La Biblio du Mois: Août 2015
Au programme de ce mois-ci, enfin l’article sur un des antidotes des AOD (anciennement appelés NACO) parmi de nombreuses revues et différentes études que nous avons jugé intéressantes de vous faire partager.
Idarucizumab comme antidote du Dabigatran ?
Specific reversal agents for non–vitamin K antagonist oral anticoagulants are lacking. Idarucizumab, an antibody fragment, was developed to reverse the anticoagulant effects of dabigatran.
We undertook this prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the determination at a central laboratory of the dilute thrombin time or ecarin clotting time. A key secondary end point was the restoration of hemostasis.
This interim analysis included 90 patients who received idarucizumab (51 patients in group A and 39 in group B). Among 68 patients with an elevated dilute thrombin time and 81 with an elevated ecarin clotting time at baseline, the median maximum percentage reversal was 100% (95% confidence interval, 100 to 100). Idarucizumab normalized the test results in 88 to 98% of the patients, an effect that was evident within minutes. Concentrations of unbound dabigatran remained below 20 ng per milliliter at 24 hours in 79% of the patients. Among 35 patients in group A who could be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. Among 36 patients in group B who underwent a procedure, normal intraoperative hemostasis was reported in 33, and mildly or moderately abnormal hemostasis was reported in 2 patients and 1 patient, respectively. One thrombotic event occurred within 72 hours after idarucizumab administration in a patient in whom anticoagulants had not been reinitiated.
Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes.
Revue des troubles hydro-électrolytiques et acide-base liés au Diabète
Revue et mise à jour sur l’utilisation péri-opératoire de la Dexmedetomidine en pédiatrie
Un peu plus loin dans la compréhension du SDRA : la voie des Midkine
Zhang, et al., AJRCCM, 2015; doi: 10.1164/rccm.201412-2326OC
Lung-protective ventilatory strategies have been widely used in patients with acute respiratory distress syndrome (ARDS), but the ARDS mortality rate remains unacceptably high and there is no proven pharmacologic therapy.
Mechanical ventilation can induce oxidative stress and lung fibrosis, which may contribute to high dependency on ventilator support and increased ARDS mortality. We hypothesized that the novel cytokine, midkine (MK), which can be up-regulated in oxidative stress, plays a key role in the pathogenesis of ARDS-associated lung fibrosis.
Blood samples were collected from 17 patients with ARDS and 10 healthy donors. Human lung epithelial cells were challenged with hydrogen chloride followed by mechanical stretch for 72 hours. Wild-type and MK gene–deficient (MK−/−) mice received two-hit injury of acid aspiration and mechanical ventilation, and were monitored for 14 days.
MEASUREMENTS AND MAIN RESULTS
Plasma concentrations of MK were higher in patients with ARDS than in healthy volunteers. Exposure to mechanical stretch of lung epithelial cells led to an epithelial–mesenchymal transition profile associated with increased expression of angiotensin-converting enzyme, which was attenuated by silencing MK, its receptor Notch2, or NADP reduced oxidase 1. An increase in collagen deposition and hydroxyproline level and a decrease in lung tissue compliance seen in wild-type mice were largely attenuated in MK−/− mice.
Mechanical stretch can induce an epithelial–mesenchymal transition phenotype mediated by the MK–Notch2–angiotensin-converting enzyme signaling pathway, contributing to lung remodeling. The MK pathway is a potential therapeutic target in the context of ARDS-associated lung fibrosis.
Les cellules souches mésenchymateuses, nouvelle thérapeutique de la pneumopathie?
Monsel, et al., AJRCCM, 2015; doi: 10.1164/rccm.201410-1765OC
Microvesicles (MVs) are anuclear fragments of cells released from the endosomal compartment or shed from surface membranes. We and other investigators demonstrated that MVs released by mesenchymal stem cells (MSCs) were as effective as the cells themselves in inflammatory injuries, such as after endotoxin-induced acute lung injury. However, the therapeutic effects of MVs in an infectious model of acute lung injury remain unknown.
We investigated the effects of human MSC MVs on lung inflammation, protein permeability, bacterial clearance, and survival after severe bacterial pneumonia.
We tested the effects of MVs derived from human MSCs on Escherichia coli pneumonia in mice. We also studied the interactions between MVs and human monocytes and human alveolar epithelial type 2 cells.
