Parmi les facteurs intervienant dans la régulation et le maintien du fonctionnement d'organes, le système nerveux autonome et la microcirculation jouent un rôle prépondérant. Chez les patients critiques, comme les patients en sepsis, des altérations de la balance sympatho-vagale et de la perfusion tissulaire peuvent survenir et avoir des conséquences majeures en matière de morbidité et mortalité. La mise en oeuvre de méthodes de détection précoces de ces perturbations pourrait donc contribuer à améliorer la survie des patients à risque. En effet, le suivi des paramètres hémodynamiques, comme classiquement réalisé lors de réanimation, peut s'avérer insuffisant pour détecter des altérations de perfusion tissulaire : lors de sepsis, des altérations microcirculatoires peuvent persister en dépit de la normalisation des paramètres macrocirculatoires et sont associées à un mauvais pronostic. Eu égard à la présence de dysfunctions microcirculatoires et du système nerveux autonome chez les patients critiques, ce travail de recherche s'est proposé d'évaluer l’impact de modulateurs du système sympathique sur la balance sympatho-vagale et la microcirculation. Pour ce faire, nous avons travaillé avec des modèles animaux et des animaux admis en centre hospitalier universitaire vétérinaire. Le suivi du système nerveux autonome s'est basé sur un nouvel index de mesure du tonus parasympathique (Parasympathetic Tone Activity ou PTA). En parallèle, la microcirculation a été évaluée par vidéomicroscopie (SDF, Sidestream Dark Field imaging). L'index PTA a démontré une performance correcte pour prédire les réactions hémodynamiques chez les chiens anesthésiés. Il a aussi permis de détecter une altération de la balance sympathique chez les chevaux admis pour une chirurgie de colique ainsi qu’une altération de la microcirculation en dépit des manoeuvres de réanimation. Les études précliniques sur l’impact de la perfusion d’esmolol et de dexmédétomidine dans un modèle porcin septique ont montré que, malgré leurs effets hémodynamiques potentiels, ces agents n’ont pas eu d’effet négatif sur la microcirculation. Ainsi, les résultats de ce travail suggèrent un effet bénéfique des modulateurs du système nerveux sympathique sur la microcicultion mais nécessite d'être confirmé à plus grande échelle / Among the factors involved in the regulation and maintenance of the organs’ functioning, the autonomic nervous system and the microcirculation play a preponderant role. In critical patients, such as septic patients, alterations in the sympathovagal balance and tissue perfusion may occur and have major consequences of morbidity and mortality. The implementation of early detection methods for these disturbances could therefore contribute to improve the survival of patients at risk. Indeed, the monitoring of hemodynamic parameters, as conventionally performed during resuscitation, may be insufficient to detect tissue perfusion alterations: during sepsis, microcirculatory changes may persist despite the normalization of macrocirculatory parameters and are associated with a bad prognosis. With regard to the presence of microcirculatory dysfunctions and autonomic nervous system alterations in critical patients, this research project proposed to evaluate the impact of modulators of the sympathetic system on the sympatho-vagal balance and microcirculation. In order to achieve this, we worked on animal models and animals admitted to the faculty’s veterinary hospital center. Monitoring of the autonomic nervous system was based on a new Parasympathetic Tone Activity (PTA) index. In parallel, the microcirculation was evaluated by videomicroscopy (SDF, Sidestream Dark Field imaging). The PTA index demonstrated a good performance in predicting hemodynamic reactions in anesthetized dogs. It also detected disturbances of the sympathetic balance in horses admitted for colic surgery as well as an alteration of microcirculation despite resuscitation maneuvers. Preclinical studies on the impact of esmolol and dexmedetomidine infusion in a septic swine model showed that, despite their potential hemodynamic effects, these agents did not have a negative effect on the microcirculation. Thus, these findings suggest a beneficial effect of the modulators of the sympathetic nervous system on the microcicultion, however, these resutls should be confirmed on a larger scale

