Hyperglycemia is prevalent in critical care, as patients experience stress-induced hyperglycemia, even with no history of diabetes. Hyperglycemia has a significant impact on patient mortality and other negative clinical outcomes such as severe infection, sepsis and septic shock. Tight glycemic control can significantly reduce these negative outcomes by reducing hyperglycemic episode, but achieving it remains clinically elusive, particularly with regard to what constitutes tight control and what protocols are optimal in terms of results and clinical effort. The model used in this thesis is validated using an independent data and readily be used for different clinical interventions. Moreover, this model also able to accurately predict clinical intervention outcomes given that the model prediction error is very small, which is better than any other reported model. In particular, model-based glycemic control methods is used to capture patient-specific physiological dynamics, such as insulin sensitivity, SI. To date, sepsis diagnosis has been a great challenge despite advancement in technologies and medical research. Critically, septic patients are often classified by practitioners according to their experience before standard test results can be assessed, as to avoid delay in treatment. Moreover, several scoring systems have also been widely used to represent sepsis condition and better standardization of sepsis definition across different centers. In this thesis, insulin sensitivity, SI, a model-based metric is used to identify sepsis condition based on the finding that SI represents metabolic condition of a patient. Additionally, several clinical and physiological variables obtained during patient’s stay in critical care are also investigated using mathematical computation and statistical analysis to identify relevant metric which can be accurately use for sepsis interventions. Even though information on SI, clinical and physiological variables of a patient are insufficient to determine the sepsis status, these informations have brought to a different perspective of diagnosing sepsis. Microcirculation dysfunction is very common in sepsis. Tracking of microcirculation state among septic patient enable better tracking of patient state particularly sepsis status. The tracking can potentially be done by using a pulse oximeter that can extract additional information related to oxygen extraction level. The processed signals are therefore represent relative absorption of oxyhemoglobin and reduced hemoglobin that can be used to assess microcirculation status. In addition, this thesis focus on the real challenge of early treatment of sepsis and sepsis diagnosis where several potential metabolic markers are investigated. Microcirculation conditions are assessed using a non-invasive method that is generally used in typical ICU settings. In particular, the concept and method used to assess microcirculation and metabolic conditions are developed in this thesis. Finally, the work presented in this thesis can act as a starting point for many other glycemic control problems in other environments. These areas include cardiac critical care and neonatal critical care that share most similarities to the environment studied in this thesis, to general diabetes where the population is growing exponentially world wide. Eventually, this added knowledge can lead clinical developments from protocol simulations to better clinical decision making.

Orientadores: Sergio Tadeu Martins Marba, Maria Heloisa Souza Blotta Lima / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-07T17:27:31Z (GMT). No. of bitstreams: 1 Caldas_JamilPedrodeSiqueira_M.pdf: 1392314 bytes, checksum: dc91ad3e61797876f39fc3c051ec4b71 (MD5) Previous issue date: 2006 / Resumo: O objetivo do estudo foi avaliar as propriedades diagnósticas de quatro exames laboratoriais na sepse neonatal tardia: leucograma, proteína C-reativa (PCR),interleucina-6 (IL-6) e fator de necrose tumoral-alfa (TNF-a). Analisaram-se 82 recémnascidos com idade entre três e 30 dias, em um período de 20 meses. Nos quadros suspeitos de sepse foram colhidas três amostras de sangue: à suspeita, 24 e 48 horas depois. O leucograma foi avaliado no dia da suspeita clinica e foi considerado alterado quando o índice neutrofílico e o numero total de neutrófilos estivessem alterados. Os marcadores séricos foram dosados por quimioluminescência e o limite de corte obtido pela construção da curva ROC. De acordo com a evolução clínica, os recém-nascidos foram classificados em três grupos: sepse comprovada por cultura, sepse clínica (culturas negativas e quadro clínico muito sugestivo de infecção) e não infectados. Os grupos foram comparáveis quanto ao peso ao nascer, idade gestacional, sexo, idade cronológica e índice de Apgar. Nos grupos sépticos, choque ocorreu em 36,2% e óbito em 8,6% das crianças. O leucograma alterou-se em 64,3% naqueles com sepse comprovada, 68,8% naqueles com sepse clínica e 25,0% nos não infectados. A mediana da PCR mostrou-se mais elevada nos grupos sépticos em relação ao não infectado, em todos os momentos, com diferença