Alexandre Mignon

Hepatic response to sepsis: interaction between coagulation and inflammatory processes.

Objectivesa) To review the hepatic response to sepsis and to establish how this response contributes to coagulation and inflammatory processes; b) to review the physiologic and biochemical mechanisms that suggest hepatic dysfunction may occur during sepsis, enhance procoagulant and proinflammatory activities, and participate in the potential evolution to multiple organ dysfunction syndrome. Data SourcesA summary of published medical literature from MEDLINE search files and published reviews on liver function in experimental and human sepsis. Data SummaryIn sepsis, the liver plays a major role in host defense mechanisms. Kupffer cells are responsible for bacterial scavenging, bacterial products inactivation, and inflammatory mediators clearance and production. Hepatocytes, via receptors for many proinflammatory cytokines, modify their metabolic pathway toward gluconeogenesis, amino-acid uptake, and increased synthesis of coagulant and complement factors and protease inhibitors. The acute-phase protein (APP) response also contributes to the procoagulant state, especially by enhancing the inhibition of protein C (&agr;1-antitrypsin and &agr;2-macroglobulin) and by decreasing liver synthesis of protein C and antithrombin (negative APPs). Elevated C-reactive protein levels (positive APPs) promote the expression of tissue factor by mononuclear cells. Increased liver production of thrombin-activatable fibrinolytic inhibitor (positive APPs) enhances fibrinolysis inhibition. Conversely, such hepatic inflammatory and coagulation processes in sepsis may alter the function of this organ. Indeed, the liver can be injured by activated Kupffer cells that release chemokines, attract blood neutrophils into the liver, and activate them. Neutrophils up-regulate their surface adhesion molecules, tissue factor, and Kupffer cells, whereas tissue factor pathway inhibitor and thrombomodulin are almost undetectable in endothelial cells. This may lead to microcirculatory disturbances, fibrin deposition, hepatocyte injury, endotoxin and bacteria spillover, and multiple organ failure. ConclusionsIn sepsis, the liver participates in host defense and tissue repair through hepatic cell cross-talk that controls most of the coagulation and inflammatory processes. When this control is not adequate, a secondary hepatic dysfunction may occur and may sometimes lead to bacterial products spillover, enhanced procoagulant and inflammatory processes, and in turn, multiple organ failure and death.

French experience of 2009 A/H1N1v influenza in pregnant women.

Background The first reports on the pandemic influenza 2009 A/H1N1v from the USA, Mexico, and Australia indicated that this disease was associated with a high mortality in pregnant women. The aim of this study was to describe and compare the characteristics of severe critically ill and non-severe pregnant women with 2009 A/H1N1v-related illness in France. Methodology/Principal Findings A national registry was created to screen pregnant women with laboratory-confirmed 2009 A/H1N1v influenza. Three hundred and fifteen patients from 46 French hospitals were included: 40 patients were admitted to intensive care units (severe outcomes), 111 were hospitalized in obstetric or medical wards (moderate outcomes), and 164 were outpatients (mild outcomes). The 2009 A/H1N1v influenza illness occurred during all pregnancy trimesters, but most women (54%), notably the severe patients (70%), were in the third trimester. Among the severe patients, twenty (50%) underwent mechanical ventilation, and eleven (28%) were treated with extracorporeal membrane oxygenation. Three women died from A/H1N1v influenza. We found a strong association between the development of a severe outcome and both co-existing illnesses (adjusted odds ratio [OR], 5.1; 95% confidence interval [CI], 2.2–11.8) and a delay in oseltamivir treatment after the onset of symptoms (>3 or 5 days) (adjusted OR, 4.8; 95% CI, 1.9–12.1 and 61.2, 95% CI; 14.4–261.3, respectively). Among the 140 deliveries after 22 weeks of gestation known to date, 19 neonates (14%) were admitted to a neonatal intensive care unit, mainly for preterm delivery, and two neonates died. None of these neonates developed 2009 A/H1N1v infection. Conclusions This series confirms the high incidence of complications in pregnant women infected with pandemic A/H1N1v observed in other countries but depicts a lower overall maternal and neonatal mortality and morbidity than indicated in the USA or Australia. Moreover, our data demonstrate the benefit of early oseltamivir treatment in this specific population.