INTRODUÇÃO: A utilização das técnicas minimamente invasivas vem se difundindo principalmente após o desenvolvimento da técnica robótica, principalmente em patologias com alta incidência como a neoplasia da próstata. Apesar da cirurgia minimamente invasiva aparentemente proporcionar menor dor no pós-operatório, ainda assim alguns pacientes necessitam opióides que possuem efeitos colaterais indesejáveis. O uso de medicações adjuvantes durante o intraoperatório, como a Dexmedetomidina (DEX) pode diminuir o seu uso pelo efeito poupador de opióides e analgésico. OBJETIVOS: Avaliar o impacto do uso da DEX em pacientes submetidos a prostatectomia radical robótica. MÉTODO: Estudo retrospectivo em cem pacientes submetidos a prostatectomia radical robótica. Quarenta e oito pacientes não utilizaram DEX, e 52 pacientes receberam dexmedetomidina na dose de 0,3 a 0,7mcg/kg/h no intraoperatório e desligado meia hora antes do final do procedimento. Durante o procedimento e no pós-operatório receberam analgésico opióide e não opióide sob prescrição ou a critério do anestesiologista. O consumo de medicação opióide e não opióide e escores de dor através do consumo de analgésicos foram avaliados durante a RPA, POI e 1PO, dividindo os pacientes em quatro grupos (sem DEX, nem Morfina; somente DEX; DEX com morfina; Morfina apenas). RESULTADOS: Nossos resultados demonstraram que a utilização de DEX no intra-operatório levou a um aumento da utilização de morfina na RPA, comparado aos grupos (28,1%, 38,5%, 25% e 15,4%, necessitaram de mais do que 5 mg de morfina na RPA) (p=0,135). Os pacientes que tomaram apenas DEX também demonstraram mais dor forte (84,6%) e menos pacientes sem dor (15,4%) (p=0,001). A DEX foi responsável pela diminuição da utilização de analgésico não opioide na RPA do grupo onde somente a DEX foi utilizada e nenhum paciente necessitou de analgésico não opioide e do grupo onde houve associação de DEX e morfina (2,8%), sendo que nos outros 2 grupos 12,5% necessitaram (p=0,083) O grupo que recebeu DEX e morfina foi o que menos recebeu morfina na RPA (59% não recebeu nenhuma morfina) (p=0,135). No POI e no 1PO, 100% dos pacientes não receberam nenhuma morfina (p=0,555). Este último grupo de pacientes também apresentou menor dor, sendo que 48,7% não apresentou dor na RPA e 51,3% na avaliação durante o POI (p=0,001). A combinação das duas drogas levou a uma impressionante redução da dor no POI (10,3%), de aproximadamente 8 vezes menos dor forte do que no grupo sem utilização de nenhuma droga (81,3%) (p=0,000). CONCLUSÃO: Portanto a utilização da DEX durante o intra-operatório não mostrou resultado favorável na diminuição do consumo de morfina, na diminuição da dor dos pacientes submetidos a prostatectomia radical robótica, mas, quando usamos morfina associado a morfina houve uma melhora nos resultados da dor e diminuição significativa de consumo de morfina no período pós-operatório / Introduction: Minimally invasive techniques are spreading in high incidence diseases like prostate cancer. Patients undergoing minimally invasive procedures seem to have a better pain control but many still require opioid analgesia that can induce undesirable side effects. The use of adjuvant agents as DEX intraoperatively can be desirable for their analgesic and opioid sparing effect. Purpose: Evaluate the impact of DEX use in patients undergoing robotic radical prostatectomy. Methods: The present retrospective study included 100 patients who underwent robotic-assisted laparoscopic prostatectomy. Forty-eight patients did not receive DEX was the control group and fifty-two received DEX infusion at a rate of 0,3-0,7mcg/kg/h and discontinued 30 minutes before the end of the procedure. Patients received opioid and non-opioid analgesia under prescription and anesthesiologist discretion. Opioid and non-opioid analgesia consumption and pain scores (measured by opioid and non-opioid analgesia consumption) were collected on postoperative period, immediate postoperative period and first postoperative period. Results: Our results demonstrated that compared with the groups(28,1%, 38,5%,25% e 15,4% had more than 5mg of morphine on postoperative care unit), patients that received DEX intraoperatively, required higher doses of morphine on postoperative care unit.The DEX group presented more patients with severe pain (84,6%) and fewer without pain(15,4%).The use of DEX intraoperatively lead to a reduction of non-opioid use in postanesthesia care unit and neither patients had non opioid analgesia , when morphine is associated to DEX 