Psychotropic medication use is widely implicated as a risk factor for injuries, and it is believed that the adverse effect profiles of these medications are exacerbated by the consumption of alcohol. The objectives of this study are (a) to examine the associations between the use of specific classes of psychotropic medications and injuries among elderly participants of the National Population Health Survey (NPHS), and (b) to determine whether and how associations between psychotropic medications and injuries are modified by the consumption of alcohol. Data from Cycles 1 (1994/95), 2 (1996/97), and 3 (1998/99) of the NPHS household longitudinal file were used in this study, selecting community-dwelling participants aged 65 years of age and older in 1994/95. Among antidepressant medications, the magnitude of the risk of injuries was higher for users of tricyclic derivatives (OR=1.4; 95%CI: 0.7 – 2.9) than SSRIs (OR=0.3; 95%CI: 0.1 – 1.0). Benzodiazepine use for any indication increased the risk of injuries, but that effect was not consistent across indications. The use of benzodiazepine antianxiety medications resulted in an increased risk of injuries (OR=2.0; 95%CI: 1.3 – 3.1), but there were no significant effects on the injury risk among benzodiazepine hypnotic and sedative users (OR=0.8; 95%CI: 0.4 – 1.7). Results pertaining to the second objective of this study raised as many questions as they resolved. Alcohol consumption decreased the odds of injury among hypnotic and sedative users, but otherwise, no consistent results were observed. Findings from this study underscore the importance of identifying appropriate alcohol measures for research among elderly populations. They also stress the need to separately consider the impact of different classes of psychotropic medications on injuries (tricyclic antidepressants separate from SSRI antidepressants and antianxiety benzodiazepines separate from hypnotic and sedative benzodiazepines).

Psychotropic medication use is widely implicated as a risk factor for injuries, and it is believed that the adverse effect profiles of these medications are exacerbated by the consumption of alcohol. The objectives of this study are (a) to examine the associations between the use of specific classes of psychotropic medications and injuries among elderly participants of the National Population Health Survey (NPHS), and (b) to determine whether and how associations between psychotropic medications and injuries are modified by the consumption of alcohol. Data from Cycles 1 (1994/95), 2 (1996/97), and 3 (1998/99) of the NPHS household longitudinal file were used in this study, selecting community-dwelling participants aged 65 years of age and older in 1994/95. Among antidepressant medications, the magnitude of the risk of injuries was higher for users of tricyclic derivatives (OR=1.4; 95%CI: 0.7 – 2.9) than SSRIs (OR=0.3; 95%CI: 0.1 – 1.0). Benzodiazepine use for any indication increased the risk of injuries, but that effect was not consistent across indications. The use of benzodiazepine antianxiety medications resulted in an increased risk of injuries (OR=2.0; 95%CI: 1.3 – 3.1), but there were no significant effects on the injury risk among benzodiazepine hypnotic and sedative users (OR=0.8; 95%CI: 0.4 – 1.7). Results pertaining to the second objective of this study raised as many questions as they resolved. Alcohol consumption decreased the odds of injury among hypnotic and sedative users, but otherwise, no consistent results were observed. Findings from this study underscore the importance of identifying appropriate alcohol measures for research among elderly populations. They also stress the need to separately consider the impact of different classes of psychotropic medications on injuries (tricyclic antidepressants separate from SSRI antidepressants and antianxiety benzodiazepines separate from hypnotic and sedative benzodiazepines).

