-discharge to facilitate a rapid return to optimal health.

Clinical outcomes of magnetic resonance imaging in blunt cervical trauma.

OBJECTIVES: To determine whether MRI of the cervical spine resulted in a change in management of patients with blunt trauma and normal plain X-ray (XR)/CT of the cervical spine. METHODS: An explicit chart review was conducted of patients seen at a Level 1 trauma centre over a 1 year period. Clinical details were extracted from the charts of patients with blunt trauma who had a normal plain XR and CT scan of the cervical spine and who underwent cervical spine MRI. A comparison of clinical details was made between those with a normal/abnormal MRI secondary to the acute injury. RESULTS: One hundred and thirty-four patients met entry criteria. Discharge non-operative management of the cervical spine was associated with a change in management by the MRI result (P < 0.0001) where MRI of the cervical spine occurred a median of 3 days (interquartile range 0-4.5, range 0-137) after the injury. The MRI occurred before discharge 90% of the time in both groups. Operative management occurred in three patients and was delayed until after first outpatient review in two patients. CONCLUSIONS: An abnormal MRI after normal plain XR and CT cervical spine studies resulted in a change in non-operative management at discharge. Early MRI resulted in one patient receiving surgery before discharge. No unstable injuries were detected by MRI that were not evident on plain XR or CT cervical spine.

Activin a release into cerebrospinal fluid in a subset of patients with severe traumatic brain injury.

Activin A is a member of the transforming growth factor-beta superfamily and has been demonstrated to be elevated during inflammation and to have neuroprotective properties following neural insults. In this study, we examined whether traumatic brain injury (TBI) induced a response in activin A or in the concentrations of its binding protein, follistatin. Thirty-nine patients with severe TBI had daily, matched cerebrospinal fluid (CSF) and serum samples collected post-TBI and these were assayed for activin A and follistatin using specific immunoassays. Concentrations of both molecules were assessed relative to a variety of clinical parameters, such as the Glasgow Coma Score, computer tomography classification of TBI, measurement of injury markers, cell metabolism and membrane breakdown products. In about half of the patients, there was a notable increase in CSF activin A concentrations in the first few days post-TBI. There were only minor perturbations in either serum activin or in either CSF or serum follistatin concentrations. The CSF activin A response was not related to any of the common TBI indices, but was strongly correlated with two common markers of brain damage, neuronal specific enolase and S100-beta. Further, activin A levels were also associated with indices of metabolism, such as lactate and pyruvate, excitotoxicity (glutamate) and membrane lipid breakdown products such as glycerol. In one of the two patients who developed a CSF infection, activin A concentrations in CSF became markedly elevated. Thus, some TBI patients have an early release of activin A into the CSF that may result from activation of inflammatory and/or neuroprotective pathways.

Current controversies in the management of patients with severe traumatic brain injury.

BACKGROUND: Traumatic brain injury is a major cause of mortality and morbidity, particularly among young men. The efficacy and safety of most of the interventions used in the management of patients with traumatic brain injury remain unproven. Examples include the 'cerebral perfusion pressure-targeted' and 'volume-targeted' management strategies for optimizing cerebrovascular haemodynamics and specific interventions, such as hyperventilation, osmotherapy, cerebrospinal fluid drainage, barbiturates, decompressive craniectomy, therapeutic hypothermia, normobaric hyperoxia and hyperbaric oxygen therapy. METHODS: A review of the literature was performed to examine the evidence base behind each intervention. RESULTS: There is no class I evidence to support the routine use of any of the therapies examined. CONCLUSION: Well-designed, large, randomized controlled trials are needed to determine therapies that are safe and effective from those that are ineffective or harmful.

Trauma reception and resuscitation.

The hospital reception phase of major trauma management requires a great number of expedient decisions. However, despite widely taught programmes advocating a standardized, algorithmic approach to decision-making, there is an ongoing rate of human errors contributing to adverse outcomes. It is now time for a fundamental change in our approach to trauma resuscitation. Point-of-care computer technology linked to real-time decision-making and trauma team coordination may achieve error reduction through standardized decision-making and a corresponding reduction in preventable mortality and morbidity.

Definitive management of acute cardiac tamponade secondary to blunt trauma.