2,8% received, and with the other two groups 12,5% (p=0,083). The DEX and morphine received less morphine than the other groups on postanesthesia care unit (59% received any morphine)(p=0,135).On immediate postoperative period and first postoperative period , 100% received any morphine(p=0,555), this group had more patients with lesser pain, 48,7% had no pain on postanesthesia care unit e 51,3% on immediate postoperative period. The combination of DEX and morphine lead to an impressive reduction of pain on immediate postoperative period(10,3%),patients had about 8 times less severe pain than the group that did not receive neither morphine or DEX(81,3%)(p=0,000).Conclusion: The use of DEX infusion was not suitable regarding morphine spare and reduction of pain of the patients undergoing robotic-assisted radical prostatectomy. An association between DEX and Morphine seems to be the best option to relieve post-op pain and decrease morphine usage

INTRODUÇÃO: A utilização das técnicas minimamente invasivas vem se difundindo principalmente após o desenvolvimento da técnica robótica, principalmente em patologias com alta incidência como a neoplasia da próstata. Apesar da cirurgia minimamente invasiva aparentemente proporcionar menor dor no pós-operatório, ainda assim alguns pacientes necessitam opióides que possuem efeitos colaterais indesejáveis. O uso de medicações adjuvantes durante o intraoperatório, como a Dexmedetomidina (DEX) pode diminuir o seu uso pelo efeito poupador de opióides e analgésico. OBJETIVOS: Avaliar o impacto do uso da DEX em pacientes submetidos a prostatectomia radical robótica. MÉTODO: Estudo retrospectivo em cem pacientes submetidos a prostatectomia radical robótica. Quarenta e oito pacientes não utilizaram DEX, e 52 pacientes receberam dexmedetomidina na dose de 0,3 a 0,7mcg/kg/h no intraoperatório e desligado meia hora antes do final do procedimento. Durante o procedimento e no pós-operatório receberam analgésico opióide e não opióide sob prescrição ou a critério do anestesiologista. O consumo de medicação opióide e não opióide e escores de dor através do consumo de analgésicos foram avaliados durante a RPA, POI e 1PO, dividindo os pacientes em quatro grupos (sem DEX, nem Morfina; somente DEX; DEX com morfina; Morfina apenas). RESULTADOS: Nossos resultados demonstraram que a utilização de DEX no intra-operatório levou a um aumento da utilização de morfina na RPA, comparado aos grupos (28,1%, 38,5%, 25% e 15,4%, necessitaram de mais do que 5 mg de morfina na RPA) (p=0,135). Os pacientes que tomaram apenas DEX também demonstraram mais dor forte (84,6%) e menos pacientes sem dor (15,4%) (p=0,001). A DEX foi responsável pela diminuição da utilização de analgésico não opioide na RPA do grupo onde somente a DEX foi utilizada e nenhum paciente necessitou de analgésico não opioide e do grupo onde houve associação de DEX e morfina (2,8%), sendo que nos outros 2 grupos 12,5% necessitaram (p=0,083) O grupo que recebeu DEX e morfina foi o que menos recebeu morfina na RPA (59% não recebeu nenhuma morfina) (p=0,135). No POI e no 1PO, 100% dos pacientes não receberam nenhuma morfina (p=0,555). Este último grupo de pacientes também apresentou menor dor, sendo que 48,7% não apresentou dor na RPA e 51,3% na avaliação durante o POI (p=0,001). A combinação das duas drogas levou a uma impressionante redução da dor no POI (10,3%), de aproximadamente 8 vezes menos dor forte do que no grupo sem utilização de nenhuma droga (81,3%) (p=0,000). CONCLUSÃO: Portanto a utilização da DEX durante o intra-operatório não mostrou resultado favorável na diminuição do consumo de morfina, na diminuição da dor dos pacientes submetidos a prostatectomia radical robótica, mas, quando usamos morfina associado a morfina houve uma melhora nos resultados da dor e diminuição significativa de consumo de morfina no período pós-operatório / Introduction: Minimally invasive techniques are spreading in high incidence diseases like prostate cancer. Patients undergoing minimally invasive procedures seem to have a better pain control but many still require opioid analgesia that can induce undesirable side effects. The use of adjuvant agents as DEX intraoperatively can be desirable for their analgesic and opioid sparing effect. Purpose: Evaluate the impact of DEX use in patients undergoing robotic radical prostatectomy. Methods: The present retrospective study included 100 patients who underwent robotic-assisted laparoscopic