Perinatal hypoxia-ischaemia is a major cause of disability, including cerebral palsy, yet a neuroprotectant which fully protects the brain remains elusive. Following a hypoxic-ischaemic insult, striatal medium-spiny neurons and hippocampal CA1 neurons are vulnerable to a complex cascade of neurotoxic events. This cascade includes energy failure, a massive release of glutamate, the formation of free radicals and caspase activation. The overall aim of this thesis was to assess the efficacy of three potential neuroprotective strategies that target this cascade from different directions. Short-term, and where appropriate, long-term, neuroprotection was investigated. The first treatment strategy aimed to suppress the generation of free radicals through treatment with the potent free radical spin trap, N-tertbutyl-(2-sulphophenyl)-nitrone (S-PBN). The second compound tested was the caspase-3 inhibitor, minocycline. Finally, the third treatment strategy combined a series of S-PBN injections with 6 hours of moderate hypothermia immediately after hypoxia-ischaemia. Hypothermia is suggested to slow the rate of the neurotoxic cascade, thus potentially allowing other neuroprotective agents greater efficacy. Using an adaptation of the Rice et al. (1981) model, hypoxia-ischaemia was induced on postnatal day (PN) 8 in the right cerebral hemisphere. For the short-term studies, the rats were perfused at 14 days-of-age. The brains were dissected out and embedded in Technovit. Forty [mu]m serial sections were cut through the right striatum and hippocampus. The total number of medium-spiny neurons in the striatum and where appropriate, the total number of neurons in the hippocampal CA1 pyramidal layer, were stereologically determined using the optical disector/Cavalieri method. For the long-term study, fine motor control was assessed in half of the animals through the staircase test from 9-11 weeks-of-age. Neuroprotection was assessed in the remaining animals. All animals were sacrificed at 12 weeks-of-age. The total number of striatal medium-spiny neurons was stereologically determined in the non-behavioural animals as described above. A series of seven injections of S-PBN (100mg/kg) did not offer statistically significant neuroprotection to the striatum at one week after perinatal hypoxia-ischaemia. Similarly, a single injection of minocycline (45mg/kg) immediately after the insult did not offer significant neuroprotection to the striatum nor the CA1 region of the hippocampus at this early time-point. In contrast, when the series of S-PBN injections was combined with 6 hours of moderate hypothermia post-hypoxia-ischaemia, sterelogical analysis revealed significant neuroprotection of the striatal medium-spiny neurons to normal levels at one week after the injury. No significant neuroprotection was seen in the CA1 region of the same animals. To assess whether this impressive striatal neuroprotection was long-lasting and whether it represented functional rescue, the final experiment in this thesis investigated rat pups at 12 weeks-of-age after exposure to hypoxia-ischaemia at PN8. Treatment with S-PBN/hypothermia offered persistent neuroprotection of striatal medium-spiny neurons and preservation of fine motor skills compared to diluent-normothermia-treated controls. The long-term behavioural outcomes were compared with normal, uninjured controls and the total number of medium-spiny neurons was compared with normal numbers from the literature. These comparisons revealed that the histological and functional integrity of the striatum was rescued to normal levels. This is the first study to identify a treatment strategy that offers complete and long-lasting preservation of striatal neuronal numbers, by accurate and unbiased stereological methods, paired with persistent preservation of fine motor control following perinatal hypoxia-ischaemia.

Rewarming mildly hypothermic subjects with distal extremity rewarming has been associated with significantly greater rewarming rate compared to shivering-only as it increases heat flow to the core by opening up of arteriovenous anastomoses in the extremities. This study compared distal extremity rewarming with Fluidotherapy® or warm water, or shivering-only. Seven healthy individuals were cooled in 8°C water to either a core temperature of 35°C or a maximum of one hour. The subjects were then rewarmed with one of the three rewarming methods (distal extremity rewarming with 44°C water or 46°C Fluidotherapy® or shivering-only) on three different occasions. There was no significant difference in the afterdrop length and duration between the three conditions. Fluidotherapy® provided rewarming rates similar to the shivering-only condition. Warm water rewarming provided higher heat donation to distal extremities and lead to a threefold higher rewarming rate compared to the other two treatments.