Συναπτική διέγερση και αναστολή βρίσκονται σε συνεχή δυναμική ισορροπία, απαραίτητη για την καλή λειτουργία του ΚΝΣ. Ένα από τα βασικά ανασταλτικά κυκλώματα του εγκεφάλου είναι αυτό της παλίνδρομης αναστολής. Το πιο χαρακτηριστικό, ίσως, παράδειγμα του κυκλώματος αυτού βρίσκεται στη CA1 περιοχή του ιππόκαμπου, η οποία προσφέρεται για ηλεκτροφυσιολογικές μελέτες in vitro, λόγω της στρωματοειδούς οργάνωσης των κυκλωμάτων ιππόκαμπου. Πρόσφατες έρευνες έχουν δείξει διαφορές στη δομή και λειτουργία των δύο πόλων του ιππόκαμπου, καθιστώντας αναγκαία τη συγκριτική τους μελέτη. Στην εργασία αυτή χρησιμοποιήθηκαν εξωκυττάριες καταγραφές από την πυραμιδική στοιβάδα σε συνδυασμό με το πρωτόκολλο διπλού ορθόδρομου ερεθισμού (περιορισμένα) και το πρωτόκολλο αντίδρομου-ορθόδρομου ερεθισμού (εκτενέστερα) για τη μελέτη του πλάτους και της διάρκειας της παλίνδρομης αναστολής σε τομές ραχιαίου και κοιλιακού ιππόκαμπου από αρσενικούς επίμυες, καθώς και της επίδρασης επί αυτής μιας σειράς καταπραϋντικών φαρμάκων που δρουν ως αλλοστερικοί ενισχυτές του GABAA υποδοχέα. Τα αποτελέσματα των πειραμάτων έδειξαν: Επαλήθευση της στρωματοειδούς οργάνωσης των κυκλωμάτων του ιππόκαμπου, με μεγαλύτερη κατευθυντικότητα των ανασταλτικών κυκλωμάτων στο ραχιαίο σε σχέση με τον κοιλιακό πόλο. Μεγαλύτερο πλάτος και διάρκεια και πιο αργή μείωση της παλίνδρομης αναστολής γενικά, και της GABAA συνιστώσας της ειδικότερα, στο ραχιαίο σε σχέση με τον κοιλιακό ιππόκαμπο. Ενίσχυση της παλίνδρομης αναστολής και στους δύο πόλους του ιππόκαμπου από διαζεπάμη, μιδαζολάμη, ζολπιδέμη, φαινοβαρβιτάλη, θειοπεντάλη, πεντοβαρβιτάλη, αλφαξαλόνη και προποφόλη. Συσχέτιση της αύξησης του πλάτους της αναστολής και της διάρκειας της ενίσχυσής της με την κλινική δράση της κάθε συγκέντρωσης φαρμάκου. Ενίσχυση της αποκλειστικά GABAA εξαρτώμενης αναστολής από υψηλές συγκεντρώσεις θειοπεντάλης και αλφαξαλόνης που δοκιμάστηκαν ενδεικτικά πολύ πέρα από τα φυσιολογικά χρονικά όριά της. Μεγαλύτερη διάρκεια ενίσχυσης της συναπτικής αναστολής από τις σχετικά υψηλότερες δόσεις φαρμάκων στο ραχιαίο σε σχέση με τον κοιλιακό πόλο. Έλλειψη δράσης του νευροστεροειδούς αλλοπρεγνανολόνη και των συνθετικών παραγώγων του στη συναπτική αναστολή. Περιορισμένος αριθμός in vivo πειραμάτων εκτίμησης της επίδρασης της αλλο-πρεγνανολόνης και των παραγώγων της στην αναστολή με το μοντέλο ελέγχου επιληπτικών κρίσεων που προκαλούνται από PTZ έδειξε πως, ενώ τα συνθετικά παράγωγα δεν είχαν καμία δράση, η αλλοπρεγνανολόνη είχε σημαντική θετική δράση / Synaptic excitation and inhibition are maintained in dynamic equilibrium, necessary for the proper function of the CNS. One of the basic inhibitory circuits of the brain is that of recurrent inhibition. The most distinctive example of recurrent inhibition occurs in the CA1 region of the hippocampus, a region particularly suited to in vitro electrophysiological investigations because of the unique lamellar organization of hippocampal circuits. Recent research has uncovered considerable differences in the structure and function of the two poles of the hippocampus necessitating a comparative study. In this study we used extracellular recordings from the pyramidal cell layer of dorsal and ventral rat hippocampal slices, in conjunction with limited use of the double orthodromic and more extensive use of the paired antidromic-orthodromic stimulation protocol in order to study the CA1 recurrent inhibition and the effects of a series of sedative drugs, with GABAA allosteric modulator properties, on it. The results of these experiments showed: A verification of the lamellar organization of hippocampal circuits. Dorsal pole inhibitory circuits showed a greater orientation specificity than ventral pole ones. A greater size and duration and a slower decay of recurrent inhibition in general, and of its GABAA-mediated component in particular, in dorsal compared to ventral hippocampus. An enhancement of recurrent inhibition in both hippocampal poles produced by diazepam, midazolam, zolpidem, phenobarbital, thiopental, pentobarbital, alfaxalone and propofol. A correlation between the enhancement of the size of recurrent inhibition or the duration of its enhancement and the clinical actions of every drug concentration tested. An enhancement of the exclusively GABAA-mediated recurrent inhibition by representative high concentrations of thiopental and alfaxalone well beyond its normal duration. A greater duration of recurrent inhibition enhancement by the relatively higher drug concentrations in dorsal compared to ventral hippocampus. A lack of action on synaptic inhibition by the neurosteroid allopregnanolone and its synthetic derivatives. A limited number of in vivo experiments assessing the effect of allopregnanolone and its derivatives on synaptic inhibition, measured as their ability to control epileptic seizures induced by acute injections of PTZ, showed that the synthetic derivatives had no effect whereas allopregnanolone had a significant positive effect.

