La perfusion intraveineuse, continue ou intermittente, est un acte courant dans les services de soins bien que non dénué de risque. Différents dispositifs médicaux peuvent être employés pour permettre l’administration parfois simultanée de plusieurs substances actives. Ces dispositifs peuvent, de par leurs caractéristiques propres, générer des fluctuations plus ou moins importantes du débit massique de principe actif, c’est-à-dire la quantité de médicament administrée au patient par unité de temps. Le premier axe de travail concernant ces dispositifs médicaux est l’étude des prescriptions des normes, en particulier les définitions, les méthodes d’essai et les seuils de conformité attendus. Les principaux éléments de physiologie et de mécanique des fluides sont abordés afin d’appréhender la problématique. Cette étude est complétée par l’analyse des données de la littérature concernant l’impact des dispositifs médicaux sur le débit massique des principes actifs délivrés par voie intraveineuse. Une revue systématique de la littérature a été effectuée. Elle porte sur les travaux in vitro ou in vivo se rapportant au sujet et concernant tout élément susceptible de modifier le débit ou la concentration du médicament perfusé. Le premier travail expérimental réalisé in vitro concerne la perfusion simultanée de trois médicaments au moyen d’un dispositif unique de perfusion présentant plusieurs points d’accès. Les trois médicaments étaient perfusés par pousse-seringues et une solution d’hydratation par gravité. Le but de cette étude était d’évaluer l'impact des caractéristiques (volume résiduel et valve anti-retour) de deux dispositifs de perfusion, un premier présentant un très faible volume résiduel (0,046 ml) et une valve anti-retour et le second présentant un volume résiduel élevé (6,16 ml) et sans valve anti-retour) sur le débit massique de trois principes actifs. La quantification simultanée de trois principes actifs en solution (dinitrate d’isosorbide, midazolam et noradrénaline) a nécessité la mise au point d’une méthode multivariée sur spectre UV (régression partial least square (PLS)). Cette technique a permis de doser en continu (1 dosage par seconde) les trois principes actifs à la sortie de la ligne de perfusion. La méthode a été validée dans les échelles de concentrations respectives de 5-60, 10-80 et 2,5-20 µg.mL-1 pour le dinitrate d’isosorbide, le midazolam et la noradrénaline, dans des mélanges binaires et 6,67 à 30, 0,83 à 7,5 et 1,67 à 23,33 µg.ml−1 pour ces mêmes produits, dans des mélanges ternaires. La mise au point du modèle a permis de retenir la zone du spectre située entre 220 et 300 nm associée à un index Q2cum optimal. L’étude de recouvrement, employant le modèle pour prédire les compositions de 8 mélanges ternaires, retrouvait des valeurs de concentrations situées dans un intervalle de 99,5 à 101 % des valeurs théoriques. Les principaux paramètres dans cette étude étaient 1) l'évolution du débit massique des trois médicaments, 2) la valeur du plateau du débit massique à l'équilibre, et 3) l’efficience de perfusion (flow change efficiency (FCE)). Le FCE est obtenu en divisant l’aire sous la courbe du débit massique expérimental en fonction du temps par l’aire sous la courbe du débit massique attendu en fonction du temps. Ce paramètre est calculé pour chaque intervalle de 5 minutes après le début de la perfusion. Les systèmes de perfusion avec un volume résiduel réduit offrent de façon significative un meilleur FCE (53,0  15,4% avec un volume résiduel très faible après 5 minutes de perfusion comparativement à 5,6  8,2% avec un système de perfusion avec un volume résiduel élevé), quel que soient les conditions de changements de débit. Une relation non-linéaire a été établie entre le volume résiduel, le temps depuis le début de la perfusion et le FCE. [...] / Intravenous infusion, whether used continuously or intermittently, is a common feature in healthcare, although not without risk. Various medical devices can be used to administer the infusion, sometimes simultaneously, of several active substances . These devices, because of their characteristics, may generate more or less significant variations in drug mass flow rate, which is the amount of drug delivered per unit of time to the patient. The first part of this work on these medical devices focuses on studying standard requirements and norms, especially definitions, as well as trial methods and expected conformity thresholds. The main elements of physiology and fluid mechanics are also addressed to offer a better grasp of the problems involved. This study is complemented by analyses of published data on the impact of medical devices on drug mass flow rate when delivered intravenously. A systematic review of publications was made, covering in vitro or in vivo studies related to the topic, targeting more particularly any infusion device likely to alter the flow or concentration of the infused drug. The first experimental in vitro work involves the simultaneous infusion of three drugs using a single infusion device with several access points. The three drugs were infused by syringe pump and a hydration solution by gravity. The purpose of this study was to assess the impact of certain features (residual volume and check valve) of two infusion devices (the former with very low residual volume and a check valve and the latter with a high residual volume and no check valve) on the mass flow of three active ingredients. Simultaneous quantification of three active ingredients in solution (isosorbide dinitrate, midazolam