Blunt cardiac injuries are a leading cause of fatalities following motor-vehicle accidents. Injury to the heart is involved in 20% of road traffic deaths. Structural cardiac injuries (i.e. chamber rupture or perforation) carry a high mortality rate and patients rarely survive long enough to reach hospital. Chamber rupture is present at autopsy in 36-65% of death from blunt cardiac trauma, whereas in clinical series it is present in 0.3-0.9% of cases and is an uncommon clinical finding. Patients with large ruptures or perforations usually die at the scene or in transit--the rupture of a cardiac cavity, coronary artery or intrapericardial portion of a major vein or artery is usually instantly fatal because of acute tamponade. The small, rare, remaining group of patients who survive to hospital presentation usually have tears in a cavity under low pressure and prompt diagnosis and surgery can now lead to a survival rate of 70-80% in experienced trauma centres. As regional trauma systems evolve, patients with severe, but potentially survivable cardiac injury are surviving to ED. Two distinct syndromes are apparent--haemorrhagic shock and cardiac tamponade. Any patient with severe chest trauma, hypotension disproportionate to estimated loss of blood or with an inadequate response to fluid administration should be suspected of having a cardiac cause of shock. For patients with severe hypotension or in extremis, the treatment of choice is resuscitative thoracotomy with pericardotomy. Closed chest cardiopulmonary resuscitation is ineffective in these circumstances. Blunt traumatic cardiac injury presenting with shock is associated with a poor prognosis. The majority of survivors of blunt or penetrating cardiac injury present to the ED/trauma centre with vital signs. The main pathophysiologic determinant for most survivors is acute pericardial tamponade. The presence of normal clinical signs or normal ECG studies does not exclude tamponade. In recent years the widespread availability and use of ultrasound for the initial assessment of severely injured patients has facilitated the early diagnosis of cardiac tamponade and associated cardiac injuries. Two cases of survival from blunt traumatic cardiac trauma are described in the present paper to demonstrate survivability in the context of rapid assessment and intervention.

The chemokine fractalkine in patients with severe traumatic brain injury and a mouse model of closed head injury.

The potential role of the chemokine Fractalkine (CX3CL1) in the pathophysiology of traumatic brain injury (TBI) was investigated in patients with head trauma and in mice after experimental cortical contusion. In control individuals, soluble (s)Fractalkine was present at low concentrations in cerebrospinal fluid (CSF) (12.6 to 57.3 pg/mL) but at much higher levels in serum (21,288 to 74,548 pg/mL). Elevation of sFractalkine in CSF of TBI patients was observed during the whole study period (means: 29.92 to 535.33 pg/mL), whereas serum levels remained within normal ranges (means: 3,100 to 59,159 pg/mL). Based on these differences, a possible passage of sFractalkine from blood to CSF was supported by the strong correlation between blood-brain barrier dysfunction (according to the CSF-/serum-albumin quotient) and sFractalkine concentrations in CSF (R = 0.706; P < 0.01). In the brain of mice subjected to closed head injury, neither Fractalkine protein nor mRNA were found to be augmented; however, Fractalkine receptor (CX3CR1) mRNA steadily increased peaking at 1 week postinjury (P < 0.05, one-way analysis of variance). This possibly implies the receptor to be the key factor determining the action of constitutively expressed Fractalkine. Altogether, these data suggest that the Fractalkine-CX3CR1 protein system may be involved in the inflammatory response to TBI, particularly for the accumulation of leukocytes in the injured parenchyma.

Elevated intracranial IL-18 in humans and mice after traumatic brain injury and evidence of neuroprotective effects of IL-18-binding protein after experimental closed head injury.

Proinflammatory cytokines are important mediators of neuroinflammation after traumatic brain injury. The role of interleukin (IL)-18, a new member of the IL-1 family, in brain trauma has not been reported to date. The authors investigated the posttraumatic release of IL-18 in murine brains following experimental closed head injury (CHI) and in CSF of CHI patients. In the mouse model, intracerebral IL-18 was induced within 24 hours by ether anesthesia and sham operation. Significantly elevated levels of IL-18 were detected at 7 days after CHI and in human CSF up to 10 days after trauma. Published data imply that IL-18 may play a pathophysiological role in inflammatory CNS diseases; therefore its inhibition may ameliorate outcome after CHI. To evaluate the functional aspects of IL-18 in the injured brain, mice were injected systemically with IL-18-binding protein (IL-18BP), a specific inhibitor of IL-18, 1 hour after trauma. IL-18BP-treated mice showed a significantly improved neurological recovery by 7 days, accompanied by attenuated intracerebral IL-18 levels. This demonstrates that inhibition of IL-18 is associated with improved recovery. However, brain edema at 24 hours was not influenced by IL-18BP, suggesting that inflammatory mediators other than IL-18 induce the early detrimental effects of intracerebral inflammation.

Prolonged intrathecal release of soluble Fas following severe traumatic brain injury in humans.

