Dissertations / Theses on the topic 'Trauma hemorrhagic shock'

Previous studies have shown an increase in survival when a minute amount of drag-reducing polymers were added to a resuscitation fluid. The purpose of this investigation was to examine the effect of adding a minute amount of the drag-reducing polymer polyethylene glycol to a resuscitation fluid, on the microcirculation of skeletal muscle during a volume-controlled hemorrhage model. The spinotrapezius muscle in twelve male Sprague Dawley rats was exteriorized for microvascular measurements of the arterioles. The diameters of the three levels of arterioles, interstitial fluid PO2, and RBC velocity in the feed arteriole were measured. Flow in the feed arteriole was calculated using the diameter and RBC velocity. Heart rate, mean arterial pressure, respiratory rate, arterial blood gases, arterial blood electrolytes, and arterial blood metabolites were measured. No significant physiological differences were observed between the DRP group and the Control group.

Over the last 20 years, much work has focused on computer-aided clinical decision support systems due to a rapid increase in the need for management and processing of medical knowledge. Among all fields of medicine, trauma care has the highest need for proper information management due to the high prevalence of complex, life-threatening injuries. In particular, hemorrhage, which is encountered in most traumatic injuries, is a dominant factor in determining survival in both civilian and military settings. This complication can be better managed using a more in-depth analysis of patient information. Trauma physicians must make precise and rapid decisions, while considering a large number of patient variables and dealing with stressful environments. The ability of a computer-aided decision making system to rapidly analyze a patient’s condition can enable physicians to make more accurate decisions and thereby significantly improve the quality of care provided to patients. The first part of this study is focused on classification of highly complex databases using a hierarchical method which combines two complementary techniques: logistic regression and machine learning. This method, hereafter referred to as Classification Using Significant Features (CUSF), includes a statistical process to select the most significant variables from the correlated database. Then a machine learning algorithm is used to identify the data into classes using only the significant variables. As the main application addressed by CUSF, a set of computer-assisted rule-based trauma decision making system are designed. Computer aided decision-making system not only provides vital assistance for physicians in making fast and accurate decisions, proposed decisions are supported by transparent reasoning, but also can confirm a physicians’ current knowledge, enabling them to detect complex patterns and information which may reveal new knowledge not easily visible to the human eyes. The second part of this study proposes an algorithm based on a set of novel wavelet features to analyze physiological signals, such as Electrocardiograms (ECGs) that can provide invaluable information typically invisible to human eyes. These wavelet-based method, hereafter referred to as Signal Analysis Based on Wavelet-Extracted Features (SABWEF), extracts information that can be used to detect and analyze complex patterns that other methods such as Fourier cannot deal with. For instance, SABWEF can evaluate the severity of hemorrhagic shock (HS) from ECG, while the traditional technique of applying power spectrum density (PSD) and fractal dimension (FD) cannot distinguish between the ECG patterns of patients with HS (i.e. blood loss), and those of subjects undergoing physical activity. In this study, as the main application of SABWEF, ECG is analyzed to distinguish between HS and physical activity, and show that SABWEF can be used in both civilian and military settings to detect HS and its extent. This is the first reported use of an ECG analysis method to classify blood volume loss. SABWEF has the capability to rapidly determine the degree of volume loss from hemorrhage, providing the chance for more rapid remote triage and decision making.

Trauma är den ledande dödsorsaken i Sverige för människor mellan 15 och 44 år och en stor andel dör till följd av blödning som uppkommer vid skadetillfället. Blödning fortsätter också vara den ledande orsaken till traumarelaterad död som kunde ha varit förebyggbar både civilt och militärt. Traumaomhändertagandet är komplext, ofta tidskritiskt och ambulanspersonalen är ofta de som först får vårda dessa patienter ute på skadeplats och därav blir ambulanspersonalens första bedömning och omhändertagande av stor betydelse. Vätskebehandling för kritiskt skadade traumapatienter i hemorragisk chock eller hotande hemorragisk chock är ett omdiskuterat ämne och Sverige saknar nationella riktlinjerna för omhändertagande och behandling prehospitalt vid hemorragisk chock och trauma och de regionala riktlinjer som finns skiljer sig ibland till viss del åt mellan länen. Syftet med studien var att undersöka effekten av ambulanssjuksköterskans vätskebehandling för patienter i hemorragisk chock vid trauma. Som metod har en litteraturöversikt genomförts där totalt 15 studier inkluderats som är publicerade mellan 2009 och 2019. I resultatet framkom två huvudteman – vätskebehandlingens effekt på mortalitet och vätskebehandlingens effekt på koagulation. Samtliga fyra studier som undersökt hur koagulationsförmågan påverkas av kristalloid hyperton och/eller isoton vätskebehandling hos patienter med eller med risk för hemorragisk chock utsatta för trauma har kommit fram till att den försämras desto mer vätska patienten får. Resultatet visade oklar evidens gällande vätskebehandlingens effekt för mortaliteten på patienter i hemorragisk chock vid trauma. Däremot påvisade ingen av studierna att mortaliteten minskade. Slutsats var att majoriteten av artiklarna talar för att stora mängder vätska prehospitalt minskar eller inte gör någon skillnad för överlevnaden för kritiskt skadade traumapatienter vid hemorragisk chock. Många faktorer spelar in och det är svårt att dra några slutsatser utifrån resultatet och mer forskning behövs inom området.
