Emmanuel Charbonney

Oral neutrophils are an independent marker of the systemic inflammatory response after cardiac bypass

BackgroundCardiopulmonary bypass (CPB) is an immuno-reactive state where neutrophils are activated and accumulate in different tissues. Edema and tissue necrosis are the most common sequelae observed, predominantly in the lungs, kidneys, and heart, heralding significant risk for postoperative complications. No method exists to noninvasively assess in vivo neutrophil activity. The objective of this study was to determine if neutrophil recruitment to the oral cavity would correlate with specific biomarkers after coronary bypass surgery (CPB).MethodsWe conducted a single site prospective observational study including non-consecutive adult patients undergoing elective, on-pump CPB. Blood and either oral cavity rinses or swabs were collected pre- and post-CPB. Absolute neutrophil counts from oral samples and serum biomarkers were measured. The association between neutrophil recruitment to the oral cavity, biomarkers and outcomes after CPB were analyzed.ResultsCPB was associated with statistically significant increases in oral and blood neutrophil counts, as well as an increase in certain biomarkers over preoperative baseline. Peripheral blood neutrophil count were increased at all time points however statistically significant differences in median oral neutrophil counts were observed only at the time point immediately postoperative, and in what seems to be two unique patient populations (p < 0.001; group 1, median: 1.6×105, Interquartile range [IQR], 1.1×105 - 4.8×105, and group 2, median: 1.9×106, IQR, 8.7×105 - 4.0×106).ConclusionsCPB is associated with a transient increase in oral neutrophils that may correlate with the systemic inflammatory response; oral neutrophils may have the ability to discriminate and identify unique patient populations based on their tissue migration.

A systematic review of vasopressor blood pressure targets in critically ill adults with hypotension

PurposeClinicians must balance the risks from hypotension with the potential adverse effects of vasopressors. Experts have recommended a mean arterial pressure (MAP) target of at least 65 mmHg, and higher in older patients and in patients with chronic hypertension or atherosclerosis. We conducted a systematic review of randomized-controlled trials comparing higher vs lower blood pressure targets for vasopressor therapy administered to hypotensive critically ill patients.MethodsWe searched MEDLINE®, EMBASE™, and the Cochrane Central Register of Controlled Trials for studies of higher vs lower blood pressure targets for vasopressor therapy in critically ill hypotensive adult patients. Two reviewers independently assessed trial eligibility based on titles and abstracts, and they then selected full-text reports. Outcomes, subgroups, and analyses were prespecified. We used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to rate the overall confidence in the estimates of intervention effects.ResultsOf 8001 citations, we retrieved 57 full-text articles and ultimately included two randomized-controlled trials (894 patients). Higher blood pressure targets were not associated with lower mortality (relative risk [RR], 1.05; 95% confidence interval [CI], 0.90 to 1.23; P = 0.54), and neither age (P = 0.17) nor chronic hypertension (P = 0.32) modified the overall effect. Nevertheless, higher blood pressure targets were associated with a greater risk of new-onset supraventricular cardiac arrhythmia (RR, 2.08; 95% CI, 1.28 to 3.38; P < 0.01).ConclusionCurrent evidence does not support a MAP target > 70 mmHg in hypotensive critically ill adult patients requiring vasopressor therapy.RésuméObjectifLes cliniciens doivent équilibrer les risques liés à l’hypotension aux complications potentielles des vasopresseurs. Des experts ont recommandé de cibler une tension artérielle moyenne (TAM) d’au moins 65 mmHg, et une TAM plus élevée chez les patients atteints d’hypertension chronique, d’athérosclérose ou plus âgés. Nous avons réalisé une revue systématique des études randomisées contrôlées comparant des cibles de tension artérielle plus élevées à plus basses chez des patients hypotendus en état critique recevant un traitement vasopresseur.MéthodeNous avons fait des recherches dans les bases de données Medline, EMBASE et dans le registre central des études contrôlées Cochrane afin d’en extraire les études comparant des cibles de tension artérielle plus élevées ou plus basses chez des patients adultes hypotendus et en état critique recevant un traitement vasopresseur. Deux examinateurs ont évalué de façon indépendante l’éligibilité des études selon leur titre et leur résumé, puis sélectionné les articles intégraux. Les critères d’évaluation, sous-groupes et analyses étaient spécifiés au préalable. Nous avons utilisé le système GRADE (Grading of Recommendations Assessment, Development and Evaluation) afin d’évaluer la confiance globale dans les estimations des effets de l’intervention.RésultatsParmi les 8001 citations, nous avons extrait 57 articles intégraux et finalement inclus deux études randomisées contrôlées (894 patients). Les cibles de tension artérielle plus élevées n’étaient pas associées à une mortalité plus basse (risque relatif [RR] 1,05; intervalle de confiance [IC] 95 %, 0,90 à 1,23; P = 0,54), et ni l’âge (P = 0,17) ni l’hypertension chronique (P = 0,32) n’ont modifié l’effet global. Cependant, les cibles de tension artérielle plus élevées étaient associées à un risque plus élevé de nouvelle apparition d’une arythmie cardiaque supraventriculaire (RR, 2,08; IC 95 %, 1,28 à 3,38; P < 0,01).ConclusionLes données probantes actuelles n’appuient pas une cible de TAM supérieure à 70 mmHg chez les patients adultes hypotendus et gravement malades nécessitant un traitement vasopresseur.

