Athletes participating in professional soccer are at an increased risk for long-term neurologic disease due to exposure of repetitive head trauma (MacKay et al., 2019). Recent studies have confirmed cases of dementia and chronic traumatic encephalopathy in retired professional soccer players who played during 1966 (McKee et al., 2014; Hales et al., 2014; Bieniek et al., 2015; Ling et al., 2017; Grinberg et al., 2016). It is suspected that repetitive sub concussive impacts from heading may be a contributing factor to the development of chronic neurological deficits (Matser et al., 1998; Witol & Webbe, 2003). It is unknown if current soccer players are at similar risk of brain trauma. Differences of soccer balls, rules changes, and evolution of the game, may have influenced total frequency and impact magnitude of heading. A comparison of frequency and impact magnitude of heading between 1966 and 2018, highlights the potential risk of chronic neurodegeneration in professional soccer players. Ten 1966 and ten 2018 FIFA World Cup matches were randomly chosen for video analysis. Total frequency of headers were documented for each game. Header exemplar reconstructions were completed in the laboratory using a 1966 Slazenger Challenge and 2018 Telstar 18 ball. A pneumatic linear impactor and projectile launcher were used to hit the ball and impact a Hybrid III head form to measure dynamic head response. A finite element model was then used to determine heading magnitudes as measured by Maximal Principal Strain (MPS). The study revealed there were no significant differences in overall frequency of headers between the 1966 and 2018 games. The year 2018 had significantly higher frequency of headers in the medium MPS category while, 1966 had significantly higher frequency in the high category. There were no significant differences of linear acceleration, angular acceleration, and MPS values when comparing the 2018 dry and 1966 dry ball at the same velocity and location. Current athletes who are heading the 2018 Telstar 18 are sustaining similar frequency and magnitudes of heading as athletes in 1966 under the same velocity and impact locations.

Over the last 20 years, advances in our understanding of the pathophysiology of severe traumatic brain injury (TBI) and in particular the contribution of secondary injury to poor outcome, has served to improve clinical management and reduce the mortality in these patients. However despite many promising preclinical studies there has been a failure to introduce a specific therapeutic intervention to further improve outcome. Inflammation, with cytokine release and leucocyte infiltration, is a significant secondary injury processes. However the inflammatory response to brain injury, its control and modulation remain incompletely described. Chemotactic cytokines, known as chemokines, are mediators of leucocyte recruitment and activation. Expression of chemokines and the resultant recruitment of leucocytes into the brain are generally thought to be integral to the enlargement of cerebral contusions which accompany clinical deterioration following severe TBI. Previous studies indicated that the main neutrophil chemokine, macrophage inflammatory protein-2 (MIP-2/CXCL2) and the monocytic chemokine, monocyte chemoattractant protein-1 (MCP-1/CCL2) are derived from glial. However the origin of these chemokines following TBI, has not been established. Furthermore, little is known about the modulation of these chemokines: The relationship of serum levels of pro-inflammatory mediators such as the human neutrophil chemokine, interleukin-8 (IL-8/CXCL8; a functional homologue of MIP-2/CXCL2), MCP-1/CCL2 and soluble interleukin-6 receptor (sIL-6R) to contusion enlargement has not been investigated. In this thesis, I investigated chemokine expression and modulation both in in-vitro, in-vivo models and in a clinical study. Initially, I compared chemokine expression in rodent and human glial cell cultures and investigated the modulation of chemokine expression by interleukin-6, the glucocorticoid dexamethasone and the immunosuppressant agent FK506. To investigate chemokine expression in-vivo I established the rat lateral fluid percussion injury (LFPI) model of TBI and measured MIP-2/CXCL2 and MCP-1/CCL2 expression in the brain following injury. Inhibition of this expression by dexamethasone and FK506 was then investigated. To identify the cellular source of chemokine expression I developed an immunohistochemical protocol for MIP-2/CXCL2 and MCP-1/CCL2. Finally, in a clinical study of serum chemokine and sIL-6R concentrations after severe TBI, I examined the relationship between these inflammatory mediators and clinical deterioration. Rat glia (microglia and astrocytes) produce chemokines with a response profile that was qualitatively similar to that of human derived cells. These chemokines were increased in the ipsilateral hemisphere following TBI. Surprisingly, immunohistochemical studies identified marked chemokine expression localised to cells with the morphology of degenerating neurones in contused tissue, rather than in glia. Furthermore, while dexamethasone significantly inhibited both MIP-2/CXCL2 and MCP-1/CCL2 expression in a rat astrocyte derived cell line, only MCP-1/CCL2 expression was reduced by steroid treatment in-vivo. Clinically, serum IL-8/CXCL8, MCP-1/CCL2 or sIL-6R were not significantly different in patients that deteriorated due to contusion enlargement from those that remained stable. However these inflammatory mediators were significantly increased in those patients that died. These studies indicate that astrocytes may not be the major source of chemokines following TBI and highlight the need for caution when inferring pathophysiological mechanisms from in-vitro studies.

