Antonín Hanuš 5. prosince 2014 This work deals with randomized clinical trials of medicaments. It examines three models of dependece of final values on initial values in case, that all variables are measured with some measurement error. For each model is derived effect of treatment estimate and its asymptotical properties, specifically consistency and asymptotical variance. The work mostly deals with linear model of analysis of covariance ANCOVA. The work fruther contents comparison of properties of estimates from all three models in case, that examined data come from a linear model. There is a comparison of asymptotical variances of estimates from all three models and for each of them there are examined conditions, when this model gives the best results. In the end there is a simulation study, which verifies all previous results. 1

Introdução: O choque séptico é complicação frequente e grave nos pacientes com câncer. Representa uma das principais causas de admissão em Unidade de Terapia Intensiva (UTI), com taxa de mortalidade em torno de 40% a 60%. O tratamento com vasopressor é parte fundamental do suporte hemodinâmico do paciente com choque séptico, sendo a norepinefrina o fármaco mais utilizado. Entretanto, aproximadamente 40% dos pacientes apresentam choque refratário a esse fármaco e vários eventos adversos são descritos, dentre eles vasoconstricção excessiva, redução do fluxo sanguíneo para os tecidos, distúrbios metabólicos e desequilíbrio imunológico. A vasopressina é um vasopressor não catecolaminérgico, que vem demonstrando ser eficiente vasopressor adjuvante no choque séptico. O objetivo desse estudo é avaliar se a vasopressina é superior à norepinefrina na mortalidade em 28 dias de pacientes com câncer e choque séptico. Métodos: Estudo unicêntrico, prospectivo, randomizado e duplo cego. Foram incluídos no estudo 250 pacientes com câncer e choque séptico no período de 20 de julho de 2013 a 6 de julho de 2016. Os pacientes foram randomizados para receber vasopressina (0,01 U/minuto a 0,06 U/minuto) ou norepinefrina (0,1 ug/kg/min a 1,0 ug/kg/min) como vasopressor no choque. A infusão dos fármacos foi titulada para manter a pressão arterial média (PAM) alvo ( >= 65 mmHg) após randomização. O desfecho primário foi mortalidade em 28 dias. Os desfechos secundários foram mortalidade em 90 dias, dias vivo e livres de ventilação mecânica, de vasopressores, e de terapia de substituição renal, e avaliação de disfunções orgânicas conforme o Sequential Organ Failure Assessment (SOFA) 24 horas e 96 horas após a randomização. Resultados: Foram elegíveis 1116 pacientes, sendo 250 pacientes incluídos no estudo e randomizados para vasopressina (n = 125) ou para norepinefrina (n = 125). Não houve perdas ou violação de protocolo. Não houve diferença na mortalidade em 28 dias (56,8% no grupo vasopressina vs. 52,8% no grupo norepinefrina, p = 0,525). A mortalidade em 90 dias também não foi diferente nos grupos, respectivamente nos grupos vasopressina e norepinefrina (72,0% vs. 75,2%, p = 0,566). Não houve diferença entre os grupos vasopressina e norepinefrina em relação aos dias vivos e livres de ventilação mecânica [20 (6-28) vs. 22 (7-28), p = 0,748], de dias livres de vasopressores [10 (1-23) vs. 12 (1-24), p = 0,669], e dias livres de terapia de substituição renal [20 (7- 28) vs. 21 (7-28), p = 0,819]. O escore SOFA não foi diferente entre os grupos vasopressina e norepinefrina 24 horas após a randomização [8 (5-11) vs. 7 (5-10), p = 0,425] e 96 horas após [7 (2-12) vs. 7 (3-12), p = 0,825]. Conclusão: A vasopressina não é superior à norepinefrina na mortalidade em 28 dias de pacientes com câncer e choque séptico / Background: Septic shock is a frequent complication in cancer patients. It is one of the most common admission causes in the intensive care unit (ICU), with mortality rates of 40% to 60%. Patients with septic shock often need the use of vasopressors for hemodynamic support and norepinephrine is the most used medication in this setting. However, 40% of patients have shock that is refractory to norepinephrine and lots of adverse effects are described, including excessive vasoconstriction, reduced blood flow to tissues and cells, and metabolic and immunologic disorders. Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock. We hypothesized that the use of vasopressin would be more effective on the treatment of septic shock in cancer patients than norepinephrine, decreasing 28-day mortality. Methods: In this prospective and randomized, double-blind trial, we assigned patients who had cancer and septic shock to receive either vasopressin (0.01 U/minute to 0.06 U/minute) or norepinephrine (10 ?g/minute to 60 ?g/minute) in addition to open-label vasopressors. All vasopressor infusions were titrated and tapered according to protocols in order to maintain a target mean arterial pressure of 65 mmHg. The primary endpoint was 28-day mortality. Secondary outcomes included 90-day mortality, days alive and free of mechanical ventilation, free of vasopressors and renal replacement therapy, and SOFA 24 h and 96h after randomization. Results: 1116 patients were eligible to the study. 250 patients were included on the study and underwent randomization: 125 patients received vasopressin and 125, norepinephrine. There was no difference between groups in 28-day mortality (56.8% in vasopressin group vs. 52.8% in norepinephrine group, p = 0.525). In addition, 90-day mortality was not different between vasopressin and norepinephrine groups (72% vs. 75.2%, p = 0.566). There was also no difference between vasopressin and norepinephrine groups in days alive and free of mechanical ventilation [20 (6- 28) vs. 22 (7-28), p = 0.748], free of vasopressors [10 (1-23) vs. 12 (1-24), p = 0.669], and renal replacement therapy [20 (7-28) vs. 21 (7-28), p = 0.819]. SOFA score was not different between vasopressin and norepinephrine groups after 24 h [8 (5-11) vs. 7 (5-10), p = 0.425] and after 96h [7 (2-12) vs. 7 (3-12), p = 0.825]. Conclusion: Vasopressin is not superior to norepinephrine in 28-day mortality rate in cancer patients with septic shock

Introdução: O choque séptico é complicação frequente e grave nos pacientes com câncer. Representa uma das principais causas de admissão em Unidade de Terapia Intensiva (UTI), com taxa de mortalidade em torno de 40% a 60%. O tratamento com vasopressor é parte fundamental do suporte hemodinâmico do paciente com choque séptico, sendo a norepinefrina o fármaco mais utilizado. Entretanto, aproximadamente 40% dos pacientes apresentam choque refratário a esse fármaco e vários eventos adversos são descritos, dentre eles vasoconstricção excessiva, redução do fluxo sanguíneo para os tecidos, distúrbios metabólicos e desequilíbrio imunológico. A vasopressina é um vasopressor não catecolaminérgico, que vem demonstrando ser eficiente vasopressor adjuvante no choque séptico. O objetivo desse estudo é avaliar se a vasopressina é superior à norepinefrina na mortalidade em 28 dias de pacientes com câncer e choque séptico. Métodos: Estudo unicêntrico, prospectivo, randomizado e duplo cego. Foram incluídos no estudo 250 pacientes com câncer e choque séptico no período de 20 de julho de 2013 a 6 de julho de 2016. Os pacientes foram randomizados para receber vasopressina (0,01 U/minuto a 0,06 U/minuto) ou norepinefrina (0,1 ug/kg/min a 1,0 ug/kg/min) como vasopressor no choque. A infusão dos fármacos foi titulada para manter a pressão arterial média (PAM) alvo ( >= 65 mmHg) após randomização. O desfecho primário foi mortalidade em 28 dias. Os desfechos secundários foram mortalidade em 90 dias, dias vivo e livres de ventilação mecânica, de vasopressores, e de terapia de substituição renal, e avaliação de disfunções orgânicas conforme o Sequential Organ Failure Assessment (SOFA) 24 horas e 96 horas após a randomização. Resultados: Foram elegíveis 1116 pacientes, sendo 250 pacientes incluídos no estudo e randomizados para vasopressina (n = 125) ou para norepinefrina (n = 125). Não houve perdas ou violação de protocolo. Não houve diferença na mortalidade em 28 dias (56,8% no