Existe na literatura um número apreciável de trabalhos clínicos experimentais concernentes com a utilização de intervenções preemptivas objetivando abolir ou minimizar o desenvolvimento da hipersensibilidade central, decorrente do trauma cirúrgico possibilitando, como consequência, a otimização do controle analgésico pós-operatório. No entanto, considerando a contradição entre resultados apresentados, que não convergem em direção favorável a um consenso de ampla aceitação de utilização de intervenções preemptivas, desenvolvemos esse ensaio clínico, a fim de testar se a administração pré- operatória de ibuprofeno, isolado ou associado à dexametasona apresentaria vantagem relevante no controle da dor pós exodontia dos terceiros molares, comparado com a ausência de intervenção analgésica pré-operatória. Para tanto, foram selecionados 42 pacientes com inclusões simétricas dos terceiros molares. Esses pacientes foram aleatoriamente divididos em dois grupos: G1 recebeu apenas o ibuprofeno ou placebo, e G2 associação do ibuprofeno e dexametasona ou placebo. Todos os pacientes foram submetidos a dois procedimentos cirúrgicos, direito e esquerdo sendo que, um dos lados recebeu a medicação ativa e o outro placebo, de forma randomizada de modo que todos os pacientes funcionaram como controles de si mesmos (boca dividida). As demais medicações de analgesia pós-operatória, (associação de codeína mais paracetamol), fornecida como resgate, bem como a antibioticoterapia foram idênticas para todos os pacientes. As variáveis analisadas foram a escala visual analógica de dor (EVA) e o número total de analgésicos de resgate consumidos com os respectivos horários de ingestão durante as primeiras 72 horas do pós-operatório. Como resultados, não encontramos diferença estatisticamente significante para nenhuma das variáveis no o grupo 1. No grupo 2, houve diferença estatisticamente significante no consumo total de analgésicos de resgate (p<0,05) e, sem diferença estatisticamente significante para a EVA, embora a distribuição gráfica desses valores, especialmente quando associada à distribuição da ingestão de medicação de resgate, nos permita interpretar uma clara tendência de melhor controle analgésico no grupo experimental. Sentimos nitidamente a dificuldade em se estabelecer parâmetros ideais para aferição de controle analgésico, tendo em vista as limitações éticas e consequente obrigatoriedade da medicação de resgate que passa a ser, então, o parâmetro mais confiável, uma vez que a sua utilização aproxima as curvas de dor dos procedimentos experimentais e controles, podendo eventualmente até invertê-las. Pudemos concluir que a administração de ibuprofeno isolado no pré-operatório não tem potência analgésica suficiente para coibir os fenômenos de sensibilização central e hipersensibilidade desencadeados pela exodontia de terceiros molares mas, a associação dele com a dexametasona mostrou-se eficaz nesse sentido, resultando em menor consumo de analgésicos e na avaliação subjetiva de um pós-operatório mais confortável para 76% dos pacientes. A associação de diferentes drogas, com mecanismos de ação diferentes e que atuem em nichos distintos na via aferente dolorosa, denominadas intervenções multimodais, parece ser o melhor caminho para se alcançar uma intervenção suficientemente potente para inibir ou controlar os mecanismos neurais que levam à hipersensibilidade pós-operatória sem aumento da toxicidade e efeitos colaterais. / Our literature search found that there were a considerable number of experimental clinical studies pertaining to the use of pre-emptive measures, in order to eliminate or minimize the development of central hypersensitivity resulting from surgical trauma, allowing as a consequence, an optimal post surgery analgesic control. However we found that the results are contradictory and do not appears favourable to the use of pre-emptive interventions. Therefore, we designed this clinical trial in order to test whether preoperative administration of ibuprofen alone or in combination with dexamethasone was advantageous in controlling pain after the extraction of third molars, when compared with the absence of preoperative analgesic intervention. To test this hypothesis we selected 42 patients with symmetrical inclusions of third molars. These patients were divided randomly into two groups, where group 1 received ibuprofen and group 2 received a combination of ibuprofen an dexamethasone. All patients underwent two surgical procedures, right and left, and for the intervention on one randomly defined side active medication was administered while, on de other side a placebo was given. Thus all patients acted as their control. The other medications for postoperative analgesia, including the association of paracetamol and codeine, delivered as rescue, and the antibiotic were identical for all patients. The variables analyzed were the visual analogue scale (VAS) and the total number of rescue analgesic consumed, with respective times of intake during the first 72 hours postoperatively. We found no statistically significant difference for any of the variables in group 1. In group 2, we found a statistical difference of p< 5% for total consumption of rescue analgesics, and no statistically significant difference for the VAS, although the graphical distribution these values, especially when associated with the distribution of intake of rescue medication suggests a tendency for better analgesic control in the experimental group. It is clearly difficult to establish optimal parameters for measurement of analgesic control, in view of ethical constrains and the consequent requirement of rescue medication, which then becomes the more reliable parameter, since its use may reverse the pain curves of the experimental procedures and controls. We conclude that the administration of ibuprofen alone has insufficient analgesic power to inhibit the establishment of central sensitization and consequent hypersensitivity triggered by the extraction of third molars while its association with dexamethasone was effective, resulting in lower analgesic consumption and a more comfortable post surgery subjective evaluation in 76% of the patients. However, the combination of different drugs with different mechanisms of action, which act in different territories of the pain pathway, known as multimodal interventions, seems to be the best way to achieve a sufficiently powerful intervention to minimize or inhibit the neural mechanisms underlying postoperative hypersensitivity without increased toxicity and side effects.

