Brain Oral Session: Traumatic Brain Injury

923. Evidence for brain trauma following five two minute rounds in boxing

M. Graham¹, C. Graham¹, P. Ryan¹, P. Evans², D. Renn², B. Davies³, N.-E. Thomas⁴, S.-M. Cooper⁴ and J. Baker⁵

¹The Newman Centre for Sport and Exercise Research, Newman University, Birmingham; ²Department of Endocrinology, Royal Gwent Hospital, Newport; ³Health and Exercise Science Research Unit, University of Glamorgan; ⁴Cardiff School of Sport, University of Wales Institute Cardiff, Cardiff; ⁵Division of Sport, University of the West of Scotland, Glasgow, UK

Objectives: Severe cerebral acute injuries, resulting in morbidity or fatality, are rare in boxing compared with other sports. ¹ The British Medical Association has campaigned for a complete ban on boxing because of alleged chronic traumatic brain injury. ² A recent epidemiological study has concluded that such evidence is weak. ³ The aim of this unique study was to analyse whether punches to the head (PTH), sustained during a boxing event, resulted in cerebral damage as quantified by elevated levels of neurochemical markers of brain tissue damage compared with punches to the body (PTB). Systemic stress was quantified by measuring serum cortisol.

Methods: Sixteen amateur boxers were divided into two groups: PTH, (n = 8, mean±s.d., age: 17.6±5.3 years; height: 168.4±13; weight: 65.4±20.3; punches to the head: 35.5±18.4), PTB (n = 8, mean±s.d., age: 19.1±3.2 years; height: 169.6±7.5; weight: 68.5±15). The PTH group received punches to the head and body, while group PTB received only punches to the body. Blood samples were taken pre- and immediately post combat for analysis of S-100B, neurone specific enolase (NSE) and cortisol.

Results: Significant increases (P<0.05) in serum concentrations of S-100B (0.35±0.61 versus 0.54±0.73 μg/L) and NSE (19.7±14 versus 31.1±26.6 ng /mL) and cortisol (372.9±201.5 versus 755.8±93ng /mL) were encountered pre- and immediately post combat in the PTH group but not in the PTB group.

Conclusions: PTH in boxing are sufficient enough to cause biochemically discernible damage of brain tissue. The risk of having an intra-cerebral haemorrhage from a mild brain injury (MBI) is 38%, with 7% requiring neurosurgical intervention. ⁴ The consequences of a MBI may be a transitory post-concussive syndrome. ⁵ Traumatic stress states are a well known pathology and consist of a psychological reaction against the trauma.

Disclosures: The authors have nothing to declare. All research complied with the Declaration of Helsinki. Ethical approval was provided by the University Ethics Committee.

926. Continuous monitoring of cerebrovascular reactivity after traumatic brain injury in children

K. Brady¹, D. Shaffner¹, J. Lee¹, R.B. Easley¹, P. Smielewski², M. Czosnyka², G. Jallo³ and A.-M. Guerguerian⁴

¹Pediatric Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; ²Academic Neurosurgery, Addenbrooke's Hospital, Cambirdge University, Cambridge, UK; ³Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; ⁴Critical Care and Pediatrics, Hospital for Sick Children, Toronto, ON, Canada

Objective: Traumatic brain injury (TBI) is the foremost cause of death and disability in infants and children. In adults with TBI, monitoring of autoregulation has been utilized to define optimal cerebral perfusion pressure, ¹ but the methods have not been applied to children. Our objective was to test the hypothesis that the pressure-reactivity index, or PRx values, indicating preserved autoregulation would be associated with survival in children with TBI.

Methods: Twenty-one patients under 18 years of age admitted between May 2006 and September 2008 with severe traumatic brain injury requiring invasive intracranial pressure monitoring were enrolled in this prospective observational cohort study. The PRx was continuously monitored as a moving, linear correlation coefficient between low frequency waves of intracranial and arterial blood pressures. Positive values of PRx approaching ¹ indicate impaired cerebrovascular reactivity, whereas negative PRx values or those close to zero indicate preserved cerebrovascular reactivity. ² The average PRx over the entire monitoring period was compared between survivors and non-survivors. Values of PRx were sorted according to the cerebral perfusion pressure at which they were obtained to construct autoregulation curves for each patient.

Results: Positive values of PRx were associated with death in this cohort. Survivors (N = 15) had a mean PRx (±s.d.) of 0.08±0.19, and non-survivors (N = 6) had a mean PRx of 0.69±0.21 (P = 0.0009). In this sample, PRx monitoring suggested impaired cerebrovascular reactivity at low levels of cerebral perfusion pressure and intact cerebrovascular reactivity at higher levels of perfusion pressure (see Figure 1).