The mechanisms underlying cell death following traumatic brain injury (TBI) are not fully understood. Apoptosis is believed to be one mechanism contributing to a marked and prolonged neuronal cell loss following TBI. Recent data suggest a role for Fas (APO-1, CD95), a type I transmembrane receptor glycoprotein of the nerve growth factor/tumor necrosis factor superfamily, and its ligand (Fas ligand, FasL) in apoptotic events in the central nervous system. A truncated form of the Fas receptor, soluble Fas (sFas) may indicate activation of the Fas/FasL system and act as a negative feedback mechanism, thereby inhibiting Fas mediated apoptosis. Soluble Fas was measured in cerebrospinal fluid (CSF) and serum of 10 patients with severe TBI (GCS< or =8) for up to 15 days post-trauma. No sFas was detected in CSF samples from patients without neurological pathologies. Conversely, after TBI 118 out of 120 CSF samples showed elevated sFas concentrations ranging from 56 to 4327 mU/ml. Paired serum samples showed above normal (8.5 U/ml) sFas concentrations in 5 of 10 patients. Serum levels of sFas were always higher than CSF levels. However, there was no correlation between concentrations measured in CSF and in serum (r(2)=0.078, p=0.02), suggesting that the concentrations in the two compartments are independently regulated. Also, no correlation was found between sFas in CSF and blood brain barrier (BBB) dysfunction as assessed by the albumin CSF/serum quotient (Q(A)), and concentrations of the cytotoxic cytokine tumor necrosis factor-alpha in CSF, respectively. Furthermore, there was no correlation with two markers of immune activation (soluble interleukin-2 receptor and neopterin) in CSF. Maximal CSF levels of sFas correlated significantly (r(2)=0.8191, p<0.001) with the early peaks of neuron-specific enolase in CSF (a marker for neuronal cell destruction), indicating that activation of the Fas mediated pathway of apoptosis may be in part the direct result of the initial trauma. However, the prolonged elevation of sFas in CSF may be caused by the ongoing inflammatory response to trauma and delayed apoptotic cell death.

Methicillin-resistant Staphylococcus aureus and beyond: what's new in the world of the golden staph?

Methicillin-resistant Staphylococcus aureus (MRSA) continues to plague our hospitals. With the appearance of isolates that are resistant to vancomycin, now, more than ever, we must direct our efforts to controlling its development and spread. New antimicrobials have become available for treatment, but may only be a short-term answer. Our efforts towards control must be directed towards infection control measures such as improved hand hygiene with user-friendly products, such as alcohol-based hand disinfectants. Intranasal mupirocin may have a place in prevention of surgical site infection, although this role has not yet been clearly defined. Other areas where MRSA control may be effected include prudent controlled use of antibiotics, including surgical prophylaxis.

Complications of intercostal catheter insertion using EMST techniques for chest trauma.

BACKGROUND: The purpose of the present study was to determine the complication rates associated with intercostal catheter insertion (ICI) performed using Early Management of Severe Trauma (EMST) guidelines on trauma patients admitted through The Alfred Trauma Centre. METHODS: The Alfred Trauma Registry identified demographic and clinical data for patients who underwent ICI in the Alfred hospital following admission for trauma. The medical histories were subsequently reviewed for complications resulting from ICI. RESULTS: There were 211 ICI performed on 173 trauma patients at The Alfred Trauma Centre between July 2001 and June 2002. The mean injury severity score was 34. Mean age was 38 (range 15-82 years), with 77% of the patients being men. Chest injury was the result of blunt trauma in 90.2% and penetrating trauma in 9.8%. ICI occurred in the Trauma Centre (84%), operating theatre (6%), intensive care unit (9%) and in the general ward (1%). Eighty per cent of patients had a unilateral ICI. The indications for ICI were pneumothorax (45.7%), haemothorax (15.0%), haemopneumothorax (28.3%) and tension pneumothorax (7.5%). There were no insertional and 11 (5.2%) positional complications. The infection rate was 2.4% comprising two superficial and three deep (empyema thoraces) infections. No statistically significant association was found between infective complications and age, injury severity score (ISS), haemothorax, penetrating trauma, prehospital needle thoracostomy and time to ICI. There was no mortality arising from ICI complications. CONCLUSION: Intercostal catheter insertion for chest trauma performed in accordance with EMST guidelines has a low complication rate. Prehospital prophylactic chest decompression for ventilated patients with chest trauma, using a lateral rather than an anterior approach, may decrease the incidence of untreated tension pneumothorax.

Post-traumatic hypoxia is associated with prolonged cerebral cytokine production, higher serum biomarker levels, and poor outcome in patients with severe traumatic brain injury.