Differential protective effects of Bcl-xL and Bcl-2 on apoptotic liver injury in transgenic mice

Fas ligand (CD95L) and tumor necrosis factor-α (TNF-α) are pivotal inducers of hepatocyte apoptosis. Uncontrolled activation of these two systems is involved in several forms of liver injury. Although the broad antiapoptotic action of Bcl-2 and Bcl-xL has been clearly established in various apoptotic pathways, their ability to inhibit the Fas/CD95- and TNF-α-mediated apoptotic signal has remained controversial. We have demonstrated that the expression of BCL-2 in hepatocytes protects them against Fas-induced fulminant hepatitis in transgenic mice. The present study shows that transgenic mice overexpressing[Formula: see text]in hepatocytes are also protected from Fas-induced apoptosis in a dose-dependent manner. Bcl-xL and Bcl-2 were protective without any change in the level of endogenous[Formula: see text]or Bax and inhibited hepatic caspase-3-like activity. In vivo injection of TNF-α caused massive apoptosis and death only when transcription was inhibited. Under these conditions,[Formula: see text]mice were partially protected from liver injury and death but PK-BCL-2 mice were not. A similar differential protective effect of Bcl-xL and Bcl-2 transgenes was observed when Fas/CD95 was activated and transcription blocked. These results suggest that apoptosis triggered by activation of both Fas/CD95 and TNF-α receptors is to some extent counteracted by the transcription-dependent protective effects, which are essential for the antiapoptotic activity of Bcl-2 but not of Bcl-xL. Therefore, Bcl-xL and Bcl-2 appear to have different antiapoptotic effects in the liver whose characterization could facilitate their use to prevent the uncontrolled apoptosis of hepatocytes.

Improving continuous wound infusion effectiveness for postoperative analgesia after cesarean delivery: a randomized controlled trial.

OBJECTIVE: To evaluate in which anatomical layer (above the fascia or below the fascia) continuous wound infusion of local anesthetic, combined with nonsteroidal antiinflammatory drugs, through a multiorifice catheter has the best effectiveness during the first 48 hours on postoperative pain intensity after elective cesarean delivery. METHODS: Fifty-six women undergoing elective cesarean delivery under spinal anesthesia were randomly allocated to receive 48-hour continuous wound infusion either above the fascia or below the fascia using ropivacaine and ketoprofene through a multiholed wound catheter. No other systemic analgesics were used, except for rescue patient-controlled intravenous morphine. Evaluation by a blinded investigator included visual analog scale scores at rest and at movement, morphine consumption, patient satisfaction, residual pain at 1 and 6 months, and undesirable side effects. RESULTS: Continuous wound infusion below the fascia resulted in significantly reduced pain at rest and total postoperative morphine consumption (15.7 mg, 95% confidence interval 9.7–20.7 mg) compared with wound administration above the fascia (26.4 mg, 95% confidence interval 18.1–34.7). No undesirable side effects or residual pain requiring treatment were recorded in both groups, whereas analgesia and satisfaction were excellent. CONCLUSION: After cesarean delivery, continuous wound infusion over 48 hours with ropivacaine and ketoprofene through a multiholed wound catheter inserted below the fascia results in better analgesia when compared with administration above the fascia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01160913. LEVEL OF EVIDENCE: I

Postpartum hemorrhage: guidelines for clinical practice from the French ă College of Gynaecologists and Obstetricians (CNGOF) in collaboration ă with the French Society of Anesthesiology and Intensive Care (SFAR)

Postpartum haemorrhage (PPH) is defined as blood loss ≥500mL after delivery and severe PPH as blood loss ≥1000mL, regardless of the route of delivery (professional consensus). The preventive administration of uterotonic agents just after delivery is effective in reducing the incidence of PPH and its systematic use is recommended, regardless of the route of delivery (Grade A). Oxytocin is the first-line prophylactic drug, regardless of the route of delivery (Grade A); a slowly dose of 5 or 10 IU can be administered (Grade A) either IV or IM (professional consensus). After vaginal delivery, routine cord drainage (Grade B), controlled cord traction (Grade A), uterine massage (Grade A), and routine bladder voiding (professional consensus) are not systematically recommended for PPH prevention. After caesarean delivery, placental delivery by controlled cord traction is recommended (grade B). The routine use of a collector bag to assess postpartum blood loss at vaginal delivery is not systematically recommended (Grade B), since the incidence of severe PPH is not affected by this intervention. In cases of overt PPH after vaginal delivery, placement of a blood collection bag is recommended (professional consensus). The initial treatment of PPH consists in a manual uterine examination, together with antibiotic prophylaxis, careful visual assessment of the lower genital tract, a uterine massage, and the administration of 5-10 IU oxytocin injected slowly IV or IM, followed by a maintenance infusion not to exceed a cumulative dose of 40IU (professional consensus). If oxytocin fails to control the bleeding, the administration of sulprostone is recommended within 30minutes of the PPH diagnosis (Grade C). Intrauterine balloon tamponade can be performed if sulprostone fails and before recourse to either surgery or interventional radiology (professional consensus). Fluid resuscitation is recommended for PPH persistent after first line uterotonics, or if clinical signs of severity (Grade B). The objective of RBC transfusion is to maintain a haemoglobin concentration (Hb) >8g/dL. During active haemorrhaging, it is desirable to maintain a fibrinogen level ≥2g/L (professional consensus). RBC, fibrinogen and fresh frozen plasma (FFP) may be administered without awaiting laboratory results (professional consensus). Tranexamic acid may be used at a dose of 1 g, renewable once if ineffective the first time in the treatment of PPH when bleeding persists after sulprostone administration (professional consensus), even though its clinical value has not yet been demonstrated in obstetric settings. It is recommended to prevent and treat hypothermia in women with PPH by warming infusion solutions and blood products and by active skin warming (Grade C). Oxygen administration is recommended in women with severe PPH (professional consensus). If PPH is not controlled by pharmacological treatments and possibly intra-uterine balloon, invasive treatments by arterial embolization or surgery are recommended (Grade C). No technique for conservative surgery is favoured over any other (professional consensus). Hospital-to-hospital transfer of a woman with a PPH for embolization is possible once hemoperitoneum is ruled out and if the patients hemodynamic condition so allows (professional consensus).