The overall aim of the present thesis was to study post-resuscitation care of cardiac arrest (CA) patients treated with target temperature management 33°C with a focus on evaluation of two prognostic tools: variations in cerebral venous saturation and acute magnetic resonance imaging (MRI) findings on the brain post-CA. An additional aim was to investigate patients’ neurological outcome and relatives’ experiences 6 months after the event. Paper I describes the cerebral oxygen saturation of blood obtained from a jugular bulb (SjvO2) catheter The results showed that patients with poor outcome tended to have higher SjvO2values,but this difference was only significant at 96 and108 hours post-CA. The main findings of Paper II were that patients with good outcome displayed a pathological pattern mainly in the frontal and parietal lobes on MRI of the brain. Patients with poor outcome had an extensive pathological pattern in several brain regions. Furthermore, very low apparent diffusion coefficient (ADC) values were associated with poor outcome regardless of brain region. Paper III investigated physical and cognitive function over time, between one month and 6 months post-CA, as well as d life satisfaction at 6 months. The results showed that impairment in physical and cognitive function is common in CA survivors but tends to decrease over time. Despite a severe illness, which has impaired the physical and cognitive functions, satisfaction with life as a whole was reported by 70% of CA survivors. In Paper IV, relatives described their experiences 6 months after a significant others CA. The analysis resulted in three themes reflecting relatives’ everyday life 6 months after the event: Difficulties managing a changed life situation, Feeling like I come second and Feeling new hope for the future. In conclusion, the results of the present thesis have increased our understanding of the two prognostic tools that were investigated; they have generated new and revealed aspects that should be taken into account during prognostication and assessing neurological outcome of this group of patients. The thesis has also shown that the healthcare needs to improve its routines for follow-ups and information provision to both patients and their relatives.

Rewarming mildly hypothermic subjects with distal extremity rewarming has been associated with significantly greater rewarming rate compared to shivering-only as it increases heat flow to the core by opening up of arteriovenous anastomoses in the extremities. This study compared distal extremity rewarming with Fluidotherapy® or warm water, or shivering-only. Seven healthy individuals were cooled in 8°C water to either a core temperature of 35°C or a maximum of one hour. The subjects were then rewarmed with one of the three rewarming methods (distal extremity rewarming with 44°C water or 46°C Fluidotherapy® or shivering-only) on three different occasions. There was no significant difference in the afterdrop length and duration between the three conditions. Fluidotherapy® provided rewarming rates similar to the shivering-only condition. Warm water rewarming provided higher heat donation to distal extremities and lead to a threefold higher rewarming rate compared to the other two treatments.

The overall aim of the thesis was to study post-resuscitation care of cardiac arrest (CA) patients with a focus on therapeutic hypothermia treatment, outcomes up to six months post-CA and relatives’ experiences during the hospital stay. In Paper I, the aim was to asses effectiveness of hypothermia treatment with cold, 4°C, intravenous crystalloid infusion combined with ice packs. In conclusion, the described cooling method was found to be useful for inducing and maintaining hypothermia, allowed good temperature control during rewarming and to be feasible in clinical practice. The aim in Paper II was to investigate biomarkers and the association of serum glial fibrillary acidic protein (GFAP) levels with outcome, and to compare GFAP with neuron-specific enolas (NSE) and S100B. The result showed increased GFAP levels in the poor outcome group, but did not show sufficient sensitivity to predict neurological outcome. Both NSE and S100B were shown to be better predictors. A combination of the investigated biomarkers did not increase the ability to predict neurological outcome. In Paper III, the aim was to investigate whether there were any changes in and correlations between anxiety, depression and health-related quality of life (HRQoL) over time, between hospital discharge and one and six months post-CA. There was improvement over time in HRQoL, but changes over time in anxiety and depression were not found. Physical problems seemed to affect HRQoL more than psychological problems. The results also indicate that the less anxiety and depression patients perceive, the better their HRQoL. In the fourth paper, the aim was to describe relatives’ experiences during the next of kin’s hospital stay after surviving a CA. The analysis resulted in three themes: The first period of chaos, Feeling secure in a difficult situation, and Living in a changed existence. In conclusion, the results of the thesis have helped to improve knowledge within the areas studied and reveal aspects that should be taken into account in the overall treatment of this group of patients. The thesis have also shown the importance of developing an overall view and establishing a chain of care from an individual’s CA until follow-up for both the patient and his/her relatives.

