Contribution of Dendritic Cell Responses to Sepsis-Induced Immunosuppression and to Susceptibility to Secondary Pneumonia

Dendritic cells (DCs) are bone marrow derived cells which continuously seed in peripheral tissue. During infection, DCs play an essential interface between innate and adaptive immunity. Pneumonia is a lung inflammation triggered by pathogens and is characterized by excessive release of inflammatory cytokines that activate innate and acquired immunity. Pneumonia induces a rapid and protracted state of susceptibility to secondary infection, a state so-called sepsis-induced immunosuppression. In this review, we focus on the role of DCs in the development of this state of immunosuppression. Early during inflammation, activated DCs are characterized by decreased capacity of antigen (cross)- presentation of newly encountered antigens and decreased production of immunogenic cytokines, and sepsis-induced immunosuppression is mainly explained by a depletion of immature DCs which had all become mature. At a later stage, newly formed respiratory immature DCs are locally programmed by an immunological scare left-over by inflammation to induce tolerance. Tolerogenic Blimp1+ DCs produce suppressive cytokines such as tumor growth factor-B and participate to the maintenance of a local tolerogenic environment notably characterized by accumulation of Treg cells. In mice, the restoration of the immunogenic functions of DCs restores the mucosal immune response to pathogens. In humans, the modulation of inflammation by glucocorticoid during sepsis or trauma preserves DC immunogenic functions and is associated with resistance to secondary pneumonia. Finally, we propose that the alterations of DCs during and after inflammation can be used as biomarkers of susceptibility to secondary pneumonia and are promising therapeutic targets to enhance outcomes of patients with secondary pneumonia

Tranexamic acid: a narrative review of its current role in perioperative medicine and acute medical bleeding

PurposeTranexamic acid (TXA) is the most widely prescribed antifibrinolytic for active bleeding or to prevent surgical bleeding. Despite numerous large multi-center randomized trials involving thousands of patients being conducted, TXA remains underutilized in indications where it has demonstrated efficacy and a lack of harmful effects. This narrative review aims to provide basic concepts about fibrinolysis and TXA’s mode of action and is focused on the most recent and important trials evaluating this drug in different hemorrhagic situations.MethodsWe selected every low bias RCT, and we highlighted their strengths and limitations throughout this review.Principal findingsWhile TXA appears to have a favorable benefit–risk ratio in most situations (trauma, obstetrics, at-risk for bleeding surgeries) evidence of benefit is lacking in certain medical settings (SAH, digestive bleeding).ConclusionAlthough in some situations the drug’s effect on significant outcomes is modest, its favorable safety profile allows it to be recommended for trauma patients, in obstetrics, and in scheduled surgeries at risk of bleeding. However, it cannot be recommended in cases of spontaneous intracranial bleeding, subarachnoid hemorrhage (SAH), or gastrointestinal bleeding

The Microbiology of Community-acquired Peritonitis in Children

BACKGROUND: microbiologic data are lacking regarding pediatric community-acquired peritonitis (CAP). METHODS: we conducted a 2-year retrospective single center study. Consecutive children undergoing CAP surgery were included. Microbiology and antimicrobial susceptibility of peritoneal isolates were analyzed. RESULTS: a total of 70 children from 3 months to 14 years of age were included. A total of 123 bacterial isolates were analyzed. Escherichia coli was the predominant aerobic organism (51% of isolates); 54.8% were susceptible to amoxicillin whereas 90.3% were susceptible to amoxicillin-clavulanate. Anaerobes accounted for 29% of isolates, and 94.3% of strains were susceptible to amoxicillin-clavulanate and 68.5% were susceptible to clindamycin. Pseudomonas aeruginosa was present in 6% of isolates and in 10% of children. The presence of E. coli resistant to amoxicillin or to amoxicillin-clavulanate was the only independent risk factor associated with postoperative peritonitis. CONCLUSION: microbiology of pediatric CAP is similar to adult CAP with a predominancy of E. coli and anaerobes. P. aeruginosa in peritoneal samples had no apparent influence on the outcome