In youth hockey the act of bodychecking is used to separate the opponent from possession of the puck by contacting the body. In one form or another bodychecking has been an integral part of hockey, especially competitive hockey. Bodychecking is associated with a high risk for concussion symptoms with a number of studies reporting a significant decrease in concussion symptom presentation when bodychecking is removed from the game (Black et al., 2016). To decrease the incidence of concussion symptom presentation and maintain body checking in the game, some leagues have introduced modified body contact rules. This study compared the brain trauma profiles, characterized by frequency and magnitude, of players playing with modified body contact rules to a standard bodychecking hockey league. U15 AAA adhered to standard bodychecking, while M15 minor only allowed shoulder-to-shoulder contact while keeping sticks on the ice and travelling in the same direction along the boards. 16 U15 AAA and 16 M15 minor hockey games were analyzed documenting head impacts, and head impact conditions that were reconstructed to examine the differences by comparing frequency and magnitudes of head impact events. There were 76 and 101 impacts in AAA and M15 minor, respectively. Most common events in AAA were head-to-glass, shoulder, and other; and in M15 minor were head-to-shoulder, head, and other. Magnitudes were grouped into very low, low, medium, high, and very high. The only magnitude levels that were significantly different when comparing total head impacts were more very low magnitude head impacts in M15 minor. Most common frequencies of magnitude levels for events in AAA were low glass, and in M15 minor were very low head, and low shoulder events. Changing the body contact rules increased the frequency of very low magnitude events and did not change the frequency of individual events between the medium and very high magnitude events. The low magnitude displayed a shift from head-to-glass to shoulder-to-head events when body contact rules were modified. These findings suggest that modifying body contact rules can result in differences in the frequencies and magnitudes of head impacts in U15 ice hockey. Changing body contact rules resulted in changes of most common events, though the frequency of magnitudes of brain trauma did not decrease with modified contact. It is important to understand the risks associated with the frequencies of events and magnitudes in both divisions.

American-style football participation is associated with high risks to a spectrum of sports-related brain injury involving acute reactions and chronic manifestations. Traditional methods of identifying injury have proven ineffective at protecting athletes and mitigating risk as they rely on the presence and recognition of inconsistent symptom expression. This is, in part, due to the lack of an objective measure of quantifying exposure. Brain trauma profiling was defined to capture a spectrum of exposure by incorporating the primary characteristics that associate with risk of neurological injury. This profile includes strain magnitude associated with impact, frequency at which impacts are experienced, time interval between impacts, over the duration of exposure. Trauma profiling methods differentiated player field position in professional American-style football where three unique trauma profiles were identified based on similarities among the characteristics of trauma. Regional strain from common head impacts showed that distribution was independent of field position regardless of variation in impact conditions. Rather, brain regions vulnerable to strains were dictated by the frequency and magnitude that govern the position profile. The extent of tissue volume involved in common head impacts was field position dependent. Skill positions tended to experience impacts involving greater tissue volumes reaching deeper white matter structures, but were infrequent. Impacts common to line positions typically involved less brain tissue of predominately superficial cortical gray matter, but were experienced at high frequency counts. The primary findings from this research show that brain trauma profiling may be used as an objective measurement tool to define exposure. The results indicate that exposure is not uniform and that brain trauma and injury risk can be described using unique combinations of these characteristics. Regional areas vulnerable to strain are dictated by the frequency and magnitude of impact and therefore in order to effectively protect against brain injury, both characteristics need to be managed. Lastly, this research demonstrates that either few impacts involving high brain volume or frequent impacts with little brain volume involvement may both result in brain dysfunction. Brain trauma profiling methods has broad application in future research. This measurement tool will be useful in identifying how injury occurs in various sports, military units, and particularly important for vulnerable populations and the developing brain. This knowledge is instrumental in establishing risk prevention strategies and public health policies for specific environments.