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Anesteziyoloji ve Reanimasyon Anabilim Dalı, 2006. / Kaynakça var.

Resumo: O obeso tem menor incidência de hipotermia intraoperatória em relação ao não obeso por apresentar limiar de vasoconstrição termorregulatória mais elevado. A combinação de métodos de aquecimento no intraoperatório parece ser melhor do que o uso isolado na prevenção de hipotermia. O objetivo da pesquisa foi avaliar se a combinação de permutador de calor e umidade (PCU) no circuito inspiratório com ar forçado aquecido ou aquecimento das soluções parenterais previne a ocorrência de hipotermia no período intraoperatório em obesas (OB) e não obesas (NOB) submetidas à anestesia venosa total. Quarenta pacientes submetidas à cirurgia abdominal ginecológica foram anestesiadas com propofol e remifentanil em infusão alvocontrolada. Todas as pacientes tinham um PCU acoplado no circuito inspiratório. As pacientes foram distribuídas aleatoriamente em 4 grupos de acordo com o índice de massa corporal (IMC) e com o manejo termal. Em 10 obesas (IMC de 30 a 34,9 kg.m-2) e 10 não obesas (IMC de 18,5 a 24,9 kg.m-2), utilizou-se ar forçado aquecido nos membros inferiores (WB). Dez obesas e 10 não obesas receberam aquecimento das soluções infundidas (HF). A temperatura central foi registrada nos momentos controle (0) e 15, 30, 60 90 e 120 minutos após instalação do circuito respiratório, e no final da cirurgia. Na Sala de Recuperação Pós-Anestésica (SRPA), a temperatura central das pacientes foi registrada durante o período de 1 hora. O IMC e a temperatura central foram correlacionados nos grupos que receberam o mesmo tratamento termal da hipotermia. O grupo OB/WB apresentou temperatura central intraoperatória mais alta em relação aos outros grupos (p<0,001). A proporção de pacientes normotérmicos no final da cirurgia e na admissão da SRPA foi mais alta em OB/WB do que nos outros grupos (p<0,05). Houve correlação positiva entre o IMC e a temperatura central no ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Obese individuals show less intraoperative (IOP) hypothermia than non-obese ones due to higher vasoconstriction threshold. A combination of warming methods may be better than an isolated one in preventing IOP hypothermia. Our aim was to evaluate whether the combination of a heat and moisture exchanger (HME) on inhaled gas with IOP forced air warming blanket (WB) or warming intravenous (IV) fluids (HF) prevents IOP hypothermia in obese (OB) and non-obese (NOB) women under intravenous anesthesia. Forty patients scheduled for gynecological abdominal surgery were anesthetized with propofol and remifentanil in a target controlled infusion. All patients had a HME on the inhaled gas. Patients were randomly distributed into 4 groups according to body mass index (BMI) and IOP thermal management. Ten OB grade I (BMI between 30 and 34.9 kg.m-2) and 10 NOB (BMI between 18.5 and 24.9 kg.m-2) had WB on the lower limbs. Ten OB and 10 NOB patients received IV HF. Core temperatures were recorded at baseline, after 15, 30, 60, 90, and 120 minutes of ventilatory system installation, and at the end of surgery. Core temperature was also followed for 60 minutes in the Post Anesthetic Care Unit (PACU). Core temperature and BMI were correlated in the groups with the same hypothermia treatment method. OB/WB group presented a higher IOP core temperature higher than the other groups (P<0.001). The proportion of normothermic patients at end of surgery and in PACU admission was higher in OB/WB than the other groups (P<0.05). There was a positive correlation between BMI and core temperature in the skin-surface warming groups (P<0.001). The combination of IOP skin-surface warming with HME on the inhaled gas in female obese patients, but not in non-obese ones, minimizes hypothermia. The combination of warming IV fluids and HME does not avoid IOP hypothermia in female obese or non-obese patients / Orientador: José Reinaldo Cerqueira Braz / Coorientador: Leandro Gobbo Braz / Banca: Pedro Thadeu Galvão Vianna / Banca: Flora Margarida Barra Bisinotto / Banca: Jair de Castro Junior / Banca: João Abrão / Doutor

