Increased inspired oxygen concentration as a factor in improved brain tissue oxygenation and tissue lactate levels after severe human head injury

OBJECT: Early impairment of cerebral blood flow in patients with severe head injury correlates with poor brain tissue O2 delivery and may be an important cause of ischemic brain damage. The purpose of this study was to measure cerebral tissue PO2, lactate, and glucose in patients after severe head injury to determine the effect of increased tissue O2 achieved by increasing the fraction of inspired oxygen (FiO2). METHODS: In addition to standard monitoring of intracranial pressure and cerebral perfusion pressure, the authors continuously measured brain tissue PO2, PCO2, pH, and temperature in 22 patients with severe head injury. Microdialysis was performed to analyze lactate and glucose levels. In one cohort of 12 patients, the PaO2 was increased to 441+/-88 mm Hg over a period of 6 hours by raising the FiO2 from 35+/-5% to 100% in two stages. The results were analyzed and compared with the findings in a control cohort of 12 patients who received standard respiratory therapy (mean PaO2 136.4+/-22.1 mm Hg). The mean brain PO2 levels increased in the O2-treated patients up to 359+/-39% of the baseline level during the 6-hour FiO2 enhancement period, whereas the mean dialysate lactate levels decreased by 40% (p < 0.05). During this O2 enhancement period, glucose levels in brain tissue demonstrated a heterogeneous course. None of the monitored parameters in the control cohort showed significant variations during the entire observation period. CONCLUSIONS: Markedly elevated lactate levels in brain tissue are common after severe head injury. Increasing PaO2 to higher levels than necessary to saturate hemoglobin, as performed in the O2-treated cohort, appears to improve the O2 supply in brain tissue. During the early period after severe head injury, increased lactate levels in brain tissue were reduced by increasing FiO2. This may imply a shift to aerobic metabolism.

Effect of detraining on bone and muscle tissue in subjects with chronic spinal cord injury after a period of electrically-stimulated cycling: a small cohort study

OBJECTIVE: To investigate adaptive changes in bone and muscle parameters in the paralysed limbs after detraining or reduced functional electrical stimulation (FES) induced cycling following high-volume FES-cycling in chronic spinal cord injury. SUBJECTS: Five subjects with motor-sensory complete spinal cord injury (age 38.6 years, lesion duration 11.4 years) were included. Four subjects stopped FES-cycling completely after the training phase whereas one continued reduced FES-cycling (2-3 times/week, for 30 min). METHODS: Bone and muscle parameters were assessed in the legs using peripheral quantitative computed tomography at 6 and 12 months after cessation of high-volume FES-cycling. RESULTS: Gains achieved in the distal femur by high-volume FES-cycling were partly maintained at one year of detraining: 73.0% in trabecular bone mineral density, 63.8% in total bone mineral density, 59.4% in bone mineral content and 22.1% in muscle cross-sectional area in the thigh. The subject who continued reduced FES-cycling maintained 96.2% and 95.0% of the previous gain in total and trabecular bone mineral density, and 98.5% in muscle cross-sectional area. CONCLUSION: Bone and muscle benefits achieved by one year of high-volume FES-cycling are partly preserved after 12 months of detraining, whereas reduced cycling maintains bone and muscle mass gained. This suggests that high-volume FES-cycling has clinical relevance for at least one year after detraining.

Tissue engineered perivascular endothelial cell implants regulate vascular injury.

Molecular biomaterial engineering permits in vivo transplantation of cells and tissues, offering the promise of restoration of physiologic control rather than pharmacologic dosing with isolated compounds. We engrafted endothelial cells on Gelfoam biopolymeric matrices with retention of viability, normal growth kinetics, immunoreactivity, and biochemical activity. The production of heparan sulfate proteoglycan and inhibition of basic fibroblast growth factor binding and activity by engrafted cells were indistinguishable from endothelial cells grown in culture. Perivascular implantation of Gelfoam-endothelial cell scaffolds around balloon-denuded rat carotid arteries reduced intimal hyperplasia 88.1%, far better than the isolated administration of heparin, the most effective endothelial mimic compound. In concert with a reduction in intimal area, cell proliferation was reduced by > 90%. To our knowledge, there have been no previous reports of extravascular cell implants controlling vasculoproliferative disease. Tissue engineered cells offer the potential for potent methods of vascular growth regulation and insight into the complex autocrine-paracrine control mechanisms within the blood vessel wall.