After sixteen intensive months, I quit my employed position as a security guard at a local hospital. By drawing on my autoethnographic experiences in the form of “ethnographic fiction writing”, as well as eight interviews with my former male colleagues, I explore how the guards’ constructions of masculinity intersect with their security assessment and subsequent application of force, chemical incarceration, and other coercive security tactics on involuntarily-committed mental health patients. The narratives are framed by the available literature on gender and masculinity within the security, police, prison and military institutions, as well as the theoretical notions of gendered institutions (Acker), hegemonic masculinity (Connell & Messerschmidt), doing gender (West & Zimmerman), and Dave Holmes’s application of Foucauldian biopolitical power to forensic healthcare settings. These concepts are used in tandem with a creative methodological tool to reveal the “messy”, “bloody” and “gendered” ways in which hospital life unfolds between the guard, the nurse, and the patient prisoner. By escaping more traditional forms of academic writing, I am able to weave raw, sensitive and reflexive thoughts and emotions into the research design and analysis. The analysis is divided into two narratives: “Us” and “Them”. “Us” emphasizes the gendered ways in which the hospital guard learns, reproduces, resists, lives up, or fails to live up to the masculine codes of the profession. Here, the guard must confront cultural demands to demonstrate physical prowess, authority and heroism during a patient battle. “Them” explores how hegemonic masculinity shapes the hierarchical and coercive relations between the guard, the nurse, and the patient, and reinforces psychiatrized discourses that promote punishment, pain, bureaucracy and control. Overall, these findings call for the abolition of physical restraint, chemical incarceration and other coercive security measures within our healthcare institutions, and encourage future research to give voice to the lived experiences of women guards and security management teams.

Healthcare analytics has traditionally relied upon linear and logistic regression models to address clinical research questions mostly because they produce highly interpretable results [1, 2]. These results contain valuable statistics such as p-values, coefficients, and odds ratios that provide healthcare professionals with knowledge about the significance of each covariate and exposure for predicting the outcome of interest [1]. Thus, they are often favored over new deep learning models that are generally more accurate but less interpretable and scalable. However, the statistical power of linear and logistic regression is contingent upon satisfying modeling assumptions, which usually requires altering or transforming the data, thereby hindering interpretability. Thus, generalized additive models are useful for overcoming this limitation while still preserving interpretability and accuracy. The major research question in this work involves investigating whether particular sedative agents (fentanyl, propofol, versed, ativan, and precedex) are associated with different discharge dispositions for patients with acute traumatic brain injury (TBI). To address this, we compare the effectiveness of various models (traditional linear regression (LR), generalized additive models (GAMs), and deep learning) in providing guidance for sedative choice. We evaluated the performance of each model using metrics for accuracy, interpretability, scalability, and generalizability. Our results show that the new deep learning models were the most accurate while the traditional LR and GAM models maintained better interpretability and scalability. The GAMs provided enhanced interpretability through pairwise interaction heat maps and generalized well to other domains and class distributions since they do not require satisfying the modeling assumptions used in LR. By evaluating the model results, we found that versed was associated with better discharge dispositions while ativan was associated with worse discharge dispositions. We also identified other significant covariates including age, the Northeast region, the Acute Physiology and Chronic Health Evaluation (APACHE) score, Glasgow Coma Scale (GCS), and ethanol level. The versatility of versed may account for its association with better discharge dispositions while ativan may have negative effects when used to facilitate intubation. Additionally, most of the significant covariates pertain to the clinical state of the patient (APACHE, GCS, etc.) whereas most non-significant covariates were demographic (gender, ethnicity, etc.). Though we found that deep learning slightly improved over LR and generalized additive models after fine-tuning the hyperparameters, the deep learning results were less interpretable and therefore not ideal for making the aforementioned clinical insights. However deep learning may be preferable in cases with greater complexity and more data, particularly in situations where interpretability is not as critical. Further research is necessary to validate our findings, investigate alternative modeling approaches, and examine other outcomes and exposures of interest. / Master of Science / Patients with Traumatic Brain Injury (TBI) often require sedative agents to facilitate intubation and prevent further brain injury by reducing anxiety and decreasing level of consciousness. It is important for clinicians to choose the sedative that is most conducive to optimizing patient outcomes. Hence, the purpose of our research is to provide guidance to aid this decision. Additionally, we compare different modeling approaches to provide insights into their relative strengths and weaknesses. To achieve this goal, we investigated whether the exposure of particular sedatives (fentanyl, propofol, versed, ativan, and precedex) was associated with different hospital discharge locations for patients with TBI. From best to worst, these discharge locations are home, rehabilitation, nursing home, remains hospitalized, and death. Our results show that versed was associated with better discharge locations and ativan was associated with worse discharge locations. The fact that versed is often used for alternative purposes may account for its association with better discharge locations. Further research is necessary to further investigate this and the possible negative effects of using ativan to facilitate intubation. We also found that other variables that influence discharge disposition are age, the Northeast region, and other variables pertaining to the clinical state of the patient (severity of illness metrics, etc.). By comparing the different modeling approaches, we found that the new deep learning methods were difficult to interpret but provided a slight improvement in performance after optimization. Traditional methods such as linear regression allowed us to interpret the model output and make the aforementioned clinical insights. However, generalized additive models (GAMs) are often more practical because they can better accommodate other class distributions and domains.