A hipotermia ocorre em mais de 70% dos pacientes no período perioperatório tornando-se um evento adverso freqüente. O estudo teve como objetivo geral analisar a temperatura corporal do paciente submetido à cirurgia eletiva no período intra-operatório e como específicos: identificar as relações entre a temperatura corporal e as variáveis sócio-demográficas (idade e sexo) e clínicas (índice de massa corporal, transfusão sanguínea e doenças crônicas); identificar as relações entre temperatura corporal e as variáveis do procedimento anestésicocirúrgico (duração da anestesia, tipo de anestesia e duração da cirurgia); identificar a relação entre temperatura corporal e a temperatura da sala de operação; analisar a variância da medida da temperatura corporal média dos pacientes explicada pelas variáveis preditoras e identificar as medidas adotadas na sala de cirurgia para a prevenção de hipotermia. Para tanto, realizou-se uma pesquisa com abordagem metodológica quantitativa, delineamento não experimental, tipo de estudo correlacional, prospectivo em um hospital filantrópico situado no interior do Estado de São Paulo. Na amostra estudada foram incluídos 70 sujeitos com idade igual ou superior a 18 anos; submetidos à cirurgia eletiva, com duração da anestesia de, no mínimo, uma hora. Para a coleta de dados elaborou-se um instrumento que foi submetido à validação aparente e de conteúdo. Na coleta de dados, a pesquisadora realizou a mensuração da temperatura e umidade da sala de operação e da temperatura corporal do paciente em diferentes momentos. Por meio do coeficiente de correlação de Pearson verificou-se correlação estatisticamente significante e negativa entre a variável temperatura média corporal dos pacientes e a duração da anestesia e a duração da cirurgia. De forma positiva, o índice de massa corporal e a temperatura média da sala de operação apresentaram correlações estatisticamente significantes com a temperatura corporal média dos pacientes. Segundo o teste t Student a variável transfusão sanguínea apresentou diferença estatisticamente significante entre as temperaturas corporais médias do grupo submetido à transfusão e do grupo não submetido à transfusão. Em relação ao tipo de anestesia, a ANOVA mostrou diferença estatisticamente significante entre as temperaturas corporais médias e os grupos (geral, regional e combinada), sendo que o grupo submetido à anestesia combinada apresentou temperaturas médias corporais mais baixas. Na regressão linear multivariada, as variáveis tipo de anestesia, duração da anestesia, o índice de massa corporal e a temperatura da sala de operação estavam diretamente relacionadas à temperatura corporal média dos sujeitos investigados. As medidas adotadas na sala de cirurgia para a prevenção de hipotermia foram o uso de lençol de algodão e o enfaixamento dos membros inferiores que consistem em métodos passivos de aquecimento cutâneo; a utilização do sistema de ar forçado aquecido (método ativo de aquecimento cutâneo) ocorreu uma única vez. Conclui-se que apesar das limitações deste estudo, pode-se inferir que a realidade aqui demonstrada, deva ser igual ou similar a de muitos hospitais brasileiros. Compete ao enfermeiro perioperatório a adoção de postura crítica diante da realidade vivenciada, bem como a busca e a implementação de evidências que assegurem a melhoria do cuidado prestado ao paciente cirúrgico. / Hypthermia affects more than 70% of patients in the intraoperative period, turning into a frequent adverse event. The general aim of this study was to analyze the body temperature of patients submitted to elective surgery in the intraoperative period. Specific goals were: to identify the relations between body temperature and sociodemographic (age and gender) and clinical (body mass index, blood transfusion and chronic diseases); to identify the relations between body temperature and variables related to the anesthetic-surgical procedure (duration of anesthesia, type of anesthesia and duration of surgery); to identify the relation between body temperature and the temperature of the operating room; to analyze the variance in patients\' mean body temperature measures, explained by predictive variables, and to identify the measures adopted in the