Relying on signs and symptoms of head injury outcomes has shown to be unreliable in capturing the vulnerabilities associated with brain trauma (Karton & Hoshizaki, 2018). To accommodate the subjectivity of self-reported symptoms, data collection using sensor monitoring and video analysis combined with event reconstruction are used to objectively measure trauma exposure (Tator, 2013; Scorza & Cole, 2019; Hoshizaki et al., 2014). Athletes are instrumented with wireless sensors designed to measure head kinematics during play. However, these systems have not been widely adopted as they are expensive, face challenges with angular acceleration measures, and often require video confirmation to remove false positives. Video analysis of head impacts, in conjunction with physical event reconstruction and finite element (FE) modeling, is also used to calculate tissue level strain. This data collection method requires specialized equipment and expertise. Effective management of head trauma in sport requires an objective, accessible, and quantifiable tool that addresses the limitations associated with current measurement systems. The purpose of this research was to determine if a simplified version of video analysis and event reconstruction using impact characteristics (velocity, location, mass, and compliance) obtained from body tracking could yield similar measures of brain strain magnitude to the standard head tracking method. Ice hockey impacts (x36) that varied in terms of competition level, event type and maximum principal strain (MPS) were chosen for analysis. 2D videos of previously completed head reconstructions were reanalyzed and each event was reconstructed again in the laboratory using impact parameters obtained from body tracking. MPS values were calculated using finite element (FE) modeling and compared to the MPS values from events that were reconstructed using impact parameters obtained from head tracking. The relationship between head and body tracking MPS data and level of agreement between MPS categories were also assessed. Overall, a significant difference was observed between MPS magnitudes obtained using impact parameters from body and head tracking data from 2D video. When analyzed by event type, only shoulder and glass events demonstrated significant differences in MPS magnitudes. A strong linear relationship was depicted between the two data collection methods and moderate level of agreement between MPS categories was observed, demonstrating that impact characteristics obtained from body tracking and 2D video can be used to measure brain tissue strain.

Memory impairment is common following traumatic brain injury (TBI). In recent years, researchers have demonstrated that the processes underlying memory formation (working memory, encoding, consolidation, and retrieval) are interrelated but dissociable events.The following study was designed to determine how these processes contribute to memory impairment following experimental TBI in the rat. Experiment 1 indicated thatTBI induces severe working memory deficits in a delayed non-matching-to-place task.Although all animals displayed intact acquisition, only injured animals displayed poor performance as the delay between the sample and choice phases was increased.Experiment 2 was designed to determine if TBI produces a transient period of posttraumatic amnesia (PTA) following TBI. During the early post-injury period, injured animals displayed intact short-term (3min) object recognition memory but impaired long-term (1 and 24hrs) memory. However, during the chronic post-injury period (days 14-17), no recognition memory deficits were observed in injured animals, indicating thatPTA resolves by 14 days post-injury. Experiment 3 was designed to determine the mechanism of anterograde memory impairment following TBI. Animals were injured and then trained to a pre-determined criterion in a 1 -day water maze procedure.Although injured animals required more trials to reach criterion, the rate of forgetting was identical among sham and injured groups up to 24hrs post-training. This suggests that the amount of information encoded into long-term memory, not more rapid forgetting, is the primary mechanism of anterograde memory impairment following TBI. InExperiment 4, animals were trained in the water maze and then injured 1 (recent memory) or 14 (recent memory) days post-training. Fourteen days post-injury, animals were given a retention probe trial followed by a reminding procedure and a second probe trial. Injured animals in both the recent and remote memory conditions displayed impaired performance on the first probe trial. However, injured animals benefited from the reminding procedure, and animals in the remote memory group were identical to shams during the second probe trial. These results indicate that retrograde memory impairment following TBI is mediated primarily by retrieval deficits at the time of testing, while the quality of the memory trace remains largely intact.