prostatectomy. Forty-eight patients did not receive DEX was the control group and fifty-two received DEX infusion at a rate of 0,3-0,7mcg/kg/h and discontinued 30 minutes before the end of the procedure. Patients received opioid and non-opioid analgesia under prescription and anesthesiologist discretion. Opioid and non-opioid analgesia consumption and pain scores (measured by opioid and non-opioid analgesia consumption) were collected on postoperative period, immediate postoperative period and first postoperative period. Results: Our results demonstrated that compared with the groups(28,1%, 38,5%,25% e 15,4% had more than 5mg of morphine on postoperative care unit), patients that received DEX intraoperatively, required higher doses of morphine on postoperative care unit.The DEX group presented more patients with severe pain (84,6%) and fewer without pain(15,4%).The use of DEX intraoperatively lead to a reduction of non-opioid use in postanesthesia care unit and neither patients had non opioid analgesia , when morphine is associated to DEX 2,8% received, and with the other two groups 12,5% (p=0,083). The DEX and morphine received less morphine than the other groups on postanesthesia care unit (59% received any morphine)(p=0,135).On immediate postoperative period and first postoperative period , 100% received any morphine(p=0,555), this group had more patients with lesser pain, 48,7% had no pain on postanesthesia care unit e 51,3% on immediate postoperative period. The combination of DEX and morphine lead to an impressive reduction of pain on immediate postoperative period(10,3%),patients had about 8 times less severe pain than the group that did not receive neither morphine or DEX(81,3%)(p=0,000).Conclusion: The use of DEX infusion was not suitable regarding morphine spare and reduction of pain of the patients undergoing robotic-assisted radical prostatectomy. An association between DEX and Morphine seems to be the best option to relieve post-op pain and decrease morphine usage

Despite great technological advances in coronary artery bypass grafting (CABG) surgery, there is a high incidence of cardiac dysfunction and neurocognitive deficits in the postoperative period. Preventive measures are essential to reducing these adverse situations that are responsible for significant morbidity and impairment on life quality of these patients. Surgery and cardiopulmonary bypass (CPB) produces important changes in the immune system, directly involved in the incidence of these complications and is credible that anesthesia choice can it modified. We hypothezised that dexmedetomidine, an (α)-2-agonist, could the inflammatory response to CABG and CPB modified. In a prospective and randomized study, we intend to demonstrate the influence of dexmedetomidine (TIVA-DEX group), as a component of a conventional total intravenous anesthesia (TIVA-propofol+sufentanil) in patients undergoing CABG, with mini-CPB, on the behavior of this inflammatory response. The TIVA-DEX group received a continuous infusion of dexmedetomidine associated to a conventional venous anesthesia (continuous infusion of propofol+sufentanil). Intraoperative dosage of cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-10 (IL-10), gamma interferon (INF-γ) and tumor necrosis factor (TNF-α) were performed, and also C-reactive protein (CRP), creatine phosphokinase (CPK), creatine phosphokinase-MB (CPK-MB), I troponin (cTnI), cortisol and glucose. The occurrence of lipid peroxidation, by the study of thiobarbituric acid reactive substances (TBARS) and the activity of delta-aminolevulinate dehydratase (δ-ALA-D) to oxidative stress verify were also avaliated. Dexmedetomidine induce a significative reduction of IL-1, IL-6, TNF-α and INF-γ, as compared to group that not receive dexmedetomidine. The levels of IL-10 were decreased in both groups along the time, at a similar pattern. Differences between groups on δ-ALA-D activity do not occur and TBARS was higher in TIVA-DEX group. We concluded that dexmedetomidine associated to TIVA was able to reduce plasma levels of proinflammatory cytokines IL-1, IL-6, TNF-α and INF-γ in patients submitted to CABG surgery under mini-CPB, as compared to a conventional TIVA. These results reinforce literature data about dexmedetomidine potentiality as an anti inflammatory agent. / Apesar dos grandes avanços tecnológicos nas cirurgias de revascularização miocárdica (CRM), ocorre uma grande incidência de disfunção cardíaca e déficit