Reduction of Secondary Degeneration after Spinal Cord Injury by Acute Delivery of Proinflammatory Growth Factors

INTRODUCTION Inflammation is a protective attempt to facilitate the removal of damaged tissue and to initiate the healing response in other tissues. However, after spinal cord injury (SCI), this response is prolonged leading to secondary degeneration and glial scarring. Here, we investigate the potential of sustained delivery of pro-inflammatory factors vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) to increase early inflammatory events and promote inflammatory resolution. Method Animal ethics approval was obtained from the Queensland University of Technology. Adult Wistar-Kyoto rats (12-16 weeks old) were subjected to laminectomies and T10 hemisections. Animals were then randomised to treatment (implantation of osmotic pump (Alzet) loaded with 5ug VEGF & 5 ug PDGF) or control groups (lesion control or lesion plus pump delivering PBS). Rats were sacrificed at one month and the spinal cords were harvested and examined by immunohistology, using anti-neurofilament-200(NF200) and anti- ionized calcium binding adapter molecule 1 (Iba1). One way ANOVA was used for statistic analysis. Results At 1 month, active pump-treated cords showed a high level of axonal filament throughout the defects as compared to the control groups. The mean lesion size, as measured by NF200, was 0.47mm2 for the lesion control, 0.39mm2 for the vehicle control and 0.078mm2 for the active pump group. Significant differences were detected between the active pump group and the two control groups (AP vs LC p= 0.017 AG vs VC p= 0.004). Iba-1 staining also showed significant differences in the post-injury inflammatory response. Discussion We have shown that axons and activated microglia are co-located in the lesion of the treated cord. We hypothesise the delivery of VEGF/PDGF increases the local vessel permeability to inflammatory cells and activates these along with the resident microglia to threshold population, which ultimately resolved the prolonged inflammation. Here, we have shown that maintaining the inflammatory signals for at least 7 days improved the morphology of the injured cord. Conclusion This study has shown that boosting inflammation, by delivery VEGF/PDGF, in the early phase of SCI helps to reduce secondary degeneration and may promote inflammation resolution. This treatment may provide a platform for other neuro-regenrative therapies.

Controversies of prophylactic hypothermia and the emerging use of brain tissue oxygen tension monitoring and decompressive craniectomy in traumatic brain-injured children

Background Despite being the leading cause of death and disability in the paediatric population, traumatic brain injury (TBI) in this group is largely understudied. Clinical practice within the paediatric intensive care unit (PICU) has been based upon adult guidelines however children are significantly different in terms of mechanism, pathophysiology and consequence of injury. Aim To review TBI management in the PICU and gain insight into potential management strategies. Method To conduct this review, a literature search was conducted using MEDLINE, PUBMED and The Cochrane Library using the following key words; traumatic brain injury; paediatric; hypothermia. There were no date restrictions applied to ensure that past studies, whose principles remain current were not excluded. Results Three areas were identified from the literature search and will be discussed against current acknowledged treatment strategies: Prophylactic hypothermia, brain tissue oxygen tension monitoring and decompressive craniectomy. Conclusion Previous literature has failed to fully address paediatric specific management protocols and we therefore have little evidence-based guidance. This review has shown that there is an emerging and ongoing trend towards paediatric specific TBI research in particular the area of moderate prophylactic hypothermia (MPH).

Preventing injuries on a state-wide basis : researchers and parliamentary committees are partners in turning injury prevention and safety research into practice and policy

Context: Parliamentary committees established in Westminster parliaments, such as Queensland, provide a cross-party structure that enables them to recommend policy and legislative changes that may otherwise be difficult for one party to recommend. The overall parliamentary committee process tends to be more cooperative and less adversarial than the main chamber of parliament and, as a result, this process permits parliamentary committees to make recommendations more on the available research evidence and less on political or party considerations. Objectives: This paper considers the contributions that parliamentary committees in Queensland have made in the past in the areas of road safety, drug use as well as organ and tissue donation. The paper also discusses the importance of researchers actively engaging with parliamentary committees to ensure the best evidence based policy outcomes. Key messages: In the past, parliamentary committees have successfully facilitated important safety changes with many committee recommendations based on research results. In order to maximise the benefits of the parliamentary committee process it is essential that researchers inform committees about their work and become key stakeholders in the inquiry process. Researchers can keep committees informed by making submissions to their inquiries, responding to requests for information and appearing as witnesses at public hearings. Researchers should emphasise the key findings and implications of their research as well as considering the jurisdictional implications and political consequences. It is important that researchers understand the differences between lobbying and providing informed recommendations when interacting with committees. Discussion and conclusions: Parliamentary committees in Queensland have successfully assisted in the introduction of evidence based policy and legislation. In order to present best practice recommendations, committees rely on the evidence presented to them including the results of researchers. Actively engaging with parliamentary committees will help researchers to turn their results into practice with a corresponding decrease in injuries and fatalities. Developing an understanding of parliamentary committees, and the typical inquiry process used by these committees, will help researchers to present their research results in a manner that will encourage the adoption of their ideas by parliamentary committees, the presentation of these results as recommendations within the report and the subsequent enactment of the committee’s recommendations by the government.