and norepinephrine) made it necessary to develop a multivariate method on UV spectrum (partial least square regression (PLS)). This technique meant that the three drugs could be dosed continuously (1 dose per second) at the catheter egress. The method was validated for concentration scales of 5-60, 10-80 and from 2.5 to 20 µg/ml for isosorbide dinitrate, midazolam and noradrenaline in binary mixtures and 6.67 to 30, 0.83 to 7.5 and 1.67 to 23.33 µg/ml for the same products, in ternary mixtures. The perfecting of the model made it possible to maintain the spectral region between 220 and 300 nm with an optimal Q2cum index. The recovery study, performed on prediction sets containing eight different ternary mixtures of isosorbide dinitrate, midazolam and noradrenalin, yielded recovery values ranging from 99.5 to 101% of the theoretic values. The main parameters assessed in this study were 1) the evolution of mass flow rate for the three drugs, 2) the value of the plateau mass flow rate, and 3) flow change efficiency (FCE).. FCE is obtained by dividing the area under the curve of the experimental mass flow in relation to time by the area under the curve of the expected mass flow in relation to time. This parameter was calculated at each 5-minute interval after the start of infusion. Infusion systems with reduced residual volume provided significantly better FCE (53.0  15.4% with very low residual volume after 5 minutes’ infusion compared to 5.6  8.2% with high residual volume), regardless of any changes in flow conditions. A nonlinear relationship was established between residual volume, time since the onset of infusion and FCE. [...]

La perfusion intraveineuse occupe une large place dans les services de soins cliniques. Les patients reçoivent de nombreux médicaments simultanément dans la même voie centrale, où des problèmes de compatibilité entre les médicaments peuvent survenir. La maitrise de ces incompatibilités médicamenteuses, génératrices de particules, représente donc un enjeu majeur dans la prise en charge des patients polymédiqués.La première partie de ce travail est une analyse de la littérature portant sur les incompatibilités médicamenteuses et leurs principales conséquences sur le plan clinique. A ce titre, un chapitre est dédié à l’ensemble des moyens de prévention de ces problèmes, parmi lesquels l’usage de filtres en ligne de perfusion ou de dispositifs de perfusion multi-lumières.La première partie de nos travaux expérimentaux est consacrée à l’évaluation de la filtration terminale comme stratégie de prévention de l’administration de particules aux patients. Dans ce contexte, nos travaux ont porté sur le noircissement des filtres en ligne observé dans un service de réanimation néonatale. L’objectif était de définir la nature de l’incompatibilité en cause et de s’assurer, dans un second temps, de l’efficacité des filtres malgré les phénomènes de noircissement. Les filtres ont été examinés par microscopie électronique et comptage particulaire. Un aminogramme de la nutrition parentérale a également été réalisé. Une interaction spécifique a été mise en évidence entre un acide aminé (la cystéine) et un oligoélément (le cuivre) dans les poches. De plus, le maintien de la fonction des filtres en ligne a été démontré.La seconde partie de nos travaux est axée sur l’évaluation de l’intérêt d’un dispositif médical multi-lumières innovant dans la prévention des incompatibilités médicamenteuses. Le premier travail mené dans cette thématique a montré in vitro son intérêt à prévenir la survenue d’incompatibilités physiques entre plusieurs associations médicamenteuses, allant de deux à six médicaments administrés simultanément. Nos résultats indiquent que la conception de ces nouveaux dispositifs de perfusion et notamment leur géométrie interne permet de minimiser le temps de contact entre les produits, et ainsi d’améliorer la compatibilité entre les produits, au même titre que le type de solution d’hydratation. Le second travail consistait à poursuivre l’évaluation de ces dispositifs de perfusion multi-lumières en reproduisant un protocole de perfusion utilisé habituellement en hématologie pédiatrique et associant plusieurs médicaments incompatibles à l’origine de précipité. Un comptage particulaire réalisé de manière dynamique a permis de montrer que l’emploi de ces dispositifs permettait de réduire significativement la charge particulaire administrée aux patients, en comparaison avec les dispositifs standard de perfusion (rampes de robinets).Les résultats de l’ensemble de nos travaux sont prometteurs pour l’amélioration de la prise en charge des patients. Ils doivent être maintenant confirmés au travers d’une étude clinique. / Intravenous infusions are extensively used in clinical wards. Patients simultaneously receive many drugs through a limited number of venous accesses, thus increasing the risk of physical drug incompatibilities. Preventing incompatibility is therefore important for the safe administration of injectable drugs of polymedicated patients.The first part of this work consisted in analysing published literature on drug incompatibilities and their clinical consequences. This chapter includes a review of tools preventing drug incompatibilities, which include in-line filtration or the use of multi-lumen infusion sets.The first part of our experimental work is dedicated to the evaluation of terminal in-line filtration for preventing the injection of drug particles to patients. In this context, our research has focused on the blackening of in-line filters, which