Comparing a trauma focused and non trauma focused intervention with war affected Congolese youth: a preliminary randomised trial

While there is broad consensus about the need for interventions to help psychologically distressed, war affected youth, there is also limited research and even less agreement on which interventions work best. Therefore, this paper presents a randomised trial of trauma focused, and non trauma focused, interventions with war affected Congolese youth. Fifty war affected Congolese youth, who had been exposed to multiple adverse life events, were randomly assigned to either a Trauma Focused Cognitive Behavioural Therapy group or a non trauma based psychosocial intervention (Child Friendly Spaces). Non clinically trained, Congolese facilitators ran both groups. A convenience sample, waiting list group was also formed. Using blind assessors, participants were individually interviewed at pre intervention, post intervention and a 6-month follow-up using self-report posttraumatic stress and internalising symptoms, conduct problems and pro social behaviour. Both treatment groups made statistically significant improvements, compared to the control group. Large, within subject, effect sizes were reported at both post intervention and follow-up. At the 6-month follow-up, only the Child Friendly Spaces group showed a significant decrease in pro social behaviour. The paper concludes that both trauma focused and non trauma focused interventions led to reductions in psychological distress in war affected youth.

BIIL 284 reduces neutrophil numbers but increases P. aeruginosa bacteremia and inflammation in mouse lungs

BACKGROUND: A clinical study to investigate the leukotriene B(4) (LTB(4))-receptor antagonist BIIL 284 in cystic fibrosis (CF) patients was prematurely terminated due to a significantly increased risk of adverse pulmonary events. We aimed to establish the effect of BIIL284 in models of Pseudomonas aeruginosa lung infection, thereby contributing to a better understanding of what could have led to adverse pulmonary events in CF patients.

METHODS: P. aeruginosa DNA in the blood of CF patients during and after acute pulmonary exacerbations and in stable patients with non-CF bronchiectasis (NCFB) and healthy individuals was assessed by PCR. The effect of BIIL 284 treatment was tested in an agar bead murine model of P. aeruginosa lung infection. Bacterial count and inflammation were evaluated in lung and other organs.

RESULTS: Most CF patients (98%) and all patients with NCFB and healthy individuals had negative P. aeruginosa DNA in their blood. Similarly, the P. aeruginosa-infected mice showed bacterial counts in the lung but not in the blood or spleen. BIIL 284 treatment decreased pulmonary neutrophils and increased P. aeruginosa numbers in mouse lungs leading to significantly higher bacteremia rates and lung inflammation compared to placebo treated animals.

CONCLUSIONS: Decreased airway neutrophils induced lung proliferation and severe bacteremia in a murine model of P. aeruginosa lung infection. These data suggest that caution should be taken when administering anti-inflammatory compounds to patients with bacterial infections.

One-Year Safety of Olodaterol Once Daily via Respimat® in Patients with GOLD 2-4 Chronic Obstructive Pulmonary Disease: Results of a Pre-Specified Pooled Analysis

The novel long-acting β2-agonist olodaterol demonstrated an acceptable safety profile in short-term phase II clinical studies. This analysis of four randomized, double-blind, placebo-controlled, parallel-group, phase III studies (1222.11, NCT00782210; 1222.12, NCT00782509; 1222.13, NCT00793624; 1222.14, NCT00796653) evaluated the long-term safety of olodaterol once daily (QD) in a large cohort of patients with moderate to very severe (Global initiative for chronic Obstructive Lung Disease 2-4) chronic obstructive pulmonary disease (COPD). The studies compared olodaterol (5 or 10 μg) QD via Respimat®, formoterol 12 μg twice daily (BID) via Aerolizer® (1222.13 and 1222.14), and placebo for 48 weeks. Patients continued receiving background maintenance therapy, with ∼60% receiving concomitant cardiovascular therapy and 25% having a history of concomitant cardiac disease. Pre-specified analyses of pooled data assessed the adverse events (AEs) and serious AEs in the whole population, and in subgroups with cardiac disease, along with in-depth electrocardiogram and Holter monitoring. In total, 3104 patients were included in the safety analysis: 876 received olodaterol 5 μg, 883 received olodaterol 10 μg, 885 received placebos, and 460 received formoterol 12 μg BID. Overall incidence of on-treatment AEs (71.2%), serious AEs (16.1%), and deaths (1.7%) were balanced across treatment groups. Respiratory and cardiovascular AEs, including major adverse cardiac events, were reported at similar frequencies in placebo and active treatment groups. The safety profiles of both olodaterol 5 μg (marketed and registered dose) and 10 μg QD delivered via Respimat® are comparable to placebo and formoterol BID in this population, with no safety signals identified.