Conclusions: Intact cerebrovascular reactivity quantified by the PRx is associated with survival after severe head trauma in children. The PRx is cerebral perfusion pressure dependent in children. In this cohort, the range of cerebral perfusion pressure in which cerebrovascular reactivity was found to be preserved was higher than the current pediatric guidelines set by the Brain Trauma Foundation.

Figure 1

Vascular reactivity is cerebral perfusion pressure dependent. Pediatric autoregulation curves were estimated for each of 21 patients by sorting discrete values of PRx according to cerebral perfusion pressure (CPP). In Panel A, the histogram was created by combining individual curves to create a mean of means (mean PRx±s.e.). Vertical lines at 40 mm Hg and 65 mm Hg indicate the current Brain Trauma Foundation CPP guidelines. High PRx scores, seen below the guideline range, indicate vasomotor paralysis. Mean PRx values within the guideline range show a trend toward improvement with increasing CPP. The trend of PRx worsening with lower CPP is significant (P<0.0001). Panel B shows the percentage of time spent by survivors and non-survivors at each CPP. Non-survivors experienced more time at low cerebral perfusion pressure than did survivors.

629. Temporal expression of AQP4 and neuroimaging in a juvenile rat model of traumatic brain injury

A. Obenaus^1,2,3, A. Adami³, B. Ternon⁴, B. Tone³, D. Spagnoli¹, R. Recker³, S. Ashwal³ and J. Badaut^3,4,5

¹Department of Radiation Medicine; ²Radiology; ³Pediatrics, Loma Linda University School of Medicine, Loma Linda, California, USA; ⁴Neurosurgery, Lausanne University Hospital, Lausanne; ⁵Clinical and Fundamental Neurosciences, University of Geneva, Geneva, Switzerland

Aim: Traumatic brain injury (TBI) in infancy and childhood is a cause of death and a permanent disability. Young animals have more brain water than adult animals and typically the juvenile brain swells more than the adult brain after TBI. However, therapeutic treatments for juvenile TBI (jTBI) are typically based on adult physiology. Aquaporin 4 (AQP4), a water channel, is a possible therapeutic candidate, but, its involvement in juvenile brain swelling has not been studied. The aim of this study was to determine the level of AQP4 expression and compare it to edema formation serially measured using MRI after jTBI.

Methods: A jTBI rat model (P17d) utilized controlled cortical impact (CCI) using a 1 mm blunt tip piston to induce the trauma directly on the cortex. MRI was performed at 1, 3, 7 and 28 days after jTBI (see Ref. 1). AQP4 immunolabeling was evaluated on tissue slices corresponding to the MRI acquisitions. AQP4 staining was quantified using an infrared-scanner (LiCor) and was examined using epifluorescence microscopy. Values were quantified in 4 regions of interest (ROIs): ipsilateral cortex (under the impact), ipsilateral striatum and contralateral cortex and striatum.

Results: Significant decreases in ADC and increased T2 values were observed at 24 h after CCI in all ROIs corresponding to the degree of edema formation. At 72 h ADC values normalized while T2-values remained significantly elevated suggesting edema resolution. In the lesion area, the number of neurons was decreased and GFAP staining was increased at 3d, corresponding to development of gliosis. Significantly increased AQP4 in the lesion was coincident with the normalization MRI changes at 3 and 7d. However, increased AQP4 expression was also observed in the astrocytic end-feet in contact with blood vessels distant to the site of CCI. At 28 days AQP4 expression normalized throughout the brain except at the lesion site where AQP4-ir and ADC-values were still elevated.

Conclusion: AQP4 induction was increased during the period of active edema resolution in the lesion and peri-lesional region as we have previously observed in a stroke model. ¹ In adult TBI, decreased AQP4 expression has been observed in the first days after trauma. ² Our findings strongly suggest that traumatic pathological mechanisms are different between young and adult animals. Our findings should be considered in the future development of new drugs acting on AQPs that potentially could be used to treat edema formation in children with TBI.

Financial support: Supported by the Swiss Science Foundation (FN 3100AO-108001 and 31003A-122166), Swissheart Foundation, Novartis foundation, Department of Pediatrics Research Fund, NASA Cooperative Agreement NCC9–149.

