Tofacitinib Treatment Suppresses CD4+ T-Cell Activation and Th1 Response, Contributing to Protection against Staphylococcal Toxic Shock.

Staphylococcal toxic shock syndrome (STSS) is a rare, yet potentially fatal disease caused by Staphylococcus aureus (S. aureus) enterotoxins, known as superantigens, which trigger an intense immune response. Our previous study demonstrated the protective effect of tofacitinib against murine toxin-induced shock and a beneficial effect against S. aureus sepsis. In the current study, we examined the effects of tofacitinib on T-cell response in peripheral blood using a mouse model of enterotoxin-induced shock. Our data revealed that tofacitinib suppresses the activation of both CD4+ and CD8+ T cells in peripheral blood. Furthermore, both gene and protein levels of Th1 cytokines were downregulated by tofacitinib treatment in mice with enterotoxin-induced shock. Importantly, we demonstrated that CD4+ cells, but not CD8+ cells, are pathogenic in mice with enterotoxin-induced shock. In conclusion, our findings suggest that tofacitinib treatment suppresses CD4+ T-cell activation and Th1 response, thereby aiding in protection against staphylococcal toxic shock in mice. This insight may guide the future development of novel therapies for STSS.

Antimicrobial peptide 2K4L inhibits the inflammatory response in macrophages and Caenorhabditis elegans and protects against LPS-induced septic shock in mice.

2K4L is a rationally designed analog of the short α-helical peptide temporin-1CEc, a natural peptide isolated and purified from the skin secretions of the Chinese brown frog Rana chensinensis by substituting amino acid residues. 2K4L displayed improved and broad-spectrum antibacterial activity than temporin-1CEc in vitro. Here, the antibacterial and anti-inflammatory activities of 2K4L in macrophages, C. elegans and mice were investigated. The results demonstrated that 2K4L could enter THP-1 cells to kill a multidrug-resistant Acinetobacter baumannii strain (MRAB 0227) and a sensitive A. baumannii strain (AB 22933), as well as reduce proinflammatory responses induced by MRAB 0227 by inhibiting NF-κB signaling pathway. Similarly, 2K4L exhibited strong bactericidal activity against A. baumannii uptake into C. elegans, extending the lifespan and healthspan of the nematodes. Meanwhile, 2K4L alleviated the oxidative stress response by inhibiting the expression of core genes in the p38 MAPK/PMK-1 signaling pathway and downregulating the phosphorylation level of p38, thereby protecting the nematodes from damage by A. baumannii. Finally, in an LPS-induced septic model, 2K4L enhanced the survival of septic mice and decreased the production of proinflammatory cytokines by inhibiting the signaling protein expression of the MAPK and NF-κB signaling pathways and protecting LPS-induced septic mice from a lethal inflammatory response. In conclusion, 2K4L ameliorated LPS-induced inflammation both in vitro and in vivo.

Prostacyclin synthase deficiency exacerbates systemic inflammatory responses in lipopolysaccharide-induced septic shock in mice.

OBJECTIVES: Sepsis is a systemic inflammatory disorder characterized by life-threateningorgan dysfunction resulting from a dysregulated host response to infection. Prostacyclin (PGI2) is a bioactive lipid produced by PGI synthase (PGIS) and is known to play important roles in inflammatory reactions as well as cardiovascular regulation. However, little is known about the roles of PGIS and PGI2 in systemic inflammatory responses such as septic shock. METHODOLOGY: Systemic inflammation was induced by intraperitoneal injection of 5 mg/kg lipopolysaccharide (LPS) in wild type (WT) or PGIS knockout (KO) mice. Selexipag, a selective PGI2 receptor (IP) agonist, was administered 2 h before LPS injection and again given every 12 h for 3 days. RESULTS: Intraperitoneal injection of LPS induced diarrhea, shivering and hypothermia. These symptoms were more severe in PGIS KO mice than in WT micqe. The expression of Tnf and Il6 genes was notably increased in PGIS KO mice. In contrast, over 95% of WT mice survived 72 h after the administration of LPS, whereas all of the PGIS KO mice had succumbed by that time. The mortality rate of LPS-administrated PGIS KO mice was improved by selexipag administration. CONCLUSION: Our study suggests that PGIS-derived PGI2 negatively regulates LPS-induced symptoms via the IP receptor. PGIS-derived PGI2-IP signaling axis may be a new drug target for systemic inflammation in septic shock.

