Abstract Early mobilization of critically ill patients is beneficial, suggesting that it should be incorporated into daily clinical practice. Early passive, active, and combined progressive ...mobilizations can be safely initiated in intensive care units (ICUs). Adult patients receiving early mobilization have fewer ventilator-dependent days, shorter ICU and hospital stays, and better functional outcomes. Pediatric ICU data are limited, but recent studies also suggest that early mobilization is achievable without increasing patient risk. In this review, we provide a current and comprehensive appraisal of ICU mobilization techniques in both adult and pediatric critically ill patients. Contraindications and perceived barriers to early mobilization, including cost and health care provider views, are identified. Methods of overcoming barriers to early mobilization and enhancing sustainability of mobilization programs are discussed. Optimization of patient outcomes will require further studies on mobilization timing and intensity, particularly within specific ICU populations.
Septic acute kidney injury (AKI) and myocardial dysfunction are leading causes of mortality with no accepted method of therapy. In this study we demonstrate the role of growth differentiating factor ...15 (GDF15) in septic AKI and myocardial dysfunction using a murine lipopolysaccharide (LPS)-induced sepsis model and an in vitro cell culture system. Data show that GDF15 deficiency augments inflammatory response and exacerbates renal and cardiac injury induced by LPS, while over-expression of GDF15 protects the kidney and heart from LPS-induced organ dysfunction. Therefore, this study highlights the therapeutic potential of GDF15 in the treatment of endotoxin-induced sepsis.
Recombinant human growth differentiation factor 15 (rhGDF15) affects dendritic cell (DC) maturation. However, whether GDF15 is expressed in DCs and its roles and signaling in DCs remain largely ...unknown. It is unclear whether GDF15-DCs can induce immune tolerance in heart transplantation (HT). This study aims to understand the impact of endogenous GDF15 on DC's development, function, underlying molecular mechanism including circular RNA (circRNA). This study will also explore GDF15-DC-mediated immune modulation in HT. Bone marrow (BM) derived DCs were cultured and treated to up- or down regulate GDF15 expression. Phenotype and function of DCs were detected. Expression of genes and circRNAs was determined by qRT-PCR. The signaling pathways activated by GDF15 were examined. The impact of GDF15 treated DCs on preventing allograft immune rejection was assessed in a MHC full mismatch mouse HT model. Our results showed that GDF15 was expressed in DCs. Knockout of GDF15 promoted DC maturation, enhanced immune responsive functions, up-regulated malat-1 circular RNA (circ_Malat 1), and activated the nuclear factor kappa B (NFκB) pathway. Overexpression of GDF15 in DCs increased immunosuppressive/inhibitory molecules, enhanced DCs to induce T cell exhaustion, and promoted Treg generation through IDO signaling. GDF15 utilized transforming growth factor (TGF) β receptors I and II, not GFAL. Administration of GDF15 treated DCs prevented allograft rejection and induced immune tolerance in transplantation. In conclusion, GDF15 induces tolerogenic DCs (Tol-DCs) through inhibition of circ_Malat-1 and the NFκB signaling pathway and up-regulation of IDO. GDF15-DCs can prevent alloimmune rejection in HT.
The lack of a reliable scoring system that predicts the development of septic shock and death precludes comparison of disease and/or treatment outcomes in animal models of sepsis. We developed a ...murine sepsis score (MSS) that evaluates seven clinical variables, and sought to assess its validity and reliability in an experimental mouse model of polymicrobial sepsis.
Stool collected from the cecum of C57BL/6 (B6) mice was dissolved in 0.9% normal saline (NS) and filtered, resulting in a fecal solution (FS) which was injected intraperitoneally into B6 mice. Disease severity was monitored by MSS during the experimental timeline. Blood and tissue samples were harvested for the evaluation of inflammatory changes after sepsis induction. The correlation between pro-inflammatory markers and MSS was assessed by the Spearman rank correlation coefficient.
Mice injected with FS at a concentration of 90 mg/mL developed polymicrobial sepsis with a 75% mortality rate at 24 hours. The MSS was highly predictive of sepsis progression and mortality, with excellent discriminatory power, high internal consistency (Cronbach alpha coefficient = 0.92), and excellent inter-rater reliability (intra-class coefficient = 0.96). An MSS of 3 had a specificity of 100% for predicting onset of septic shock and death within 24 hours. Hepatic dysfunction and systemic pro-inflammatory responses were confirmed by biochemical and cytokine analyses where the latter correlated well with the MSS. Significant bacterial dissemination was noted in multiple organs. Furthermore, the liver, spleen, and intestine demonstrated histopathological evidence of injury.
The MSS reliably predicts disease progression and mortality in an animal model of polymicrobial sepsis. More importantly, it may be used to assess and compare outcomes among various experimental models of sepsis, and serve as an ethically acceptable alternative to death as an endpoint.