INTRODUÇÃO: O traumatismo cranioencefálico (TCE) é atualmente uma das maiores causas de incapacidade, custo econômico e morte em todo o mundo. O prognóstico do paciente com TCE depende tanto da lesão encefálica primária, que ocorre no momento do trauma, como da lesão secundária, que ocorre após o evento traumático, em decorrência da evolução da lesão inicial ou de suas complicações intracranianas e sistêmicas. Dentre estas complicações sistêmicas destacam-se os distúrbios hidroeletrolíticos, em especial os distúrbios de sódio, por ser este o principal íon extracelular e o mais importante soluto osmoticamente ativo, estando diretamente ligado à formação de edema cerebral. Estudos recentes têm demonstrado que a hipernatremia é um fator de risco independente para pior prognóstico em pacientes críticos e neurocríticos. Não estão claros, entretanto, a frequência e o impacto clínico da hipernatremia no prognóstico de pacientes com TCE grave em nosso meio. Objetivou-se neste estudo identificar a incidência e os fatores preditivos da hipernatremia na fase aguda em pacientes com TCE grave em uma amostra de pacientes internados em unidade de terapia intensiva (UTI) e verificar se a hipernatremia na fase aguda constitui um fator de risco independente para o óbito intra-hospitalar. MÉTODOS: Estudo observacional, transversal, retrospectivo, unicêntrico, com dados coletados a partir da revisão dos prontuários dos pacientes adultos internados entre 1º de janeiro de 2011 a 17 de maio de 2015 na UTI da UE-HCFMRP com diagnóstico de TCE grave. Foram excluídos pacientes com traumas ocorridos há mais de 5 dias da admissão na UTI ou que tiveram tempo de internação na UTI inferior a 24 horas. Os fatores de risco para hipernatremia (definida como dois ou mais valores de sódio sérico > 145 mEq/L na primeira semana após o trauma), os preditores de óbito intra-hospitalar e de desfecho funcional desfavorável pela Glasgow Outcome Scale na alta hospitalar foram determinados através de análise multivariada por regressão logística linear, Para esta análise, foram também excluídos os pacientes que desenvolveram diabetes insípido e morte encefálica. RESULTADOS:Foram incluídos 254 pacientes, dos quais 89,4% eram do sexo masculino. A média de idade foi 34,11±12,46 anos, sendo os acidentes de trânsito o principal mecanismo de trauma encontrado. A média do valor do sódio sérico na admissão hospitalar foi 136,3±4,6 mEq/L; apenas 5 pacientes já foram admitidos com hipernatremia. A taxa de mortalidade geral foi 26,8%; hipernatremia foi identificada em 40,6% dos casos. Os fatores de risco independentes para a ocorrência de hipernatremia foram a glicemia de admissão (OR:1,01;IC95%:1,002-1,017), instabilidade hemodinâmica na admissão (OR:3,995;IC95%:1,35-11,8), presença de contusão cerebral na TC de crânio inicial (OR:3,208;IC95%:1,502-6,853) e o balanço hídrico positivo na primeira semana após o trauma (OR:1,113;IC95%:1,027-1,206). Os fatores de risco independentes para óbito intra-hospitalar foram glicemia (OR:1,014;IC95%:1,005-1,022), hipertensão intracraniana (OR:3,037;IC95%:1,074-8,592) e hipernatremia grave (OR:4,532;IC95%:1,798-11,423); já os preditores de GOS desfavorável na alta hospitalar foram glicemia (OR:1,01;IC95%:1,003-1,018), pneumonia (OR:3,115;IC95%:1,179- 8,231), hipernatremia (OR:2,592;IC95%:1,261-5,327) e hipernatremia grave (OR:3,933;IC95%:1,732-8,291). CONCLUSÕES: A hipernatremia é uma complicação frequente entre os pacientes com TCE grave e é independentemente associada à maior mortalidade intra-hospitalar e pior desfecho funcional na alta hospitalar. / INTRODUCTION: Traumatic brain injury (TBI) is currently one of the major causes of disability, economic cost and death in the world. The prognosis of a TBI patient depends on the severity of the brain injuries, both the primary injury, that occurs at the time of the trauma, and secondary injury, which occurs after the traumatic event and is related to the progress of the initial lesion or its intracranial and systemic complications. Prevention and treatment of secondary injuries has been shown to change the evolution of those patients and is one of the pillars of management of TBI. Secondary injuries include hydroelectrolytic disorders, especially disorders of sodium, that is the main extracellular ion and the most important osmotically active solute, being directly related to the formation of cerebral edema. Recent studies have shown that hypernatremia is an independent risk factor for worse prognosis