Anti-inflammatory effect of proanthocyanidins from blueberry through NF-κß/NLRP3 signaling pathway in vivo and in vitro.

BACKGROUND: Systemic inflammatory response syndrome (SIRS) is an uncontrolled systemic inflammatory response. Proanthocyanidins (PC) is a general term of polyphenol compounds widely existed in blueberry fruits and can treat inflammation-related diseases. This study aimed to explore the regulatory effect of PC on lipopolysaccharide (LPS)-induced systemic inflammation and its potential mechanism, providing effective strategies for the further development of PC. METHODS: Here, RAW264.7 macrophages were stimulated with LPS to establish an inflammation model in vitro, while endotoxin shock mouse models were constructed by LPS in vivo. The function of PC was investigated by MTT, ELISA kits, H&E staining, immunohistochemistry, and Western blot analysis. RESULTS: Functionally, PC could demonstrate the potential to mitigate mortality in mice with endotoxin shock, as well as attenuated the levels of inflammatory cytokines (IL-6, TNF-α) and biochemical indicators (AST, ALT, CRE and BUN). Moreover, it had a significant protective effect on lung and kidney tissues damage. Mechanistically, PC exerted anti-inflammatory effects by inhibiting the activation of the NF-κB/NLRP3 signaling pathway. CONCLUSION: PC might have the potential ability of anti-inflammatory effects via modulation of the NF-κB/NLRP3 signaling pathway.

Bruton's tyrosine kinase inhibition limits endotoxic shock by suppressing IL-6 production by marginal zone B cells in mice.

Sepsis is a systemic inflammatory response to a severe, life-threatening infection with organ dysfunction. Although there is no effective treatment for this fatal illness, a deeper understanding of the pathophysiological basis of sepsis and its underlying mechanisms could lead to the development of new treatment approaches. Here, we demonstrate that the selective Bruton's tyrosine kinase (Btk) inhibitor acalabrutinib augments survival rates in a lipopolysaccharide (LPS)-induced septic model. Our in vitro and in vivo findings both indicate that acalabrutinib reduces IL-6 production specifically in marginal zone B (MZ B) cells rather than in macrophages. Furthermore, Btk-deficient MZ B cells exhibited suppressed LPS-induced IL-6 production in vitro. Nuclear factor-kappa B (NF-κB) signaling, which is the downstream signaling cascade of Toll-like receptor 4 (TLR4), was also severely attenuated in Btk-deficient MZ B cells. These findings suggest that Btk blockade may prevent sepsis by inhibiting IL-6 production in MZ B cells. In addition, although Btk inhibition may adversely affect B cell maturation and humoral immunity, antibody responses were not impaired when acalabrutinib was administered for a short period after immunization with T-cell-independent (TI) and T-cell-dependent (TD) antigens. In contrast, long-term administration of acalabrutinib slightly impaired humoral immunity. Therefore, these findings suggest that Btk inhibitors may be a potential option for alleviating endotoxic shock without compromising humoral immunity and emphasize the importance of maintaining a delicate balance between immunomodulation and inflammation suppression.

GSNOR negatively regulates the NLRP3 inflammasome via S-nitrosation of MAPK14.

Hyperactivation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous diseases. However, the precise molecular mechanisms that modulate the transcriptional regulation of NLRP3 remain largely unknown. In this study, we demonstrated that S-nitrosoglutathione reductase (GSNOR) deficiency in macrophages leads to significant increases in the Nlrp3 and Il-1ß expression levels and interleukin-1ß (IL-1ß) secretion in response to NLRP3 inflammasome stimulation. Furthermore, in vivo experiments utilizing Gsnor-/- mice revealed increased disease severity in both lipopolysaccharide (LPS)-induced septic shock and dextran sodium sulfate (DSS)-induced colitis models. Additionally, we showed that both LPS-induced septic shock and DSS-induced colitis were ameliorated in Gsnor-/- Nlrp3-/- double-knockout (DKO) mice. Mechanistically, GSNOR deficiency increases the S-nitrosation of mitogen-activated protein kinase 14 (MAPK14) at the Cys211 residue and augments MAPK14 kinase activity, thereby promoting Nlrp3 and Il-1ß transcription and stimulating NLRP3 inflammasome activity. Our findings suggested that GSNOR is a regulator of the NLRP3 inflammasome and that reducing the level of S-nitrosylated MAPK14 may constitute an effective strategy for alleviating diseases associated with NLRP3-mediated inflammation.

