The ability of the brain to keep a stable and adequate cerebral blood flow (CBF) independently of fluctuations in systemic blood pressure is referred to as cerebral pressure autoregulation (CPA). When the brain is injured by trauma or hemorrhage, this ability may be impaired, leaving the brain vulnerable to events of high or low blood pressure. The aims of this thesis were to study CPA in patients with severe traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH), the relation between CPA and other physiological parameters, and the influence of CPA on outcome. Four retrospective studies are included in the thesis. All patients were treated at the neurointensive care unit, Uppsala University hospital. In paper I, 58 TBI patients were studied. In patients with impaired CPA, cerebral perfusion pressure between 50-60 mm Hg was associated with favorable outcome while CPP > 70 and >80 mm Hg was associated with unfavorable outcome. In patients with intact CPA there was no association between CPP and outcome. In paper II, 107 TBI patients were studied. High CPP was associated with unfavorable outcome in patients with focal injuries. In patients with diffuse injury and impaired CPA, CPP > 70 mm Hg was associated with favorable outcome. In paper III, 47 SAH patients were studied. CBF was measured bedside with Xenon-enhance CT (Xe-CT). Patients with impaired CPA had lower CBF, both in the early (day 0-3) and late (day 4-14) acute phase of the disease. In paper IV, 64 SAH patients were studied. Optimal CPP (CPPopt) was calculated automatically as the level of CPP where CPA works best for the patient, i.e., where PRx is lowest. Patients with actual CPP below their calculated optimum had higher amounts of low-flow regions (CBF < 10 ml/100g/min). The findings in this thesis emphasize the importance of taking CPA into account in the management of TBI and SAH patients, and suggest that treatment should be individualized depending on status of autoregulation. PRx and CPPopt may be used bedside to guide management according to status of autoregulation. In the future CPA-guided management should be tested in prospective studies

Over the past century, resuscitation of victims of hemorrhage with crystalloid or colloid solutions has proven time and again to enhance survival. Recent animal studies have shown even further improvement if drag reducing polymers (DRPs) were added in nanomolar concentrations to these resuscitation fluids. Nevertheless, our fundamental understanding of how the microcirculation responds to hemorrhage is incomplete, as well as how properties of resuscitation fluids may modulate microvascular blood flow and tissue oxygen delivery. In the present study, we examined the systemic and microcirculatory responses to hemorrhage, as they relate to hemodynamics and oxygenation, and how resuscitation fluids modify these responses. Fourteen anesthetized, male Sprague-Dawley rats were subjected to a volume hemorrhage that reduced their blood volume by 30%. After 30 minutes of hemorrhagic hypotension, the animals were resuscitated either with a conventional colloid solution of Hespan (6% hetastarch), or Hespan plus 10 parts per million of the drag reducing polymer polyethylene oxide. A volume of either fluid equal to the shed blood volume was infused over a period of one hour. All the animals were observed for two hours following the initiation of fluid resuscitation or until they expired, with measurements made at 30-minute intervals during this time. Unlike previous studies, this study found no significant improvement in blood flow and tissue oxygenation, and no significant difference between the Control and DRP groups.

Every year, approximately 3000 people die as the result of physical trauma in Sweden (Gedeborg, Chen, Thiblin, & Byberg, 2012). Many of these deaths occurs outside of the hospital and are preventable, including some caused by hemorrhage. One hemorrhage control device is the tourniquet which can be used in a civilian pre-hospital setting. The effects of stress on a laypersons tourniquet application ability is unknown and to date only one study have examined the effects of stress on tourniquet application in a military population (Schreckengaust, Littlejohn, & Zarow, 2014). The purpose of this study was to investigate how the performance of two first aid interventions, tourniquet application and cardiopulmonary resuscitation (CPR), is affected by stress in immediate (layperson) and first (professional) responders. A total of 55 participants followed a brief educational program about hemorrhage control. Their ability to apply a tourniquet and perform CPR was tested in a calm classroom scenario and a stressful scenario, which consisted of paintball fire and an obstacle course. Stress was assessed through subjective reports of stress, physiological heart rate and heart rate variability measurements, and subjective workload and with a secondary task. The results showed differences of elicited stress reaction between the conditions and groups. Tourniquet and CPR performance was moderately affected by stress. Participants across all groups experienced more stress reactions during the stressful scenario, and laypersons did experience more stress reactions than professional first responders. In conclusion, the method did make participants experience more stress reactions in terms of psychological, physiological and performance adaptations in the stressful scenario. However, the results need to be replicated and a list of suggested improvements are given, such as: examining the fidelity of the scenarios, validating the tourniquet application assessment method, and examining the relationship between tourniquet application performance and self-assessed performance.