in critically ill and neurocritical ill patients. In this context, it is still unclear what is the frequency and what are the predictors of hypernatremia in patients with severe TBI and whether hypernatremia has a negative impact on the prognosis of those patients. The objective of this study was to identify the incidence and predictive factors of hypernatremia in the acute phase in patients with severe TBI in a sample of patients admitted to an academic tertiary ICU in Brazil and to verify if hypernatremia in the acute phase of TBI constitutes an independent risk factor for death in those patients. METHODS: Observational, transversal, retrospective, monocentric study with data collected from the review of medical records of hospitalized adult patients between January 1, 2011 and May 17, 2015 in the UE-HCFMRP ICU with diagnosis of severe TBI. Patients with trauma that occurred more than 5 days after admission to ICU or who had an ICU stay of less than 24 hours were excluded; and demographic, clinical and evolution data were collected, including ICU length of stay, hospital length of stay, functional outcome at hospital discharge and mortality rate. Risk factors for hypernatremia (considered present when there were two or more serum sodium values> 145 mEq / L in the first week after the trauma) and the predictors of death and unfavorable functional outcome by Glasgow Outcome Scale were determined bymultivariate analysis by linear logistic regression, and for this analysis, patients who developed hypernatremia associated with diabetes insipidus and brain death were excluded. RESULTS: A total of 254 patients were included, 89.4% were male. The mean age was 34.11±12.46 years, and traffic accidents were the main trauma mechanism. The mean serum sodium value at hospital admission was 136.3± 4.6 mEq / L; only 5 patients were admitted with hypernatremia. The overall mortality rate was 26.8%; hypernatremia was identified in 40.6% of the cases. The independent risk factors for the occurrence of hypernatremia were admission blood glucose (OR:1.01;95%CI:1.002-1.017), hemodynamic instability at admission (OR:3.995;95%CI:1.35-11.8), presence of brain contusion at the initial brain CT scan (OR:3.208;95%CI:1.502-6.853), and positive fluid balance in the first week after trauma (OR:1.113;95%CI:1.027-1.206). The independent risk factors for death were glycemia (OR:1.014;95%CI:1.005-1.022), intracranial hypertension (OR:3.037;95%CI:1.074-8.592) and severe hypernatremia (OR:4.532; 95%CI:1.798-11.423); the predictors of unfavorable GOS at hospital discharge were glycemia (OR:1.01;95%CI:1.003-1.018), pneumonia (OR:3.115;95%CI:1,179-8.231), hypernatremia (OR:2.592;95%CI:1.261-5.327) and severe hypernatremia (OR:3.933; 95%CI:1.732-8.291). CONCLUSIONS: Hypernatremia is a frequent complication among patients with severe TBI and is independently associated with higher mortality and worse functional outcome at hospital discharge in those patients.

Introdução: A fragilidade dos sinais clínicos de fratura de base do crânio (FBC) para o diagnóstico dessa lesão, contraposta pela relevância atribuída a esses sinais, motivou a atual investigação, tendo em vista, sobretudo, a importância do diagnóstico dessa fratura nas intervenções iniciais ao doente traumatizado. Objetivos: Descrever o desempenho dos sinais clínicos de FBC para o diagnóstico dessa lesão; verificar o desempenho do hematoma periorbital e/ou rinorreia para diferenciar a fratura de fossa anterior das demais fraturas da base do crânio; descrever o tempo pós-trauma de aparecimento dos sinais clínicos em vítimas com e sem FBC; descrever o desempenho dos sinais de FBC na identificação precoce desse tipo de lesão; verificar a associação entre a presença de sinais clínicos de FBC e as variáveis idade do paciente e gravidade do trauma craniencefálico (TCE). Método: Estudo prospectivo do tipo follow up realizado por meio de observação estruturada de vítimas de TCE até 48 horas após trauma. Foram estudados indivíduos com idade 12 anos, com TCE contuso, atendidos na Unidade de Emergência Cirúrgica da Casa de Saúde Santa Marcelina entre agosto de 2012 e janeiro de 2013. Essa investigação foi focada nos sinais de FBC clássicos, apreciados rotineiramente na prática assistencial: hematoma periorbital, hematoma retroauricular, otorreia e rinorreia. Nas análises, o padrão-ouro para diagnóstico de FBC foi a tomografia computadorizada ou a visualização direta dessa fratura em cirurgia. Para avaliar o desempenho