L'administration préalable à l'intubation d'une anesthésie/sédation ou prémédication est recommandée depuis longtemps chez le nouveau-né. Néanmoins, il n'existe pas de consensus sur ses modalités précises et les pratiques dans ce domaine sont extrêmement hétérogènes. Les objectifs de cette thèse étaient de :Décrire les pratiques de prémédication avant l'intubation des nouveau-nés observées au lit du patient, dans des services de réanimation néonatale ou pédiatrique en région parisienne (étude EPIPPAIN)Explorer les déterminants éventuels de l'administration ou non d'une prémédicationRapporter l'expérience d'un service de réanimation néonatale (CHI Créteil) sur la mise en place d'un changement de pratique de prémédication avant intubationDans l'étude EPIPPAIN, 56% des intubations étaient précédées d'une prémédication spécifique pour le geste. Aucun facteur lié à l'enfant ou au service n'a été identifié comme significativement associé à l'utilisation ou non d'une prémédication. L'association atropine-sufentanil-atracurium a permis, dans une population de très grands prématurés (âge gestationnel < 32 SA), un taux de succès de 74% de la première tentative d'intubation, dans de bonnes conditions. Les désaturations et l'élévation prolongée de la PCO2 transcutanée étaient fréquentes.Il existe une marge de progression importante concernant la fréquence et la qualité des prémédications utilisées avant intubation néonatale dans les services français. Une démarche d'amélioration des pratiques est faisable. Cependant d'autres travaux sont nécessaires afin d'affiner la balance bénéfice/risque pour les nouveau-nés et de mettre en place, à grande échelle, de bonnes pratiques. / Premedication prior to neonatal intubation has been recommended for a long time. However no consensus exists to date for a standardised premedication regimen. Practices are consequently extremely heterogeneous. The objectives of the present thesis were to: Describe actual premedication practices at patients’ bedside in neonatal and pediatric ICUs located in the Paris area (EPIPPAIN study). Explore potential risk factors associated with the use or non-use of a specific premedication prior to neonatal intubation. Report a single unit (CHI Créteil) experience with the implementation of a new premedication protocol In the EPIPPAIN study 56% of intubations were preceded by a specific premedication. No patient or centre’s characteristic was identified as significantly associated with the use or non-use of a specific premedication. The association atropine-sufentanil-atracurium in a population of very premature infants (born before 32 weeks of gestational age) resulted in a 74% rate of successful first intubation attempt with good conditions. Desaturations and persistent elevated transcutaneous PCO2 were frequent There is a potential for large improvement in the frequency and nature of premedication use for neonatal intubations in French NICUs. A quality improvement process is feasible. However, more research and actions are needed in order to refine the risk/benefit ratio of available regimens for neonates and to implement good practices at a large scale.