Development of a rectally administrable Dnase1 to treat septic shock by targeting NETs.

AIMS: Neutrophil extracellular trap (NET), which is formed by DNA threads, induces septic shock by aggravating systemic inflammation. An intravenous administration of deoxyribonuclease is regarded as a compelling modality for treating septic shock. However, alternative routes should be chosen when cutaneous veins are all collapsed due to hypotension. In this study, we genetically engineered this enzyme to develop a rectal suppository formulation to treat septic shock. MAIN METHODS: Dnase1 was mutated at two amino acid residues to increase its stability in the blood and fused with a cell-penetrating peptide CR8 to increase its absorption through the rectal mucosa, which is designated AR-CR8. The life-saving effect of AR-CR8 was evaluated in a LPS-induced shock mouse model. KEY FINDINGS: AR-CR8 was shown to remove NETs effectively in human neutrophils. When AR-CR8 was administered to the mouse rectum, the deoxyribonuclease activity in the mouse serum was significantly increased. In the LPS-induced shock model, 90 % of the control mice died over 72 h after LPS injection. In contrast, the rectal administration of AR-CR8 showed a mortality rate of 30 % by 72 h after LPS injection. The Log-rank test revealed that the survival rate is significantly higher in the AR-CR8 group. The NET markers in the mouse serum were enhanced by LPS, and significantly downregulated in the AR-CR8 group. These results suggest that AR-CR8 ameliorates LPS-induced shock by degrading NETs. SIGNIFICANCE: The engineered DNASE1 could be developed as a rectal suppository formulation to treat septic shock urgently at out-of-hospital places where no syringe is available.

Sodium-glucose cotransporter-2 inhibitor in risk of sepsis/septic shock among patients with type 2 diabetes mellitus-a retrospective analysis of nationwide medical claims data.

This research is an attempt to investigate the benefit of sodium-glucose cotransporter-2 inhibitor (SGLT2I) use in patients with diabetes mellitus (DM) for outcomes of sepsis/septic shock. We used Taiwan's national data set to identify patients and patients' characteristics to investigate sepsis/septic shock among diabetes patients who use SGLT2I compared to those who do not. We have compared the two groups for several relevant categories of potential risk factors for sepsis/septic shock and adjusted the Cox regression models accordingly. The adapted diabetes complications severity index (DCSI) was used for stratifying the advancing disease of DM. Compared to patients with DCSI = 0, patients with DCSI ≥ 2 had a significantly higher risk of sepsis/septic shock (adjusted HR = 1.52, 95% CI = 1.37-1.68). A significantly lower risk of sepsis/septic shock events was observed in the SGLT2I cohort than in the non-SGLT2I cohort with the DCSI groups [adjusted HR = 0.6 (DCSI group = 0), adjusted HR = 0.61 (DCSI group = 1), adjusted HR = 0.55 (DCSI group ≥ 2)]. Patients who received SGLT2I for a cumulative duration of ≥ 90 days had a significantly lower risk of sepsis/septic shock than patients with a duration of < 90 days (adjusted HR = 0.36, 95% CI = 0.34-0.39). We described a decreased risk of sepsis/septic shock among diabetic patients who took SGLT2I.

Deficiency of long-chain acyl-CoA synthetase 4 leads to lipopolysaccharide-induced mortality in a mouse model of septic shock.

Long-chain acyl-CoA synthetase 4 (ACSL4) converts free highly unsaturated fatty acids (HUFAs) into their acyl-CoA esters and is important for HUFA utilization. HUFA-containing phospholipids produced via ACSL4-dependent reactions are involved in pathophysiological events such as inflammatory responses and ferroptosis as a source for lipid mediators and/or a target of oxidative stress, respectively. However, the in vivo role of ACSL4 in inflammatory responses is not fully understood. This study sought to define the effects of ACSL4 deficiency on lipopolysaccharide (LPS)-induced systemic inflammatory responses using global Acsl4 knockout (Acsl4 KO) mice. Intraperitoneal injection of LPS-induced more severe symptoms, including diarrhea, hypothermia, and higher mortality, in Acsl4 KO mice within 24 h compared with symptoms in wild-type (WT) mice. Intestinal permeability induced 3 h after LPS challenge was also enhanced in Acsl4 KO mice compared with that in WT mice. In addition, plasma levels of some eicosanoids in Acsl4 KO mice 6 h post-LPS injection were 2- to 9-fold higher than those in WT mice. The increased mortality observed in LPS-treated Acsl4 KO mice was significantly improved by treatment with the general cyclooxygenase inhibitor indomethacin with a partial reduction in the severity of illness index for hypothermia, diarrhea score, and intestinal permeability. These results suggest that ACSL4 deficiency enhances susceptibility to endotoxin at least partly through the overproduction of cyclooxygenase-derived eicosanoids.