Dans le milieu clinique des soins intensifs, l’induction du coma médicamenteux (i.e. iatrogénique) par les sédatifs et les analgésiques est souvent associée à une augmentation significative du délirium. De plus, l’utilisation de sédatifs et d’analgésiques comme le fentanyl et le midazolam sans interruption et sans ajustement aux besoins du patient augmentent la durée de séjour, les coûts et la mortalité. Le but de cette étude était d’explorer les facteurs de variabilité pouvant influencer la survenue du coma iatrogénique et du délirium tel que : les facteurs génétiques/sociodémographiques et la co-administration de médicaments substrats ou inhibiteurs de CYP3A4/3A5 ou de la glycoproteine P. L’étude prospective à visée observationnelle a été effectuée à l’unité de soins intensifs de l’hôpital Maisonneuve-Rosemont avec 53 patients perfusés avec fentanyl ou midazolam. La faisabilité du modèle pharmacocinétique du fentanyl a été mise en évidence à partir des échantillons sanguins des patients et était compatible avec les données cliniques. Cette étude montre donc que contrairement au profil génomique de CYP3A5 (p value = 0,521) et MDR1 (p value = 0,828), les effets des interactions médicamenteuses entre les inhibiteurs CYP3A4/CYP3A5 et fentanyl/midazolam représentent un facteur de risque pour le coma iatrogénique (p value = 0,014). Ces effets peuvent être facilement identifiés et sont prévisibles; résultats qui seront utiles aux praticiens – intensivistes dans le choix d’une thérapie pharmacologique appropriée pour prévenir les complications morbides comme le coma iatrogénique et le délirium. / When sedatives such as midazolam or opiate analgesics such as fentanyl administered to critically ill patients and medication-induced coma occurs, increased delirium is observed. In addition, there is an increase in the length of stay in ICU, in costs and mortality. The purpose of this study was to explore the factors of variability affecting the incidence of iatrogenic coma and delirium: genetics/socio demographics factors, co-administration of substrates/inhibitors of CYP3A4/3A5 or P-gp. We performed a prospective cohort observational study of 53 hospitalized patients treated with fentanyl or/and midazolam in the intensive care unit of the Maisonneuve-Rosemont hospital The feasibility of pharmacokinetics modeling using blood samples from critically ill patients was demonstrated and was compatible with clinical data. This study suggests that contrary to genomic variants in the CYP3A5 (p value = 0,521) and MDR1 (p value = 0,828) genes, the effect of drugs and drugs interactions between inhibitors of CYP3A4/3A5 and fentanyl/ midazolam constitutes the main risk factor for iatrogenic coma (p value - 0,014). These effects are easily identifiable and predictable, and are very important for intensive care workers to make the appropriate choice of medication in order to prevent morbid complications such as iatrogenic coma and delirium.

O propofol é um sedativo eficiente, largamente empregado em anestesia e geralmente associado a grande números de analgésicos opióides em cirurgias de grande porte, como a cirurgia cardíaca de revascularização do miocárdio (RM) com ou sem circulação extracorpórea (CEG). Devido às suas características farmacocinéticas é administrado através de infusão alvo controlada (TCI) de forma a manter os níveis plasmáticos ótimos para obtenção de sedação e profundidade de anestesia adequadas durante a intervenção cirúrgica. O objetivo do presente estudo foi investigar a farmacocinética e farmacodinâmica do propofol administrado através de TCI em pacientes submetidos a RM com e sem CEC. Na administração da medicação hipnótica, fez-se necessária a validação do Diprifusor (AstraZeneca), incluindo a bomba de infusão e o software programado com o modelo farmacocinético de 3 compartimentos, que necessita apenas da inclusão de dados individuais do paciente, tais como peso corporal. A validação desse sistema compreendeu a estimativa do erro de previsão do Diprifusor pela utilização da razão das concentrações obtida, experimentalmente medida, e a prevista pelo modelo do software da bomba de infusão. No presente estudo comparativo, selecionaram-se 20 pacientes com base nos critérios de inclusão, que foram divididos em 2 grupos, Controle e CEC. Os pacientes foram informados em detalhes sobre os dados que cercam esse protocolo de pesquisa e assinaram o termo de consentimento livre esclarecido para participação no estudo. O protocolo for submetido e aprovado pelo CEP de todas as Instituições envolvidas (FCFUSP, InCor e CAPPesq). A taxa de infusão requerida, bem como a faixa de concentração obtida para manter o alvo de 2 µg/mL e o índice bispectral de 40 (BIS) durante a cirurgia cardíaca foram monitorados. Subsequentemente, ao final da cirurgia, a taxa de infusão e a faixa de concentração do propofol plasmático requeridos para atingir o alvo de 1 µg/mL também foram monitorados. Neste período, a sedação e a medida da profundidade da anestesia foram monitorados através do BIS e da Escala de Ramsay. O efeito medido através do BIS durante a infusão, no intra-operatório, atingiu o valor máximo de 40 da escala nos dois grupos. Da mesma forma, ao final da cirurgia, obteve-se nível 6 de sedação na escala de Ramsay em ambos os grupos, quando o alvo foi ajustado para 1 µg/mL. Adicionalmente pela interrupção da infusão, no pós-operatório