Interventions to improve the appropriate use of polypharmacy in older people: a Cochrane systematic review

Objective: To summarise the findings of an updated Cochrane review of interventions aimed at improving the appropriate use of polypharmacy in older people. Design: Cochrane systematic review. Multiple electronic databases were searched including MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (from inception to November 2013). Hand searching of references was also performed. Randomised controlled trials (RCTs), controlled clinical trials, controlled before-and-after studies and interrupted time series analyses reporting on interventions targeting appropriate polypharmacy in older people in any healthcare setting were included if they used a validated measure of prescribing appropriateness. Evidence quality was assessed using the Cochrane risk of bias tool and GRADE (Grades of Recommendation, Assessment, Development and Evaluation).
Setting: All healthcare settings. 
Participants: Older people (≥65 years) with ≥1 long-term condition who were receiving polypharmacy (≥4 regular medicines).
Primary and secondary outcome measures: Primary outcomes were the change in prevalence of appropriate polypharmacy and hospital admissions. Medication-related problems (eg, adverse drug reactions), medication adherence and quality of life were included as secondary outcomes.
Results: 12 studies were included: 8 RCTs, 2 cluster RCTs and 2 controlled before-and-after studies. 1 study involved computerised decision support and 11 comprised pharmaceutical care approaches across various settings. Appropriateness was measured using validated tools, including the Medication Appropriateness Index, Beers’ criteria and Screening Tool of Older Person’s Prescriptions (STOPP)/ Screening Tool to Alert doctors to Right Treatment (START). The interventions demonstrated a reduction in inappropriate prescribing. Evidence of effect on hospital admissions and medication-related problems was conflicting. No differences in health-related quality of life were reported.
Conclusions: The included interventions demonstrated improvements in appropriate polypharmacy based on reductions in inappropriate prescribing. However, it remains unclear if interventions resulted in clinically significant improvements (eg, in terms of hospital admissions). Future intervention studies would benefit from available guidance on intervention development, evaluation and reporting to facilitate replication in clinical practice.

Corneal complications associated with topical ophthalmic use of nonsteroidal antiinflammatory drugs.

PURPOSE:

To explore the potential association between adverse corneal events and the use of topical nonsteroidal antiinflammatory drugs (NSAIDs).

SETTING:

Practice-based reports.

METHODS:

A detailed case-reporting form and request for medical records were sent to all practices reporting cases of corneal or conjunctival pathology in association with the use of topical NSAIDs to the American Society of Cataract and Refractive Surgery. Cases were classified as "mild," "moderate," or "severe" according to predetermined clinical criteria.

RESULTS:

Records of 140 eyes (129 patients) were reviewed; 51 cases (36.4%) were mild, 55 (39.3%) moderate, and 34 (24.3%) severe. An association with a specific topical NSAID was confirmed in 117 cases (81.8%). Most confirmed cases (53.8%) involved generic diclofenac (Falcon). Cases associated with brand diclofenac (Voltaren, CIBA Vision) and ketorolac (Acular, Allergan) were more likely to have ocular comorbidity and to have received significantly higher total doses of NSAIDs. Neither "off-label" use nor use of any specific agent was associated with severe compared to mild or moderate disease. However, patients with more severe adverse events were more likely to have a history of diabetes, previous surgery in the affected eye, and surgery other than cataract. Cases not occurring in the perioperative period had significantly worse outcomes, had significantly more ocular comorbidities, and received nearly 3 times the dose of NSAIDs.