Trauma is the leading cause of death in Sweden for people between the age of 15 and 44 years and a large proportion of people die because of bleeding that occurs at the time of the injury. Bleeding also continues to be the leading cause of trauma-related death that could have been preventable both in a civilian and military setting. Trauma care is complex, often time-critical, and the ambulance nurses are often the first to care for these patients on the scene and therefore the first assessment and care of these patients is of great importance. Fluid resuscitation for critically injured trauma patients in hemorrhagic shock or threatening hemorrhagic shock is a debated topic and Sweden lacks national guidelines for trauma care and treatment prehospital. The regional guidelines sometimes for some manner differ between the counties in Sweden. The aim of this study was to determine the impact of fluid resuscitation for patients with hemorrhagic shock after trauma. As a method, a literature review was carried out, which included a total of 15 studies published between 2009 and 2019. The result revealed two main themes - the impact of fluid resuscitation on mortality and the impact of fluid resuscitation on coagulation. All four studies that examined how coagulation ability is affected by crystalloid hypertonic and/or isotonic fluid resuscitation in patients at risk of hemorrhagic shock after trauma, the severity seems to be dependent on the amount of fluid infused, the more fluid the more severe coagulation abnormalities. The result showed unclear evidence of the effect of fluid resuscitation in mortality for trauma patients in hemorrhagic shock. However, none of the studies showed it decreased in mortality. In conclusion, the majority of articles show that large amount of fluid given in prehospital care have no impact or did have a negative impact on survival of critically injured trauma patients in hemorrhagic shock. Many factors come into play and it is difficult to draw any conclusions based on the results and more research are needed.

Le blessé de guerre est un blessé grave qui associe choc hémorragique et polytraumatisme. Malgré les progrès thérapeutiques des dernières années, l'hémorragie reste la première cause de décès évitable chez ce type de blessés. Les patients qui survivent aux premières heures de leurs blessures voient leur pronostic vital et fonctionnel menacé par les complications secondaires. Les protocoles de prise en charge des blessés de guerre basés sur le principe de damage control ressuscitation et la transfusion massive de sang total ont permis de réduire considérablement les décès par choc hémorragique. Toutefois, les contraintes logistiques des théâtres d'opérations extérieures et les afflux massifs de blessés ne permettent pas d'administrer du sang total à tous, en tout lieu. Le développement de produits sanguins labiles modifiés qui répondent aux contraintes opérationnelles pourrait améliorer la survie des blessés. Pour répondre à cet objectif, nous avons développé deux formulations de plasma lyophilisé hyperconcentré porcin, l'une sans (PLYO-H) et l'autre avec lyophilisat plaquettaire (PLYO-H/LP). Les produits obtenus présentaient des critères de qualité de production optimaux. Le PLYO-H et le PLYO-H/LP étaient riches en protéines, dont l'albumine, et présentent une hyperosmolarité à deux fois celle du plasma. Dans le PLYO-H/LP, les plaquettes lysées au cours du processus de fabrication ont libéré dans le plasma des facteurs de coagulation, dont le fibrinogène, en quantité importante. L'intérêt thérapeutique des PLYO-H et PLYO-H/LP a été évalué à l'aide d'un modèle porcin représentatif du blessé de guerre. La comparaison entre les animaux traités par PLYO, PLYO-H, PLYO-H/LP ou sang total n'a pas montré de supériorité d'un groupe par rapport aux autres. Toutefois, l'analyse des paramètres de la fonction cardiovasculaire et de l'hémostase a révélé des effets bénéfiques du PLYO-H et du PLYO- H/LP qui ouvrent la porte à des études complémentaires portant cette fois sur des formulations issues de plasmaphérèse humaine