imediato, BIS e Ramsay foram registrados simultaneamente até o final do período de estudo (18-20 horas) para todos os pacientes. Efetuou-se coleta de amostras sanguíneas durante as infusões alvo (2 µg/mL e 1 µg/mL) e após a interrupção da infusão para o estudo da farmacocinética . Requereu-se volume de sangue inferior a 90 mL para o monitoramento plasmático e a modelagem farmacocinética. Utilizou-se a cromatografia líquida de alta eficiência, com deteto r de fluorescência (CLAE-F). O método mostrou-se bastante simples, seletivo, sensível e robusto e utilizou coluna C18 e fase móvel binária em baixo fluxo. Os limites de confiança estabelecidos para o método analítico foram: 0,1-10 µg/mL (linearidade, r2 0,9977), 0,05 µg/mL (LD), 0,1 µg/mL(LQ), 93,9% (recuperação absoluta), 8,4 e 8,8% (precisão intra e inter dias), 91,8 e 93,3% (exatidão intra e inter dias). Adicionalmente, demonstrou-se boa estabilidade para o fármaco através de estudos de curta e longa duração, tempo de bandeja (tempo e condição de análise) e ciclos de congelamento e descongelamento, além de estudo de estabilidade das soluções padrão do propofol e do timol (padrão interno). No perioperatório, as concentrações plasmáticas evidenciaram alta flutuação, principalmente durante a intervenção para o grupo CONTROLE comparado ao grupo CEC, indicando maior erro de previsão na taxa de infusão estimada pelo software da bomba para manter o alvo no Controle. A modelagem farmacocinética foi efetuada pela aplicação do modelo aberto de 3 compartimentos que mostrou significativo aumento na eliminação do fármaco (ClT, ß, γ) no grupo CEC relativamente ao CONTROLE, uma vez que as concentrações plasmáticas obtidas no grupo CEC foram inferiores àquelas obtidas no outro grupo. A profundidade de anestesia alcançada foi de 6 na escala de Ramsay e 40 (BIS) durante a TCI , efeito máximo atingido durante essa cirurgia de alto porte. A função matemática sigmoidal foi escolhida com base na alta correlação obtida (r2 >0,9) pela modelagem PK¬PO. A curva de correlação do efeito BIS versus propofol plasmático indica que os grupos CEC e CONTROLE são diferentes, uma vez que apenas os pacientes do CONTROLE retornaram ao valor basal (BIS: 100) no período entre 6 e 8 horas do início da cirurgia e instalação da TCI de propofol. Por outro lado, registrou-se prolongamento do tempo de recuperação da hipnose (tempo de despertar) nos pacientes CEC, que se estendeu até 18 horas. Adicionalmente a modelagem indicou que a concentração efetiva (EC50) é da ordem de 4 vezes menor no grupo CEC comparado ao CONTROLE. Finalmente, apesar das menores concentrações plasmáticas para o propofol no grupo CEC, consequência da elevada depuração plasmática, o efeito máximo do hipnótico durante a intervenção foi semelhante nos dois grupos, sendo que a principal diferença entre eles reside na sedação residual registrada nos pacientes CEC. Esses resultados podem ser justificados em parte pelo aumento da fração livre de propofol no plasma e provavelmente em função de alteração na interação fármaco¬receptor, decorrência da CEC na cirurgia de revascularização do miocárdio. Em conclusão, a CEC afeta a farmacocinética e a farmacodinâmica do propofol no paciente cirúrgico. Por outro lado o dispositivo (Diprofusor, AstraZeneca) para a administração alvo controlada necessita de ajustes e adaptação para a TCI de propofol neste tipo de cirurgia, incluindo-se ainda no ajuste, a diferenciação para o paciente que possui a CEC associada. / Propofol is an effective sedative, largely applied in anesthesia and in general it is associated to opioids for analgesia in major surgeries, like the cardiac surgery to coronary artery bypass grafting (CABG) with or without cardiopulmonary bypass (CPB). It is administered by a target controlled infusion system (TCI) to maintain the optimal depth of sedation and anesthesia during the intervention, due to its pharmacokinetic characteristics. The objective of this study was to investigate the influence of CPB in pharmacokinetics and in pharmacodynamics of propofol, applying PK-PD modeling. For drug administration, Diprifusor (AstraZeneca), including pump plus software must enter individual data as body weight from the patient, once pharmacokinetic parameters were included previously. To validate this system of infusion, the prediction error by target controlled infusion must be estimated by comparison between obtained and predict concentration plasma ratio. In the present protocol, 20 patients (10 CONTROL and 10 CPB) were selected based on inclusion criteria for the comparative study. Patients were informed in details about the investigation and before the protocol starts, they signed the informed written consent to participate of the study. Protocol was approved by the local ethical committees of all institutions involved. Rate of infusion and the range of obtained plasma propofol concentrations required to reach 2 µg/mL and to maintain the bispectral index (BIS:40) during cardiac surgery were monitored. Subsequently, at the end of surgery, both rate of infusion and range of obtained plasma propofol concentrations required to reach 1 µg/mL were monitored either. Depth of sedation was assessed with BIS during all period reaching maximum effect in 40 at level of sedation in the operative period. At the end of surgery, the Ramsay score achieved sedation level 6, when the target plasma