CONCLUSIONS:

While topical NSAIDs as a class may be associated with severe adverse events, such events appeared to require potentiation in the form of high total doses, ocular comorbidities, or both with Acular and Voltaren. Severe adverse events might have been more likely to occur at lower doses and in routine postoperative settings with generic diclofenac.

Abordagem farmacoepidemiológica da terapêutica no idoso: um ensaio em meio hospitalar

Introdução: O envelhecimento demográfico e o aumento da esperança de vida, criam condições para uma maior incidência de doenças degenerativas. Vários aspectos críticos envolvem a medicação no idoso, tais como: polimedicação frequente, com risco acrescido de ocorrência de reacções adversas, relacionadas com interacções medicamentosas e eventual medicação desaconselhada, em que o risco pode ser superior ao benefício. Estes aspectos são particularmente críticos no idoso hospitalizado. Objectivo: Este estudo teve como objectivo estimar a prevalência da polimedicação em idosos hospitalizados e analisar a medicação considerada inadequada nesta população. Participantes e metodologia: Seguiu-se um modelo retrospectivo descritivo transversal, reportando-se os dados a um período de um ano e meio, incidindo sobre o último internamento. A natureza da medicação, foi analisada de acordo com o Formulário Terapêutico Nacional, Resumo das Caracteristicas do Medicamento e com critérios de Beers-2002.Englobou 100 idosos (>65 anos) utentes do Hospital Cuf Descobertas, em regime de internamento. Os dados pessoais e clínicos e respectivo mapa farmacoterapêutico, foram introduzidos em base de dados construída para este estudo, em Access 2003 SP2. Procedeu-se à analise estatística (SPSS 13,0), descritiva, com cálculo de medidas de tendência central; análise univariada para todas as variáveis relevantes e análise bi-variada para quantificar a prevalência da polimedicação por sexo e grupo etário. Resultados:Dos doentes estudados (65-98 anos), maioritariamente femininos, 7 apresentavam 4 patologias em simultâneo, 13:3 patologias, 27:2 patologias e 30:1 patologia. Em 23 não se verificou qualquer patologia crónica. A hipertensão (n=49:27,5%) e a patologia cardiovascular (n=41:23%) foram as mais frequentemente encontradas na amostra em estudo sendo as de menor frequência a patologia reumática (n=1:0,56%), a osteoporose e os problemas psíquicos (n=2:1,12%. A prevalência de polimedicação foi de 84% e nº de medicamentos prescrito em simultâneo variou entre 2 e 23.Não se observou associação entre a polimedicação, a idade: e o sexo. Em apenas um caso foi identificado um medicamento desaconselhado em função do diagnóstico (metoclopramida:Parkinson), e independentemente do diagnóstico a amiodariona foi o mais frequente (25%), hidroxizina (22%), ticlopidina (2%) e cetorolac (1%). Conclusões: A polimedicação é um fenómeno muito frequente nos idosos hospitalizados; o número de medicamentos envolvidos pode ser elevado e a prevalência de medicamentos que requerem uma ponderação sobre o risco/benefício no idoso, indicia a vantagem da revisão da terapêutica, impondo-se a implementação de estratégias informativas sobre os mesmos. Background: The demographic aging and expansion of life expectancy create conditions for increased occurrence of degenerative illnesses. Several critical aspects involve the medication of the elderly, such as: frequent polipharmacy with increased occurrence of adverse drug reactions, related to medication interactions and inappropriate prescribing, in which the benefits can be inferior to the risks.These aspects are particularly critical in the hospitalized elderly. Aim: This study aimed to estimate the prevalence of polipharmacy in hospitalized elderly and to analyze the medication considered inappropriate in this population. Participants and Methodology: A cross sectional model was followed, in which the data used relate to a period of a year and a half, focussing on the last hospitalization. The nature of the medication was analysed according to National Therapeutic Formulary, Drug Characteristics Summary and according to Beers-2002.It considered 100 elderly (>65 years) hospitalized at Hospital Cuf Descobertas. The personal and clinical data and the corresponding pharmacotherapeutic registration were introduced in a database created for this study in Access 2003 SP2. Descriptive statistics was calculated trough SPSS 13,0,.Exploraty analysis consisted in measures of average and spread for all variable considered relevant and univariate and bivariate analysis to quantify the prevalence of polipharmacy by sex and age and to relate polipharmacy with inappropriate medication. Results: Of the patients studied (65-98 years), the majority were women, 7 presented 4 pathologies, 13:3 pathologies, 27:2 pathologies and 30:1 pathology. In 23 patients there was any chronic pathology. Hypertension (n=49:27,5%) and cardiovascular disease (n=41:23%) were the most frequent disease in our study, and the minimal values were observed in rheumatism (n=1:0,56%), osteoporosis and psychic disorders (n=2:1,12%. The prevalence of polipharmacy was of 84% and the amount of medication simultaneously prescribed varied between 2 and 23.No association was observed between polipharmacy and age or gender. In only one case inappropriate medication was identified concerning diagnosis (metoclopramid: Parkinson), and independent of diagnosis the amiodaron was the most frequent (25%), hydroxyzin (22%), ticlopidin (2%). and ketorolac (1%). Conclusions: Polipharmacy is very prevalent among elderly people admitted to the hospital; the number of inappropriate medication can also be very high and this evidence should be collected in order to accomplish good drug use reviews and informative strategies in the hospital setting.