An observational study of the fresh frozen plasma: Red blood cell ratio in postpartum hemorrhage

BACKGROUND:Postpartum hemorrhage is the leading cause of maternal death worldwide. Recent data from trauma patients and patients with hemorrhagic shock have suggested that an increased fresh frozen plasma:red blood cell (FFP:RBC) ratio may be of benefit in massive bleeding. We addressed this issue in cases of severe postpartum hemorrhage. METHODS:We reviewed data from all patients diagnosed with severe postpartum hemorrhage during a 4-year period (2006–2009). Patients who were treated with sulprostone and required transfusion within 6 hours of delivery were included in the study and were divided into 2 groups according to their response to sulprostone: bleeding controlled with sulprostone alone (sulprostone group) and bleeding requiring an additional advanced interventional procedure including arterial angiographic embolization and/or surgical procedures (arterial ligation, B-Lynch suture, or hysterectomy; intervention group). The requirement or no requirement for advanced procedures constituted the primary end point of the study. Propensity scoring was used to assess the effect of a high FFP:RBC ratio on bleeding control. RESULTS:Among 12,226 deliveries during the study period, 142 (1.1%) were complicated by severe postpartum hemorrhage. Bleeding was controlled with sulprostone alone in 90 patients (63%). Advanced interventional procedures were required for 52 patients (37%). Forty-one patients were transfused with both RBCs and FFP. The FFP:RBC ratio increased over the study period (P < 0.001), from 1:1.8 at the start to 1:1.1 at the end of the study period. After propensity score modeling (inverse probability of treatment weighting), a high FFP:RBC ratio was associated with lower odds for advanced interventional procedures (odds ratio [95% confidence interval], 1.25 [1.07–1.47]; P = 0.008). There were no deaths, severe organ dysfunction, or other complications as a consequence of severe postpartum hemorrhage. CONCLUSIONS:In this retrospective study, a higher FFP:RBC ratio was associated with a lower requirement for advanced interventional procedures in the setting of postpartum hemorrhage. The benefits of transfusion using a higher FFP:RBC ratio should be confirmed by randomized-controlled trials.

Trauma care systems in France.

The French Republic includes approximatively 60 millions inhabitants for almost 550,000 km(2). Prehospital management is organised at department level (96). This management involves a regulatory system initiated from a unique phone number (15 national). The medical regulator sends either first-aid providers or a medical team. On-site care is highly developed and prehospital medically assisted care is really the first phase of the treatment of the injured. The team ensures that the victim is in the best condition for transport and participates in monitoring. Intra-hospital care begins either in an emergency room, with a physician qualified in Emergency Medicine, or in a recovery room, with a surgical intensive-care team. There is no specialisation in trauma in France. All specialist surgeons treat those aspects of trauma pathology that concern them. All surgeons operate on trauma patients and with regard to the organ concerned: digestive, orthopaedic, em leader. The challenge nevertheless remains that of maintaining facilities at a sufficient level to deal with everyday pathology, known for the seriousness of its consequences in both human and financial terms, within an increasingly sparse hospital infrastructure. Suggestions are emerging in response to these preoccupations. Organisation at the European level of hand emergency units (FESUM) is a targeted example.