dos sinais clínicos de FBC, foi calculado seu valor preditivo positivo (VPP) e negativo (VPN), a sensibilidade, a especificidade e a acurácia. O teste quiquadrado foi aplicado para verificar as associações entre as variáveis. Resultados: A casuística foi composta de 136 vítimas com TCE, das quais 28 tiveram FBC. Os sinais clínicos de FBC observados nas primeiras 48 horas pós-trauma apresentaram VPP = 25,7%, VPN = 94,3%, sensibilidade de 92,8%, especificidade de 30,5% e acurácia de 43,4%. Quando detectados na primeira hora, os sinais clínicos tiveram o seguinte desempenho: VPP = 27,1%, VPN = 86,4%, sensibilidade de 67,8%, especificidade de 52,8% e acurácia de 55,9%. Vítimas com e sem FBC tiveram evidências clínicas desse tipo de fratura após a primeira hora do trauma, 21,0% entre 1 e 6 horas e 9,0% após 6 horas. Entre os indivíduos com FBC e sinais clínicos, 26,9% tiveram manifestação mais tardia desse tipo de lesão. A presença de sinais clínicos de FBC em vítimas de TCE se associou com a sua gravidade (p = 0,041 e 0,002), porém não esteve relacionada com a idade (p = 0,350). Nas vítimas com FBC, as evidências clínicas específicas de lesão de fossa anterior tiveram acurácia de 53,6%, VPP = 42,8%, VPN = 85,5%, sensibilidade de 90,0% e especificidade de 33,3%. Conclusão: Os resultados do atual estudo contraindiciam a valorização dos sinais de FBC na decisão do uso da via nasal para introdução de cateter e cânulas no atendimento inicial da vítima de trauma, visto que é baixa a acurácia desses sinais, sua presença tem pouco valor clínico e a ausência apresenta bom valor preditivo tardiamente. / Introduction: The fragility of the clinical signs for skull base fracture (SBF) diagnosis and, on the other hand, the importance attributed to these signals motivated this research, especially because of the importance of the fracture diagnosis in the first interventions on the trauma patient. Objectives: To describe the performance of clinical signs on the SBF diagnosis; to verify the performance of periorbital hematoma and/or rhinorrhea to differentiate a anterior fossa fracture from other skull base fractures; to describe the trauma clinical signs onset in victims with or without SBF; to describe the signs performance in the early identification of SBF; to verify the association between SBF clinical signs and age of the patient and severity of head injury (SHI) variables. Methods: Prospective follow-up conducted through structured observation of skull brain trauma (SBT) victims within 48 hours after trauma. The study was about subjects aged 12 years with blunt SBT, treated at the Emergency Surgical Unit at the Santa Marcelina Hospital between August 2012 and January 2013. This investigation was focused on classical SBF signs routinely examinated in healthcare practice: periorbital hematoma, retroauricular hematoma, otorrhea and rhinorrhea. In the analysis, the gold standard for SBF diagnosis was computed tomography or direct visualization of the fracture on surgery. To evaluate the performance of SBF clinical signs, it was calculated its positive predictive value (PPV) and negative predictive value (NPV), sensitivity, specificity and accuracy. The chi-square test was used to assess relationships between variables. Results: The sample consisted of 136 SBT victims, 28 of whom had SBF. Clinical signs of SBF observed in the first 48 hours post-trauma showed PPV 25.7%, NPV 94.3%, sensitivity 92.8%, specificity 30.5% and accuracy 43.4%. When detected in the first hour, the clinical signs performed as follows: PPV 27.1%, NPV 86.4%, sensitivity 67.8%, specificity 52.8% and accuracy 55.9%. Victims with or without SBF showed clinical evidence of this kind of fracture after the first hour of injury, 21,0% between 1 and 6 hours and 9,0% after 6 hours. Among individuals with SBF and clinical signs, 26.9% had a later manifestation of this lesion. The presence of SBF clinical signs in SBT was associated with severity (p = 0.041 and 0.002), but was not related with age (p = 0.350). In victims with SBF, specific clinical evidence of anterior fossa injury had an accuracy of 53.6%, PPV 42.8%, NPV 85.5%, sensitivity 90,0% and specificity 33.3%. Conclusion: The results of this study contraindicated the recovery of SBF signs in the decision of the nasal cannula use and catheter placement in the initial care of the trauma victim, since the accuracy of these signals is low, their presence has little clinical value and the absence has good predictive value later.