Secondary hypoxia is a known contributor to adverse outcomes in patients with traumatic brain injury (TBI). Based on the evidence that hypoxia and TBI in isolation induce neuroinflammation, we investigated whether TBI combined with hypoxia enhances cerebral cytokine production. We also explored whether increased concentrations of injury biomarkers discriminate between hypoxic (Hx) and normoxic (Nx) patients, correlate to worse outcome, and depend on blood-brain barrier (BBB) dysfunction. Forty-two TBI patients with Glasgow Coma Scale ≤8 were recruited. Cerebrospinal fluid (CSF) and serum were collected over 6 days. Patients were divided into Hx (n=22) and Nx (n=20) groups. Eight cytokines were measured in the CSF; albumin, S100, myelin basic protein (MBP) and neuronal specific enolase (NSE) were quantified in serum. CSF/serum albumin quotient was calculated for BBB function. Glasgow Outcome Scale Extended (GOSE) was assessed at 6 months post-TBI. Production of granulocye macrophage-colony stimulating factor (GM-CSF) was higher, and profiles of GM-CSF, interferon (IFN)-γ and, to a lesser extent, tumor necrosis factor (TNF), were prolonged in the CSF of Hx but not Nx patients at 4-5 days post-TBI. Interleukin (IL)-2, IL-4, IL-6, and IL-10 increased similarly in both Hx and Nx groups. S100, MBP, and NSE were significantly higher in Hx patients with unfavorable outcome. Among these three biomarkers, S100 showed the strongest correlations to GOSE after TBI-Hx. Elevated CSF/serum albumin quotients lasted for 5 days post-TBI and displayed similar profiles in Hx and Nx patients. We demonstrate for the first time that post-TBI hypoxia is associated with prolonged neuroinflammation, amplified extravasation of biomarkers, and poor outcome. S100 and MBP could be implemented to track the occurrence of post-TBI hypoxia, and prompt adequate treatment.

Attenuated neurological deficit, cell death and lesion volume in Fas-mutant mice is associated with altered neuroinflammation following traumatic brain injury.

Progressive neurodegeneration following traumatic brain injury (TBI) involves the Fas and TNF-receptor1 protein systems which have been implicated in mediating delayed cell death. In this study, we used two approaches to assess whether inhibition of these pathways reduced secondary brain damage and neurological deficits after TBI. Firstly, we investigated whether the expression of non-functional Fas in lpr mice subjected to TBI altered tissue damage and neurological outcome. Compared to wild-type, lpr mice showed improved neurological deficit (p=0.0009), decreased lesion volume (p=0.017), number of TUNEL+ cells (p=0.011) and caspase-3+ cells (p=0.007). Changes in cellular inflammation and cytokine production were also compared between mouse strains. Accumulation of macrophages/microglia occurred earlier in lpr mice, likely due to enhanced production of the chemotactic mediators IL-12(p40) and MCP-1 (p<0.05). Cortical production of IL-1α and IL-6 increased after injury to a similar extent regardless of strain (p<0.05), while TNF and G-CSF were significantly higher in lpr animals (p<0.05). Secondly, we assessed whether therapeutic inhibition of FasL and TNF via intravenous injection of neutralizing antibodies in wild-type mice post-TBI could reproduce the beneficial effects observed in lpr animals. No differences were found with this approach in animals treated with anti-FasL and anti-TNF antibodies alone or the combination of both. Altogether, reduced neurological deficits and lesion volume in lpr mice was associated with altered cellular and humoral inflammation, possibly contributing to neuroprotection, whereas neutralization of FasL and TNF had no effect. In future studies, the lpr mouse strain may be utilized as a model to further characterize molecular and cellular mechanisms protecting against secondary brain damage after TBI.

Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks.

Chemokines and their receptors have crucial roles in the trafficking of leukocytes, and are of particular interest in the context of the unique immune responses elicited in the central nervous system (CNS). The chemokine system CC ligand 2 (CCL2) with its receptor CC receptor 2 (CCR2), as well as the receptor CXCR2 and its multiple ligands CXCL1, CXCL2 and CXCL8, have been implicated in a wide range of neuropathologies, including trauma, ischemic injury and multiple sclerosis. This review aims to overview the current understanding of chemokines as mediators of leukocyte migration into the CNS under neuroinflammatory conditions. We will specifically focus on the involvement of two chemokine networks, namely CCL2/CCR2 and CXCL8/CXCR2, in promoting macrophage and neutrophil infiltration, respectively, into the lesioned parenchyma after focal traumatic brain injury. The constitutive brain expression of these chemokines and their receptors, including their recently identified roles in the modulation of neuroprotection, neurogenesis, and neurotransmission, will be discussed. In conclusion, the value of evidence obtained from the use of Ccl2- and Cxcr2-deficient mice will be reported, in the context of potential therapeutics inhibiting chemokine activity which are currently in clinical trial for various inflammatory diseases.