Effect on renal function of tenofovir co-administered with either efavirenz or boosted lopinavir or boosted atazanavir: the Swiss HIV Cohort Study

Reduced re'nal function has been reported with tenofovir disoproxil fumarate (TDF). It is not clear whether TDF co-administered with a boosted protease inhibitor (PI) leads to a greater decline in renal function than TDF co-administered with a non-nucleoside reverse transcriptase inhibitor (NNRTI).Methods: We selected ail antiretroviral therapy-naive patients in the Swiss HIV Cohort Study (SHCS) with calibrated or corrected serum creatinine measurements starting antiretroviral therapy with TDF and either efavirenz (EFV) or the ritonavir-boosted PIs, lopinavir (LPV/r) or atazanavir (ATV/r). As a measure of renal function, we used the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to estimate the glomerular filtration rate (eGFR). We calculated the difference in eGFR over time between two therapies using a marginal model for repeated measures. In weighted analyses, observations were weighted by the product of their point of treatment and censoring weights to adjust for differences both in the sort of patients starting each therapy and in the sort of patients remaining on each therapy over time.Results: By March 2011, 940 patients with at least one creatinine measurement on a first therapy with either TDF and EFV (n=484), TDF and LPVlr (n=269) or TDF and ATV/r (n=187) had been followed for a median of 1. 7, 1.2 and 1.3 years, respectively. Table 1 shows the difference in average estimated GFR (eGFR) over time since starting cART for two marginal models. The first model was not adjusted for potential confounders; the second mode! used weights to adjust for confounders. The results suggest a greater decline in renal function during the first 6 months if TDF is used with a PI rather than with an NNRTI, but no further difference between these therapies after the first 6 months. TDF and ATV/r may lead to a greater decline in the first 6 months than TDF and LPVlr.Conclusions: TDF co-administered with a boosted PI leads to a greater de cline in renal function over the first 6 months of therapy than TDF co-administered with an NNRTI; this decline may be worse with ATV/r than with LPV/r.

Outcome of patients with acute coronary syndrome in hospitals of different sizes. A report from the AMIS Plus Registry.