propofol was adjusted to 1 µg/mL; Additionally, at the end of infusion in the postoperative period, BIS and Ramsay were monitored simultaneously up to 18-20 hours for all patients. Blood samples were collected and propofol plasma levels were monitored during (TCI : 2 µg/mL) and after surgery (TCI: 1 µg/mL). Blood samples also were collected at the end of infusion for pharmacokinetics. Volumes of blood lower than 90 mL were necessary for drug monitoring and pharmacokinetic purposes. Plasma levels were determined by a quite simple, selective, sensitive and robustness analytical method HPLC, using fluorescence detector, C18 column, and binary system at low flow rate. Confidence limits were: 0.1-10 µg/mL (linearity, r2 0.9977), 0.05 µg/mL(LD), 0.1 flg/mL(LQ), 93.9% (absolute recovery), 8.4 and 8.8% (intra and inter day precision), 91.8 and 93.3% (accuracy intra and inter day). Additionally, good stability was shown for the drug and its internal standard (tymol). Plasma levels showed a large fluctuation for the CONTROL compared to CPB in the perioperative period, mainly during the surgical intervention, indicating a higher predicting error for CONTROL group. Pharmacokinetics applying three compartment open model showed significant increases on drug elimination (ClT, β, γ) for CPB compared to CONTROL, once plasma levels for CPB Group were lower than CONTROL in the period of study. Depth of sedation reached level 6 Ramsay score and 40 (BIS) during TCI, the maximum effect recorded during this major surgery. A sigmoidal mathematical function was choosed (r2>O.9) after PK-PD modeling. BIS effect versus propofol plasma concentration curve indicates that CPB patients are different from CONTROL, once only CONTROL patients recovered to baseline up to 6-8 hours of the starting of surgery, while a prolongation of recovery up to 18 hours, measured by awakening time, was observed in CPB patients; additionally, the effective concentration (EC50) was 4 times lower for CPB compared to CONTROL Group. Finally, in spite of lower plasma concentration in CPB, as a consequence of higher clearance, similar maximum effect were reached in both groups during the intervention and the main difference is based on a residual sedation in CPB patients after surgery. In fact, this data can be justified probably due to changes in free drug plasma levels and in drug-receptor interaction as a result of cardiopulmonary bypass in CABG surgery. In conclusion, cardiopulmonary bypass affects the pharmacokinetics and pharmacodynamics of propofol in CABG patients and the device for TCI (Diprifusor, AstraZeneca) must be adjusted for cardiac surgery with differences in CPB included.

O propofol é um sedativo eficiente, largamente empregado em anestesia e geralmente associado a grande números de analgésicos opióides em cirurgias de grande porte, como a cirurgia cardíaca de revascularização do miocárdio (RM) com ou sem circulação extracorpórea (CEG). Devido às suas características farmacocinéticas é administrado através de infusão alvo controlada (TCI) de forma a manter os níveis plasmáticos ótimos para obtenção de sedação e profundidade de anestesia adequadas durante a intervenção cirúrgica. O objetivo do presente estudo foi investigar a farmacocinética e farmacodinâmica do propofol administrado através de TCI em pacientes submetidos a RM com e sem CEC. Na administração da medicação hipnótica, fez-se necessária a validação do Diprifusor (AstraZeneca), incluindo a bomba de infusão e o software programado com o modelo farmacocinético de 3 compartimentos, que necessita apenas da inclusão de dados individuais do paciente, tais como peso corporal. A validação desse sistema compreendeu a estimativa do erro de previsão do Diprifusor pela utilização da razão das concentrações obtida, experimentalmente medida, e a prevista pelo modelo do software da bomba de infusão. No presente estudo comparativo, selecionaram-se 20 pacientes com base nos critérios de inclusão, que foram divididos em 2 grupos, Controle e CEC. Os pacientes foram informados em detalhes sobre os dados que cercam esse protocolo de pesquisa e assinaram o termo de consentimento livre esclarecido para participação no estudo. O protocolo for submetido e aprovado pelo CEP de todas as Instituições envolvidas (FCFUSP, InCor e CAPPesq). A taxa de infusão requerida, bem como a faixa de concentração obtida para manter o alvo de 2 µg/mL e o índice bispectral de 40 (BIS) durante a cirurgia cardíaca foram monitorados. Subsequentemente, ao final da cirurgia, a taxa de infusão e a faixa de concentração do propofol plasmático requeridos para atingir o alvo de 1 µg/mL também foram monitorados. Neste período, a sedação e a medida da profundidade da anestesia foram monitorados através do BIS e da Escala de Ramsay. O efeito medido através do BIS durante a infusão, no intra-operatório, atingiu o valor máximo de 40 da escala nos dois grupos. Da mesma forma, ao final da cirurgia, obteve-se nível 6 de sedação na escala de Ramsay em ambos os grupos, quando o alvo foi ajustado para 1 µg/mL. Adicionalmente pela interrupção da infusão, no pós-operatório imediato, BIS e Ramsay foram registrados simultaneamente até o final do período de estudo (18-20 horas) para todos os pacientes. Efetuou-se coleta de amostras sanguíneas durante as infusões alvo (2 µg/mL e 1 µg/mL) e após a interrupção da infusão para o estudo da farmacocinética . Requereu-se