MEASUREMENTS AND MAIN RESULTS
Administration of MVs derived from human MSCs improved survival in part through keratinocyte growth factor secretion and decreased the influx of inflammatory cells, cytokines, protein, and bacteria in mice injured with bacterial pneumonia. In primary cultures of human monocytes or alveolar type 2 cells, the uptake of MVs was mediated by CD44 receptors, which were essential for the therapeutic effects. MVs enhanced monocyte phagocytosis of bacteria while decreasing inflammatory cytokine secretion and increased intracellular ATP levels in injured alveolar epithelial type 2 cells. Prestimulation of MSCs with a toll-like receptor 3 agonist further enhanced the therapeutic effects of the released MVs.
MVs derived from human MSCs were as effective as the parent stem cells in severe bacterial pneumonia.
Hyperchlorémie & Surmortalité
Acute Kidney Injury in Critical Illness Study Group, CCM, 2015, doi: 10.1097/CCM.0000000000001161
Hyperchloremia is frequently observed in critically ill patients in the ICU. Our study aimed to examine the association of serum chloride (Cl) levels with hospital mortality in septic ICU patients.
Retrospective cohort study.
Setting: Urban academic medical center ICU.
Patients: ICU adult patients with severe sepsis or septic shock who had Cl measured on ICU admission were included. Those with baseline estimated glomerular filtration rate less than 15 mL/min/1.73 m2 or chronic dialysis were excluded.
MEASUREMENTS AND MAIN RESULTS
Of 1,940 patients included in the study, 615 patients (31.7%) had hyperchloremia (Cl ≥ 110 mEq/L) on ICU admission. All-cause hospital mortality was the dependent variable. Cl on ICU admission (Cl0), Cl at 72 hours (Cl72), and delta Cl (ΔCl = Cl72 – Cl0) were the independent variables. Those with Cl0 greater than or equal to 110 mEq/L were older and had higher cumulative fluid balance, base deficit, and Sequential Organ Failure Assessment scores. Multivariate analysis showed that higher Cl72 but not Cl0was independently associated with hospital mortality in the subgroup of patients with hyperchloremia on ICU admission (adjusted odds ratio for Cl72 per 5 mEq/L increase = 1.27; 95% CI, 1.02–1.59; p = 0.03). For those who were hyperchloremic on ICU admission, every within-subject 5 mEq/L increment in Cl72 was independently associated with hospital mortality (adjusted odds ratio for ΔCl 5 mEq/L = 1.37; 95% CI, 1.11–1.69; p = 0.003).
In critically ill septic patients manifesting hyperchloremia (Cl ≥ 110 mEq/L) on ICU admission, higher Cl levels and within-subject worsening hyperchloremia at 72 hours of ICU stay were associated with all-cause hospital mortality. These associations were independent of base deficit, cumulative fluid balance, acute kidney injury, and other critical illness parameters.
Durée de vie d’un circuit de dialyse au citrate versus héparine
Gattas et al., CCM, 2015, doi: 10.1097/CCM.0000000000001004
To determine whether regional anticoagulation of continuous renal replacement therapy circuits using citrate and calcium prolongs circuit life and/or affects circulating cytokine levels compared with regional anticoagulation using heparin and protamine.
Multicenter, parallel group randomized controlled trial.
Setting: Seven ICUs in Australia and New Zealand.
Patients: Critically ill adults requiring continuous renal replacement therapy.
Interventions: Patients were randomized to receive one of two methods of regional circuit anticoagulation: citrate and calcium or heparin and protamine.
MEASUREMENTS AND MAIN RESULTS
The primary outcome was functional circuit life measured in hours, assessed using repeated events survival analysis. In addition, we measured changes in interleukin-6, interleukin-8, and interleukin-10 blood levels. We randomized 212 subjects who were treated with 857 continuous renal replacement therapy circuits (median 2 circuits per patient [interquartile range, 1–6], 390 in citrate group vs 467 in heparin group). The groups were well matched for baseline characteristics. Patients receiving regional continuous renal replacement therapy anticoagulation with heparin and protamine were more likely to experience circuit clotting than those receiving citrate and calcium (hazard ratio, 2.03 [1.36–3.03]; p < 0.0005; 857 circuits). The median lifespan of the first study circuit in each patient was 39.2 hours (95% CI, 32.1–48.0 hr) in the citrate and calcium group versus 22.8 hours (95% CI, 13.3–34.0 hr) in the heparin and protamine group (log rank p = 0.0037, 204 circuits). Circuit anticoagulation with citrate and calcium had similar effects on cytokine levels compared with heparin and protamine anticoagulation. There were more adverse events in the group assigned to heparin and protamine anticoagulation (11 vs 2; p = 0.011).
Regional citrate and calcium anticoagulation prolongs continuous renal replacement therapy circuit life compared with regional heparin and protamine anticoagulation, does not affect cytokine levels, and is associated with fewer adverse events.
Revue sur l’oedème pulmonaire neurogénique