To assess the impact of admission to different hospital types on early and 1-year outcomes in patients with acute coronary syndrome (ACS). Between 1997 and 2009, 31 010 ACS patients from 76 Swiss hospitals were enrolled in the AMIS Plus registry. Large tertiary institutions with continuous (24 hour/7 day) cardiac catheterisation facilities were classified as type A hospitals, and all others as type B. For 1-year outcomes, a subgroup of patients admitted after 2005 were studied. Eleven type A hospitals admitted 15987 (52%) patients and 65 type B hospitals 15023 (48%) patients. Patients admitted into B hospitals were older, more frequently female, diabetic, hypertensive, had more severe comorbidities and more frequent non-ST segment elevation (NSTE)-ACS/unstable angina (UA). STE-ACS patients admitted into B hospitals received more thrombolysis, but less percutaneous coronary intervention (PCI). Crude in-hospital mortality and major adverse cardiac events (MACE) were higher in patients from B hospitals. Crude 1-year mortality of 3747 ACS patients followed up was higher in patients admitted into B hospitals, but no differences were found for MACE. After adjustment for age, risk factors, type of ACS and comorbidities, hospital type was not an independent predictor of in-hospital mortality, in-hospital MACE, 1-year MACE or mortality. Admission indicated a crude outcome in favour of hospitalisation during duty-hours while 1-year outcome could not document a significant effect. ACS patients admitted to smaller regional Swiss hospitals were older, had more severe comorbidities, more NSTE-ACS and received less intensive treatment compared with the patients initially admitted to large tertiary institutions. However, hospital type was not an independent predictor of early and mid-term outcomes in these patients. Furthermore, our data suggest that Swiss hospitals have been functioning as an efficient network for the past 12 years.

Comparison of clinical and angiographic prognostic risk scores in elderly patients presenting with acute coronary syndrome and referred for percutaneous coronary intervention.

BACKGROUND: Multiple risk prediction models have been validated in all-age patients presenting with acute coronary syndrome (ACS) and treated with percutaneous coronary intervention (PCI); however, they have not been validated specifically in the elderly. METHODS: We calculated the GRACE (Global Registry of Acute Coronary Events) score, the logistic EuroSCORE, the AMIS (Acute Myocardial Infarction Swiss registry) score, and the SYNTAX (Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery) score in a consecutive series of 114 patients ≥75 years presenting with ACS and treated with PCI within 24 hours of hospital admission. Patients were stratified according to score tertiles and analysed retrospectively by comparing the lower/mid tertiles as an aggregate group with the higher tertile group. The primary endpoint was 30-day mortality. Secondary endpoints were the composite of death and major adverse cardiovascular events (MACE) at 30 days, and 1-year MACE-free survival. Model discrimination ability was assessed using the area under receiver operating characteristic curve (AUC). RESULTS: Thirty-day mortality was higher in the upper tertile compared with the aggregate lower/mid tertiles according to the logistic EuroSCORE (42% vs 5%; odds ratio [OR] = 14, 95% confidence interval [CI] = 4-48; p <0.001; AUC = 0.79), the GRACE score (40% vs 4%; OR = 17, 95% CI = 4-64; p <0.001; AUC = 0.80), the AMIS score (40% vs 4%; OR = 16, 95% CI = 4-63; p <0.001; AUC = 0.80), and the SYNTAX score (37% vs 5%; OR = 11, 95% CI = 3-37; p <0.001; AUC = 0.77). CONCLUSIONS: In elderly patients presenting with ACS and referred to PCI within 24 hours of admission, the GRACE score, the EuroSCORE, the AMIS score, and the SYNTAX score predicted 30 day mortality. The predictive value of clinical scores was improved by using them in combination.

Le financement de la haute technologie dans le système de santé : le cas de la pharmacogénomique

L’exercice d’allocation de ressources en santé, relevant du Ministère de la santé, se voit fortement influencé autant par les besoins variés de la population que par les exigences des intervenants en santé. Quel rôle ces différents intérêts peuvent-ils jouer dans l’intégration de nouvelles technologies dans la distribution des soins de santé ? La pharmacogénomique, branche émergente de la pharmacologie intégrant les données issues du projet génome humain au processus de développement du médicament, est perçue comme une technologie qui permettrait de personnaliser la médecine. Son intégration aux processus de développement ou de prescription de médicaments promet de minimiser l’apparition d’effets secondaires néfastes découlant de la prise de médicaments. Serait-il alors judicieux pour le gouvernement du Québec, considérant la conjoncture actuelle d’allocation de ressources, d’investir dans la pharmacogénomique en tant que nouvel outil de développement du médicament ou nouveau mode pronostic de médication pour sa population ? Nous aborderons cette question à l’aide de critères de sélection dictés par Caulfield et ses collaborateurs (2001)[1] pour évaluer la pertinence de l’investissement public dans la mise sur pied d’un test génétique, soit l’acceptabilité, l’utilité, la non-malfaisance et la présence d’un bénéfice clair – à coût raisonnable – pour la population. La génomique avoisinant la génétique, ces facteurs s’avèrent applicables dans notre discussion.