Transcutaneous cranial electrical stimulation (Limoge's currents) decreases early buprenorphine analgesic requirements after abdominal surgery

Transcutaneous cranial electrical stimulation with Limoges currents (TCES) consists of high frequency, low intensity currents which decreased anesthetic requirements during elective surgery.This action is likely to be mediated by the release of central endogenous opioids. In the present study, we hypothesized that TCES applied intraoperatively may decrease early postoperative narcotic requirements. Thirty-nine ASA physical status I and II patients undergoing elective abdominal surgery were enrolled in this prospective, randomized, double-blind, placebo-controlled study. Just before induction of anesthesia, patients were connected to the electrical stimulator and randomly allocated to be either stimulated (TCES group, n = 20) or not (control group, n = 19) during surgery. The managing anesthesiologist was unaware of which group the patient was assigned. Postoperatively, patients were given a patient-controlled analgesia (PCA) device delivering buprenorphine for the first four postoperative hours. The recorded variables included postoperative buprenorphine requirements, pain scores (0-10 visual analog scale [VAS]), sedation (0-4 scale), and intraoperative isoflurane requirements. Patients were comparable with respect to age, sex ratio, weight, duration of surgery, intraoperative hemodynamics, fentanyl requirements, and time from skin closure to tracheal extubation. Buprenorphine requirements were significantly reduced in the TCES group versus the control group (2.36 vs 3.43 micro gram centered dot kg-1 centered dot h-1; P = 0.002). Intraoperative isoflurane anesthetic requirements, as well as hourly postoperative scores for pain and sedation, were the same for the two groups. These data indicate that TCES reduces narcotic requirements for early postoperative analgesia. This technique might have potential to facilitate early postoperative analgesia in patients undergoing elective abdominal surgery. (Anesth Analg 1996;83:771-5)

A Serious Game for Massive Training and Assessment of French Soldiers Involved in Forward Combat Casualty Care (3D-SC1): Development and Deployment.

Background The French Military Health Service has standardized its military prehospital care policy in a ‘‘Sauvetage au Combat’’ (SC) program (Forward Combat Casualty Care). A major part of the SC training program relies on simulations, which are challenging and costly when dealing with more than 80,000 soldiers. In 2014, the French Military Health Service decided to develop and deploy 3D-SC1, a serious game (SG) intended to train and assess soldiers managing the early steps of SC. Objectives The purpose of this paper is to describe the creation and production of 3D-SC1 and to present its deployment. Methods A group of 10 experts and the Paris Descartes University Medical Simulation Department spin-off, Medusims, coproduced 3D-SC1. Medusims are virtual medical experiences using 3D real-time videogame technology (creation of an environment and avatars in different scenarios) designed for educational purposes (training and assessment) to simulate medical situations. These virtual situations have been created based on real cases and tested on mannequins by experts. Trainees are asked to manage specific situations according to best practices recommended by SC, and receive a score and a personalized feedback regarding their performance. Results The scenario simulated in the SG is an attack on a patrol of 3 soldiers with an improvised explosive device explosion as a result of which one soldier dies, one soldier is slightly stunned, and the third soldier experiences a leg amputation and other injuries. This scenario was first tested with mannequins in military simulation centers, before being transformed into a virtual 3D real-time scenario using a multi-support, multi–operating system platform, Unity. Processes of gamification and scoring were applied, with 2 levels of difficulty. A personalized debriefing was integrated at the end of the simulations. The design and production of the SG took 9 months. The deployment, performed in 3 months, has reached 84 of 96 (88%) French Army units, with a total of 818 hours of connection in the first 3 months. Conclusions The development of 3D-SC1 involved a collaborative platform with interdisciplinary actors from the French Health Service, a university, and videogame industry. Training each French soldier with simulation exercises and mannequins is challenging and costly. Implementation of SGs into the training program could offer a unique opportunity at a lower cost to improve training and subsequently the real-time performance of soldiers when managing combat casualties; ideally, these should be combined with physical simulations.

In Vitro Plasma-Induced Endothelial Oxidative Stress and Circulating Markers of Endothelial Dysfunction in Preeclampsia: An Observational Study

Objective: To investigate plasma-induced endothelial reactive oxygen species (ROS) production in vitro and its relation to endothelial dysfunction in preeclampsia (PE). Methods: Plasma was drawn from 17 PE patients, 17 matched healthy pregnant (HP) women, 17 matched non-pregnant healthy volunteers (NP), and 10 septic shock (SC) patients. In vitro plasma-induced ROS production was assessed in cultured human endothelial cells. In vivo endothelial activation and injury were assessed through measurements of plasma von Willebrand factor (vWF) and soluble thrombomodulin (sTM) concentrations, respectively. Results: Endothelial ROS production was not induced by PE, HP, and NP plasmas. However, it was significantly increased in SC compared to other groups (p < .005). Pregnancy (PE and HP) was associated with higher vWF compared to NP. Among pregnancies, vWF was higher in PE compared to HP women (p < .05). sTM was unchanged between PE, HP and NP. In SC, vWF and sTM were significantly increased compared to other groups (p < .01). Simultaneously, endothelial ROS production and sTM concentration were correlated (p = .673; p < .05). Conclusion. Plasma does not induce in vitro endothelial ROS production in PE women for which endothelial dysfunction is limited to activation but not injury. By contrast, SC patients demonstrate both endothelial activation and injury, closely related to plasma-induced endothelial oxidative stress.