have been observed during the infusion of binary parenteral nutrition (BPN) delivered in a neonatal intensive care unit. The purposes of our study were, first, to examine the elemental content of precipitates isolated from infused BPN bags and so determine the main physicochemical interactions occurring in them and, second, to evaluate the blackening effect of in-line filters on filtration capacity. Filter membranes were examined by scanning electron microscopy and energy dispersion spectroscopy. Amino acid (AA) profiles were obtained from BPN mixtures to determine the concentrations of each AA. A specific interaction was identify between cysteine and copper in our BPN. Despite the gradual blackening of in-line filters during BPN bag infusion, the filter membranes continued to filter solutions efficiently and safely.The second part of our work focused on the assessment of the impact of new multilumen infusion access devices on the occurrence of known drug incompatibility.The first study used a well-documented incompatible combination of two to six drugs and three different carrier fluids. The multilumen infusion access device was able to prevent the occurrence of drug incompatibilities in nearly half of the drug combinations tested. This study confirmed that the characteristics of an infusion device have an impact on drug physical incompatibilities. The main hypothesis is those fluid dynamics differ according to infusion device and accesses, which modify the contact time between drugs and the infusion vehicle.The second in vitro study focused on a pediatric multidrug protocol for patients diagnosed with lymphoblastic leukemia and receiving allogeneic transplantation. A dynamic particle count test was used over 24 hours to evaluate the overall particulate contamination. The use of a multi-lumen infusion set reduces significantly overall particulate contamination compared to the standard infusion set.These results pave the way to performing a randomized controlled clinical trial assessing the multilumen infusion access device.

Ce travail de doctorat s’inscrit dans un projet de recherche destiné à évaluer la charge particulaire issue des incompatibilités physico-chimiques d’origine médicamenteuse de patients admis en réanimation pour un état de choc septique ou un syndrome de détresse respiratoire aigüe. Le corollaire est de faire le lien avec la survenue de certaines complications (syndrome inflammatoire et dysfonction d’organe) susceptibles de menacer le pronostic vital. En effet, la dysfonction microcirculatoire caractéristique de ces patients pourrait être majorée par la contamination particulaire aboutissant ainsi à une aggravation de l’hypo-perfusion tissulaire et à la survenue du syndrome de défaillance multi viscérale.La première partie de ce travail a consisté en une analyse de la littérature portant sur les incompatibilités médicamenteuses et leurs principales conséquences cliniques sous forme d’une revue systématique. Un des messages essentiels est l’intérêt grandissant de la filtration en ligne comme moyen de prévention de la contamination particulaire bien mis en évidence par certains essais contrôlés randomisés en particulier pédiatriques.La seconde partie de ce travail était de mener, dans une première phase, une étude d’observation clinique au lit du malade des dispositifs de perfusion intraveineux habituellement utilisés et des médicaments le plus souvent administrés à ces patients de réanimation du CHU de Lille. La deuxième phase consistait à reproduire in vitro le montage de perfusion utilisé en clinique avec les différentes solutions médicamenteuses dans le but de quantifier la charge particulaire à laquelle sont exposés les patients. Le comptage particulaire a été réalisé de manière dynamique, selon une technique innovante, grâce à un analyseur de particule connecté au montage de perfusion.Ce travail nous a permis finalement d’évaluer le risque particulaire pour ces patients fragiles et de proposer une stratégie de prévention des incompatibilités médicamenteuses. / Our PhD work aimed to evaluate the particulate exposure induced by drug incompatibilities in patients admitted in ICU for a septic shock or acute respiratory distress syndrome. The purpose was to establish a link with the occurrence of certain complications (inflammatory syndrome and organ dysfunctions) susceptible to aggravate life threatening. Indeed, the microcirculatory dysfunction characteristic of these patients could be increased by the particulate contamination, compromising tissue perfusion and leading to the occurrence of multi organ failureThe first part of this study consisted in a systematic literature review on the clinical implications of drug incompatibilities. One of the essential messages is the growing interest of inline filtration to prevent particulate contamination, highlighted by randomized controlled trials especially in pediatric ICU.The second part of the study was to conduct, in a first phase, an observational study, at the ICU patients’ bedsides, of the commonly used intravenous drugs and infusion sets. The second phase was to reproduce in vitro the previous observed infusion lines using the observed drugs combination, in order to quantify the particulate exposure, during a simulated 6-hour infusion period. The particle counting was performed using an innovative dynamic image analysis device.Our work indicates the amount of particulate matter potentially administered to critically-ill adult patients and paves the way to a strategy of prevention of drug incompatibilities.