The Development, Validation and Implementation of a Broad-Based ADME Genotyping Assay into Research and Clinical Trials

Afin d’adresser la variabilité interindividuelle observée dans la réponse pharmacocinétique à de nombreux médicaments, nous avons créé un panel de génotypage personnalisée en utilisant des méthodes de conception et d’élaboration d’essais uniques. Celles-ci ont pour but premier de capturer les variations génétiques présentent dans les gènes clés impliqués dans les processus d'absorption, de distribution, de métabolisme et d’excrétion (ADME) de nombreux agents thérapeutiques. Bien que ces gènes et voies de signalement sont impliqués dans plusieurs mécanismes pharmacocinétiques qui sont bien connues, il y a eu jusqu’à présent peu d'efforts envers l’évaluation simultanée d’un grand nombre de ces gènes moyennant un seul outil expérimental. La recherche pharmacogénomique peut être réalisée en utilisant deux approches: 1) les marqueurs fonctionnels peuvent être utilisés pour présélectionner ou stratifier les populations de patients en se basant sur des états métaboliques connus; 2) les marqueurs Tag peuvent être utilisés pour découvrir de nouvelles corrélations génotype-phénotype. Présentement, il existe un besoin pour un outil de recherche qui englobe un grand nombre de gènes ADME et variantes et dont le contenu est applicable à ces deux modèles d'étude. Dans le cadre de cette thèse, nous avons développé un panel d’essais de génotypage de 3,000 marqueurs génétiques ADME qui peuvent satisfaire ce besoin. Dans le cadre de ce projet, les gènes et marqueurs associés avec la famille ADME ont été sélectionnés en collaboration avec plusieurs groupes du milieu universitaire et de l'industrie pharmaceutique. Pendant trois phases de développement de cet essai de génotypage, le taux de conversion pour 3,000 marqueurs a été amélioré de 83% à 97,4% grâce à l'incorporation de nouvelles stratégies ayant pour but de surmonter les zones d'interférence génomiques comprenant entre autres les régions homologues et les polymorphismes sous-jacent les régions d’intérêt. La précision du panel de génotypage a été validée par l’évaluation de plus de 200 échantillons pour lesquelles les génotypes sont connus pour lesquels nous avons obtenu une concordance > 98%. De plus, une comparaison croisée entre nos données provenant de cet essai et des données obtenues par différentes plateformes technologiques déjà disponibles sur le marché a révélé une concordance globale de > 99,5%. L'efficacité de notre stratégie de conception ont été démontrées par l'utilisation réussie de cet essai dans le cadre de plusieurs projets de recherche où plus de 1,000 échantillons ont été testés. Nous avons entre autre évalué avec succès 150 échantillons hépatiques qui ont été largement caractérisés pour plusieurs phénotypes. Dans ces échantillons, nous avons pu valider 13 gènes ADME avec cis-eQTL précédemment rapportés et de découvrir et de 13 autres gènes ADME avec cis eQTLs qui n'avaient pas été observés en utilisant des méthodes standard. Enfin, à l'appui de ce travail, un outil logiciel a été développé, Opitimus Primer, pour aider pour aider au développement du test. Le logiciel a également été utilisé pour aider à l'enrichissement de cibles génomiques pour d'expériences séquençage. Le contenu ainsi que la conception, l’optimisation et la validation de notre panel le distingue largement de l’ensemble des essais commerciaux couramment disponibles sur le marché qui comprennent soit des marqueurs fonctionnels pour seulement un petit nombre de gènes, ou alors n’offre pas une couverture adéquate pour les gènes connus d’ADME. Nous pouvons ainsi conclure que l’essai que nous avons développé est et continuera certainement d’être un outil d’une grande utilité pour les futures études et essais cliniques dans le domaine de la pharmacocinétique, qui bénéficieraient de l'évaluation d'une longue liste complète de gènes d’ADME.