<p>Uprkos op&scaron;te prihvaćenom stavu da u trudnoći lekove treba izbegavati, veliki broj trudnica tokom trudnoće uzima lekove sa manje ili vi&scaron;e opravdanja. Primena lekova u trudnoći zahteva dodatnu patnju, jer se mora voditi računa o zdravlju majke i zdravlju jo&scaron; nerođenog&nbsp; deteta. Većina lekova koji nalaze primenu u trudnoći, nisu ispitani u kontrolisanim studijama na trudnicama, već se njihov uticaj naljudski fetus, bazira na predpostavkama i kliničkim istraživanjima na životinjama. Odsustvo studija dovodi do toga da se trudnicama obično prepisuju lekovi u dozi za odrasle osobe, koje ne prate fiziolo&scaron;ke promene u trudnoći. Tokom trudnoće u telu trudnica dolazi do promena u funkciji organa i organskih sistema, a zbog nastalih promena menja se i sudbina leka u organizmu. Sistemske bolesti trudnice poput hipertenzije i dijabetesa dovode do hemodinamskih promena i utiču na nastanak patolo&scaron;kih promena posteljice, &scaron;to sve zajedno menja farmakokinetiku lekova i njihov transplacentrarni transport. Ukupno 75 trudnica je uključeno u studiju i podeljeno u tri grupe: zdrave trudnice-kontrolna grupa (n=31), trudnice sa hipertenzijom (n=30) i trudnice sa dijabetesom (n=14). Sve trudnice su u premedikaciji primile iste lekove koji su deo standardne kliničke&nbsp; procedure. Trudnice su primile jednu dozu diazepama intramuskularnom injekcijom (10mg/2ml), a intravenski su primile pojedinačne doze cefuroksima (1,5g), metoklopramida (10mg/2ml) i ranitidina (50mg/2ml). Od svakog para majka-dete ukupno je analizirano po 5 uzoraka. Uzorci krvi od majke uzimani su u tri vremenske tačke: nakon davanja leka, u momentu ekstrakcije deteta i nakon porođaja. Uzorci&nbsp; krvi&nbsp; deteta&nbsp; uzimani su&nbsp; nakon&nbsp; porođaja iz pupčane vene i arterije. Prikupljeni uzorci plazme analizirani su metodom tečne hromatografije visokih performansi (HPLC). Istraživanje je pokazalo da lekovi&nbsp; primenjeni u premedikaciji&nbsp; carskog reza prolaze transplacentarnu membranu i da se ni jedan&nbsp; od&nbsp; lekova&nbsp; primenjenih&nbsp; u studiji nije akumulirao u fetusu i nije imao neželjeno dejsvo na novorođenče. Cefuroksim, ranitidin i metoklopramid pokazali su nizak feto-maternalni transfer, dok je diazepam pokazao visok&nbsp; feto-maternalni transfer. Izmerene koncentracije cefuroksima u plazmi trudnica u momentu porođaja bile su &ge;8 &mu;g/ml, &scaron;to je koncentracija veća od MIC za većinu patogena odgovornih za nastavak infekcija u aku&scaron;erstvu. Koncentracije cefuroksima u fetalnoj plazmi bile su &ge;4&mu;g/ml &scaron;to je veće od&nbsp; MIC koncentracija za veliki broj patogena. Gestacijska starost trudnoće nije uticala na obim prolaska cefuroksima&nbsp; kroz placentu, koji je prolazi uglavnom pasivnom difuzijom. Farmakokinetski parametri cefuroksima razlikovali su se kod hipertenzivnih i dijabetičnih trudnica, u odnosu kontrolnu grupu, ali ove bolesti nisu imale značajan uticaj na smanjenje terapijske efikasnosti cefuroksima. Farmakokinetika cefuroksima kod hipertenzivnih&nbsp; trudnica&nbsp; ukazala je na bržu eliminaciju cefuroksima iz krvi majke i na veću distribuciju leka u okolna tkiva. U dijabetičnoj grupi trudnica i novorođenčadi koncentracije cefuroksima su bile vi&scaron;e u odnosu na druge ispitivane grupe, dok je feto-maternalni odnos bio niži, &scaron;to ukazuje na postojanje strukturalne i funkcionalne pomenu posteljice u dijabetesu. Hipertenzija i dijabetes trudnica nisu imali uticaj na prodor ranitidina kroz placentu. Hipertenzija i dijabetes trudnica nisu uticali na većinu farmakokinetskih parametara ranitidina, mada je zabeleženo smanjenje volumena distribucije u ovim grupama trudnica, &scaron;to bi moglo da ukazuje na njihovu hemodinamsku nestabilnost i povećanje slobodne frakcije ranitidina. Koncentracija metoklopramida bila veća u krvi majki u odnosu na krv fetusa. Transport metoklopramida iz fetusa ka majci bio je dominantniji, a naročito u hipertenzivnoj i dijabetičnoj grupi trudnica. Hipertenzija i dijabetes trudnica uticali su na zadržavanje metoklopramida u fetusu. Koncentracije dijazepama u majčinoj i fetalnoj krvi bile su vi&scaron;e u kontrolnoj i hipertenzivnoj grupi trudnica. Hipertenzija i dijabetes trudnica povećavaju&nbsp; transfer diazepama kroz placentu, povećanjem koncentracije slobodnih masnih kiselina, steroidnih hormona, smanjenjem vezivnog kapaciteta potencijalna opasnost od neželjenog dejstva diazepama i njegovih metabolita na fetus i novorođenče. Ova doktorska studija ukazuju na potrebu obimnijih farmakokinetskih istraživanja kako na zdravim tako i na bolesnim trudnicama, koja će dati zaključke utvrđene na dokazima i pomoći u individualnom terapijskom pristupu svakoj trudnici.</p> / <p>In spite of&nbsp; the widespread opinion&nbsp; that&nbsp; drugs should be avoided in pregnancy, a great number of&nbsp; pregnant&nbsp; women&nbsp; take drugs with more or less justification.