neurocognitivo no período pós-operatório. As medidas preventivas são essenciais para a redução destas situações adversas, responsáveis pelo comprometimento da qualidade de vida dos pacientes. A cirurgia e a circulação extra-corpórea (CEC) produzem alterações importantes no sistema imunológico, diretamente envolvidas na incidência das complicações e acredita-se que a escolha anestésica possa modificá-las. Em estudo prospectivo e randomizado, pretendemos demonstrar a influência da dexmedetomidina (grupo AIVT-DEX), um anestésico (α)-2-agonista, associado à anestesia intravenosa total (AIVT) no comportamento da resposta inflamatória em pacientes submetidos à CRM, sob mini-circulação extracorpórea (mini-CEC). O grupo AIVT-DEX recebeu infusão contínua de dexmedetomidina associado à técnica de AIVT convencional e o outro grupo foi submetido à AIVT convencional (infusão contínua de propofol e sufentanil). Os grupos foram comparados pela dosagem plasmática trans-operatória de citocinas, como a interleucina-1(IL-1), a interleucina-6 (IL-6), a interleucina-10 (IL-10), o interferon gama (INF-γ) e o fator de necrose tumoral alfa (TNF-α), bem como a proteína C reativa (PCR), creatinofosfoquinase (CPK), creatinofosfoquinase miocárdio específica (CPK-MB), troponina I (cTnI), cortisol e glicose. A peroxidação lipídica foi avaliada pelo estudo das substâncias reativas ao ácido tiobarbitúrico (TBARS) e a presença de estresse oxidativo pela atividade da enzima delta-aminolevulinato desidratase (δ-ALA-D). O uso da dexmedetomidina induziu redução significativa de IL-1, IL-6, TNF-α e INF-γ se comparado ao grupo sem dexmedetomidina. Houve redução progressiva dos níveis de IL-10 ao longo do tempo, de forma semelhante entre os grupos. Não houve diferença entre os grupos para a atividade da enzima δ-ALA-D e os níveis de TBARS foram maiores no grupo AIVT-DEX. Concluímos que a dexmedetomidina associada à AIVT convencional foi capaz de reduzir os níveis plasmáticos das citocinas pró-inflamatórias IL-1, IL-6, TNF-α e INF-γ em pacientes submetidos à CRM sob mini-CEC, se comparados aos pacientes que receberam apenas a AIVT convencional. Estes resultados reforçam os dados da literatura quanto à potencialidade da dexmedetomidina como agente modulador da resposta inflamatória no período trans- operatório.

No description available.

co-diplomation avec l'Université de Lille (France) / Introduction : La dexmédétomidine, un agoniste α-2 adrénergique, est de plus en plus utilisée pour la sédation et l’analgésie des nouveau-nés nécessitant un support ventilatoire grâce à son absence d’effet dépressif respiratoire. Cependant, elle impacte le système cardio-vasculaire via le système nerveux autonome et pourrait modifier la balance des systèmes sympathiques et parasympathiques (S/PS) et ainsi augmenter la survenue de bradycardie et d’hypotension. Objectifs : Cette étude a pour objectif de décrire l’utilisation de la dexmédétomidine et d’analyser l’impact de la perfusion continue sur le système cardio-vasculaire et sur la balance du système S/PS des nouveau-nés admis aux soins intensifs pédiatriques. Méthodes : Nous avons inclus les nouveau-nés (< 28 jours) qui ont reçu une perfusion de dexmédétomidine. Les données ont été collectées à partir d’une base de données haute résolution qui collecte prospectivement, outre les données du dossier clinique informatisé, toutes les données issues des moniteurs et des pousses-seringues. La balance S/PS a été estimée via l’analyse de la variabilité du rythme cardiaque (VRC) sur les électrocardiogrammes, extraits de la base de données, en calculant le rapport basses fréquences / hautes fréquences (LH/HF). Les concentrations plasmatiques (CP) de dexmédétomidine ont été simulées en utilisant un modèle pharmacocinétique de population développé dans une population similaire à la nôtre. Les variables ont été comparées sur différentes périodes au cours des 12 premières heures de perfusion à l'aide d'analyses ANOVA et la relation avec les variables pharmacocinétiques a été calculée par régression linéaire. Résultats : Vingt-trois nouveau-nés ont été inclus dans l’étude. Par rapport aux valeurs témoins, la fréquence cardiaque (FC) a diminué de 19±4 bpm (p=0,002) et la pression artérielle moyenne (PAM) a diminué de 8,6±2,5 mmHg (p=0,023) pendant les 12 premières heures de perfusion. La FC diminuait avec l’augmentation de la CP simulée (coefficient de régression de -8,6 [95% IC : -1,9 ; -6,3]). Le rapport LF/HF a