volume de sangue inferior a 90 mL para o monitoramento plasmático e a modelagem farmacocinética. Utilizou-se a cromatografia líquida de alta eficiência, com deteto r de fluorescência (CLAE-F). O método mostrou-se bastante simples, seletivo, sensível e robusto e utilizou coluna C18 e fase móvel binária em baixo fluxo. Os limites de confiança estabelecidos para o método analítico foram: 0,1-10 µg/mL (linearidade, r2 0,9977), 0,05 µg/mL (LD), 0,1 µg/mL(LQ), 93,9% (recuperação absoluta), 8,4 e 8,8% (precisão intra e inter dias), 91,8 e 93,3% (exatidão intra e inter dias). Adicionalmente, demonstrou-se boa estabilidade para o fármaco através de estudos de curta e longa duração, tempo de bandeja (tempo e condição de análise) e ciclos de congelamento e descongelamento, além de estudo de estabilidade das soluções padrão do propofol e do timol (padrão interno). No perioperatório, as concentrações plasmáticas evidenciaram alta flutuação, principalmente durante a intervenção para o grupo CONTROLE comparado ao grupo CEC, indicando maior erro de previsão na taxa de infusão estimada pelo software da bomba para manter o alvo no Controle. A modelagem farmacocinética foi efetuada pela aplicação do modelo aberto de 3 compartimentos que mostrou significativo aumento na eliminação do fármaco (ClT, ß, γ) no grupo CEC relativamente ao CONTROLE, uma vez que as concentrações plasmáticas obtidas no grupo CEC foram inferiores àquelas obtidas no outro grupo. A profundidade de anestesia alcançada foi de 6 na escala de Ramsay e 40 (BIS) durante a TCI , efeito máximo atingido durante essa cirurgia de alto porte. A função matemática sigmoidal foi escolhida com base na alta correlação obtida (r2 >0,9) pela modelagem PK¬PO. A curva de correlação do efeito BIS versus propofol plasmático indica que os grupos CEC e CONTROLE são diferentes, uma vez que apenas os pacientes do CONTROLE retornaram ao valor basal (BIS: 100) no período entre 6 e 8 horas do início da cirurgia e instalação da TCI de propofol. Por outro lado, registrou-se prolongamento do tempo de recuperação da hipnose (tempo de despertar) nos pacientes CEC, que se estendeu até 18 horas. Adicionalmente a modelagem indicou que a concentração efetiva (EC50) é da ordem de 4 vezes menor no grupo CEC comparado ao CONTROLE. Finalmente, apesar das menores concentrações plasmáticas para o propofol no grupo CEC, consequência da elevada depuração plasmática, o efeito máximo do hipnótico durante a intervenção foi semelhante nos dois grupos, sendo que a principal diferença entre eles reside na sedação residual registrada nos pacientes CEC. Esses resultados podem ser justificados em parte pelo aumento da fração livre de propofol no plasma e provavelmente em função de alteração na interação fármaco¬receptor, decorrência da CEC na cirurgia de revascularização do miocárdio. Em conclusão, a CEC afeta a farmacocinética e a farmacodinâmica do propofol no paciente cirúrgico. Por outro lado o dispositivo (Diprofusor, AstraZeneca) para a administração alvo controlada necessita de ajustes e adaptação para a TCI de propofol neste tipo de cirurgia, incluindo-se ainda no ajuste, a diferenciação para o paciente que possui a CEC associada. / Propofol is an effective sedative, largely applied in anesthesia and in general it is associated to opioids for analgesia in major surgeries, like the cardiac surgery to coronary artery bypass grafting (CABG) with or without cardiopulmonary bypass (CPB). It is administered by a target controlled infusion system (TCI) to maintain the optimal depth of sedation and anesthesia during the intervention, due to its pharmacokinetic characteristics. The objective of this study was to investigate the influence of CPB in pharmacokinetics and in pharmacodynamics of propofol, applying PK-PD modeling. For drug administration, Diprifusor (AstraZeneca), including pump plus software must enter individual data as body weight from the patient, once pharmacokinetic parameters were included previously. To validate this system of infusion, the prediction error by target controlled infusion must be estimated by comparison between obtained and predict concentration plasma ratio. In the present protocol, 20 patients (10 CONTROL and 10 CPB) were selected based on inclusion criteria for the comparative study. Patients were informed in details about the investigation and before the protocol starts, they signed the informed written consent to participate of the study. Protocol was approved by the local ethical committees of all institutions involved. Rate of infusion and the range of obtained plasma propofol concentrations required to reach 2 µg/mL and to maintain the bispectral index (BIS:40) during cardiac surgery were monitored. Subsequently, at the end of surgery, both rate of infusion and range of obtained plasma propofol concentrations required to reach 1 µg/mL were monitored either. Depth of sedation was assessed with BIS during all period reaching maximum effect in 40 at level of sedation in the operative period. At the end of surgery, the Ramsay score achieved sedation level 6, when the target plasma propofol was adjusted to 1 µg/mL; Additionally, at the end of infusion in the postoperative period, BIS and Ramsay were monitored simultaneously up to 18-20 hours for all patients. Blood samples were collected and propofol plasma levels were monitored during (TCI : 2 µg/mL) and after surgery (TCI: 1 µg/mL). Blood samples also were collected at the end of infusion for pharmacokinetics. Volumes of blood lower than 90 mL were necessary for drug monitoring and pharmacokinetic purposes. Plasma levels were determined by a quite simple, selective, sensitive and robustness analytical method HPLC, using fluorescence detector, C18 column, and binary system at low flow rate. Confidence limits were: 0.1-10 µg/mL (linearity, r2 0.9977), 0.05 µg/mL(LD), 0.1 flg/mL(LQ), 93.9% (absolute recovery), 8.4 and 8.8% (intra and inter day precision), 91.8 and 93.3% (accuracy intra and inter day). Additionally, good stability was shown for the drug and its internal standard (tymol). Plasma levels showed a large fluctuation for the CONTROL compared to CPB in the perioperative period, mainly during the surgical intervention, indicating a higher predicting error for CONTROL group. Pharmacokinetics applying three compartment open model showed significant increases on drug elimination (ClT, β, γ) for CPB compared to CONTROL, once plasma levels for CPB Group were lower than CONTROL in the period of study. Depth of sedation reached level 6 Ramsay score and 40 (BIS) during TCI, the maximum effect recorded during this major surgery. A sigmoidal mathematical function was choosed (r2>O.9) after PK-PD modeling. BIS effect versus propofol plasma concentration curve indicates that CPB patients are different from CONTROL, once only CONTROL patients recovered to baseline up to 6-8 hours of the starting of surgery, while a prolongation of recovery up to 18 hours, measured by awakening time, was observed in CPB patients; additionally, the effective concentration (EC50) was 4 times lower for CPB compared to CONTROL Group. Finally, in spite of lower plasma concentration in CPB, as a consequence of higher clearance, similar maximum effect were reached in both groups during the intervention and the main difference is based on a residual sedation in CPB patients after surgery. In fact, this data can be justified probably due to changes in free drug plasma levels and in drug-receptor interaction as a result of cardiopulmonary bypass in CABG surgery. In conclusion, cardiopulmonary bypass affects the pharmacokinetics and pharmacodynamics of propofol in CABG patients and the device for TCI (Diprifusor, AstraZeneca) must be adjusted for cardiac surgery with differences in CPB included.

Dans le milieu clinique des soins intensifs, l’induction du coma médicamenteux (i.e. iatrogénique) par les sédatifs et les analgésiques est souvent associée à une augmentation significative du délirium. De plus, l’utilisation de sédatifs et d’analgésiques comme le fentanyl et le midazolam sans interruption et sans ajustement aux besoins du patient augmentent la durée de séjour, les coûts et la mortalité. Le but de cette étude était d’explorer les facteurs de variabilité pouvant influencer la survenue du coma iatrogénique et du délirium tel que : les facteurs génétiques/sociodémographiques et la co-administration de médicaments substrats ou inhibiteurs de CYP3A4/3A5 ou de la glycoproteine P. L’étude prospective à visée observationnelle a été effectuée à l’unité de soins intensifs de l’hôpital Maisonneuve-Rosemont avec 53 patients perfusés avec fentanyl ou midazolam. La faisabilité du modèle pharmacocinétique du fentanyl a été mise en évidence à partir des échantillons sanguins des patients et était compatible avec les données cliniques. Cette étude montre donc que contrairement au profil génomique de CYP3A5 (p value = 0,521) et MDR1 (p value = 0,828), les effets des interactions médicamenteuses entre les inhibiteurs CYP3A4/CYP3A5 et fentanyl/midazolam représentent un facteur de risque pour le coma iatrogénique (p value = 0,014). Ces effets peuvent être facilement identifiés et sont prévisibles; résultats qui seront utiles aux praticiens – intensivistes dans le choix d’une thérapie pharmacologique appropriée pour prévenir les complications morbides comme le coma iatrogénique et le délirium. / When sedatives such as midazolam or opiate analgesics such as fentanyl administered to critically ill patients and medication-induced coma occurs, increased delirium is observed. In addition, there is an increase in the length of stay in ICU, in costs and mortality. The purpose of this study was to explore the factors of variability affecting the incidence of iatrogenic coma and delirium: genetics/socio demographics factors, co-administration of substrates/inhibitors of CYP3A4/3A5 or P-gp. We performed a prospective cohort observational study of 53 hospitalized patients treated with fentanyl or/and midazolam in the intensive care unit of the Maisonneuve-Rosemont hospital The feasibility of pharmacokinetics modeling using blood samples from critically ill patients was demonstrated and was compatible with clinical data. This study suggests that contrary to genomic variants in the CYP3A5 (p value = 0,521) and MDR1 (p value = 0,828) genes, the effect of drugs and drugs interactions between inhibitors of CYP3A4/3A5 and fentanyl/ midazolam constitutes the main risk factor for iatrogenic coma (p value - 0,014). These effects are easily identifiable and predictable, and are very important for intensive care workers to make the appropriate choice of medication in order to prevent morbid complications such as iatrogenic coma and delirium.

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