Interactions médicamenteuses et réactions adverses aux soins intensifs: le rôle des sédatifs et des analgésiants

Les patients admis aux soins intensifs (SI) souffrent de comorbidités qui affectent leur pronostic. Deux problèmes sont potentiellement associés aux sédatifs et compliquent le séjour de 35 à 50% des malades : le délirium, un état confusionnel aigu; et le coma ‘iatrogénique’, une altération de la conscience induite pharmacologiquement. L’importance de l’association entre clinique et médicaments a un intérêt pour prévenir ces syndromes cliniques morbides. Nous voulions étudier le délirium et le coma iatrogénique, les doses administrées de midazolam et de fentanyl, leurs niveaux plasmatiques, les variantes génétiques de métabolisme et de transport et les facteurs inflammatoires et ce, chez 100 patients admis aux soins intensifs. Nos données soulignent l’importance des interactions médicamenteuses dans l’incidence du coma iatrogénique, et réfutent l’association entre les benzodiazépines et le délirium. Ces résultats clarifient la pathophysiologie du délirium, corroborent le manque d’association délirium-benzodiazépines avec un marqueur biologique, c.-à-d. les niveaux sériques, et ouvrent le débat quant aux agents les plus utiles pour traiter l’anxiété et le délirium. Finalement, plusieurs caractéristiques pharmacocinétiques des benzodiazépines administrées aux soins intensifs publiées récemment complètent les données de notre étude quant à la sédation en soins critiques. Un chapitre sur l’importance de la pharmacogénomique en soins intensifs et un débat publié quant au pro et con de l'utilisation des benzodiazépines aux SI, sont soumis en complément de l’étude clinique décrite ci-haut effectuée dans le cadre de cette maîtrise.

Rôle de la PKC delta dans la fonction plaquettaire en réponse à la thrombine via le récepteur GPIb alpha

La famille des protéines kinases C (PKC) est essentielle pour la fonction plaquettaire en réponse à la thrombine qui signale et active les plaquettes via les proteases activated receptors (PAR-1 et PAR-4) et le GPIbα. Ces derniers constituent les récepteurs de moyenne/faible et de hautes affinités pour la thrombine, respectivement. L’isoforme PKCδ régule positivement ou négativement la fonction des plaquettes tout dépendamment de la nature du stimulus. Cependant, son importance dans la fonction plaquettaire en réponse à la thrombine en aval de la GPIbα reste inconnue. L’objectif principal de ce projet de doctorat était de déterminer l'implication de l'axe thrombine/GPIbα/PKCδ dans la fonction plaquettaire et d’évaluer le rôle de cet axe dans la régulation de la thrombose. Dans les plaquettes humaines, le prétraitement avec l'inhibiteur spécifique de la PKCδ δ(V1-1)TAT, a significativement potentialisé l'activation et l’agrégation des plaquettes en réponse à de faibles concentrations de α-thrombine, mais pas en réponse à la γ-thrombine ou aux agonistes des PARs. Ce phénomène de potentialisation a été associé à une sécrétion accrue de granules, de génération de thromboxane A2 (TXA2) et une phosphorylation de la PKCδ sur la Tyr311, qui ont toutes été prévenues par l’inhibition spécifique du GPIbα à l’aide d’un anticorps monoclonal bloquant. En outre, l'inhibition de la p38 MAPK, ERK1/2 et le TXA2 a inversé ce processus de potentialisation. Les plaquettes murines déficientes en PKCδ étaient aussi plus réactives à la thrombine et ont montré une augmentation significative de l'agrégation, alors qu’une étude menée in vivo chez la souris PKCδ- /- a montré, suite à une stimulation par α-thrombine, une réaction thrombotique accrue caractérisée par une diminution significative du temps de saignement ainsi qu’une formation de thrombo-embolies pulmonaires. En bloquant le GPIbα, ces effets ont été renversés. Cette étude ouvre de nouvelles perspectives quant au rôle de la PKCδ dans les plaquettes en aval de GPIbα, où elle régule négativement la fonction plaquettaire en réponse à la thrombine. Ainsi, l'axe thrombine/GPIbα/PKCδ dans les plaquettes pourrait représenter un régulateur critique de la fonction plaquettaire et l'hémostase, et le dysfonctionnement de cette voie pourrait conduire à des événements thrombotiques.