Orientador: Antônio José de Araújo Aguiar / Banca: Stélio Pacca L. Luna / Banca: Silvia Gaido Cortopassi / Banca: Denise Tabacchi Fantoni / Banca: Reinaldo C. Braz / Resumo: O emprego de procedimentos de anestesia intravenosa total em cães tem sido mais freqüente, devido ao melhor conhecimento do perfil farmacocinético dos fármacos empregados. Como ainda não existe um único fármaco que produza todas as características desejáveis em uma anestesia geral, há a necessidade de se associar ao hipnótico, agentes com propriedades analgésicas. O objetivo desse estudo foi avaliar os efeitos hemodinâmicos causados pela associação do cloridrato de dexmedetomidina, nas doses de 1 e 2 μg/kg/h, e propofol na dose de 0,3 mg/kg/min, administrada em infusão intravenosa contínua em cães, bem como o tempo de recuperação anestésica após duas horas de infusão. Seis cães, clinicamente sadios, sem raça definida, pesando 17,6±1,8 kg, foram submetidos a três tratamentos com intervalo de uma semana e em seqüência aleatória. Todos os animais foram inicialmente anestesiados com isofluorano a 5V% com fluxo de 3 l/min de O2. Após a indução e intubação, os animais foram posicionados em decúbito lateral esquerdo e mantidos com isofluorano na concentração de 1,8V%. As veias cefálicas e a artéria dorsal podal foram cateterizadas e um cateter de Swan Ganz 5F foi introduzido pela veia jugular. Após fixação dos cateteres na pele, a administração do isofluorano foi interrompida. Os cães permaneceram despertos por 1 hora, e após esse período, foi realizada a avaliação das variáveis hemodinâmicas. Em seguida os cães receberam um dos seguintes tratamentos: Controle: indução com propofol (6 mg/kg/30s) e solução de NaCl 0,9% (5 ml/10min) seguida de manutenção com propofol (0.3 mg/kg/min) e NaCl 0,9% (4 ml/h); Dex 1: indução com propofol (6 mg/kg/30s) e cloridrato de dexmedetomidina (1 μg/kg/10min) seguida de manutenção com propofol (0.3 mg/kg/min)... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Total intravenous anesthesia in dogs has been more frequently used, the pharmacokinetic profile of the new drugs is better understood. No injectable anesthetic produces all of the components of a general anesthesia, it is required to associate additional analgesics with hypnotic. The aim of this study was to evaluate the hemodynamic effects caused by the association of 1 and 2 μg/kg/h of dexmedetomidine and 0,3 mg/kg/min of propofol, administered by continuous intravenous infusion, as well time of anesthetic recovery after 2 hours of infusion. Six healthy dogs weighting 17,6±1,8 kg were randomly allocated to 3 treatments with at least one week intervals between each treatment. All animals were initially anesthetized with 5V% of isoflurane and 3 l/min of oxygen. After induction and intubation, the animals were posicionated in left lateral recumbence and maintained with 1.8% end tidal. All animals were instrumented with a cephalic veins and arterial catheter and a Swan Ganz catheter in order to a monitor hemodynamic parameters. After instrumentation isoflurane was interrupted and animals were awake and remained awake for one hour. After that, baselines parameters were taken. Dogs received each one of these treatments: Control: was induced with propofol (6 mg/kg/30s) and saline (5 ml/10 min), maintenance was with propofol (0.3 mg/kg/min) and saline (4 ml/h). Dex 1 was induced with propofol (6 mg/kg30s) and dexmedetomidine (1 μg/kg10 min), maintenance with propofol (0.3 mg/kg/min) and dexmedetomidine (1 μg/kg/h). Dex 2 was induced with propofol (6 mg/kg30s) and dexmedetomidine (2 μg/kg/10min), maintenance with propofol (0.3 mg/kg/min) and dexmedetomidine (2 μg/kg/h) during 120 minutes. The parameters (HR, SBP, MAP, DAP, CI, SI, CVP, PAP, POPA, SVRI, PVRI, RR, ETCO2, SaO2, pHa, PaO2, PaCO2, HCO3, Hb, CaO2, IDO2, temperature) were taken at 15, 30, 60, 90 e 120 minutes after induction... (Complete abstract click electronic access below) / Doutor