grupo vasopressina vs. 52,8% no grupo norepinefrina, p = 0,525). A mortalidade em 90 dias também não foi diferente nos grupos, respectivamente nos grupos vasopressina e norepinefrina (72,0% vs. 75,2%, p = 0,566). Não houve diferença entre os grupos vasopressina e norepinefrina em relação aos dias vivos e livres de ventilação mecânica [20 (6-28) vs. 22 (7-28), p = 0,748], de dias livres de vasopressores [10 (1-23) vs. 12 (1-24), p = 0,669], e dias livres de terapia de substituição renal [20 (7- 28) vs. 21 (7-28), p = 0,819]. O escore SOFA não foi diferente entre os grupos vasopressina e norepinefrina 24 horas após a randomização [8 (5-11) vs. 7 (5-10), p = 0,425] e 96 horas após [7 (2-12) vs. 7 (3-12), p = 0,825]. Conclusão: A vasopressina não é superior à norepinefrina na mortalidade em 28 dias de pacientes com câncer e choque séptico / Background: Septic shock is a frequent complication in cancer patients. It is one of the most common admission causes in the intensive care unit (ICU), with mortality rates of 40% to 60%. Patients with septic shock often need the use of vasopressors for hemodynamic support and norepinephrine is the most used medication in this setting. However, 40% of patients have shock that is refractory to norepinephrine and lots of adverse effects are described, including excessive vasoconstriction, reduced blood flow to tissues and cells, and metabolic and immunologic disorders. Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock. We hypothesized that the use of vasopressin would be more effective on the treatment of septic shock in cancer patients than norepinephrine, decreasing 28-day mortality. Methods: In this prospective and randomized, double-blind trial, we assigned patients who had cancer and septic shock to receive either vasopressin (0.01 U/minute to 0.06 U/minute) or norepinephrine (10 ?g/minute to 60 ?g/minute) in addition to open-label vasopressors. All vasopressor infusions were titrated and tapered according to protocols in order to maintain a target mean arterial pressure of 65 mmHg. The primary endpoint was 28-day mortality. Secondary outcomes included 90-day mortality, days alive and free of mechanical ventilation, free of vasopressors and renal replacement therapy, and SOFA 24 h and 96h after randomization. Results: 1116 patients were eligible to the study. 250 patients were included on the study and underwent randomization: 125 patients received vasopressin and 125, norepinephrine. There was no difference between groups in 28-day mortality (56.8% in vasopressin group vs. 52.8% in norepinephrine group, p = 0.525). In addition, 90-day mortality was not different between vasopressin and norepinephrine groups (72% vs. 75.2%, p = 0.566). There was also no difference between vasopressin and norepinephrine groups in days alive and free of mechanical ventilation [20 (6- 28) vs. 22 (7-28), p = 0.748], free of vasopressors [10 (1-23) vs. 12 (1-24), p = 0.669], and renal replacement therapy [20 (7-28) vs. 21 (7-28), p = 0.819]. SOFA score was not different between vasopressin and norepinephrine groups after 24 h [8 (5-11) vs. 7 (5-10), p = 0.425] and after 96h [7 (2-12) vs. 7 (3-12), p = 0.825]. Conclusion: Vasopressin is not superior to norepinephrine in 28-day mortality rate in cancer patients with septic shock

In this thesis, we analyze treatment effect estimate in randomized clinical studies. Treatment effect estimates are constructed on the basis of three models. The first part of this thesis is about the behaviour of these estimates when the treatment effects vary with patients. We find out that all types of estimates are consistent and we derived their asymptotic distribution. The estimates are compared by their asymptotic variances. The theoretical conclusions are confirmed by a simulation study. The second part describes the case where measurements of baseline and final values contain an error. Two estimates are analyzed. We find out that both estimates are consistent. We derive their asymptotic distribution and compare their variances.