Canulacion arterial axilar versus femoral para cirugía del arco aórtico

Objetivo: Determinar si la canulación arterial axilar para perfusión selectiva anterograda cerebral (PSAC) con hipotermia moderada reduce la morbilidad, mortalidad y el pronóstico neurológico en pacientes llevados a cirugía del arco aórtico. Pacientes y métodos: Se hace una revisión retrospectiva de 2 cohortes de pacientes a quienes se les realizo cirugía del arco aórtico urgente o electiva, para comparar dos técnicas de canulación arterial diferente; la canulación axilar para perfusión selectiva anterograda cerebral con hipotermia moderada y la canulación femoral con hipotermia profunda, en un periodo de tiempo comprendido entre Diciembre del 2002 y Agosto del 2008 en el servicio de cirugía cardiovascular de la Fundación Cardioinfantil Instituto de Cardiología. Resultados: 68 pacientes, 50 hombres y 18 mujeres fueron llevados a cirugía de arco aórtico 19 pacientes (27%) con diagnóstico de aneurisma de aorta ascendente y arco aórtico y 49 pacientes (72%) con disección aortica tipo A aguda o crónica. A 55 pacientes (80.9%) se les hizo canulación axilar y a 13 pacientes (19,1%) se les hizo canulación femoral. No se encontraron diferencias en las variables preoperatorias entre los dos grupos. La mortalidad global fue de 13,2% (9 pacientes), todas las muertes se presentaron en pacientes con diagnóstico de disección aortica tipo A. El 55% de los pacientes (38/68) se operaron de urgencia. No se presentaron diferencias estadísticamente significativas en la mortalidad entre el grupo de canulación axilar, 8 muertes (14,5%) y el grupo de canulación femoral 1 muerte (7,7%) con (p=0.5). No se encontraron diferencias en la incidencia de déficit neurológico permanente entre los dos grupos, presentándose solamente dos pacientes con accidente cerebrovascular ambos en el grupo de canulación axilar (P=0.48). Conclusiones: la canulación axilar con perfusión cerebral selectiva anterograda en hipotermia moderada representa un método seguro de protección cerebral, con una mortalidad aceptable y una incidencia baja de complicaciones neurológicas permanentes, no encontramos diferencias en la mortalidad o la aparición de eventos neurológicos, cuando se comparo con la técnica de canulación arterial femoral. No se presentaron complicaciones asociadas al sitio de canulación en ninguno de los dos grupos.

Prevalencia de resistencia plaquetaria a clopidogrel en pacientes sometidos a intervencion coronaria percutanea

Los agentes antiplaquetarios son el principal tratamiento para pacientes con síndromes coronarios agudos, han demostrado reducción en el riesgo de muerte, infarto del miocardio, y necesidad de revascularización urgente. Algunos pacientes presentan eventos cardiacos mayores a pesar de recibir estos medicamentos. El impacto de la resistencia a los medicamentos ha sido material de múltiples estudios. En Colombia no existen estadísticas sobre la resistencia al Clopidogrel.En nuestro estudio la prevalencia de resistencia a Clopidogrel por el método de agregometria plaquetaria por transferencia de luz con muestras tomadas entre el día 7 y el 10 post angioplastia, está por encima del promedio internacional en nuestra población, lo que amerita la realización de nuevos estudios por las implicaciones pronosticas que pudieran tener en términos de eventos cardiovasculares adversos.