216. Treatment of acute subdural hematoma with erythropoietin: potential of subdural versus systemic application

O. Kempski¹, M. Rahimi¹, M. Wähmann¹, H. Bächli², E. Güresir³, A. Raabe⁴ and B. Alessandri¹

¹Institute for Neurosurgical Pathophysiology, University Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany; ²Department of Neurosurgery, University Clinics of Basel, Basel, Switzerland; ³Department of Neurosurgery, Johann Wolfgang Goethe—University, Frankfurt a.M., Germany; ⁴Department of Neurosurgery, University Clinics, Inselspital Bern, Bern, Switzerland

Objective: Erythropoietin is a endogenous cytokine which production is induced under hypoxic conditions to increase erythrocyte concentration. Recently, receptors for EPO have also been discovered in the central nervous system and a neuroprotective function of EPO was found following traumatic brain injury. Trauma to the brain is often associated with acute subdural hemorrhage (ASDH) that worsens outcome of patients substantially. Despite early evacuation of the blood clot many patients still die or remain severely disabled. The goals of the present study were to evaluate the neuroprotective potential of EPO in the treatment of ASDH and to compare systemic versus subdural application.

Method: Sprague-Dawley rats were anesthetized with chloral hydrate and a catheter was placed in the tail artery and jugular vein. A craniotomy was prepared for the insertion of a L-shaped, blunted needle into the subdural space and closed with acrylic glue and dental cement. ASDH was produced by infusion of 400 μL unheparanized autologous venous blood (50 μL/min) into the subdural space. Ipsilateral CBF and contralateral ICP were monitored for at least 60 mins and lesion volume was assessed 48 h after ASDH. Three separate experimental series were conducted:

• (1)

  Measurement of EPO concentration in the ipsilateral hemisphere 45 mins after intravenous EPO injection (n = 3/group).

• (2)

  Neuroprotection by intravenous EPO treatment: NaCl or EPO (200, 2000, 20,000 IU per animal, n = 8 to 10/group) were injected i.v. at 30 mins after ASDH 3) Neuroprotection by subdural EPO application: 60 mins after ASDH the craniotomy was opened and the subdural blood evacuated.

After closing of the craniotomy 150 μL NaCl or EPO (0.02/0.2/2/200 IU) were applied through a small burr hole directly onto the cortical surface (n = 9/group).

Results: After injection of NaCl, EPO 200, 2000 and 20,000 IU tissue concentrations of EPO reached 1.7±0.2, 11.7±0.2. 88.4±4 and 672±63 mIU/mL homogenate, respectively. In all series ICP and CBF values did not differ between groups during the entire monitoring period. Lesion volume after i.v. injection of NaCl or EPO (series 2) was 38.2±1.9 (NaCl), 28.8±2.8 (200 IU), 24.2±1.3 (2000 IU) and 46.5±±4.7 mm³ (20,000 IU). EPO 200 and 2000 IU reduced lesion volume significantly whereas 20,000 IU was neurotoxic. (P<0.05, one-way ANOVA with Student-Newman-Keuls post-hoc test). If EPO was applied subdurally (series 3) after evacuation of the blood clot a concentration of 0.02 IU (11.2±6.2 mm³) was sufficient to reduce lesion volume significantly when compared to NaCl (49.7±43.3 mm³) whereas 200 IU (173.2±114 mm³) increased lesion volume significantly. No significance was found for comparison of NaCl- with 0.2 IU (43.9±23 mm³) and 2 IU (67.9±31.1 mm³, one-way ANOVA on ranks).

Conclusion: Brain damage due to acute subdural hematoma can be reduced by EPO with and without evacuation of the subdural blood volume. The needed EPO concentration for neuroprotection is 10,000 times lower with subdural application. High concentrations of EPO were neurotoxic independent of the route of application. Thus, subdural dosing of EPO after surgery might be a cost effective treatment but EPO has to be managed carefully in patients in order to avoid adverse effects on lesion development.

185. SNP improves cerebral hemodynamics during normotension but fails to prevent sex dependent impaired cerebral autoregulation during hypotension after brain injury

W.M. Armstead¹, J.W. Kiessling¹, W.A. Kofke¹ and M.S. Vavilala²

¹Anesthesiology and Critical Care, Univ of Pennsylvania, Philadelphia, Pennsylvania; ²Anesthesia, University of Washington, Seattle, Washington, USA

Objectives: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in children and boys are disproportionately represented. Hypotension is common and worsens outcome after TBI because it can cause ischemia when cerebral autoregulation is impaired. Since CBF may contribute to neuronal cell integrity, optimal management of CPP for limiting tissue hypoxia at low CPP or edema at high CPP is a critical determinant of outcome after TBI. If decreased CBF after TBI worsens outcome, it was hypothesized that administration of a cerebrovasodilator, such as sodium nitroprusside (SNP), may improve CBF and cerebral autoregulation in a sex dependent manner.