War casualties associate multiple injuries with shock hemorrhage. Despite the therapeutic progress of recent years, hemorrhage is the leading cause of preventable deaths and secondary multiple organ failure can lead to vital and functional prognosis. Management of war-injured patients based on damage control resuscitation and massive transfusion of whole blood reduced considerably the number of deaths. Nevertheless, during foreign operations whole blood is sometimes lacking because of logistic limitations and massive casualties. Modified blood products that are free from constraints could help war-injured patients to survive. To achieve this objective, we developed two French hyper-concentrated lyophilized plasmas with (FLYP-H/LP) or not (FLYP-H) lyophilized platelets. The production of these products is of a high quality. FLYP-H and FLYP-H/LP are high protein products, especially albumin, which confer them a hyperosmolarity twice that of plasma. In FLYP-H/LP, platelets were lysed during the manufacturing process and liberated high quantities of coagulation factors, such as fibrinogen. The therapeutic effects of FLYP-H and FLYP-H/LP were evaluated thanks to our war-injured porcin model. Statistical analysis highlighted the beneficial effects of FLYP-H and FLYP-H/LP on cardiovascular function and hemostasis. These results open the door to more analysis but on human FLYP-H and FLYP-H/LP

L’association lésionnelle d’une contusion pulmonaire et d’un état de choc hémorragique est fréquente et constitue un réel chalenge thérapeutique. La prise en charge de ce choc va nécessiter une réanimation hémodynamique dans laquelle le remplissage vasculaire tient une place centrale. Mais dans ce contexte de poumon contus, il devra être raisonné car délétère sur le plan pulmonaire, notamment en terme d'oedème et d'altération de la compliance. Ce remplissage devra donc être titré, basé sur des objectifs tensionnels clairs et un monitorage hémodynamique fiable. L'utilisation de solutés à haut pouvoir d'expansion volémique (sérum salé hypertonique, colloïdes) présente un intérêt, de même que l'introduction précoce de vasopresseurs. Le monitorage hémodynamique permettra de conduire cette réanimation sur des objectifs de pression artérielle, sur des indices de précharge dépendance et sur la mesure de l'eau pulmonaire extravasculaire. Notre travail, basé sur des études expérimentales et cliniques, a pour objectif de caractériser les modalités actuelles de prise en charge d’une contusion pulmonaire, sur les plans hémodynamiques et respiratoires
Pulmonary contusion is often associated with hemorrhagic shock, constituting a challenge in trauma care. For patients who have sustained lung contusions, fluid resuscitation should be carefully performed, because injured lungs are particularly vulnerable to massive fluid infusions with an increased risk of pulmonary edema and compliance impairment. Fluid administration should be included in an optimized and goal directed resuscitation, based on blood pressure objectives and hemodynamical monitoring. The use of fluids with high volume-expanding capacities (hypertonic saline, colloids) is probably interesting, as well as early introduction of vasopressors. Hemodynamic monitoring will allow to conduct resuscitation on blood pressure objectives, on preload parameters and on extravascular lung water measurement.Our work, based on experimental and clinical studies, objective to characterize the current modalities of ventilatory and hemodynamical aspect of pulmonary contusion care

Introdução - O choque hemorrágico é a maior complicação e causa de morbi-mortalidade em doentes com trauma. Neste estudo, pretendemos avaliar o impacto do ácido tranexâmico em doentes com choque hemorrágico por trauma num hospital terciário. Material e métodos - Este estudo, realizado no Centro Hospitalar e Universitário São João, incluiu doentes adultos, admitidos no Serviço de Medicina Intensiva, por choque hemorrágico secundário a trauma. Definimos choque hemorrágico como pressão arterial sistólica ≤90 mmHg e/ou frequência cardíaca ≥110 bpm. Na ausência destes parâmetros, prevaleceu o juízo clínico do médico assistente. Efetuámos coorte de doentes com e sem administração de acido tranexâmico: avaliámos mortalidade global, tempo de ventilação mecânica invasiva, tempo de internamento na Unidade de Cuidados Intensivos e no hospital, unidades de glóbulos rubros transfundidas e eventos trombóticos. Resultados - Incluíram-se 105 doentes dos 1045 que foram admitidos por trauma entre Janeiro 2017 e Dezembro 2018: destes, 38 receberam ácido tranexâmico (36,2%) versus 67 sem ácido tranexâmico (63,8%). O grupo tratado com ácido tranexâmico