surgery room to prevent hypothermia. Therefore, a quantitative prospective correlation study with a nonexperimental design was carried out at a philanthropic hospital located in the interior of São Paulo State, Brazil. The study sample included 70 subjects aged 18 years or older; submitted to elective surgery, who received anesthesia during at least one hour. For data collection, an instrument was elaborated and submitted to face and content validation. During the collection, the researcher measured the temperature and humidity of the operating room and the patient\'s body temperature at different times. Pearson\'s correlation coefficient was used to identify a statistically significant and negative correlation between three variables: patients\' mean body temperature, the duration of anesthesia and the duration of the surgery. In the positive sense, the body mass index and mean operating room temperature displayed statistically significant correlations with the patients\' mean body temperature. According to Student\'s t-test, the blood transfusion variable presented a statistically significant difference between the mean body temperatures of the group submitted to transfusion and the group that was not submitted to transfusion. As to the type of anesthesia, ANOVA showed a statistically significant difference between mean body temperatures and anesthesia groups (general, regional and combined), with the group submitted to combined anesthesia presenting lower mean body temperatures. In the multivariate linear regression, the variables type of anesthesia, duration of anesthesia, body mass index and operating room temperature were directly related with the research subjects\' mean body temperature. The measures adopted in the surgery room to prevent hypothermia were the use of cotton sheets and the wrapping of lower members, which are passive cutaneous warming methods; the forced-air warming system (active cutaneous warming method) was used once. It is concluded that, despite the study limitations, it can be inferred that the reality pictured here should be equal or similar to that of many Brazilian hospitals. Perioperative nurses should adopt a critical attitude towards this reality, and also look for and implement evidence that guarantees the improvement of care delivery to surgical patients.

A hipotermia ainda é um problema que responde por uma proporção de complicações no período pós-operatório que podem ser preveníveis. Apesar da melhora nas técnicas anestésico-cirúrgicas, estima-se que ocorre em mais de 70% dos pacientes no período perioperatório, sendo uma preocupação para a equipe de saúde. Frente a isso, melhorias no treinamento dos profissionais de enfermagem com relação à hipotermia se faz necessário. Os objetivos do estudo foram: Avaliar a influência de intervenções educativas sobre o conhecimento da hipotermia dos Auxiliares de Enfermagem e da assistência de enfermagem no período intraoperatório, identificar a diferença do conhecimento sobre hipotermia do Auxiliar de Enfermagem, após a intervenção educativa e comparar a assistência de enfermagem prestada ao paciente cirúrgico, antes e após a intervenção educativa. Para tanto, realizou-se uma pesquisa com abordagem metodológica quantitativa, quase experimental, com um grupo de comparação antes e depois. Participaram do estudo 35 auxiliares de enfermagem. Para a coleta de dados, elaborou-se um questionário e um roteiro de observação da assistência direta ao paciente que foram validados pela técnica Delphi. Do total dos profissionais, 91% eram do sexo feminino, 65,7% tinham se formado em instituição privada; 45,7% pertenciam à faixa etária de 20 a 30 anos, 48,6% com tempo de formação entre 1 a 5 anos e 91,4% com tempo de atuação no Centro Cirúrgico entre 1 a 5 anos. O teste t mostrou diferença estatisticamente significante em relação ao conhecimento (p=0,00) e observação direta (p=0,00) após a intervenção educativa; entretanto, o teste de análise de variância para medidas repetidas não mostrou diferença significativa do conhecimento e na assistência direta ao paciente, após a intervenção educativa quando relacionado às variáveis sociodemográficas estudadas. Pelo teste t, todos