Methods: CBF via microspheres, pial artery diameter, blood velocity via transcranial Doppler and intracranial pressure (ICP) were measured before and after fluid percussion brain injury (FPI, 2atm) in untreated and SNP (0.1 mg/kg i.v.) pre- and post-injury treated (30 mins) male and female newborn pigs during normotension and hypotension (blood withdrawal to decrease MAP by 45%). Autoregulatory index (ARI) = % change CVR/% change CPP where CVR = Vcerebral blood vessel/MAP-ICP.

Results: SNP (0.1 mg/kg i.v.) alone produced equivalent percent cerebrovasodilation in male and female piglets. Reductions in pial artery diameter, cortical and hippocampal CBF, and CPP concomitant with elevated ICP after FPI were greater in male compared to female piglets during normotension; this was blunted by SNP treatment pre- or post-FPI (−22%±2% and −11%±1% reduction in artery diameter in absence versus −3%±1% and −6%±1% in presence of SNP, for male and female piglets). During hypotension, pial artery dilation was impaired more in the male (17%±1% versus 2%±1%) than the female (33%±1% versus 17%±1%) after FPI. However, SNP did not improve hypotensive pial artery dilation after FPI in the female (17%±1% versus 14%±2%) and paradoxically caused vasoconstriction after FPI in the male (2%±1% versus −9%±2%). Autoregulatory pial artery dilation during hypotension was unchanged by SNP in the absence of FPI (20%±2% versus 21%±2% for the male). Papaverine induced pial artery vasodilation was unchanged by FPI and SNP, indicating that impairment of cerebral autoregulation by SNP is not an epiphenomenon. Cortical and hippocampal CBF, CPP, velocity, and ARI were unchanged during hypotension in sham pigs but decreased markedly during combined hypotension and FPI in male but less so in female pigs. However, SNP did not prevent reductions in CBF, CPP, middle cerebral artery flow velocity, or ARI during combined hypotension and FPI in either sex.

Conclusions: These data indicate that despite improved cerebral hemodynamics after FPI during normotension, normalization of CPP via decreased ICP with cerebrovasodilator administration does not restore CBF or autoregulation during hypotension after FPI. Indeed, CPP based therapy aggravates sex dependent loss of autoregulation after FPI. These data suggest that therapies directed at a purely hemodynamic increase in CPP will fail to improve outcome during combined injury of TBI and hypotension.

473. Full contact karate increases serum levels of S-100B, and NSE, biochemical markers of brain tissue damage

M. Graham¹, P. Ryan¹, P. Evans², B. Davies³ and J. Baker⁴

¹The Newman Centre for Sport and Exercise Research, Newman University, Birmingham; ²Department of Endocrinology, Royal Gwent Hospital, Newport; ³Health and Exercise Science Research Unit, University of Glamorgan, Cardiff; ⁴Division of Sport, University of the West of Scotland, Glasgow, UK

Objectives: Mild brain injuries (MBI) are usually defined by an initial unconsciousness limited to 30 mins, a Glasgow coma score between 13 and 15, the absence of intra-cranial lesion on computerised tomography (CT) and a post-traumatic amnesia period between 1 and 24 h. ¹ Neurobiochemical markers of brain damage have increased in interest in both experimental and clinical neurotraumatology. ² The aim of the study was to analyse whether technical knockouts (TKOs) or kicks to the head (KTH) in full contact karate elicited significantly greater increased serum concentrations of biochemical markers of brain tissue damage, than kicks to the body (KTB).

Methods: Twenty four full contact karate practitioners were divided into three groups: TKO, (n = 6, mean±s.d., age 33.5±3.8 years), KTH (n = 6, mean±s.d., age 27.3±7.8 years), and KTB (n = 12, mean±s.d., age 28.2±6.5 years). The TKO and KTH groups both received direct kicks to the head, while group KTB received only blows to the body. Blood samples were taken before and immediately after combat for analysis of S-100B and neurone specific enolase (NSE).

Results: Significant increases in serum concentrations of S-100B (P<0.05) were encountered before and after combat in the TKO group (0.16±0.25 versus 0.42±0.39) and after combat in groups TKO and KTH compared with KTB (0.42±0.39 versus 0.32±0.14 versus 0.12±0.16, μg /L) and significant increases in NSE before and after combat in the TKO group (11.9±5.9 versus 20.2±11.4 ng /mL).

Conclusions: Head kicks in full contact karate are sufficient enough to cause biochemically discernible damage of brain tissue. The severity of traumatic brain injury is associated with the early post-traumatic release of protein S-100B and NSE ³ and their early kinetics after traumatic brain injury reflect a different type of intracranial pathology as demonstrated in cranial CT and have become an extremely sensitive prognostic marker. ⁴