apresentou maior gravidade (APACHE II p=0,038) e mortalidade na Unidade de Cuidados Intensivos, tanto na população global (p=0,003) como no subgrupo estratificado por traumatismo crânio-encefálico (p=0,037). Não se observaram diferenças estatisticamente significativas nos outcomes secundários. Discussão - Os doentes com choque hemorrágico por trauma admitidos no Serviço de Medicina Intensiva e tratados com ácido tranexâmico apresentam maior mortalidade, provavelmente pela maior gravidade clínica. Não encontrámos no mesmo grupo aumento do número de eventos trombóticos. Conclusões - Torna-se necessário complementar com mais estudos e coortes mais numerosas para avaliar o verdadeiro benefício do uso de ácido tranexâmico nestes doentes. Palavras-chave: Ácido Tranexâmico; Trauma; Choque hemorrágico
Introduction - Hemorrhagic shock is the major complication and cause of morbi-mortality in trauma patients. We aimed to study the impact of tranexamic acid in trauma patients with hemorrhagic shock in a tertiary hospital. Material and methods - Our study, performed at Centro Hospitalar e Universitário São João, included adult trauma patients with hemorrhagic shock admitted to the Intensive Care Department. We defined hemorrhagic shock as Systolic Blood Pressure ≤90 mmHg and/or Heat Rate ≥110 bpm. In the absence of these, the clinical judgment of the attending physician prevailed. We did patients cohort with and without tranexamic acid use: we assessed global mortality, invasive mechanical ventilation duration, Intensive Care Unit and hospital length of stay, red blood cells units transfused and vascular occlusive events. Results - 105 patients were included from the 1045 admitted for trauma between January 2017 and December 2018: of those, 38 received tranexamic acid (36,2%) versus 67 without it (63,8%). Tranexamic acid group registered a higher severity (APACHE II p=0,038) and mortality in the Intensive Care Unit either in the global population (p=0,003) or in the stratified Traumatic Brain Injury subgroup (p=0,037). We found no statistically significant differences in the secondary outcomes. Discussion - Trauma patients with hemorrhagic shock admitted in the Intensive Care Department and treated with tranexamic acid had higher mortality, probably explained by the higher severity observed. We didnt find increased vascular occlusive events in tranexamic acid group. Conclusions - It is necessary to complement these findings with more studies and larger cohorts to assess the real benefits of tranexamic acid use in these patients.

Introdução - O choque hemorrágico é a maior complicação e causa de morbi-mortalidade em doentes com trauma. Neste estudo, pretendemos avaliar o impacto do ácido tranexâmico em doentes com choque hemorrágico por trauma num hospital terciário. Material e métodos - Este estudo, realizado no Centro Hospitalar e Universitário São João, incluiu doentes adultos, admitidos no Serviço de Medicina Intensiva, por choque hemorrágico secundário a trauma. Definimos choque hemorrágico como pressão arterial sistólica ≤90 mmHg e/ou frequência cardíaca ≥110 bpm. Na ausência destes parâmetros, prevaleceu o juízo clínico do médico assistente. Efetuámos coorte de doentes com e sem administração de acido tranexâmico: avaliámos mortalidade global, tempo de ventilação mecânica invasiva, tempo de internamento na Unidade de Cuidados Intensivos e no hospital, unidades de glóbulos rubros transfundidas e eventos trombóticos. Resultados - Incluíram-se 105 doentes dos 1045 que foram admitidos por trauma entre Janeiro 2017 e Dezembro 2018: destes, 38 receberam ácido tranexâmico (36,2%) versus 67 sem ácido tranexâmico (63,8%). O grupo tratado com ácido tranexâmico apresentou maior gravidade (APACHE II p=0,038) e mortalidade na Unidade de Cuidados Intensivos, tanto na população global (p=0,003) como no subgrupo estratificado por traumatismo crânio-encefálico (p=0,037). Não se observaram diferenças estatisticamente significativas nos outcomes secundários. Discussão - Os doentes com choque hemorrágico por trauma admitidos no Serviço de Medicina Intensiva e tratados com ácido tranexâmico apresentam maior mortalidade, provavelmente pela maior gravidade clínica. Não encontrámos no mesmo grupo aumento do número de eventos trombóticos. Conclusões - Torna-se necessário complementar com mais estudos e coortes mais numerosas para avaliar o verdadeiro benefício do uso de ácido tranexâmico nestes doentes. Palavras-chave: Ácido Tranexâmico; Trauma; Choque hemorrágico