&nbsp; Administration of drugs in pregnancy requires additional attention because the health of&nbsp; both the mother and&nbsp; her unborn child must be protected. Majority of drugs administered in pregnancy have not been tested&nbsp; within the controlled studies performed on pregnant women, but&nbsp; their effect on the human foetus is based on assumptions and clinical trials performed on animals. This absence of studies results in the situation that pregnant&nbsp; women are usually prescribed drugs in a dose&nbsp; for adults, which does not take into account the physiological changes happening in pregnancy. During pregnancy, the pregnant woman&rsquo;s body undergoes changes in the<br />functions of organs and organ systems. These changes further affect the destiny of a&nbsp; drug in the organism. In pregnant women, systemic diseases such as hypertension&nbsp;&nbsp; and diabetes mellitus lead to hemodynamic changes and cause pathological&nbsp; changes in placenta, thus changing the pharmacokinetics of drugs and their transplacental transport. The study sample consisted of 75 pregnant women, who were divided into three groups as follows: the control group included healthy pregnant&nbsp; women (n=31), a group of pregnant women&nbsp; with&nbsp; hypertension (n=30) and&nbsp; a group of&nbsp; those&nbsp; with&nbsp; diabetes mellitus (n=14). All of them were administered the same drugs as a part of standard clinical procedure in premedication. The pregnant women received a single dose of diazepam by intramuscular injection (10mg/ml), and individual doses of cefuroxime (1.5mg), metoclopramide (10mg/2ml) and ranitidine (50mg/2ml). Five samples taken from each mother-infant pair were analyzed. Blood samples were taken from the mother three times: after drug administration, at the moment of extraction of baby and after delivery. Baby&rsquo;s blood samples were taken from the umbilical cord vein and artery after delivery. Plasma samples were analyzed by the method of high-performance liquid chromatography (HPLC). The research has shown that drugs administered in premedication of caesarean section went through the transplacental membrane and that none of the tested drugs accumulated in the foetus and had an adverse effect on the newborn. Cefuroxime, ranitidine and metoclopramide were shown to have a low transfer between the mother and her foetus, whereas diazepam showed a high foetal-maternal transfer. Cefuroxime concentrations measured in the pregnant woman&rsquo;s and foetal plasma at the moment of delivery were &ge;8&mu;g/ml and &ge;4&mu;g/ml, respectively, that&nbsp; being above the minimum inhibitory concentration (MIC) for most pathogens responsible for the development of infection in obstetrics. Gestational age had no effect on the range of cefuroxime flow through the placenta, which happens mostly by&nbsp; passive diffusion. Pharmacokinetic parameters of cefuroxime differed in the pregnant&nbsp; women having hypertension and diabetes mellitus from the controls; however, these diseases did not significantly reduce the therapeutic efficacy of cefuroxime. Pharmacokinetics of cefuroxime indicated faster elimination of&nbsp; cefuroxime into the maternal blood and greater distribution of the drug into the surrounding tissues in the hypertensive pregnant women. In the group consisting of pregnant women and newborns having diabetes, the cefuroxime concentrations were higher than in other groups, whereas foetal-maternal relation was lower, which suggests the presence of structural and functional change in the placenta in diabetes. Hypertension and diabetes mellitus had no affect either on the flow of ranitidine through the placenta in the pregnant women or on&nbsp; the&nbsp; majority of pharmacokinetic parameters of ranitidine, although a certain reduction in the volume&nbsp; of distribution was recorded in these groups of pregnant women, which could suggest their hemodynamic instability and increased free fractions of ranitidine. The concentration of metocloporamide was higher in the maternal blood than in the&nbsp; foetal blood, and&nbsp; the transport of metocloporamide from the foetus towards the mother was more dominant, particularly in&nbsp; the&nbsp; group of&nbsp; hypertensive and diabetic&nbsp;&nbsp;&nbsp; pregnant women. Metoclopramide tended to retain in the foetuses of mothers having&nbsp; hypertension and diabetes. The concentrations of diazepam in maternal and foetal blood were higher in the controls&nbsp; and hypertensive&nbsp; pregnant&nbsp; women. Hypertension and diabetes in pregnant&nbsp; women increase the transfer of diazepam through the placenta by increasing the concentration of free fatty acids and steroid hormones and by reducing the binding capacity of carrier proteins and the concentration of plasma&nbsp;&nbsp; proteins, thus increasing the potential danger of adverse effects of diazepam and its metabolites on the foetus and the newborn. This doctoral study suggests the necessity for more extensive pharmacokinetic research including both healthy and affected pregnant women that would lead to conclusions based on evidence and help to develop individual therapeutic approach to each pregnant woman.</p>