Prevention of pelvic sepsis in major open pelviperineal injury

Compound pelvic fractures are deemed to be one of the most severe orthopaedic injuries with an extremely high morbidity and mortality. After the initial resuscitation phase the prevention of pelvic sepsis is one of the main treatment goals for patients with an open pelvic fracture. If there is a suspicion of a rectal injury or if the wounds are in the perineal area, The Princess Alexandra Hospital's management plan includes early faecal diversion combined with vigorous soft tissue debridement, VAC(®) therapy and (if indicated) external fixation of the pelvic fracture. We present our flowchart for the treatment of trauma patients with compound pelvic fractures illustrated by a case report describing a 32 year old patient who sustained an open pelvic ring injury in a workplace accident. The aim of this paper is to underline the importance of a safe, straightforward approach to compound pelvic fractures.

Combined VEGF and PDGF treatment reduces secondary degeneration after spinal cord injury

Trauma to the spinal cord creates an initial physical injury damaging neurons, glia, and blood vessels, which then induces a prolonged inflammatory response, leading to secondary degeneration of spinal cord tissue, and further loss of neurons and glia surrounding the initial site of injury. Angiogenesis is a critical step in tissue repair, but in the injured spinal cord angiogenesis fails; blood vessels formed initially later regress. Stabilizing the angiogenic response is therefore a potential target to improve recovery after spinal cord injury (SCI). Vascular endothelial growth factor (VEGF) can initiate angiogenesis, but cannot sustain blood vessel maturation. Platelet-derived growth factor (PDGF) can promote blood vessel stability and maturation. We therefore investigated a combined application of VEGF and PDGF as treatment for traumatic spinal cord injury, with the aim to reduce secondary degeneration by promotion of angiogenesis. Immediately after hemisection of the spinal cord in the rat we delivered VEGF and PDGF and to the injury site. One and 3 months later the size of the lesion was significantly smaller in the treated group compared to controls, and there was significantly reduced gliosis surrounding the lesion. There was no significant effect of the treatment on blood vessel density, although there was a significant reduction in the numbers of macrophages/microglia surrounding the lesion, and a shift in the distribution of morphological and immunological phenotypes of these inflammatory cells. VEGF and PDGF delivered singly exacerbated secondary degeneration, increasing the size of the lesion cavity. These results demonstrate a novel therapeutic intervention for SCI, and reveal an unanticipated synergy for these growth factors whereby they modulated inflammatory processes and created a microenvironment conducive to axon preservation/sprouting.

The effects of dietary fish oil on inflammation, fibrosis and oxidative stress associated with obstructive renal injury in rats.

Scope: We examined whether dietary supplementation with fish oil modulates inflammation, fibrosis and oxidative stress following obstructive renal injury. Methods and results: Three groups of Sprague-Dawley rats (n = 16 per group) were fed for 4 wk on normal rat chow (oleic acid), chow containing fish oil (33 g eicosapentaenoic acid and 26 g docosahexaenoic acid per kg diet), or chow containing safflower oil (60 g linoleic acid per kg diet). All diets contained 7% fat. After 4 wk, the rats were further subdivided into four smaller groups (n = 4 per group). Unilateral ureteral obstruction was induced in three groups (for 4, 7 and 14 days). The fourth group for each diet did not undergo surgery, and was sacrificed as controls at 14 days. When rats were sacrificed, plasma and portions of the kidneys were removed and frozen; other portions of kidney tissue were fixed and prepared for histology. Compared with normal chow and safflower oil, fish oil attenuated collagen deposition, macrophage infiltration, TGF-beta expression, apoptosis, and tissue levels of arachidonic acid, MIP-1 alpha, IL-1 beta, MCP-1 and leukotriene B(4). Compared with normal chow, fish oil increased the expression of HO-1 protein in kidney tissue. Conclusions: Fish oil intake reduced inflammation, fibrosis and oxidative stress following obstructive renal injury.