Empiric antimicrobial therapy for ventilator-associated pneumonia after brain injury

International audienceIssues regarding recommendations on empiric antimicrobial therapy for ventilator-associated pneumonia (VAP) have emerged in specific populations.To develop and validate a score to guide empiric therapy in brain-injured patients with VAP, we prospectively followed a cohort of 379 brain-injured patients in five intensive care units. The score was externally validated in an independent cohort of 252 brain-injured patients and its extrapolation was tested in 221 burn patients.The multivariate analysis for predicting resistance (incidence 16.4%) showed two independent factors: preceding antimicrobial therapy ≥48 h (p\textless0.001) and VAP onset ≥10 days (p\textless0.001); the area under the receiver operating characteristic curve (AUC) was 0.822 (95% CI 0.770-0.883) in the learning cohort and 0.805 (95% CI 0.732-0.877) in the validation cohort. The score built from the factors selected in multivariate analysis predicted resistance with a sensitivity of 83%, a specificity of 71%, a positive predictive value of 37% and a negative predictive value of 96% in the validation cohort. The AUC of the multivariate analysis was poor in burn patients (0.671, 95% CI 0.596-0.751).Limited-spectrum empirical antimicrobial therapy has low risk of failure in brain-injured patients presenting with VAP before day 10 and when prior antimicrobial therapy lasts \textless48 

Pulmonary infections complicating ARDS.

Pulmonary infection is one of the main complications occurring in patients suffering from acute respiratory distress syndrome (ARDS). Besides traditional risk factors, dysregulation of lung immune defenses and microbiota may play an important role in ARDS patients. Prone positioning does not seem to be associated with a higher risk of pulmonary infection. Although bacteria associated with ventilator-associated pneumonia (VAP) in ARDS patients are similar to those in patients without ARDS, atypical pathogens (Aspergillus, herpes simplex virus and cytomegalovirus) may also be responsible for infection in ARDS patients. Diagnosing pulmonary infection in ARDS patients is challenging, and requires a combination of clinical, biological and microbiological criteria. The role of modern tools (e.g., molecular methods, metagenomic sequencing, etc.) remains to be evaluated in this setting. One of the challenges of antimicrobial treatment is antibiotics diffusion into the lungs. Although targeted delivery of antibiotics using nebulization may be interesting, their place in ARDS patients remains to be explored. The use of extracorporeal membrane oxygenation in the most severe patients is associated with a high rate of infection and raises several challenges, diagnostic issues and pharmacokinetics/pharmacodynamics changes being at the top. Prevention of pulmonary infection is a key issue in ARDS patients, but there is no specific measure for these high-risk patients. Reinforcing preventive measures using bundles seems to be the best option

High sodium continuous veno‐venous hemodialysis with regional citrate anticoagulation and online dialysate generation in patients with acute liver failure and cerebral edema

Introduction: Acute liver failure is associated with a high mortality rate. Induction of plasma hypertonicity with mannitol or hypertonic saline remains the cornerstone in the management of resultant cerebral edema. Significant disadvantages of this approach include poor or unpredictable control of serum sodium concentration and volume expansion, among others.Methods: We used high sodium continuous veno‐venous hemodialysis with regional citrate anticoagulation and online dialysate generation to accurately control the serum sodium in eleven patients with acute liver failure, renal failure, and cerebral edema. We used a Fresenius 2008 K/K2 machine in hemodialysis mode to deliver a blood flow of 60 ml/minute and dialysate flow of 400 ml/minute. Our previously published protocol results in complete removal of infused citrate by the dialyzer. On‐line clearance calculations were used to model the time required to reach the target serum sodium.Findings: All patients achieved serum sodium within 2 mEq/L of target without fluctuations or rebound. Nine patients survived without requiring liver transplantation and two died despite reaching the prescribed serum sodium target. We did not encounter any citrate toxicity.Discussion: We describe a novel approach for delivering continuous osmotherapy to patients with acute liver failure, renal failure, and cerebral edema. In comparison to standard therapy, the described modality enables precise titration of serum sodium without undesirable fluctuations in extracellular fluid volume. A particular advantage is zero delivery of citrate to this vulnerable group of patients with acute liver failure.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143708/1/hdi12572.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143708/2/hdi12572_am.pd