Made available in DSpace on 2014-06-11T19:35:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-02-29Bitstream added on 2014-06-13T21:07:06Z : No. of bitstreams: 1 castro_vb_dr_botfm.pdf: 811446 bytes, checksum: c21c255ab07d1f8809f7e545477272d8 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O emprego de procedimentos de anestesia intravenosa total em cães tem sido mais freqüente, devido ao melhor conhecimento do perfil farmacocinético dos fármacos empregados. Como ainda não existe um único fármaco que produza todas as características desejáveis em uma anestesia geral, há a necessidade de se associar ao hipnótico, agentes com propriedades analgésicas. O objetivo desse estudo foi avaliar os efeitos hemodinâmicos causados pela associação do cloridrato de dexmedetomidina, nas doses de 1 e 2 μg/kg/h, e propofol na dose de 0,3 mg/kg/min, administrada em infusão intravenosa contínua em cães, bem como o tempo de recuperação anestésica após duas horas de infusão. Seis cães, clinicamente sadios, sem raça definida, pesando 17,6±1,8 kg, foram submetidos a três tratamentos com intervalo de uma semana e em seqüência aleatória. Todos os animais foram inicialmente anestesiados com isofluorano a 5V% com fluxo de 3 l/min de O2. Após a indução e intubação, os animais foram posicionados em decúbito lateral esquerdo e mantidos com isofluorano na concentração de 1,8V%. As veias cefálicas e a artéria dorsal podal foram cateterizadas e um cateter de Swan Ganz 5F foi introduzido pela veia jugular. Após fixação dos cateteres na pele, a administração do isofluorano foi interrompida. Os cães permaneceram despertos por 1 hora, e após esse período, foi realizada a avaliação das variáveis hemodinâmicas. Em seguida os cães receberam um dos seguintes tratamentos: Controle: indução com propofol (6 mg/kg/30s) e solução de NaCl 0,9% (5 ml/10min) seguida de manutenção com propofol (0.3 mg/kg/min) e NaCl 0,9% (4 ml/h); Dex 1: indução com propofol (6 mg/kg/30s) e cloridrato de dexmedetomidina (1 μg/kg/10min) seguida de manutenção com propofol (0.3 mg/kg/min)... / Total intravenous anesthesia in dogs has been more frequently used, the pharmacokinetic profile of the new drugs is better understood. No injectable anesthetic produces all of the components of a general anesthesia, it is required to associate additional analgesics with hypnotic. The aim of this study was to evaluate the hemodynamic effects caused by the association of 1 and 2 μg/kg/h of dexmedetomidine and 0,3 mg/kg/min of propofol, administered by continuous intravenous infusion, as well time of anesthetic recovery after 2 hours of infusion. Six healthy dogs weighting 17,6±1,8 kg were randomly allocated to 3 treatments with at least one week intervals between each treatment. All animals were initially anesthetized with 5V% of isoflurane and 3 l/min of oxygen. After induction and intubation, the animals were posicionated in left lateral recumbence and maintained with 1.8% end tidal. All animals were instrumented with a cephalic veins and arterial catheter and a Swan Ganz catheter in order to a monitor hemodynamic parameters. After instrumentation isoflurane was interrupted and animals were awake and remained awake for one hour. After that, baselines parameters were taken. Dogs received each one of these treatments: Control: was induced with propofol (6 mg/kg/30s) and saline (5 ml/10 min), maintenance was with propofol (0.3 mg/kg/min) and saline (4 ml/h). Dex 1 was induced with propofol (6 mg/kg30s) and dexmedetomidine (1 μg/kg10 min), maintenance with propofol (0.3 mg/kg/min) and dexmedetomidine (1 μg/kg/h). Dex 2 was induced with propofol (6 mg/kg30s) and dexmedetomidine (2 μg/kg/10min), maintenance with propofol (0.3 mg/kg/min) and dexmedetomidine (2 μg/kg/h) during 120 minutes. The parameters (HR, SBP, MAP, DAP, CI, SI, CVP, PAP, POPA, SVRI, PVRI, RR, ETCO2, SaO2, pHa, PaO2, PaCO2, HCO3, Hb, CaO2, IDO2, temperature) were taken at 15, 30, 60, 90 e 120 minutes after induction... (Complete abstract click electronic access below)

Made available in DSpace on 2014-06-11T19:23:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-05-27Bitstream added on 2014-06-13T19:49:54Z : No. of bitstreams: 1 000721479.pdf: 1511062 bytes, checksum: b30577204312e567fe62e47106cdefce (MD5) / Multimodal analgesia is being increasingly used in veterinary medicine and in that context, tramadol has demonstrated effectiveness in controlling moderate to severe pain. The present study aimed to investigate the influence of three rates of tramadol at continuous infusion for trans and post- operative analgesia of dogs undergoing orthopedic surgeries. Further possible changes in cardiovascular and respiratory parameters, side effects as well as analgesia and plasma concentration of tramadol and M1 wee recorded. Thirty dogs were homogeneously distributed according to the surgical procedures and have been subjected to three groups: G1: 2.0 mg/kg/h; G2: 2.5 mg/kg/h; G3: 3 mg/kg/h. Pre-anaesthetic medication