Vasopressor use following traumatic injury: protocol for a systematic review

Introduction Worldwide, traumatic casualties are projected to exceed 8 million by year 2020. Haemorrhagic shock and brain injury are the leading causes of death following trauma. While intravenous fluids have traditionally been used to support organ perfusion in the setting of haemorrhage, recent investigations have suggested that restricting fluid therapy by tolerating more severe hypotension may improve survival. However, the safety of permissive hypotension remains uncertain, particularly among patients who have suffered a traumatic brain injury. Vasopressors preferentially vasoconstrict blood vessels that supply non-vital organs and capacitance vessels, thereby mobilising the unstressed blood volume. Used as fluid-sparing adjuncts, these drugs can complement resuscitative measures by correcting hypotension without diluting clotting factors or increasing the risk for tissue oedema. Methods and analysis We will identify randomised control trials comparing early resuscitation with vasopressors versus placebo or standard care in adults following traumatic injury. Data sources will include MEDLINE, EMBASE, CENTRAL, clinical trial registries and conference proceedings. Two reviewers will independently determine trial eligibility. For each included trial, we will conduct duplicate independent data extraction and risk of bias assessment. We will assess the overall quality of the data for each individual outcome using the GRADE approach. Ethics and dissemination We will report this review in accordance with the PRISMA statement. We will disseminate our findings at critical care and trauma conferences and through a publication in a peer-reviewed journal. We will also use this systematic review to create clinical guidelines (http://www.magicapp.org), which will be disseminated in a standalone publication. Trial registration number CRD42016033437.

Tyrosine Phosphorylation of Caspase-8 Abrogates Its Apoptotic Activity and Promotes Activation of c-Src

Src family tyrosine kinases (SFKs) phosphorylate caspase-8A at tyrosine (Y) 397 resulting in suppression of apoptosis. In addition, the phosphorylation of caspase-8A at other sites including Y465 has been implicated in the regulation of caspase-8 activity. However, the functional consequences of these modifications on caspase-8 processing/activity have not been elucidated. Moreover, various Src substrates are known to act as potent Src regulators, but no such role has been explored for caspase-8. We asked whether the newly identified caspase-8 phosphorylation sites might regulate caspase-8 activation and conversely, whether caspase-8 phosphorylation might affect Src activity. Here we show that Src phosphorylates caspase-8A at multiple tyrosine sites; of these, we have focused on Y397 within the linker region and Y465 within the p12 subunit of caspase-8A. We show that phosphomimetic mutation of caspase-8A at Y465 prevents its cleavage and the subsequent activation of caspase-3 and suppresses apoptosis. Furthermore, simultaneous phosphomimetic mutation of caspase-8A at Y397 and Y465 promotes the phosphorylation of c-Src at Y416 and increases c-Src activity. Finally, we demonstrate that caspase-8 activity prevents its own tyrosine phosphorylation by Src. Together these data reveal that dual phosphorylation converts caspase-8 from a pro-apoptotic to a pro-survival mediator. Specifically, tyrosine phosphorylation by Src renders caspase-8 uncleavable and thereby inactive, and at the same time converts it to a Src activator. This novel dynamic interplay between Src and caspase-8 likely acts as a potent signal-integrating switch directing the cell towards apoptosis or survival.