Os mecanismos responsáveis pelas manifestações hemorrágicas durante a leptospirose severa ainda são pouco compreendidos. Este trabalho avaliou os efeitos diretos e indiretos das leptospiras sobre moléculas do sistema de coagulação. Foi verificado que leptospiras virulentas são eficientes em bloquear a atividade da enzima trombina por meio do sequestro de seu sítio de ligação ao substrato, gerando uma menor formação do coágulo de fibrina, acarretando em sangramento e consequente disseminação do patógeno para outros sítios de infecção. Foi mostrado também que a inflamação causada pela resposta imune contra as bactérias causa uma ativação da coagulação, muito provavelmente via expressão de Fator Tissular, o que ocasiona um consumo e consequente esgotamento dos fatores e inibidores de coagulação, culminando em hemorragia e formação de trombos, os quais podem levar à falência de órgãos. Estes resultados melhoram o entendimento da patogênese da leptospirose e podem favorecer o desenvolvimento de terapias para as manifestações hemorrágicas. / The mechanisms responsible for the hemorrhagic manifestations during severe leptospirosis are still poorly understood. This work evaluated the direct and indirect effects of leptospires upon molecules of the coagulation system. It has been shown that virulent leptospires are effective in blocking the activity of the enzyme thrombin by sequestration of its substrate binding site, generating less fibrin clot formation, leading to bleeding and consequent dissemination of the pathogen to other sites of infection. It has also been shown that the inflammation caused by the immune response against the bacteria causes an activation of the coagulation, most probably via expression of Tissue Factor, which causes a consumption and consequent depletion of coagulation factors and inhibitors, culminating in hemorrhage and thrombus formation, which can lead to organ failure. These results improve the understanding of the pathogenesis of leptospirosis and may favor the development of therapies for hemorrhagic manifestations.