The role of neuromuscular inhibition in hamstring strain injury recurrence

Hamstring strain injuries are amongst the most common and problematic injuries in a wide range of sports that involve high speed running. The comparatively high rate of hamstring injury recurrence is arguably the most concerning aspect of these injuries. A number of modifiable and nonmodifiable risk factors are proposed to predispose athletes to hamstring strains. Potentially, the persistence of risk factors and the development of maladaptations following injury may explain injury recurrence. Here, the role of neuromuscular inhibition following injury is discussed as a potential mechanism for several maladaptations associated with hamstring re-injury. These maladaptations include eccentric hamstring weakness, selective hamstring atrophy and shifts in the knee flexor torque-joint angle relationship. Current evidence indicates that athletes return to competition after hamstring injury having developed maladaptations that predispose them to further injury. When rehabilitating athletes to return to competition following hamstring strain injury, the role of neuromuscular inhibition in re-injury should be considered.

Lysosomal secretion of Flightless I upon injury has the potential to alter inflammation

Intracellular Flightless I (Flii), a gelsolin family member, has been found to have roles modulating actin regulation, transcriptional regulation and inflammation. In vivo Flii can regulate wound healing responses. We have recently shown that a pool of Flii is secreted by fibroblasts and macrophages, cells typically found in wounds, and its secretion can be upregulated upon wounding. We show that secreted Flii can bind to the bacterial cell wall component lipopolysaccharide and has the potential to regulate inflammation. We now show that secreted Flii is present in both acute and chronic wound fluid.

Exercise and Cellular Mechanisms of Muscle Injury

The general aim of this book is to provide a comprehensive summary of the characteristics of exercise-induced muscle damage and the mechanisms of tissue inflammation. The authors present a large amount of our own original data and have summarised the research of others.

Urinary biomolecular indicators of exercise-induced over exertion injury

Poor health and injury represent major obstacles to the future economic security of Australia. The national economic cost of work-related injury is estimated at $57.5 billion p/a. Since exposure to high physical demands is a major risk factor for musculoskeletal injury, monitoring and managing such physical activity levels in workers is a potentially important injury prevention strategy. Current injury monitoring practices are inadequate for the provision of clinically valuable information about the tissue specific responses to physical exertion. Injury of various soft tissue structures can manifest over time through accumulation of micro-trauma. Such micro-trauma has a propensity to increase the risk of acute injuries to soft-tissue structures such as muscle or tendon. As such, the capacity to monitor biomarkers that result from the disruption of these tissues offers a means of assisting the pre-emptive management of subclinical injury prior to acute failure or for evaluation of recovery processes. Here we have adopted an in-vivo exercise induced muscle damage model allowing the application of laboratory controlled conditions to assist in uncovering biochemical indicators associated with soft-tissue trauma and recovery. Importantly, urine was utilised as the diagnostic medium since it is non-invasive to collect, more acceptable to workers and less costly to employers. Moreover, it is our hypothesis that exercise induced tissue degradation products enter the circulation and are subsequently filtered by the kidney and pass through to the urine. To test this hypothesis a range of metabolomic and proteomic discovery-phase techniques were used, along with targeted approaches. Several small molecules relating to tissue damage were identified along with a series of skeletal muscle-specific protein fragments resulting from exercise induced soft-tissue damage. Each of the potential biomolecular markers appeared to be temporally present within urine. Moreover, the regulation of abundance seemed to be associated with functional recovery following the injury. This discovery may have important clinical applications for monitoring of a variety of inflammatory myopathies as well as novel applications in monitoring of the musculoskeletal health status of workers, professional athletes and/or military personnel to reduce the onset of potentially debilitating musculoskeletal injuries within these professions.

A poly(lactic-co-glycolic acid) knitted scaffold for tendon tissue engineering: an in vitro and in vivo study

We have designed a composite scaffold for potential use in tendon or ligament tissue engineering. The composite scaffold was made of a cellularized alginate gel that encapsulated a knitted structure. Our hypothesis was that the alginate would act as a cell carrier and deliver cells to the injury site while the knitted structure would provide mechanical strength to the composite construct. The mechanical behaviour and the degradation profile of the poly(lactic-co-glycolic acid) knitted scaffolds were evaluated. We found that our scaffolds had an elastic modulus of 750 MPa and that they lost their physical integrity within 7 weeks of in vitro incubation. Autologous rabbit mesenchymal stem cell seeded composite scaffolds were implanted in a 1-cm-long defect created in the rabbit tendon, and the biomechanical properties and the morphology of the regenerated tissues were evaluated after 13 weeks. The regenerated tendons presented higher normalized elastic modulus of (60%) when compared with naturally healed tendons (40%). The histological study showed a higher cell density and vascularization in the regenerated tendons.