os itens do questionário referente ao conhecimento sobre hipotermia e ao roteiro de assistência direta ao paciente mostraram diferença significativa, após a intervenção educativa. Concluiu-se que, apesar das limitações deste estudo, se pôde inferir que a intervenção educativa foi efetiva, visto que a diferença nas médias do conhecimento e na assistência direta aumentaram após a intervenção, uma vez que os conceitos sobre hipotermia foram ancorados, ampliados e modificados na estrutura cognitiva dos profissionais de enfermagem, conforme a teoria de aprendizagem significativa de David Ausubel. / Hypothermia is still a problem that responds for a percentage of the complications in the post operatory period that can be preventable. Despite the improvement in the anesthesia surgery techniques, it is estimated that it happens in more than 70% of the patients in the peri operatory period, being a worrying for the health team. Because of this, improvements in the nursery professionals training in relation to hypothermia are necessary. The goals of this study were: to evaluate the influence of the educational interventions over the hypothermia knowledge of the Nursery Assistants and the nursery assistance in the intra-operatory period, to identify the difference of knowledge over hypothermia of the Nursery Assistance, after the educational intervening and compare the nursery assistance given to the surgical patient, before and after the educational intervening. For such, a research was held with a quantitative methodological approach, nearly experimental, with a comparison group before and after. 35 nursery assistants participated on the study. For the data survey, a questionnaire was elaborated and a script for observation of the direct assistance to the patient which was validated by the Delphi Technique. From the total of the professionals, 91% were female, 65.7% were graduated from a private institution, 45.7% were between 20 and 30 years of age, 48.6% have been graduated for 1 to five years and 91.4% have been acting in the Surgical Center for 1 to 5 years. The t test shows statistical meaningful difference of knowledge (p=0.00) and of direct observance (p=0.00) after the educational intervening as for the socio-demographical variants studied. By the t test, all the items in the questionnaire referring to the knowledge in hypothermia and to the script in the direct assistance to the patient showed meaningful difference, after the educational intervening. It was concluded that, in spite of the limitations of this study, it is possible to infer that the educational intervening was effective, given that the difference in the averages of knowledge and in the direct assistance increased after the intervening, once the concepts on hypothermia were anchored, broadened and modified in the cognitive structure of the nursery professionals, according to the meaningful learning theory from David Ausubel.

A isquemia cerebral causada pela parada cardíaca leva ao desapareciemnto neuronal. studamos os mecanismos de morte celular envolvidos na isquemia in vitro em linhagem de neuroblastoma.O insulto isquêmicao foi reproduzido cultivando as células sem fatores de crescimento, sem glicose e em embiente hipóxico produzido por um sistema de anaerobiose. Os resultados sugerem que a privação de oxigênio, glicose e fatores de cresciemtno do meio de cultura reproduzem o fenômeno semelhante a isquemia. INvestigamos ainda a participação de processo apoptótico e sua modulação térmica. Observams que a hipotermia produz neuroproteção, enquanto a hipertermia agrava o processo de morte celular por apoptose. / Cardiac arrest causes cerebral ischemia and neuronal disappearance. We investigate celular death mechanisms elucidated by a model of ischemia in neuroblastoma cell line. The ischemic insult was reproduced by deprivation of growth factors and glucose in a hypoxic environment produced by an anaerobiosis system. Our results validate the experimental model and revel the participation of an apoptotic process in the celular loss induced by ischemia. We also demonstrated that hypothermia can be used as a neuroprotector agent whereas hyperthermia aggavates celular damage.