Vasopressor Use for Severe Hypotension—A Multicentre Prospective Observational Study

Background The optimal approach to titrate vasopressor therapy is unclear. Recent sepsis guidelines recommend a mean arterial pressure (MAP) target of 65 mmHg and higher for chronic hypertensive patients. As data emerge from clinical trials comparing blood pressure targets for vasopressor therapy, an accurate description of usual care is required to interpret study results. Our aim was to measure MAP values during vasopressor therapy in Canadian intensive care units (ICUs) and to compare these with stated practices and guidelines. Method In a multicenter prospective cohort study of critically ill adults with severe hypotension, we recorded MAP and vasopressor doses hourly. We investigated variability across patients and centres using multivariable regression models and Analysis of variance (ANOVA), respectively. Results We included data from 56 patients treated in 6 centers. The mean (standard deviation [SD]) age and Acute Physiology and Chronic Health Evaluation (APACHE) II score were 64 (14) and 25 (8). Half (28 of 56) of the patients were at least 65 years old, and half had chronic hypertension. The patient-averaged MAP while receiving vasopressors was 75 mm Hg (6) and the median (1st quartile, 3rd quartile) duration of vasopressor therapy was 43 hours (23, 84). MAP achieved was not associated with history of underlying hypertension (p = 0.46) but did vary by center (p<0.001). Conclusions In this multicenter, prospective observational study, the patient-level average MAP while receiving vasopressors for severe hypotension was 75 mmHg, approximately 10 mmHg above current recommendations and stated practices. Moreover, our results do not support the notion that clinicians tailor vasopressor therapy to individual patient characteristics such as underlying chronic hypertension but MAP achieved while receiving vasopressors varied by site.

The First 2 Years of Activity of a Specialized Organ Procurement Center: Report of an Innovative Approach to Improve Organ Donation.

The number of patients requiring organ transplants continues to outgrow the number of organs donated each year. In an attempt to improve the organ donation process and increase the number of organs available, we created a specialized multidisciplinary team within a specialized organ procurement center (OPC) with dedicated intensive care unit (ICU) beds and operating rooms. The OPC was staffed with ICU nurses, operating room nurses, organ donor management ICU physicians, and multidisciplinary staff. All organ donors within a designated geographic area were transferred to and managed within the OPC. During the first 2 years of operation, 126 patients were referred to the OPC. The OPC was in use for a total of 3527 h and involved 253 health workers. We retrieved 173 kidneys, 95 lungs, 68 livers, 37 hearts, and 13 pancreases for a total of 386 organs offered for transplantation. This translates to a total of 124.6 persons transplanted per million population, which compares most favorably to recently published numbers in developed countries. The OPC clearly demonstrates potential to increase the number of deceased donor organs available for transplant. Further studies are warranted to better understand the exact influence of the different components of the OPC on organ procurement.

Capnographic waveforms obtained in experimental Thiel cadaver model after intubation

We read with interest the study of Silvestri et al. [1] describing apnographic waveforms obtained in two frozen cadavers, after ntubation. These observations highlight the possibilities of realstic simulation, but might present limitations in reproducibility 2]. Here, we report our experience of a more physiologic scenario ased on an experimental Thiel cadaver model where we directly dministrated CO2 in the lung. These observations interestingly omplete those reported by Silvestri et al. particularly given the ossibility of extending this model to CO2 simulation during Cariopulmonary Resuscitation (CPR). Methods. Thiel cadavers were harvested from a specific donation program t the anatomy laboratory of Université du Québec à Troisivières (UQTR). The experiment was conducted in accordance ith Canadian regulations following ethic committee approval CER-14-201-08-03.17). Two cadavers were intubated via direct aryngoscopy. After placement verification by chest auscultation nd chest X-ray, the endotracheal tube (ET) was connected to a onnal T60 ventilator (ALMS, Antony France). The absence of CO2 as confirmed via two different CO2 sensors (mean stream and ide stream), immediately after intubation. Then, CO2 was insufated at low flow (2/min of 10% CO2) through a catheter positioned nto the proximal bronchial tree. The typical End Tidal CO2 (ETCO2) aveform was recorded at the airways opening during ventilation, llustrating the CO2 and alveolar gas mixture in the lung (Fig. 1A). he ET was removed and the cadavers were stored at room temerature (20 ◦C) overnight.