Infection with (SAg)-producing bacteria may precede or follow infection with or vaccination against influenza A viruses (IAVs). However, how SAgs alter the breadth of IAV-specific CD8+ T cell (TCD8) ...responses is unknown. Moreover, whether recall responses mediating heterosubtypic immunity to IAVs are manipulated by SAgs remains unexplored. We employed wild-type (WT) and mutant bacterial SAgs, SAg-sufficient/deficient Staphylococcus aureus strains, and WT, mouse-adapted and reassortant IAV strains in multiple in vivo settings to address the above questions. Contrary to the popular view that SAgs delete or anergize T cells, systemic administration of staphylococcal enterotoxin B (SEB) or Mycoplasma arthritidis mitogen before intraperitoneal IAV immunization enlarged the clonal size of 'select' IAV-specific TCD8 and reshuffled the hierarchical pattern of primary TCD8 responses. This was mechanistically linked to the TCR Vβ makeup of the impacted clones rather than their immunodominance status. Importantly, SAg-expanded TCD8 retained their IFN-γ production and cognate cytolytic capacities. The enhancing effect of SEB on immunodominant TCD8 was also evident in primary responses to vaccination with heat-inactivated and live attenuated IAV strains administered intramuscularly and intranasally, respectively. Interestingly, in prime-boost immunization settings, the outcome of SEB administration depended strictly upon the time point at which this SAg was introduced. Accordingly, SEB injection before priming raised CD127highKLRG1low memory precursor frequencies and augmented the anamnestic responses of SEB-binding TCD8. By comparison, introducing SEB before boosting diminished recall responses to IAV-derived epitopes drastically and indiscriminately. This was accompanied by lower Ki67 and higher Fas, LAG-3 and PD-1 levels consistent with a pro-apoptotic and/or exhausted phenotype. Therefore, SAgs can have contrasting impacts on anti-IAV immunity depending on the naïve/memory status and the TCR composition of exposed TCD8. Finally, local administration of SEB or infection with SEB-producing S. aureus enhanced pulmonary TCD8 responses to IAV. Our findings have clear implications for superinfections and prophylactic vaccination.
Myocardial contractile dysfunction in sepsis is associated with the increased morbidity and mortality. Although the underlying mechanisms of the cardiac depression have not been fully elucidated, an ...exaggerated inflammatory response is believed to be responsible. Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome is an intracellular platform that is involved in the maturation and release of interleukin (IL)-1β. The aim of the present study is to evaluate whether sepsis activates NLRP3 inflammasome/caspase-1/IL-1β pathway in cardiac fibroblasts (CFs) and whether this cytokine can subsequently impact the function of cardiomyocytes (cardiac fibroblast-myocyte cross-talk). We show that treatment of CFs with lipopolysaccharide (LPS) induces upregulation of NLRP3, activation of caspase-1, as well as the maturation (activation) and release of IL-1β. In addition, the genetic (small interfering ribonucleic acid siRNA) and pharmacological (glyburide) inhibition of the NLRP3 inflammasome in CFs can block this signaling pathway. Furthermore, the inhibition of the NLRP3 inflammasome in cardiac fibroblasts ameliorated the ability of LPS-challenged CFs to impact cardiomyocyte function as assessed by intracellular cyclic adenosine monophosphate (cAMP) responses in cardiomyocytes. Salient features of this the NLP3 inflammasome/ caspase-1 pathway were confirmed in in vivo models of endotoxemia/sepsis. We found that inhibition of the NLRP3 inflammasome attenuated myocardial dysfunction in mice with LPS and increased the survival rate in mice with feces-induced peritonitis. Our results indicate that the activation of the NLRP3 inflammasome in cardiac fibroblasts is pivotal in the induction of myocardial dysfunction in sepsis.
Sepsis results from a heavy-handed response to infection that may culminate in organ failure and death. Many patients who survive acute sepsis become immunosuppressed and succumb to opportunistic ...infections. Therefore, to be successful, sepsis immunotherapies must target both the initial and the protracted phase of the syndrome to relieve early immunopathology and late immunosuppression, respectively. Invariant NKT (
NKT) cells are attractive therapeutic targets in sepsis. However, repeated treatments with α-galactosylceramide, the prototypic glycolipid ligand of
NKT cells, result in anergy. We designed a double-hit treatment that allows
NKT cells to escape anergy and exert beneficial effects in biphasic sepsis. We tested the efficacy of this approach in the sublethal cecal ligation and puncture mouse model, which mirrors polymicrobial sepsis with progression to an immunosuppressed state. Septic mice were treated with (C2
, 3
, 4
)-1-
-(α-d-galactopyranosyl)-
-tetracosanoyl-2-amino-1,3,4-nonanetriol (OCH), a T
2-polarizing
NKT cell agonist, before they received α-galactosylceramide. This regimen reduced the morbidity and mortality of cecal ligation and puncture, induced a transient but robust IFN-γ burst within a proinflammatory cytokine/chemokine landscape, transactivated NK cells, increased MHC class II expression on macrophages, and restored delayed-type hypersensitivity to a model hapten, consistent with recovery of immunocompetence in protracted sepsis. Structurally distinct T
2-polarizing agonists varied in their ability to replace OCH as the initial hit, with their lipid chain length being a determinant of efficacy. The proposed approach effectively exploits
NKT cells' versatility in biphasic sepsis and may have translational potentials in the development of new therapies.