in all cases was given intramuscularly with acepromazine (0.04 mg/kg) and tramadol (2.0 mg/kg). Fifteen minutes later, anaesthesia was induced with intravenous propofol (3mg/kg) associated with midazolam (0.2 mg/kg) and maintained with isoflurane. Blood samples were obtained for assessment of serum cortisol and determining plasma concentrations of tramadol and M1. Postoperative analgesia was assessed through the scales University of Melbourne and interval level pain scale for assessment of acute pain in dogs Trans-operative analgesia was sufficient to most animals and the residual analgesia during post-operative period was short. Cardiovascular and respiratory stability were observed, with no adverse effects

Resumo:A analgesia multimodal é cada vez mais empregada em medicina veterinária e, o tramadol, um analgésico opioide de ação central, tem demonstrado efetividade no controle da dor moderada. Com este trabalho, objetivou-se verificar a eficácia analgésica transoperatória promovida pelo tramadol, quando administrado por infusão contínua, em cães submetidos a cirurgias ortopédicas; observar as possíveis alterações cardiorrespiratórias e efeitos adversos; avaliar as concentrações plasmáticas de tramadol e do metabólito M1 e verificar o período de analgesia pós-operatória residual. Para isso, foram selecionados 30 cães distribuídos equitativamente de acordo com os procedimentos cirúrgicos em um dos três grupos com diferentes taxas de infusão de tramadol: G1: 2,0 mg/kg/h; G2: 2,5 mg/kg/h; G3: 3 mg/kg/h. A medicação pré-anestésica foi composta por acepromazina (0,04 mg/kg) e tramadol (2 mg/kg) pela via intramuscular e após 15 minutos, realizou-se a indução com propofol (3 mg/kg) e midazolam (0,2 mg/kg) e a manutenção anestésica foi realizada com isofluorano. Realizou-se a dosagem de cortisol sérico e a concentração plasmática de tramadol e do metabólito O- desmetil tramadol (M1). A dor pós-operatória foi avaliada por meio da Escala de contagem variável de Dor da Universidade de Melbourne e a Escala intervalar de avaliação de dor. O tramadol promoveu estabilidade cardiovascular e respiratória com ausência de efeitos adversos e analgesia transoperatória satisfatória na maioria dos cães submetidos a diferentes tipos de procedimentos ortopédicos, entretanto não houve incremento em seu efeito analgésico de maneira dose- dependente, as concentrações de M1 foram inferiores aos descritos na literatura e o período de analgesia pós operatória residual foi considerado curto / Abstract:Multimodal analgesia is being increasingly used in veterinary medicine and in that context, tramadol has demonstrated effectiveness in controlling moderate to severe pain. The present study aimed to investigate the influence of three rates of tramadol at continuous infusion for trans and post- operative analgesia of dogs undergoing orthopedic surgeries. Further possible changes in cardiovascular and respiratory parameters, side effects as well as analgesia and plasma concentration of tramadol and M1 wee recorded. Thirty dogs were homogeneously distributed according to the surgical procedures and have been subjected to three groups: G1: 2.0 mg/kg/h; G2: 2.5 mg/kg/h; G3: 3 mg/kg/h. Pre-anaesthetic medication in all cases was given intramuscularly with acepromazine (0.04 mg/kg) and tramadol (2.0 mg/kg). Fifteen minutes later, anaesthesia was induced with intravenous propofol (3mg/kg) associated with midazolam (0.2 mg/kg) and maintained with isoflurane. Blood samples were obtained for assessment of serum cortisol and determining plasma concentrations of tramadol and M1. Postoperative analgesia was assessed through the scales University of Melbourne and interval level pain scale for assessment of acute pain in dogs Trans-operative analgesia was sufficient to most animals and the residual analgesia during post-operative period was short. Cardiovascular and respiratory stability were observed, with no adverse effects / Orientador:Valéria Nobre Leal de Souza Oliva / Banca:Paulo Sérgio Patto dos Santos / Banca:Juan Carlos Duque Moreno / Mestre