Em função da categoria dos estressores, vias neurais específicas são envolvidas e respostas distintas podem ser induzidas. A literatura tem reportado que o estrógeno (E 2 ) através de seus receptores de tipos (ER) e (ER) influencia a atividade do eixo hipotálamo hipófise adrenal (HPA). Além disso, há evidências de que o E2 exerça efeitos protetores em situação de choque hemorrágico. O objetivo deste trabalho foi verificar a participação dos receptores ER e ER na atividade do eixo HPA durante estresse hemorrágico. Foram utilizadas ratas Wistar ovariectomizadas que receberam injeções s.c. de DMSO (veículo), PPT (agonista ER) ou DPN (agonista ER), durante 3 dias. No segundo dia, as ratas foram canuladas para coleta seriada de sangue na manhã seguinte. Os animais receberam (controle) ou não (hemorrágicos) reposição imediata com salina. Os hormônios corticosterona (CORT), ocitocina (OT) e vasopressina (AVP) foram dosados por radioimunoensaio. Ao final do experimento, os ratos foram perfundidos e os cérebros processados para imuno-histoquímica de FOS, tirosina hidroxilase (TH) e hormônio liberador de corticotrofina (CRH). Nos animais tratados com veículo, a hemorragia gradual moderada aumentou a secreção de CORT, OT e AVP, a expressão de neurônios TH ativados na região A1C1 e de FOS no mpPVN. O PPT reduziu a secreção de CORT, na situação controle atuando no LC e mpPVN; e também após hemorragia atuando no LC, NTS, A1C1 e mpPVN. O DPN reduziu a secreção de CORT apenas após estresse hemorrágico atuando no LC, A1C1 e mpPVN. O PPT bloqueou o aumento da secreção de OT e aumentou a secreção de AVP, após hemorragia. O DPN, por sua vez, reduziu a concentração plasmática de OT e aumentou a concentração plasmática de AVP, independentemente da hemorragia. Em conclusão: o estrógeno pode exercer uma ação inibitória sobre a secreção basal de CORT somente através da ação do ER sobre o LC e mpPVN; a secreção de CORT aumenta em resposta à hemorragia gradual moderada e o estrógeno pode exercer um controle inibitório nessa resposta através de ER atuando sobre LC, NTS, A1C1 e mpPVN, bem como através de ER atuando sobre LC, A1C1 e mpPVN. / Depending on the stressors category, specific neural pathways are involved and different responses can be selected. It has been reported in the literature that estrogen (E2 ) can affect hypothalamus pituitary adrenal (HPA) axis activity through its receptors type (ER) and (ER). Moreover, there is evidence that E 2 has protecting properties after hemorrhagic shock. The aim of this work was to assess the participation of ER and ER on HPA axis activity during hemorrhagic stress. It was used ovariectomized Wistar rats that received s.c. injections of: DMSO (vehicle), PPT (ER agonist) or DPN (ER agonist), during 3 days. In the second day the rats were catheterized for serial blood collect in the next morning. Animals received (control) or not (hemorrhagic) immediate reposition with same volume of isotonic saline. The hormones corticosterone (CORT), oxytocin (OT) and vasopressin (AVP) were measured by radioimmunoassay. At the end of the experiment, animals were perfused and their brains were processed for immuno-histochemistry for FOS, tyrosine hydroxylase (TH) and corticotropin releasing hormone (CRH). In vehicle treated animals, the gradual hemorrhage enhanced CORT, OT and AVP secretion, TH activated neurons expression in A1C1 and FOS expression in mpPVN. PPT decreased plasma CORT in control situation acting on LC and mpPVN, and also after hemorrhage acting on LC, NTS, A1C1 and mpPVN. DPN reduced plasma CORT only after hemorrhagic stress acting on LC, A1C1 and mpPVN. PPT blocked the increase of OT secretion and increased AVP secretion, after hemorrhage. The agonist DPN reduced OT and increased AVP levels, despite hemorrhage. In conclusion: E2 can exert an inhibitory effect on CORT basal secretion only through ER action on LC and mpPVN; CORT secretion increases after gradual moderate hemorrhage and E2 inhibit this secretion through ER action on LC, NTS, A1C1 and mpPVN, as well through ER action on LC, A1C1 and mpPVN.

No description available.

by Joseph Jao Yiu Sung. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references (p. 201-220). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