Sepsis‐elicited immunosuppression elevates the risk of secondary infections. We used a clinically relevant mouse model and serial peripheral blood samples from patients to assess the antimicrobial ...activities of mucosa‐associated invariant T (MAIT) cells in sepsis. Hepatic and splenic MAIT cells from B6‐MAITCAST mice displayed increased CD69 expression and a robust interferon‐γ (IFNγ) production capacity shortly after sublethal cecal ligation and puncture, but not at a late timepoint. Peripheral blood MAIT cell frequencies were reduced in septic patients at the time of intensive care unit (ICU) admission, and more dramatically so among nonsurvivors, suggesting the predictive usefulness of early MAIT cell enumeration. In addition, at ICU admission, MAIT cells from sepsis survivors launched stronger IFNγ responses to several bacterial species compared with those from patients who subsequently died of sepsis. Of note, while low human leukocyte antigen (HLA)‐DR+ monocyte frequencies, widely regarded as a surrogate indicator of sepsis‐induced immunosuppression, were gradually corrected, the numerical insufficiency of MAIT cells was not resolved over time, and their CD69 expression continued to decline. MAIT cell responses to bacterial pathogens, a major histocompatibility complex–related protein 1 (MR1) ligand, and interleukin (IL)‐12 and IL‐18 were also progressively lost during sepsis and did not recover by the time of ICU/hospital discharge. We propose that MAIT cell dysfunctions contribute to post‐sepsis immunosuppression.
Sepsis elevates the risk of secondary infections. Using a clinically relevant mouse model and serial blood samples from septic patients, we demonstrate that mucosa‐associated invariant T (MAIT) cells are quickly activated in early sepsis before losing their antimicrobial functions. We propose that progressive MAIT cell dysfunctions contribute to sepsis‐elicited immunosuppression.
Background Current practice guidelines for management of gallstone pancreatitis (GSP) recommend early cholecystectomy for patient stabilization and bile duct clearance, preferably at index admission. ...Historically, this has been difficult to achieve due to lack of emergency surgical resources. We investigated whether implementation of an acute care surgery (ACS) model would allow better adherence to current practice guidelines for GSP. Study Design A retrospective review was conducted of all patients admitted with the diagnosis of GSP to 2 tertiary care university teaching hospitals from January 2002 to October 2013. Diagnosis was confirmed on review of clinical, biochemical, and radiographic criteria. Patients were divided into pre-ACS (2002 to 2009) and post-ACS (2010 to 2013) eras. Only 1 of the 2 hospitals implemented an ACS service in the latter era. Data were collected on demographics, admissions, cholecystectomy timing, and emergency department visits. Results Before implementation of an ACS service, the rate of index cholecystectomy was 3% at both hospital sites. The rate of index cholecystectomy increased significantly with the addition of ACS, from 2.4% to 67% (p < 0.001). The presence of an ACS team was highly predictive of index cholecystectomy (odds ratio = 10.4; 95% CI 2.0 to 55.1). Patients who did not undergo cholecystectomy during the index admission had an overall readmission rate of 24.9% at both sites. In the ACS hospital, repeat emergency department visits decreased from 24.8% to 8.3% (p < 0.001) and readmission rate decreased from 16.8% to 7.3% (p = 0.04) in the pre-and post-ACS eras, respectively. Conclusions Implementation of an ACS service resulted in a higher rate of index cholecystectomy and decreased emergency department visits and readmissions for biliary disease, and allowed for increased adherence to clinical practice guidelines for GSP.
Providing optimal care to patients with acute respiratory illness while preventing hospital transmission of COVID-19 is of paramount importance during the pandemic; the challenge lies in achieving ...both goals simultaneously. Controversy exists regarding the role of early intubation versus use of non-invasive respiratory support measures to avoid intubation. This review summarizes available evidence and provides a clinical decision algorithm with risk mitigation techniques to guide clinicians in care of the hypoxemic, non-intubated, patient during the COVID-19 pandemic. Although aerosolization of droplets may occur with aerosol-generating medical procedures (AGMP), including high flow nasal oxygen and non-invasive ventilation, the risk of using these AGMP is outweighed by the benefit in carefully selected patients, particularly if care is taken to mitigate risk of viral transmission. Non-invasive support measures should not be denied for conditions where previously proven effective and may be used even while there is suspicion of COVID-19 infection. Patients with de novo acute respiratory illness with suspected/confirmed COVID-19 may also benefit. These techniques may improve oxygenation sufficiently to allow some patients to avoid intubation; however, patients must be carefully monitored for signs of increased work of breathing. Patients showing signs of clinical deterioration or high work of breathing not alleviated by non-invasive support should proceed promptly to intubation and invasive lung protective ventilation strategy. With adherence to these principles, risk of viral spread can be minimized.
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