Objetivos: O objetivo do estudo foi avaliar comparativamente a incidência de complicações pós-operatórias em pacientes cirúrgicos submetidos a diferentes estratégias de nutrição parenteral: Precoce vs. Tardia. Desenho: Estudo fase IV de superioridade, unicêntrico, prospectivo e randomizado. Local: Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Brasil. Participantes: Adultos, com idade maior ou igual a dezoito anos, portadores de neoplasia gastrointestinal (esôfago, estômago e/ou intestino), metastática ou não, submetidos à cirurgia oncológica eletiva não paliativa. Intervenção: Os pacientes foram randomizados em dois grupos para nutrição parenteral precoce ou tardia. No grupo Precoce, a nutrição parenteral total era iniciada no segundo dia de pós-operatório e, no grupo Tardio, os pacientes recebiam nutrição parenteral a partir do 7º dia de pós-operatório. Os pacientes e os analisadores de desfechos desconheciam o grupo de tratamento. A análise foi feita de acordo com intenção de tratar. Desfecho primário: Desfecho composto de complicações pós-operatórias em 30 dias incluindo complicações respiratórias, cardiovasculares, renais, neurológicas, infecciosas e cirúrgicas. Desfechos secundários: Os desfechos secundários foram mortalidade em 30 dias, necessidade de unidade de terapia intensiva, tempo total de internação na unidade de terapia intensiva e no hospital, readmissão na unidade de terapia intensiva, tempo de ventilação mecânica, tempo de uso de vasopressores, disfunção hepática e reinternação hospitalar. Resultados: No período de 08 de maio de 2013 a 07 de outubro de 2017, foram analisados para elegibilidade 658 pacientes, tendo sido randomizados 167 para o grupo nutrição parenteral Precoce e 168 pacientes para o grupo nutrição parenteral Tardia. Em 30 dias, o grupo Precoce apresentou 46 complicações (27,5%) e o grupo Tardio apresentou 68 complicações (40,5%) [Intervalo de confiança 95% da diferença entre os grupos - 12,9 (-22,7 a -2,8), p=0,013]. Em relação aos desfechos secundários, não houve diferenças entre os grupos. Conclusão: Em pacientes com câncer submetidos à cirurgia gastrointestinal eletiva, a estratégia nutricional parenteral Precoce foi superior à nutricional parenteral Tardia na prevenção de complicações pós-operatórias. Registro: www.clinicaltrials.gov: NCT0183 9617 / Objectives: The objective of this study was to compare the incidence of postoperative complications in surgical patients submitted to different parenteral nutrition strategies: Early vs. Late. Design: Phase IV study of superiority, unicentric, prospective and randomized. Location: Cancer Institute of the State of São Paulo, Faculty of Medicine, University of São Paulo, Brazil. Participants: Adults, age equal or higher than eighteen years, gastrointestinal neoplasia (esophagus, stomach and / or intestine), metastatic or not, submitted to non-palliative elective oncologic surgery. Intervention: Patients were randomized into two groups: Early parenteral nutrition or Late parenteral nutrition. In the Early group, total parenteral nutrition was started on the second postoperative day, and in the Late group, patients received parenteral nutrition on the 7th postoperative day. Patients and outcome assessors were blinded to the treatment group. The analysis was performed according to intent to treat. Primary outcome: A composite endpoint of postoperative complications in 30 days including respiratory, cardiovascular, renal, neurological, infectious and surgical complications. Secondary outcomes: Secondary outcomes were 30-day mortality, need for intensive care unit, total length of hospital and intensive care unit stay, intensive care unit readmission, duration of mechanical ventilation, duration of vasopressors, hepatic dysfunction and hospital readmission. Results: Between May 8, 2013 and October 7, 2017, 658 patients were assessed for eligibility, and 167 were randomized to the Early group and 168 patients to the Late group. At 30 days, the Early group had 46 complications (27.5%) and the Late group had 68 complications (40.5%) - [absolute difference, 95% Confidence Interval of the absolute difference -12.9 (-22.7 to -2.8), p = 0.013]. The secondary outcomes were not different between the groups. Conclusion: In patients with cancer undergoing elective gastrointestinal surgery, Early parenteral nutritional strategy was superior than the Late strategy in avoiding postoperative complications. Registration: www.clinicaltrials.gov: NCT01839617