Hemorragia pós-parto (HPP) é tradicionalmente definida como perda sanguínea maior ou igual a 500 ml em partos vaginais e acima de 1000 ml em partos cesarianos e/ou queda de 10% do hematócrito comparado ao exame feito à admissão da parturiente e/ou sangramento importante que requeira hemotransfusão. Estima-se que 25 a 30% das mortes maternas são decorrentes da HPP. Além disso, este quadro pode causar impacto na qualidade de vida de mulheres e neonatos, devido às complicações, além da necessidade de intervenções. Objetivo: Estimar prevalência de HPP, efeito do tipo de parto e intervenções obstétricas sobre os valores hematimétricos (hematócrito e hemoglobina) em uma amostra de mulheres primíparas atendidas em hospital de ensino. Metodologia: A amostra constituiu-se de 100 primíparas, independente da via de parto. A coleta de dados foi realizada a partir de dados retrospectivos obtidos de prontuários (impresso e eletrônico), cartão de pré-natal, dentre outras fontes de consulta, respaldadas por formulário testado previamente em estudo piloto. Resultados: A prevalência de HPP na amostra de estudo foi de 16%. Através da análise simples (teste F), encontrou-se significância estatística para as seguintes variáveis: diabetes, síndromes hipertensivas, anemia diagnosticada durante a gestação, analgesia, tipo de parto e peso do recém-nascido. Porém através da regressão linear múltipla, observou-se significância apenas para as variáveis: diabetes e analgesia. Mulheres portadoras de diabetes apresentaram maiores perdas hemáticas; enquanto que mulheres que realizaram analgesia durante o trabalho de parto, apresentaram menores perdas. Dentre as complicações mais frequentes no período compreendido do puerpério imediato à alta hospitalar detectou-se: necessidade de ocitócito terapêutico adicional (20 UI); nível de hemoglobina < 9 mg/dl; lipotímia; necessidade de suplementação com sulfato ferroso (em dose terapêutica); 22 mulheres apresentaram algum tipo de sintoma (fraqueza, desânimo, entre outros); 62 mulheres apresentaram anemia no período puerperal. Houve correlação positiva (0,89) entre os níveis de queda do hematócrito e da hemoglobina, sendo que para queda de hematócrito >= 10%, a queda de hemoglobina foi de 2,99 mg/dl. Não foram constatadas outras associações significativas. Considerações finais: Acreditamos que a dosagem de hemoglobina e hematócrito 48 horas pós-parto é uma importante ferramenta para auxiliar no diagnóstico precoce e mais fidedigno dos quadros, devendo esta prática ser adotada como rotina nas instituições. Ressaltamos mais uma vez que análise laboratorial não exime o profissional de avaliação clínica rigorosa e minuciosa. Assim, esta prática vem complementar a assistência clínica no puerpério e em hipótese alguma se deve substituí-la. Dada a magnitude do problema e a escassez de estudos sobre a temática acreditamos que todos os trabalhos sobre a questão são louváveis e podem contribuir para a melhoria da assistência ao ciclo gravídico-puerperal. / Postpartum hemorrhage (PPH) is traditionally defined as blood loss greater than or equal to 500 ml in vaginal parturition and over 1000 ml in cesarean sections and/or 10% drop in hematocrit compared to examination by the admission of the mother and/or major bleeding requiring blood transfusion. It is estimated that 25-30% of maternal deaths are due to PPH. Moreover, this framework can impact quality of life of women, newborns, due to its complications, and the need for interventions. Objective: To estimate the prevalence of PPH and effect of type of delivery and obstetric interventions on the hematological values (hemoglobin and hematocrit) in a sample of primiparous women attended at a teaching hospital. Methodology: The sample consisted of 100 primiparous, regardless of mode of delivery. Data collection was performed with retrospective data obtained from medical records, pregnancy card, among other sources of information, backed-up by a form previously tested in a pilot study. Results: The prevalence of PPH in the study sample was 16%. Through simple analysis (F test), statistical significance was found for the following variables: diabetes, hypertensive disorders, anemia diagnosed during pregnancy, analgesia, mode of delivery and weight of the newborn. But through multiple linear regression, we found significance only for the variables: diabetes and analgesia. Women with diabetes had higher blood loss, whereas women who underwent analgesia during labor, showed smaller losses. The following complications were identified: need for additional oxytocin therapy (20UI), hemoglobin < 9 mg/dl, syncope, need for supplementation with iron (terapheutic dose), 22 women had some type of symptoms (weakness, prostration, etc), 62 women had anemia in the postpartum period. A positive correlation (0.89) between the levels of low hematocrit and hemoglobin, while those for the fall of hematocrit >= 10%, the drop in hemoglobin was 2.99 mg/dl. No association with other variables was found. Final considerations: We believe that dosage of hemoglobin and hematocrit 48 hours after delivery is an important tool for early diagnosis and the most reliable for detection of the frameworks, so, should this practice be adopted as routine in institutions. We emphasize once again that laboratoring testing does not relieve the professional of a rigorous and thorough clinical evaluation. Thus, this practice come to complement the clinical care in puerperium and in no way should replace it. Given the magnitude of the problem and the scarcity of studies on the subject believe that all study on the issue is commendable and may contribute to the improvement of care in pregnancy and childbirth.