Gegenstand der Dissertationsschrift ist die Untersuchung des Effektes einer Hemmung der Leukotrienbiosynthese auf die Entwicklung des Schädel-Hirn-Traumas (SHT) nach experimenteller fokaler Kontusionsverletzung im Rattenmodell. Die Ergebnisse der Arbeit wurden im Jahre 2011 in einer Publikation veröffentlicht. Das SHT ist eine schwerwiegende globale Erkrankung mit hoher Inzidenz und Mortalität. Diese führt zu hohen Kosten für das Gesundheitssystem, zum einen durch die akute Behandlung im Krankenhaus, zum anderen durch die sich daran anschließenden rehabilitativen Maßnahmen. Nach der primär biomechanischen Verletzung des Hirns, die nicht beeinflussbar ist, bietet die anschließende sekundäre Hirnschädigung aufgrund verschiedener Stoffwechselprozesse Angriffspunkte für eine (medikamentöse) Therapie des SHT. Die sekundären Hirnschäden werden maßgeblich durch die Entwicklung eines perikontusionellen Hirnödems und dem daraus resultierenden Anstieg des intrakraniellen Druckes beeinflusst. Wie in vorangegangenen Untersuchungen gezeigt werden konnte, kam es nach experimentellem SHT zu einem signifikanten Anstieg der Leukotrienwerte im Liquor von Ratten. Dies warf die Frage nach der Rolle der Leukotriene (LT) im posttraumatischen Hirnstoffwechsel bezüglich der Ödementwicklung auf. Ziel dieser Arbeit war der Nachweis einer direkten Beteiligung von Leukotrienen an der sekundären Hirnschädigung und das Aufzeigen eines möglichen therapeutischen Zuganges durch Substitution von Leukotrienbiosynthesehemmern. Dafür wurde bei adulten Ratten ein fokales SHT induziert. Anschließend wurden in zwei Therapiegruppen zwei unterschiedlich wirkende Leukotrieninhibitoren mehrmalig oral verabreicht und die Ausprägung des SHTs nach 24 bzw. 72 Stunden mittels Magnetresonanztomographie (MRT) und immunhistochemischen Aufarbeitung der Hirne mit einer nicht therapierten Kontrollgruppe verglichen. Bei einem dieser LT-Inhibitoren handelte es sich um ein Weihrauchpräparat, das als Nahrungsergänzungsmittel bereits zu erhalten ist und somit auch potentiell am Menschen zur Anwendung kommen kann. Die Ergebnisse waren vielversprechend und zeigten in beiden Therapiegruppen ein verringertes Kontusionsvolumen im MRT und immunhistochemisch einen geringeren Verlust von Neuronen im perikontusionellen Bereich. Somit scheinen Leukotriene einen Anteil an den sekundären Schädigungsprozessen nach SHT zu tragen. Weitere Untersuchungen, vor allem bezüglich eines eventuell verbesserten klinischen Outcome durch Leukotrienbiosynthesehemmung, erscheinen sinnvoll um den potentiellen Einsatz von LT-Synthesehemmstoffen in der Therapie des SHT in Erwägung ziehen zu können.

Introdução: A fragilidade dos sinais clínicos de fratura de base do crânio (FBC) para o diagnóstico dessa lesão, contraposta pela relevância atribuída a esses sinais, motivou a atual investigação, tendo em vista, sobretudo, a importância do diagnóstico dessa fratura nas intervenções iniciais ao doente traumatizado. Objetivos: Descrever o desempenho dos sinais clínicos de FBC para o diagnóstico dessa lesão; verificar o desempenho do hematoma periorbital e/ou rinorreia para diferenciar a fratura de fossa anterior das demais fraturas da base do crânio; descrever o tempo pós-trauma de aparecimento dos sinais clínicos em vítimas com e sem FBC; descrever o desempenho dos sinais de FBC na identificação precoce desse tipo de lesão; verificar a associação entre a presença de sinais clínicos de FBC e as variáveis idade do paciente e gravidade do trauma craniencefálico (TCE). Método: Estudo prospectivo do tipo follow up realizado por meio de observação estruturada de vítimas de TCE até 48 horas após trauma. Foram estudados indivíduos com idade 12 anos, com TCE contuso, atendidos na Unidade de Emergência Cirúrgica da Casa de Saúde Santa Marcelina entre agosto de 2012 e janeiro de 2013. Essa investigação foi focada nos sinais de FBC clássicos, apreciados rotineiramente na prática assistencial: hematoma periorbital, hematoma retroauricular, otorreia e rinorreia. Nas análises, o padrão-ouro para diagnóstico de FBC foi a tomografia computadorizada ou a visualização direta dessa fratura em cirurgia. Para avaliar o desempenho dos sinais clínicos de FBC, foi calculado seu valor preditivo positivo (VPP) e negativo (VPN), a sensibilidade, a especificidade e a acurácia. O teste quiquadrado