estatisticamente significativa. A IL-6 alterou-se nos três momentos, com diferença estatisticamente significativa entre os grupos sépticos e o de crianças não infectadas. Nos grupos sépticos, a mediana da IL-6 mostrou-se mais elevada na primeira aferição, caindo a seguir. No grupo sem infecção,a mediana da IL-6 permaneceu inalterada. A mediana do TNF-a alterou-se nos três momentos no grupo com sepse comprovada, com diferença estatisticamente significativa em relação ao grupo não infectado, mas não entre este e aquele com sepse clínica. O leucograma revelou a acurácia mais baixa dos quatro exames (68,2%). A PCR mostrou a acurácia mais elevada dos testes, especialmente na segunda medida (89,4%). A Il-6 mostrou-se mais útil na primeira aferição, com acurácia de 81,0% (próxima àquela da PCR na primeira medida ¿ 81,8%) e sua acurácia caiu a seguir (71,2% e 68,2%). O TNF-a manteve uma acurácia praticamente constante (77,2 ¿ 77,0 ¿ 74,1%). Quando os marcadores foram associados, a acurácia aumentou significativamente: leucograma e segunda medida da PCR - 97,5%, segunda medida da PCR e primeira IL-6 - 92,3% e segunda medida da PCR e segunda do TNF-a - 95,1%. Para a associação leucograma e segunda medida da PCR, a sensibilidade e o valor preditivo negativo atingiram 100%. Na ocorrência de choque não houve diferença nas medianas dos exames. Quanto ao óbito, houve diferença significativa na terceira medida dos três marcadores séricos e na primeira da IL-6. Em conclusão, observou-se que a PCR mostrou a melhor acurácia dos quatro testes, com desempenho superior ao da IL-6 e TNF-a, e o leucograma mostrou a pior performance. A associação dos exames aumenta consideravelmente a precisão diagnóstica na sepse neonatal tardia. A manutenção dos níveis séricos elevados dos três marcadores alerta para a possibilidade de evolução para óbito / Abstract: This study evaluated the diagnostic properties of four laboratorial tests used in late neonatal sepsis. The tests were: white blood cell count (WBC), C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a). It analyzed 82 newborns aged 3 and 30 days in 20 months. Three blood samples were obtained, at three moments: at clinical suspicion, 24 hour and 48 hour after. WBC was evaluated once a time, at the clinical suspicion. Sera markers were made by chemiluminescence¿s essay and the cut-off values were obtained by ROC curve. WBC was considered altered when neutrophilic index and total neutrophilic, both, were abnormal. In according to clinical evolution, newborns were classified in three groups: definite sepsis (comproved by culture), clinical sepsis (suggestive clinical aspect but negative cultures), and non-infected infants. Groups were comparable in relation to birth weight, gestational age, gender or Apgar score and age at clinical suspicion. Shock and infection-related death happened in 32,6% and 8,6% in septic groups, respectively. WBC was abnormal in 64,3% in proved septic group, 68,8% in clinical sepsis group, and in 25% non-infected infants. CRP medians were more elevated in both septic groups than in non-infected infants, in all the moments (statistically significant difference). CRP was abnormal since the first measurement. In the non-infected group, CRP median presented low and quite constant values. IL-6 was abnormal at the three moments, and there was statistically significant difference between septic and non-infected groups. Septic group IL-6 medians were more elevated at the first measurement and then it felt progressively. In the non-infected group, IL-6 median presented with no elevation. TNF-a was elevated at the three measurements in the definite septic group, and there was statistically difference for non-infected group medians. For the clinical septic group and the non-infected one there was no significant difference. WBC showed the lowest diagnostic accuracy of the four tests (68,2%). CRP presented the most elevated accuracy, especially for the second measurement (89,4%). IL-6 obtained its best performance at the first determination (81,0% - quite equal to first CRP accuracy ¿ 81,8%). Then, its accuracy felt to 71,2% and 68,2%. TNF-a presented accuracy constant (77,2% ¿ 77,0% ¿ 74,1%). When the four markers were associated, accuracy elevated markedly, and the best values were obtained for: WBC + second CRP (97,5%), second CRP and first IL-6 (92,3%) and second CRP and TNF-a (95,1%). For WBC and second CRP association, sensibility and negative predictive values reached 100%.In relationship to shock, there were no significant differences in the medians of no markers. To death, it was shown that it was accompanied by high medians of the third measurements of the three markers, an in the first median of IL-6. In summary, it was found that WBC showed regular accuracy, and it was overcome by CRP (measured serially), by IL-6 (when it was measured at the moment of clinical suspicion) and by TNF-a. Tests association increased diagnostic accuracy markedly in the late neonatal sepsis. Sustained high blood levels of such markers may be a prognostic indicator (death) / Mestrado / Pediatria / Mestre em Saude da Criança