Ciclopirox mitigates inflammatory response in LPS-induced septic shock via inactivation of SORT1-mediated wnt/ß-Catenin signaling pathway.

OBJECTIVE: Septic shock, the most severe stage of sepsis, is a deadly inflammatory disorder with high mortality. Ciclopirox (CPX) is a broad-spectrum antimycotic agent which also exerts anti-inflammatory effects in human diseases. However, whether CPX can relieve inflammatory response in LPS-induced septic shock remains unclear. MATERIALS AND METHODS: Male C57BL/6 mice LPS were injected intraperitoneally with LPS to simulate septic shock in vivo. RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were subject to LPS treatment to simulate septic shock in vitro. ELISA was applied to detect the level of pro-inflammatory cytokines. Cell viability was assessed by CCK-8 assay. Protein levels was detected by western blotting. RESULTS: CPX enhanced the survival rate and attenuated inflammation in mice with LPS-induced septic shock. Similarly, CPX dose-dependently mitigated LPS-induced inflammation in BMDMs. It was also found that Sortilin 1 (SORT1) was upregulated in both in vivo and in vitro models of LPS-induced septic shock. In addition, SORT1 overexpression counteracted the alleviative effects of CPX on the inflammation response of LPS-challenged BMDMs by activating the Wnt/ß-Catenin signaling. Furthermore, BML-284 (a Wnt/ß-Catenin agonist) treatment also abrogated CPX-mediated moderation of LPS-triggered inflammatory reaction in BMDMs. CONCLUSIONS: In sum, we found that CPX protected against LPS-induced septic shock by mitigating inflammation via SORT1-mediated Wnt/ß-Catenin signaling pathway.

Identification of D359-0396 as a novel inhibitor of the activation of NLRP3 inflammasome.

AIMS: Pyroptosis is a unique pro-inflammatory form of programmed cell death which plays a critical role in promoting the pathogenesis of multiple inflammatory and autoimmune diseases. However, the current drug that is capable of inhibition pyroptosis has not been translated successfully in the clinic, suggesting a requirement for drug screening in depth. METHODS: We screened more than 20,000 small molecules and found D359-0396 demonstrates a potent anti-pyroptosis and anti-inflammation effect in both mouse and human macrophage. In vivo, EAE (a mouse model of MS) and septic shock mouse model was used to investigate the protective effect of D359-0396. In vitro experiments we used LPS plus ATP/nigericin/MSU to induce pyroptosis in both mouse and human macrophage, and finally the anti-pyroptosis function of D359-0396 was assessed. RESULTS: Our findings show that D359-0396 is well-tolerated without remarkable disruption of homeostasis. Mechanistically, while D359-0396 is capable of inhibiting pyroptosis and IL-1ß release in macrophages, this process depends on the NLRP3-Casp1-GSDMD pathway rather than NF-κB, AIM2 or NLRC4 inflammasome signaling. Consistently, D359-0396 significantly suppresses the oligomerization of NLRP3, ASC, and the cleavage of GSDMD. In vivo, D359-0396 not only ameliorates the severity of EAE (a mouse model of MS), but also exhibits a better therapeutic effect than teriflunomide, the first-line drug of MS. Similarly, D359-0396 treatment also significantly protects mice from septic shock. CONCLUSION: Our study identified D359-0396 as a novel small-molecule with potential application in NLRP3-associated diseases.

Bioactive compound C498-0670 alleviates LPS-induced sepsis via JAK/STAT and NFκB signaling pathways.