montré une tendance à la diminution sans retrouver de différence statistiquement significative (p=0,077). Conclusion : La FC et la PAM semblent diminuées sous dexmédétomidine tout en restant dans des valeurs normales pour le nouveau-né. L’ampleur de la diminution de la FC semble reliée à l’augmentation des CP. De plus, la tendance de diminution de la balance S/PS suggère une réduction du contrôle sympathique chez le nouveau-né recevant la dexmédétomidine. Cependant, l’ensemble de ces résultats doit encore être confirmé par des études plus larges et prospectives. / Introduction: Dexmedetomidine, an adrenergic α-2 agonist, has been increasingly used for sedation and analgesia in neonates due to its lack of respiratory depressant effect. However, it impacts the cardiovascular system via the autonomic nervous system. It could modify the sympathetic/parasympathetic balance (S/PS balance) and result in an increased risk of bradycardia and hypotension. Objectives: This study aimed to describe the utilization of intravenous dexmedetomidine infusion and characterize its impact on the hemodynamics, including S/PS balance, in critically ill neonates. Methods: We retrospectively included neonates (<28 days) who received a dexmedetomidine infusion. Data were collected from a high-fidelity database that prospectively collects all data from the monitors, infusion pumps, and electronic medical records. The S/PS balance was assessed by analyzing heart rate variability from database electrocardiograms. This was done using the low/high frequency (LF/HF) ratio with frequency band adapted for neonatal population. Dexmedetomidine plasma concentrations (PC) were simulated using a published population pharmacokinetic model. The variables were compared at different times during the first 12 hours of infusion using ANOVA analyses and their association with pharmacokinetics variables was evaluated using linear regression. Results: A total of 23 neonates were included. When compared to baseline values, heart rate (HR) values decreased by 19±4 bpm (p=0.002), and mean arterial pressure (MAP) decreased by 8.6±2.5 mmHg (p=0.023) 12 hours following the initiation of infusion. HR decreased proportionally with increased simulated PC over 12 hours (regression coefficient: -8.6 [95% IC: -10.9 - 6.3]). The LF/HF ratio tended to decrease over the same period, although this was not statistically significant (p=0.077). Conclusion: In critically ill neonates, HR and MAP decreased on dexmedetomidine infusion but remained within normal neonatal values. The decrease in HR was associated with higher simulated PC. Moreover, the decreasing trend of S/PS balance suggest a reduction in sympathetic control in the neonate receiving dexmedetomidine. However, these results need to be confirmed with larger prospective studies.

While task-based functional magnetic resonance imaging (fMRI) has helped us understand the functional role of many regions in the human brain, many diseases and complex behaviors defy explanation. Alternatively, if no task is performed, the fMRI signal between distant, anatomically connected, brain regions is similar over time. These correlations in “resting state” fMRI have been strongly linked to behavior and disease. Previous work primarily calculated correlation in entire fMRI runs of six minutes or more, making understanding the neural underpinnings of these fluctuations difficult. Recently, coordinated dynamic activity on shorter time scales has been observed in resting state fMRI: correlation calculated in comparatively short sliding windows and quasi-periodic (periodic but not constantly active) spatiotemporal patterns. However, little relevance to behavior or underlying neural activity has been demonstrated. This dissertation addresses this problem, first by using 12.3 second windows to demonstrate a behavior-fMRI relationship previously only observed in entire fMRI runs. Second, simultaneous recording of fMRI and electrical signals from the brains of anesthetized rats is used to demonstrate that both types of dynamic activity have strong correlates in electrophysiology. Very slow neural signals correspond to the quasi-periodic patterns, supporting the idea that low-frequency activity organizes large scale information transfer in the brain. This work both validates the use of dynamic analysis of resting state fMRI, and provides a starting point for the investigation of the systemic basis of many neuropsychiatric diseases.