Au cours de l’administration simultanée de plusieurs médicaments injectables, sont utilisées une ligne principale de perfusion et une ou plusieurs ligne(s) en dérivation. La ligne principale est directement reliée au cathéter et permet l’administration des solutions utilisées pour l’apport hydro-électrolytique ou de maintenir une voie d’abord veineuse perméable. Les autres thérapeutiques vont être perfusées en dérivation de cette ligne principale. La prise en charge des patients relevant de soins intensifs et de réanimation nécessite une polymédication. Les traitements d’urgence impliquent majoritairement des médicaments à marge thérapeutique étroite. Lors de l’administration de médicaments en solutions concentrées, de faibles perturbations du débit d’administration peuvent engendrer de fortes perturbations cliniques et notamment, pour les médicaments vasoactifs, créer une instabilité hémodynamique. C’est pourquoi il est important d’étudier la problématique de la perfusion simultanée, de déterminer l’impact sur le débit massique des lignes de perfusion et la technique optimale des changements de seringues pour prévenir les variations intempestives du débit de perfusion. Ce mémoire présente un travail de développement et d’évaluation d’une démarche d’optimisation d’un système de perfusion complexe. Il consiste à étudier au travers d’évaluations in vitro et d’études cliniques la conception d’une ligne de perfusion en évaluant notamment un dispositif médical innovant afin de proposer, in fine, une solution applicable dans un service de soins intensifs. La première partie consiste à présenter l’ensemble des dispositifs médicaux de perfusion utilisés dans un département d’anesthésie-réanimation. La seconde partie s’intéresse à l’administration d’un médicament couramment perfusé sur la voie proximale: la noradrénaline. Les études in vitro, corroborées par des données cliniques, ont permis de montrer la supériorité de l’administration de noradrénaline à 0,5 mg/mL perfusée en Y avec une solution saline isotonique à débit fixe de 5 mL/h. Cette multiperfusion fait intervenir l’utilisation d’un prolongateur trois voies à faible volume résiduel, permettant d’optimiser les conditions de relais de seringues, connues comme étant à l’origine d’instabilités hémodynamiques chez les patients traités par catécholamines. Un programme hospitalier de recherche clinique interrégional est déposé dans le but d’établir des recommandations de perfusion des catécholamines.La troisième partie aborde l’administration des médicaments sur voie distale en sélectionnant l’insuline comme marqueur-médicament. Les résultats de cette étude clinique prospective randomisée contrôlée ont montré que l’utilisation d’un dispositif médical innovant, le dispositif Edelvaiss-Multiline 8 (Doran International) caractérisé par un tube multilumières à faible volume résiduel qui permet de dédier une voie à une seule thérapeutique, permettait de réduire significativement le temps passé en hypoglycémie pour 1000 heures de perfusion d’insuline au cours de perfusion continue d’insuline en soins intensifs périopératoires.Enfin, dans une dernière partie, les critères clés d’un montage optimisé de multiperfusion sont élaborés et sont mis en application dans un département d’anesthésie-réanimation dans le but d’optimiser et uniformiser la ligne de perfusion des patients. Ce travail a permis de valider les caractéristiques clés de la ligne de perfusion définis dans de précédentes études non cliniques : la nature du matériau des dispositifs médicaux utilisés, l’utilisation de valves appropriées, la minimisation des volumes internes des tubulures de perfusion, l’utilisation de systèmes de perfusion automatisés permettant de contrôler au mieux le débit d’administration des médicaments. / For the simultaneous administration of injectable drugs, the infusion line includes a main line with one or several derivative lines. The main line, which is directly connected to the catheter, is dedicated to hydration infusion or to maintain a permeable vein. Other medications will be added on the derivative lines.Intensive care unit patients frequently require lots of medications in the same time. Most of emergency drugs are substances with narrow therapeutic range. When concentrated solutions are employed, tiny mass flow rate disturbances can provoke clinical damages, such as haemodynamic instability. So, several parameters have been studied on simultaneous infusions: mass flow rate and syringes changeovers.The purpose of this work was to develop and optimize complex infusion line systems. An innovative infusion medical device has been evaluated in clinical trials and in vitro studies. The final objective was to design an optimized infusion line, which could be applied to ICUs.The whole medical devices used in ICUs was first listed. Then, noradrenaline has been used