Introduction - Hemorrhagic shock is the major complication and cause of morbi-mortality in trauma patients. We aimed to study the impact of tranexamic acid in trauma patients with hemorrhagic shock in a tertiary hospital. Material and methods - Our study, performed at Centro Hospitalar e Universitário São João, included adult trauma patients with hemorrhagic shock admitted to the Intensive Care Department. We defined hemorrhagic shock as Systolic Blood Pressure ≤90 mmHg and/or Heat Rate ≥110 bpm. In the absence of these, the clinical judgment of the attending physician prevailed. We did patients cohort with and without tranexamic acid use: we assessed global mortality, invasive mechanical ventilation duration, Intensive Care Unit and hospital length of stay, red blood cells units transfused and vascular occlusive events. Results - 105 patients were included from the 1045 admitted for trauma between January 2017 and December 2018: of those, 38 received tranexamic acid (36,2%) versus 67 without it (63,8%). Tranexamic acid group registered a higher severity (APACHE II p=0,038) and mortality in the Intensive Care Unit either in the global population (p=0,003) or in the stratified Traumatic Brain Injury subgroup (p=0,037). We found no statistically significant differences in the secondary outcomes. Discussion - Trauma patients with hemorrhagic shock admitted in the Intensive Care Department and treated with tranexamic acid had higher mortality, probably explained by the higher severity observed. We didnt find increased vascular occlusive events in tranexamic acid group. Conclusions - It is necessary to complement these findings with more studies and larger cohorts to assess the real benefits of tranexamic acid use in these patients.

Acute Respiratory Distress Syndrome (ARDS) following hemorrhagic shock/resuscitation (S/R) is an important contributor to late morbidity and mortality in trauma patients. S/R promotes ARDS by inducing oxidative stress that primes cells of the innate immune system for excessive responsiveness to small inflammatory stimuli, termed the “twohit” hypothesis. Activated alveolar macrophages (AM) play a central role and when recovered from S/R animals exhibit an exaggerated responsiveness to lipopolysaccharide (LPS) with increased activation of the proinflammatory transcription factor NF-κB, and augmented expression of cytokines. LPS triggers AM signalling through Toll like receptor 4 (TLR4), which resides in plasma membrane lipid rafts. The objective of this work is to define cellular mechanisms of macrophage priming by oxidative stress following shock resuscitation. The main hypothesis investigated is that altered cellular distribution of TLR4 can lead to macrophage priming and antioxidant resuscitation strategies can diminish these effects. AM of rodents, exposed in vivo to oxidant stress following S/R, increase their surface levels of TLR4, which in turn results in augmented NF-κB translocation in response to small doses of LPS. Furthermore, in vitro H2O2 treatment of RAW 264.7 macrophages results in similar TLR4 surface translocation. Depletion of intracellular calcium, disruption of the cytoskeleton or inhibition of the Src kinases prevents the H2O2-induced TLR4 translocation, suggesting the involvement of receptor exocytosis. Further, fluorescent resonance energy iii transfer between TLR4 and lipid rafts as well as biochemical raft analysis demonstrated that oxidative stress redistributes TLR4 to surface lipid rafts. Preventing the oxidant-induced movement of TLR4 to lipid rafts using methyl-ß-cyclodextrin precluded the increased responsiveness of cells to LPS after H2O2 treatment. Further, AM priming by oxidative stress can be diminished by early exposure to resuscitation regimens with direct or indirect systemic antioxidant effects, such as 25% albumin, N-acetylcysteine and hypertonic saline. Hyperosmolarity was found to modulate AM TLR4 gene and protein expression. Collectively, these studies suggest a novel mechanism whereby oxidative stress might prime the responsiveness of cells of the innate immune system. Targeting the TLR4 signalling pathway early during shock resuscitation may represent an anti-inflammatory strategy able to ameliorate late morbidity and mortality following S/R.