foi aplicado para verificar as associações entre as variáveis. Resultados: A casuística foi composta de 136 vítimas com TCE, das quais 28 tiveram FBC. Os sinais clínicos de FBC observados nas primeiras 48 horas pós-trauma apresentaram VPP = 25,7%, VPN = 94,3%, sensibilidade de 92,8%, especificidade de 30,5% e acurácia de 43,4%. Quando detectados na primeira hora, os sinais clínicos tiveram o seguinte desempenho: VPP = 27,1%, VPN = 86,4%, sensibilidade de 67,8%, especificidade de 52,8% e acurácia de 55,9%. Vítimas com e sem FBC tiveram evidências clínicas desse tipo de fratura após a primeira hora do trauma, 21,0% entre 1 e 6 horas e 9,0% após 6 horas. Entre os indivíduos com FBC e sinais clínicos, 26,9% tiveram manifestação mais tardia desse tipo de lesão. A presença de sinais clínicos de FBC em vítimas de TCE se associou com a sua gravidade (p = 0,041 e 0,002), porém não esteve relacionada com a idade (p = 0,350). Nas vítimas com FBC, as evidências clínicas específicas de lesão de fossa anterior tiveram acurácia de 53,6%, VPP = 42,8%, VPN = 85,5%, sensibilidade de 90,0% e especificidade de 33,3%. Conclusão: Os resultados do atual estudo contraindiciam a valorização dos sinais de FBC na decisão do uso da via nasal para introdução de cateter e cânulas no atendimento inicial da vítima de trauma, visto que é baixa a acurácia desses sinais, sua presença tem pouco valor clínico e a ausência apresenta bom valor preditivo tardiamente. / Introduction: The fragility of the clinical signs for skull base fracture (SBF) diagnosis and, on the other hand, the importance attributed to these signals motivated this research, especially because of the importance of the fracture diagnosis in the first interventions on the trauma patient. Objectives: To describe the performance of clinical signs on the SBF diagnosis; to verify the performance of periorbital hematoma and/or rhinorrhea to differentiate a anterior fossa fracture from other skull base fractures; to describe the trauma clinical signs onset in victims with or without SBF; to describe the signs performance in the early identification of SBF; to verify the association between SBF clinical signs and age of the patient and severity of head injury (SHI) variables. Methods: Prospective follow-up conducted through structured observation of skull brain trauma (SBT) victims within 48 hours after trauma. The study was about subjects aged 12 years with blunt SBT, treated at the Emergency Surgical Unit at the Santa Marcelina Hospital between August 2012 and January 2013. This investigation was focused on classical SBF signs routinely examinated in healthcare practice: periorbital hematoma, retroauricular hematoma, otorrhea and rhinorrhea. In the analysis, the gold standard for SBF diagnosis was computed tomography or direct visualization of the fracture on surgery. To evaluate the performance of SBF clinical signs, it was calculated its positive predictive value (PPV) and negative predictive value (NPV), sensitivity, specificity and accuracy. The chi-square test was used to assess relationships between variables. Results: The sample consisted of 136 SBT victims, 28 of whom had SBF. Clinical signs of SBF observed in the first 48 hours post-trauma showed PPV 25.7%, NPV 94.3%, sensitivity 92.8%, specificity 30.5% and accuracy 43.4%. When detected in the first hour, the clinical signs performed as follows: PPV 27.1%, NPV 86.4%, sensitivity 67.8%, specificity 52.8% and accuracy 55.9%. Victims with or without SBF showed clinical evidence of this kind of fracture after the first hour of injury, 21,0% between 1 and 6 hours and 9,0% after 6 hours. Among individuals with SBF and clinical signs, 26.9% had a later manifestation of this lesion. The presence of SBF clinical signs in SBT was associated with severity (p = 0.041 and 0.002), but was not related with age (p = 0.350). In victims with SBF, specific clinical evidence of anterior fossa injury had an accuracy of 53.6%, PPV 42.8%, NPV 85.5%, sensitivity 90,0% and specificity 33.3%. Conclusion: The results of this study contraindicated the recovery of SBF signs in the decision of the nasal cannula use and catheter placement in the initial care of the trauma victim, since the accuracy of these signals is low, their presence has little clinical value and the absence has good predictive value later.