as the reference drug to study central venous catheter proximal line. A 0.5 mg/mL noradrenaline solution Y-infused with a saline (5mL/h) has been shown by clinical and in vitro data to be the best solution. Nevertheless, this conclusion was valid only with the use of a very low dead-space volume Y-extension set. Thanks to this device, syringe changeovers optimization is possible.The central venous catheter distal line has been studied in a second time through an open randomized controlled prospective clinical trial. Primary endpoint of the study was the impact of two different insulin infusion lines (Edelvaiss-Multiline 8, Doran International versus standard line) on glycaemic variability. Doran’s innovative device consists of an exten¬sion set with eight accesses connected to nine separated lumens in a single tube. This allows to dedicate an isolated way for insulin. With its use, a significant decrease of hypoglycaemia occurring in 1000h of infusion period was clinically demonstrated. Finally, all the data were synthetized to optimize an ICU multi-infusion line. The one, which has been designed for surgery and intensive care units, was tested on patients.To conclude, items responsible for mass flow rate disturbances have been identified: medical devices material, addition of appropriated valves, internal volume line minimization and use of automated infusion systems (as pumps). The ideal infusion line has to take into account all these parameters.

Infusion pumps are used in all departments of a hospital, in the emergency care unit as well as in pediatrics. The pumps administer intravenous medications for the purpose of helping patients to manage pain and are unfortunately not spared from emerging errors. Due to the complexity of the process involved in infusion pumps, errors regarding delay in administration are encountered. Especially vulnerable to errors are pediatric patients, due to the high risk of over- or under-dosing. This study aims to investigate the effects on administration delay by analysing the medical supply and system utilized for the infusion pumps. This is accomplished through implementation of Compartmental Modeling in Pharmacokinetics in combination with a self developed mathematical model for estimating the administration delay. Simulations were performed for analysing how various sizes of medical supply effected delay time. The result from the computed mathematical model indicates that increased volumes on utilized equipment will increase delay time. The combined use of a decreased flow rate and smaller equipment sizes will have the greatest affects on the delay in administration. The result obtained from the computed compartmental model can be useful for medical staff to be able to estimate the delay in administration. However, further validation is required before the utilization of the model can be applied in hospitals. / Infusionspumpar används på alla avdelningar på ett sjukhus, inom akutvården samt inom pediatrik. Pumparna administrerar olika mediciner i syfte att hjälpa patienten att hantera smärta och är tyvärr inte förskonade från att fel kan förekomma. På grund av komplexiteten i processen, involverad i infusionspumpar, uppstår fel gällande förseningar i administrering av medicin. Speciellt sårbara för dessa typer av förseninigar är pediatriska patienter, på grund av den förhöjda risker gällande över- eller underdosering. Denna studie syftar till att undersöka effekterna gällande administreringsfördröjning genom att analysera det medicinska utrustningen och systemet som används för infusionspumparna. Detta uppnås genom implementering av kompartmentmodellering i farmakokinetik i kombination med en egenutvecklad matematisk modell för att uppskatta administreringsfördröjningen. Simuleringar utfördes för att analysera effekterna av olika storlekar på medicinsk utrustning i förhållande till fördröjningen av administreringe. Resultatet från den beräknade matematiska modellen indikerar att ökade volymer gällande den medicinska utrustningen kommer att öka fördröjningstiden. Den kombinerade användningen av en minskad flödeshastighet och mindre utrustningsstorlekar kommer att ha störst inverkan på förseningen i administreringen. Resultatet som erhålls från den beräknade kompartmentmodellen kan vara användbar för sjukvårdspersonal för att kunna uppskatta förseningen i administrationen. Ytterligare validering krävs dock innan användningen av modellen kan tillämpas på sjukhus.