碩士
輔仁大學
營養科學系碩士班
105
Hemorrhagic shock patients have huge loss of blood, may lead to energy and oxygen deficit and hypoxia. It shall be given as soon as possible to stop bleeding and fluid resuscitation. However, resuscitation may augment oxidative stress which leads to systemic inflammation, multiple organ failure, and even death. Recent studies indicated that antioxidant vitamins, energy metabolism-associated vitamins, and glutamine may alleviate oxidative stress, elevate energy synthesis, and provide energy for immune cells, respectively. Therefore, the aim of this study was to investigate the effects of single and combined treatment of glutamine and multiple vitamins on inflammatory response and target organ damage in rats with trauma hemorrhagic shock and resuscitation (THR). Male SD rats were divided into 6 groups including a normal control group, an intubation sham-operated group, and 5 groups with 5 cm midline laparotomy and catheterization in the left carotid artery and right jugular vein. The blood was withdrawn from the carotid artery within 10 min until a mean arterial pressure was 30 to 35 mmHg in THR rats. After maintained with low blood pressure for 60 minutes, rats were resuscitated with shed blood and equal volume of lactate Ringer’s solution (LR) without or with L-alanyl-L-glutamine, multiple vitamins or L-alanyl-L-glutamine plus multiple vitamins within 10 min. Sham-operated group and THR rats were infused with continuous, slow rate of LR with or without L-alanyl-L-glutamine and multiple vitamins. Rats were executed after infused with continuous, slow rate of LR solution for 42 hours. The results showed that THR rats significantly increased serum glutamic-pyruvic transaminase and decreased plasma and lung interleukin (IL)-4. In the THR rats, glutamine significantly increased red blood cell sulphydryl group and jejunum interferon (IFN)-γ and decreased liver tumor necrosis factor (TNF)-a. Multiple vitamins significantly increased plasma myeloperoxidase (MPO) activity, lung and jejunum IL-8 and decreased serum albumin and lung IL-10. Glutamine and multiple vitamins significantly increased serum blood urea nitrogen and lung MPO activity and decreased serum cholesterol, liver and kidney IL-8. Glutamine or multiple vitamins significantly increased plasma malondialdehyde, jejunum IL-4 and IL-6. Glutamine with or without multiple vitamins significantly increased jejunum MPO activity and decreased liver IL-4 and jejunum cell apoptosis. Multiple vitamins with or without glutamine significantly increased crypt depth and muscularis thickness and decreased red blood cell malondialdehyde and liver IL-6. Glutamine and/or multiple vitamins significantly decreased plasma IFN- γ, liver protein carbonyl and IL-10, liver and kidney intercellular adhesion molecule. Taken together, limit volume resuscitation and slow rate of infusion may improve hemodynamics unstable in THR rats. Supplementation of glutamine and multiple vitamins in resuscitation solution can alleviate liver oxidative stress, system and kidney inflammation and jejunum apoptosis, further may decrease target organ injury.

碩士
輔仁大學
營養科學系碩士班
105
Hemorrhagic shock is an emergent condition that usually caused by trauma, surgery, and parturition. When patients suffer from rapid blood loss, the hypovolemia may result in the decreases in energy and oxygen delivery which cause multiple organ failure (MOF). In clinical practice, patients are administered with resuscitation fluid rapidly to improve blood pressure and oxygen supply. However, resuscitation may elevate the production of reactive oxygen species (ROS) which induce inflammatory response and organ damages. Studies showed that fish oil have the anti-inflammatory activity. When fish oil concentration of the cell membrane is increased, the immune cells have decreased ability to produce pro-inflammatory cytokines. In addition, glutamine has been confirmed to be the main source of energy for immune cells and intestinal cells. Therefore, the aim of the present study was to investigate the effects of single or combination treatment of fish oil- and glutamine-supplemented resuscitation fluids on the THR-induced inflammatory responses and antioxidant activity. Male SD rats were divided into 6 groups, expect the control (NC group) and sham-operated (SM group) groups the other THR groups were suffered with 5 cm midline laparotomy and catheterization in the left carotid artery and right jugular vein. The blood was withdrawn from the left carotid artery to reach a mean arterial pressure 30 to 35 mmHg within 10 min for hemorrhagic shock induction. After 60 minutes of hypovolemia, rats were resuscitated with shed blood and equal volume of lactate Ringer’s solution without (TH group) or with L-alanyl-L-glutamine (GN group), fish oil (FA group) or L-alanyl-L-glutamine plus fish oil (GF group) within 10 minutes and followed by continuouslow infusion rate (~1.4 ml/h) of resuscitation fluids. After 42 h, rats were executed and we expect to demonstrate that glutamine- and fish oil-supplemented resuscitation fluids may attenuate THR-induced inflammatory response and target organ injury in rats. The results show that THR may decreased RBC count, hemoglobin and hematocrit, and the loss of blood albumin and the decrease of antioxidant capacity.Then THR model may lead to decrease plasma, pulmonary and intestinal MPO activity and the pulmonary content of interleukin (IL)-8, the content of IL-4 and IL-8 in the kidney were decreased.The utilization of protein in plasma and lipid peroxidation, SOD and GPx activities in RBC could be increased. THR rats were supplemented with L-alanyl-L-glutamine resuscitation fluid to reduce the plasma pro-inflammatory cytokines, liver protein carbonylation and RBC lipid peroxidation. However, THR rats were supplemented with fish oil resuscitation fluid may decrease the concentration of pro-inflammatory cytokines in plasma, liver, kidney and reduce the pulmonary adhesion factor secretion, but also reduce the lipid peroxidation of RBC. In addition, THR rats were supplemented with L-alanyl-L-glutamine and fish oil resuscitation fluids may significantly reduce the plasma, kidney and pro-inflammatory cytokine secretion and increase the anti-inflammatory in the kidney and jejunum, and may lead to enhance the plasma and RBC antioxidative capacity. In summary, our THR model in this study may reduce the systemic antioxidative capacity and enhance jejunum inflammation. THR rats were supplemented with L-alanyl-L-glutamine and fish oil resuscitation fluids may alleviate inflammatory response and increase the antioxidant effect to reduce the THR-induced inflammatory response and target organ injury.