abstract: There are limited studies exploring the direct relationship between coconut oil and cholesterol concentrations. Research in animals and a few intervention trials suggest that coconut oil increases the good cholesterol (high density lipoprotein, HDL) and thus reduces the risk of cardiovascular disease. Preliminary research at Arizona State University (ASU) has found similar results using coconut oil as a placebo, positive changes in HDL cholesterol concentrations were observed. The goal of this randomized, double blind, parallel two arm study, was to further examine the beneficial effects of a 2g supplement of coconut oil taken each day for 8 weeks on cholesterol concentrations, specifically the total cholesterol to HDL cholesterol ratio, compared to placebo. Forty-two healthy adults between 18-40 years of age, exercising less than 150 minutes each week, non smoking, BMI between 22-35 and not taking any medications that could effect blood lipids were recruited from the ListServs at ASU. Participants were randomized to receive either a placebo capsule of flour or a coconut oil capsule (Puritan’s Pride brand, coconut oil softgels, 2g each) and instructed to take the capsules for 8 weeks. Results indicated no significant change in total cholesterol to HDL ratio between baseline and 8 weeks in the coconut oil and placebo groups (p=0.369), no significant change in HDL (p=0.648), no change in LDL (p=0.247), no change in total cholesterol (p=0.216), and no change in triglycerides (p=0.369). Blood lipid concentrations were not significantly altered by a 2g/day dosage of coconut oil over the course of 8 weeks in healthy adults, and specifically the total cholesterol to HDL ratio did not change or improve. / Dissertation/Thesis / Masters Thesis Nutrition 2017

Objetivos: O objetivo do estudo foi avaliar comparativamente a incidência de complicações pós-operatórias em pacientes cirúrgicos submetidos a diferentes estratégias de nutrição parenteral: Precoce vs. Tardia. Desenho: Estudo fase IV de superioridade, unicêntrico, prospectivo e randomizado. Local: Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Brasil. Participantes: Adultos, com idade maior ou igual a dezoito anos, portadores de neoplasia gastrointestinal (esôfago, estômago e/ou intestino), metastática ou não, submetidos à cirurgia oncológica eletiva não paliativa. Intervenção: Os pacientes foram randomizados em dois grupos para nutrição parenteral precoce ou tardia. No grupo Precoce, a nutrição parenteral total era iniciada no segundo dia de pós-operatório e, no grupo Tardio, os pacientes recebiam nutrição parenteral a partir do 7º dia de pós-operatório. Os pacientes e os analisadores de desfechos desconheciam o grupo de tratamento. A análise foi feita de acordo com intenção de tratar. Desfecho primário: Desfecho composto de complicações pós-operatórias em 30 dias incluindo complicações respiratórias, cardiovasculares, renais, neurológicas, infecciosas e cirúrgicas. Desfechos secundários: Os desfechos secundários foram mortalidade em 30 dias, necessidade de unidade de terapia intensiva, tempo total de internação na unidade de terapia intensiva e no hospital, readmissão na unidade de terapia intensiva, tempo de ventilação mecânica, tempo de uso de vasopressores, disfunção hepática e reinternação hospitalar. Resultados: No período de 08 de maio de 2013 a 07 de outubro de 2017, foram analisados para elegibilidade 658 pacientes, tendo sido randomizados 167 para o grupo nutrição parenteral Precoce e 168 pacientes para o grupo nutrição parenteral Tardia. Em 30 dias, o grupo Precoce apresentou 46 complicações (27,5%) e o grupo Tardio apresentou 68 complicações (40,5%) [Intervalo de confiança 95% da diferença entre os grupos - 12,9 (-22,7 a -2,8), p=0,013]. Em relação aos desfechos secundários, não houve diferenças entre os grupos. Conclusão: Em pacientes com câncer submetidos à cirurgia gastrointestinal eletiva, a estratégia nutricional parenteral Precoce foi superior à nutricional parenteral Tardia na prevenção de complicações pós-operatórias. Registro: www.clinicaltrials.gov: NCT0183 9617 / Objectives: The objective of this study was to compare the incidence of postoperative complications in surgical patients submitted to different parenteral nutrition strategies: Early vs. Late. Design: Phase IV study of superiority, unicentric, prospective and randomized. Location: Cancer Institute of the State of São Paulo, Faculty of Medicine, University of São Paulo, Brazil. Participants: Adults, age equal or higher than eighteen years, gastrointestinal neoplasia (esophagus, stomach and / or intestine), metastatic or not, submitted to non-palliative elective oncologic surgery. Intervention: Patients were randomized into two groups: Early parenteral nutrition or