Introduction. Devant les nombreux facteurs pouvant influencer le risque hémorragique despatients sous anticoagulant, le concept de médecine personnalisée pourrait avoir unimpact favorable dans la prise en charge globale de ces patients.Hypothèse et objectif. L’hypothèse de ce travail de thèse est que l’utilisation et l’analysede registre de « vraie vie » pourrait permettre de définir des « profils » hémorragique depatient permettant une prise en charge personnalisée des patients.Matériel et Méthode. Ce travail de thèse a utilisé deux registres de vraie vie, le registreRIETE (registre international multicentrique prospectif) et le registre RATED (registremonocentrique).Résultats. Nous avons montré l’importance du recueil biologique dans l’analyse desaccidents hémorragiques sous anticogulants avec une perte plus élevée de facteurs decoagulation, lors d’hémorragie gastro-intestinales par rapport aux intracraniennes sousAVK. A l’inverse, ce risque est diminué de moitié en cas de mutation du facteur V Leiden.Grâce au registre RIETE, nous nous sommes ensuite intéressés aux métrorragies sousanticoagulant (peu décrites dans la littérature) où seulement 0,17% des femmesprésentaient des saignements utérins majeurs. Nous avons par la suite montré que lespatients fragiles (CrCl ≤50 mL / min, un âge ≥75 ans ou un poids corporel ≤50 kg) ont unrisque deux fois plus élevé de saignement grave. Enfin, afin de montrer lacomplémentarité des registres de vraie vie et des données d’essais randomisés, nousnous sommes intéressés aux patients exclus de ces essais randomisés et avons montréégalement un risque hémorragique 4 fois plus élevé.Conclusion. Ce travail de thèse a permis de démontrer l’intérêt de travailler non pastoutes hémorragies confondues mais hémorragies par hémorragies, avec un intérêt deréalisation de registres prospectifs de vraie vie avec la mise en oeuvre de bio-banquepermettant une analyse plus personnalisée de la prise en charge des patients. / Introduction. Given many risk factors that may influence the risk of hemorrhage underanticoagulant therapy, the concept of personalized medicine could have a favorableimpact in the overall management of these patients.Hypothesis and objective. The hypothesis of this thesis is that the use and analyze of "reallife" registries could allow to define hemorrhagic "profiles" allowing a personalizedmanagement of the patients.Material and method. This thesis work has used two real life registries, the RIETE registry(international, multicentric and prospective register) and RATED (monocentric register).Results. We showed the importance of biological database in the analysis of hemorrhagicevents under anticoagulants with a higher loss of coagulation factors in gastrointestinalbleeding compared with intracranial bleeding under AVK. Conversely, this bleeding risk istwo times lower in case of factor V Leiden mutation. Thanks to the RIETE registry, wewere interested in abnormal uterine bleeding under anticoagulant therapy (few studies inthe literature) with major uterine bleeding only for 0.17% of women. Then, we showed thatfragile patients (CrCl ≤50 mL / min, age ≥75 years or body weight ≤50 kg) have a 2-foldhigher risk for major bleeding. Finally, in order to show the complementarity between datafrom real life registries and randomized trial, we assessed patients normally excluded fromthese randomized trials and also showed a 4-fold higher bleeding risk in these excludedpatients.Conclusion. This thesis work allowed us to demonstrate the interest of working not only onoverall hemorrhages but on each type of hemorrhage separately, with a particular interestto create real life prospective registries with the implementation of bio-bank allowing amore personalized analysis of the intake of patients.

Spontaneous intracerebral hemorrhage, the non-traumatic rupture of cerebral blood vessels, is the most devastating form of stroke. The disease is dynamic, unpredictable, and patients can worsen acutely within the first 24 hours secondary to hematoma expansion: re-bleeding of a baseline hemorrhage. Hematoma expansion is a major predictor of mortality and poor long-term outcome. This secondary analysis thesis proposes to advance the current understanding of this phenomenon through three separate research endeavors: 1) a scoping review of hematoma expansion prediction scores, 2) an independent validation of a non-contrast prediction score, and 3) an assessment and revision of the dichotomous definition of hematoma expansion used in clinical trials. These three projects will offer different contributions that will advance the science of intracerebral hemorrhage, a field where treatment options, outcome measures, and basic definitions, are all under active debate.