Introduction: Alors que le choc hémorragique représente la première cause de mortalité précoce chez les patients subissant un traumatisme sévère, la défaillance d’organes est responsable d’une mortalité tardive chez cette population. Les alarmines, molécules libérées en situation d’ischémie-reperfusion et capables d’induire une réponse inflammatoire systémique et locale, représentent potentiellement une cible thérapeutique afin de minimiser la défaillance d’organes post-traumatique. L’acide urique est une molécule pro-inflammatoire et pro-apoptotique libérée en situation de choc hémorragique dont les effets au niveau des organes sont peu investigués. Le premier volet de ce mémoire présente une preuve de concept que l’acide urique joue un rôle clé dans l’atteinte hépatique et intestinale dans un modèle animal de choc hémorragique, et sera présenté sous forme de manuscrit soumis. Le deuxième volet de ce mémoire présente des données préliminaires d’une étude clinique prospective visant à évaluer la cinétique de l’acide urique chez une cohorte de patients traumatisés. Volet animal: Un choc hémorragique a été induit chez des rats Wistar en retirant du volume circulant titré à une tension artérielle moyenne (TAM) de 30-35 mmHg pendant 60 minutes. Les rats ont été réanimés avec une solution composée de sang retiré et de lactate ringer (1 :1), avec ou sans Uricase, une enzyme recombinante qui métabolise l’acide urique. Les résultats démontrent une diminution significative de plusieurs marqueurs d’hépatolyse (AST, ALT), inflammatoire (ICAM-1, MPO, TNF-alpha, IL-1, Caspase-1) et apoptotique (Caspase-3, -8, Bax/BCL-2, pAKT/AKT) au sein du groupe uricase. L’intervention sur l’acide urique a également pu prévenir l’augmentation de la perméabilité intestinale suite au choc hémorragique, de même que la translocation de produits bactériens en circulation (LPS). Volet clinique: Vingt patients subissant un choc hémorragique traumatique ont été recrutés de façon prospective à l’Hôpital Sacré-Cœur de Montréal, dans le cadre d’un projet pilote soutenu par le consortium de trauma du FRSQ. Des prélèvements d’acide urique sérique ont été effectués de façon sériée pendant 7 jours. Les critères de faisabilité, notamment les taux de consentement (95%) et d’observance des prélèvements sériés (90% pour le premier prélèvement, 65% pour les prélèvements aux 4 heures, et 73% pour les prélèvements aux 8 heures) ont été jugés acceptables. Les cinétiques d’acide urique étaient reproductibles dans l’ensemble de la cohorte (R2 = 0.87). L’aire sous la courbe était significativement plus élevée chez les patients avec un score de défaillance d’organes plus élevé à 72h (SOFA6). Conclusions: Bien que les mécanismes demeurent à élucider, ces travaux démontrent que l’acide urique est important médiateur dans l’atteinte des organes suivant un choc hémorragique. Cette molécule représente potentiellement une cible thérapeutique dont l’objectif ultime est de minimiser la défaillance d’organes suite au choc hémorragique.