Systemic angiopoietin-1/2 dysregulation following cardiopulmonary bypass in adults

Aim: Vascular leakage following cardiopulmonary bypass contributes to morbidity. Angiopoietin-1 and -2 are biomarkers of endothelial dysfunction. Our aim was to characterize Ang-1 and -2 association with clinical characteristics and outcomes. Methods: Observational cohort study measuring Ang-1/-2 with a panel of cytokines in adults undergoing cardiopulmonary bypass. Results: Ang-2 levels increased immediately postop whereas Ang-1 levels decreased over time. No significant correlation was found with other inflammatory mediators. High correlation was found between the hospital length of stay and Ang-2 increase at 24 h (rho = 0.590; p < 0.0001). The predictors of Ang-2 increase were female gender, cross clamp time, transfusion of blood and absence of angiotensin-converting enzyme inhibitor as a pre-op medication. Conclusion: Angiopoietins can detect vascular leakage early and could impact patients management to decrease length of stay after cardiac surgery.

Early vasopressor use following traumatic injury: a systematic review

Objectives Current guidelines suggest limiting the use of vasopressors following traumatic injury; however, wide variations in practice exist. Although excessive vasoconstriction may be harmful, these agents may help reduce administration of potentially harmful resuscitation fluids. This systematic review aims to compare early vasopressor use to standard resuscitation in adults with trauma-induced shock. Design Systematic review. Data sources We searched MEDLINE, EMBASE, ClinicalTrials.gov and the Central Register of Controlled Trials from inception until October 2016, as well as the proceedings of 10 relevant international conferences from 2005 to 2016. Eligibility criteria for selecting studies Randomised controlled trials and controlled observational studies that compared the early vasopressor use with standard resuscitation in adults with acute traumatic injury. Results Of 8001 citations, we retrieved 18 full-text articles and included 6 studies (1 randomised controlled trial and 5 observational studies), including 2 published exclusively in abstract form. Across observational studies, vasopressor use was associated with increased short-term mortality, with unadjusted risk ratios ranging from 2.31 to 7.39. However, the risk of bias was considered high in these observational studies because patients who received vasopressors were systematically sicker than patients treated without vasopressors. One clinical trial (n=78) was too imprecise to yield meaningful results. Two clinical trials are currently ongoing. No study measured long-term quality of life or cognitive function. Conclusions Existing data on the effects of vasopressors following traumatic injury are of very low quality according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. With emerging evidence of harm associated with aggressive fluid resuscitation and, in selected subgroups of patients, with permissive hypotension, the alternatives to vasopressor therapy are limited. Observational data showing that vasopressors are part of usual care would provide a strong justification for high-quality clinical trials of early vasopressor use during trauma resuscitation. Trial registration number CRD42016033437.

Pharmacological interventions for agitation in patients with traumatic brain injury: protocol for a systematic review and meta-analysis.

BackgroundTraumatic brain injury (TBI) is a worldwide leading cause of mortality and disability. Among TBI complications, agitation is a frequent behavioural problem. Agitation causes potential harm to patients and caregivers, interferes with treatments, leads to unnecessary chemical and physical restraints, increases hospital length of stay, delays rehabilitation, and impedes functional independence. Pharmacological treatments are often considered for agitation management following TBI. Several types of agents have been proposed for the treatment of agitation. However, the benefit and safety of these agents in TBI patients as well as their differential effects and interactions are uncertain. In addition, animal studies and observational studies have suggested impaired cognitive function with the use of certain antipsychotics and benzodiazepines. Hence, a safe and effective treatment for agitation, which does not interfere with neurological recovery, remains to be identified.Methods/designWith the help of Health Sciences librarian, we will design a search strategy in the following databases: PubMed, Ovid MEDLINE®, EMBASE, CINAHL, PsycINFO, Cochrane Library, Google Scholar, Directory of Open Access Journals, LILACS, Web of Science, and Prospero. A grey literature search will be performed using the resources suggested in CADTH’s Grey Matters. We will include all randomized controlled, quasi-experimental, and observational studies with control groups. The population of interest is all patients, including children and adults, who have suffered a TBI. We will include studies in which agitation, not further defined, was the presenting symptom or one of the presenting symptoms. We will also include studies where agitation was not the presenting symptom but was measured as an outcome variable and studies assessing the safety of these pharmacological interventions in TBI patients. We will include studies evaluating all pharmacological interventions including beta-adrenergic blockers, typical and atypical antipsychotics, anticonvulsants, dopamine agonists, psychostimulants, antidepressants, alpha-2-adrenergic agonists, hypnotics, and anxiolytics.DiscussionAlthough agitation is frequent following TBI and pharmacological agents that are often used, there is no consensus on the most efficacious and safest strategy to treat these complications. There is a need for an updated systematic review to summarize the evidence in order to inform practice and future research.Systematic review registrationPROSPERO CRD42016033140