Late parenteral nutrition. In the Early group, total parenteral nutrition was started on the second postoperative day, and in the Late group, patients received parenteral nutrition on the 7th postoperative day. Patients and outcome assessors were blinded to the treatment group. The analysis was performed according to intent to treat. Primary outcome: A composite endpoint of postoperative complications in 30 days including respiratory, cardiovascular, renal, neurological, infectious and surgical complications. Secondary outcomes: Secondary outcomes were 30-day mortality, need for intensive care unit, total length of hospital and intensive care unit stay, intensive care unit readmission, duration of mechanical ventilation, duration of vasopressors, hepatic dysfunction and hospital readmission. Results: Between May 8, 2013 and October 7, 2017, 658 patients were assessed for eligibility, and 167 were randomized to the Early group and 168 patients to the Late group. At 30 days, the Early group had 46 complications (27.5%) and the Late group had 68 complications (40.5%) - [absolute difference, 95% Confidence Interval of the absolute difference -12.9 (-22.7 to -2.8), p = 0.013]. The secondary outcomes were not different between the groups. Conclusion: In patients with cancer undergoing elective gastrointestinal surgery, Early parenteral nutritional strategy was superior than the Late strategy in avoiding postoperative complications. Registration: www.clinicaltrials.gov: NCT01839617

Introduction: Hysterectomy is the most common major gynecological operation in the Western World and approximately 5000 benign hysterectomies are performed in Sweden every year. Consequently it is a surgical procedure that affects many women. The procedure comprises challenges concerning perioperative health care, perceived postoperative symptoms, quality of life aspects and health economics. The concept of fast track is a multimodal strategy to reduce hormonal surgical stress response and achieve an enhanced postoperative recovery and is today considered to be evidence based in relation to colorectal surgery. Spinal anesthesia, as an important part of fast track, provides benefits of extended effect on analgesia and reduced postoperative morbidity. It is reasonable to believe that employing the strategies of fast track including spinal anesthesia could also provide substantial benefits for women requiring surgical removal of the uterus. Aims: To determine whether duration of hospital stay, presence and intensity of postoperative symptoms, duration of sick leave and cost-effectiveness differ between women undergoing benign fast track abdominal hysterectomy in spinal anesthesia with intrathecal morphine (SA) and in standard general anesthesia (GA). Material & Methods: 180 women participated in this open randomized multicenter study with five participating hospitals in the southeast region of Sweden. One hundred and sixty two completed the study; 82 women were randomized to SA and 80 to GA. A fast track model comprising premedication without sedatives, intravenous fluid regulation, analgesics based on non-opioids, pre-emptive antiemetic therapy, early enteral nutrition and mobilization and standard criteria for discharge were used. End points were duration of hospital stay, use of analgesics, perceived postoperative symptoms, occurrence of postoperative complications, duration of sick leave and health economic evaluations. Results: Duration of hospital stay did not differ between the two modes of anesthesia. Vomiting and pruritus occurred significantly more often after SA. Complication rates did not differ between groups. Women with SA experienced less overall discomfort and had a reduced need for opioids postoperatively. Abdominal pain, drowsiness and fatigue occurred less often and with lower intensity among the women in the SA group. Health related quality of life improved faster and the duration of sick leave was shorter in women after SA. Total costs (hospital costs plus costs for productivity loss) were lower for the SA group. Within the first 29 days after hysterectomy the women in the SA group gained more QALYs than women in the GA group. Conclusions: The duration of hospitalisation after fast track abdominal hysterectomy was less than 50 hours and mode of anesthesia did not influence this. SA displayed considerable advantages regarding postoperative symptoms and recovery. SA was considered cost-effective in comparison with GA due to lower total costs and more QALYs gained. Our study indicates that SA should be recommended as the first choice of anesthesia in benign abdominal hysterectomy.