While hemorrhagic shock is the first cause of early mortality among severe trauma patients, organ failure leads to late mortality and morbidity in this population. Alarmins, molecules released after ischemia-reperfusion, are able to activate local and systemic inflammatory pathways and potentially represent a therapeutic target to minimize organ failure. Uric acid is a pro-inflammatory and pro-apoptotic molecule released after hemorrhagic shock and its role pertaining to organ failure is incompletely studied. The first part of this thesis presents a proof of concept that uric acid plays a key role in liver and intestinal damage in an animal model of hemorrhagic shock; it will be presented in the format of a submitted article. The second part of this thesis presents preliminary data from a prospective observational clinical study evaluating uric acid kinetics in a cohort of trauma patients. Animal study Hemorrhagic shock was induced with blood withdrawal among Wistar rats for a target mean arterial blood pressure of 30-35 mmHg for 60 minutes. Animals were resuscitated with a 1 :1 mix of Ringer Lactate and drawn blood with or without Uricase, a recombinant enzyme that metabolizes uric acid. Results show a statistically significant decrease in hepatocellular damage (plasma AST and ALT), inflammatory markers (ICAM-1, MPO, TNF-alpha, IL-1, Caspase-1) and apoptotic markers (Caspase-3, -8, Bax/BCL-2, pAKT/AKT) among the Uricase group. The intervention on uric acid also prevented increased intestinal permeability and bacterial product (LPS) translocation. Clinical study Twenty patients sustaining major trauma with hemorrhagic shock were prospectively recruited at Montreal Sacré-Cœur Hospital, in the context of a pilot study funded by the FRSQ trauma consortium. Uric acid concentration was determined serially for 7 days after trauma. Feasibility criteria, notably consent rate (95%), sampling observance rate (90% for first sample, 65% for samples every 4 hours, and 73% for samples every 8 hours) were considered acceptable. Uric acid kinetics were reproducible among the entire cohort (R2 = 0.87). The area under the curve was significantly increased among patients with higher sequential organ failure assessment score at 72h (SOFA³6). Conclusions Although mechanisms remain to be elucidated, these studies show that uric acid is an important mediator for the development of organ damage after hemorrhagic shock. This molecule potentially represents a therapeutic target with the ultimate goal of minimizing organ failure after hemorrhagic shock.

碩士
中山醫學大學
醫學研究所
106
Objective：Patients with trauma-hemorrhagic shock suffer from extensive blood loss and energy and oxygen deficiency that causes multiple organ failure and even death. To provide large volume of resuscitation fluid to recover blood pressure is the traditional clinical strategy; however, extensive production of free radicals may worsen the clinical outcome. We previously showed that arginine, citrulline, or glutamine may not alter inflammatory response in rats with hemorrhagic shock. Herein, we compared the impacts of arginine-, glutamine-, and amino acid mixture-supplemented resuscitation fluids on inflammatory responses and target organ damages in rats with trauma-hemorrhagic shock and limited-volume of resuscitation fluids. Methods and Materials：Male SD rats were suffered from carotid arterial and jugular vein cannulations with 5 cm midline laparotomy and blood loss to mean arterial pressure at 35 mmHg or sham operation (SHA group). After 60 minutes, rats were resuscitated with shed blood and equal volume of lactate Ringer’s solution without (THR group) or with L-alanine (ALA group), L-arginine plus L-alanine (ARG group), L-alanyl-L-glutamine (GLN group), or L-amino acid mixture plus L-alanine (AMX group) within 10 minutes and followed by continuous infusion for 42 h (~1.3 ml/h). After sacrifice, blood and organs were collected for further analysis about inflammatory response and organ damage. Results：The THR group had significantly decreased plasma IFN-γ and spleen weight, increased circulating platelet and renal nitrate/nitrite (NOx), and significant jejunal atrophy compared to the SHA group. The ALA group had alleviated increases in circulating platelet, renal NOx and jejunal atrophy, decreased circulating hemoglobin, hematocrit, plasma pro-inflammatory mediators, and renal apoptosis, and increased cell proliferation in the lung; the ARG group had increased lung wet-to-dry weight and IL-4 and jejunal apoptosis; the GLN group had increased spleen weight, circulating hemoglobin and hematocrit and renal myeloperoxidase activity and apoptosis and had alleviated jejunal atrophy; and the AMX group had reversed circulating hemoglobin and hematocrit, decreased jejunal atrophy and renal NOx, and increased lung, liver, and renal cell proliferation, renal apoptosis, and lung myeloperoxidase activity. These results suggest that amino acid supplemented-resuscitation fluids have beneficial effects on hematology and have differential effects on organ inflammatory response and damages. Conclusion：Amino acid-supplemented resuscitation fluids may have potentials to be a clinical useful nutrition therapy for patients with trauma-hemorrhagic shock and the use of amino acid supplementation should be organ-dependent.