Corticotherapy for traumatic brain-injured Patients - The Corti-TC trial: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Traumatic brain injury (TBI) is a main cause of severe prolonged disability of young patients. Hospital acquired pneumonia (HAP) add to the morbidity and mortality of traumatic brain-injured patients. In one study, hydrocortisone for treatment of traumatic-induced corticosteroid insufficiency (CI) in multiple injured patients has prevented HAP, particularly in the sub-group of patients with severe TBI. Fludrocortisone is recommended in severe brain-injured patients suffering from acute subarachnoid hemorrhage. Whether an association of hydrocortisone with fludrocortisone protects from HAP and improves neurological recovery is uncertain. The aim of the current study is to compare corticotherapy to placebo for TBI patients with CI.</p> <p>Methods</p> <p>The CORTI-TC (Corticotherapy in traumatic brain-injured patients) trial is a multicenter, randomized, placebo controlled, double-blind, two-arms study. Three hundred and seventy six patients hospitalized in Intensive Care Unit with a severe traumatic brain injury (Glasgow Coma Scale ≤ 8) are randomized in the first 24 hours following trauma to hydrocortisone (200 mg.day^-1for 7 days, 100 mg on days 8-9 and 50 mg on day-10) with fludrocortisone (50 μg for 10 days) or double placebo. The treatment is stopped if patients have an appropriate adrenal response. The primary endpoint is HAP on day-28. The endpoint of the ancillary study is the neurological status on 6 and 12 months.</p> <p>Discussion</p> <p>The CORTI-TC trial is the first randomized controlled trial powered to investigate whether hydrocortisone with fludrocortisone in TBI patients with CI prevent HAP and improve long term recovery.</p> <p>Trial registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01093261">NCT01093261</a></p

CpG-ODN and MPLA Prevent Mortality in a Murine Model of Post-Hemorrhage-Staphyloccocus aureus Pneumonia

Infections are the most frequent cause of complications in trauma patients. Post-traumatic immune suppression (IS) exposes patients to pneumonia (PN). The main pathogen involved in PN is Methicillin Susceptible Staphylococcus aureus (MSSA). Dendritic cells () may be centrally involved in the IS. We assessed the consequences of hemorrhage on pneumonia outcomes and investigated its consequences on DCs functions. A murine model of hemorrhagic shock with a subsequent MSSA pneumonia was used. Hemorrhage decreased the survival rate of infected mice, increased systemic dissemination of sepsis and worsened inflammatory lung lesions. The mRNA expression of Tumor Necrosis Factor-alpha (TNF-α), Interferon-beta (IFN-β) and Interleukin (IL)-12p40 were mitigated for hemorrhaged-mice. The effects of hemorrhage on subsequent PN were apparent on the pDCs phenotype (reduced MHC class II, CD80, and CD86 molecule membrane expression). In addition, hemorrhage dramatically decreased CD8+ cDCs- and CD8- cDCs-induced allogeneic T-cell proliferation during PN compared with mice that did not undergo hemorrhage. In conclusion, hemorrhage increased morbidity and mortality associated with PN; induced severe phenotypic disturbances of the pDCs subset and functional alterations of the cDCs subset. After hemorrhage, a preventive treatment with CpG-ODN or Monophosphoryl Lipid A increased transcriptional activity in DCs (TNF-α, IFN-β and IL-12p40) and decreased mortality of post-hemorrhage MSSA pneumonia