The JAK/STAT and NFκB signaling pathways are two major inflammatory signaling pathways that are usually activated simultaneously in the body's inflammatory response to bacterial or viral infections. Hyperactivation of these two prominent signaling pathways is associated with various immune-related diseases and mortality, pointing to an urgent need for drug development targeting JAK/STAT and/or NFκB signaling. In this study, we screened 18,840 compounds using our well-established dual STAT-NFκB driven luciferase reporter based high-throughput screening system and identified a bioactive compound C498-0670, which inhibits both JAK/STAT and NFκB signaling. C498-0670 inhibits the activation of STATs and p-IKKα/ß in both the immortalized cell lines and primary peritoneal macrophages, while suppressing the expression of LPS-induced inflammatory mediators in vitro. In addition, the overall anti-inflammatory effects of C498-0670 were investigated using transcriptome sequencing and bioinformatics approaches. C498-0670 was predicted to alleviate sepsis/septic shock by disease/function analysis using IPA software, which was further verified in the LPS-induced mouse sepsis model in vivo. C498 reduced LPS-induced liver and kidney damage, myeloid cell infiltration, and pro-inflammatory cytokine and chemokine production in vivo. Furthermore, the SPR-HPLC-MS-based target fishing approach was used to identify the putative drug targets, and the high affinities of JAK2 (JAK/STAT signaling), NFKBIA (NFκB signaling), and IL-1ß, NLRP1b (inflammasome signaling) for C498-0670 were verified by molecular docking approach. These results suggest that C498-0670 can be used as a dual-target inhibitor of JAK/STAT and NFκB signaling pathways for the treatment of various inflammatory diseases, especially septic shock.

Effect of midodrine on the prognosis of patients with septic shock: a systematic review and meta-analysis.

OBJECTIVE: This study aims to assess the efficacy and safety of midodrine on treating patients with septic shock. MATERIALS AND METHODS: Literature search was conducted in PubMed, the Cochrane Library, and Embase. The Mantel-Haenszel method was used to calculate pooled relative risks (RRs) and 95% confidence intervals (95% CI). The mean differences (MD) or standardized mean difference (SMD) were calculated using the inverse variance for continuous variables. Data analysis was performed using Review Manager 5.3. RESULTS: A total of 6 studies were finally included in this meta-analysis. Adding midodrine to patients with septic shock was associated with a reduction in hospital mortality [risk ratio (RR) 0.76; 95% CI, 0.57-1.00; p=0.05] and intensive care unit (ICU) mortality (RR 0.59; 95% CI, 0.41-0.87; p=0.008). However, there were no significant differences in the duration of intravenous vasopressors [standardized mean difference (SMD) -0.18; 95% CI, -0.47-0.11; p=0.23], intravenous vasopressor reinstitution (RR 0.58; 95% CI, 0.19-1.80; p=0.35), the length of ICU stay [mean difference (MD) -0.53 days; 95% CI, -2.24-1.17; p=0.54], and the length of hospital stay (MD -2.40 days; 95% CI, -5.26-0.46; p=0.10) between midodrine group and intravenous vasopressor alone group. CONCLUSIONS: The additional use of midodrine might reduce hospital mortality and ICU mortality in patients with septic shock. More high-quality randomized controlled trials are needed to verify this conclusion.

The Protective Effects of Goitrin on LPS-Induced Septic Shock in C57BL/6J Mice via Caspase-11 Non-Canonical Inflammasome Inhibition.

Septic shock is defined as a subset of sepsis, which is associated with a considerably high mortality risk. The caspase-11 non-canonical inflammasome is sensed and activated by intracellular lipopolysaccharide (LPS) leading to pyroptosis, it plays a critical role in septic shock. However, there are few known drugs that can control caspase-11 non-canonical inflammasome activation. We report here that goitrin, an alkaloid from Radix Isatidis, shows protective effects in LPS-induced septic shock and significant inhibitory effect in caspase-11 non-canonical inflammasome pathway. Male C57BL/6J were injected intraperitoneally with LPS (20 mg/kg) to induce experimental septic shock. The results demonstrated that the survival rates of mice pretreated with goitrin or Toll-like receptor 4 (TLR4) inhibitor TKA-242 increased, and LPS-induced hypothermia and lung damage improved by inhibiting inflammatory response. Elucidating the detailed mechanism, we surprisingly found goitrin is really different from TAK-242, it independent of the TLR4 signal activation, but significantly inhibited the activation of caspase-11 non-canonical inflammasome, including cleaved caspase-11 and N-terminal fragment of gasdermin D (GSDMD-NT). Furthermore, with a nonlethal dose of the TLR3 agonist poly(I:C)-primed and subsequently challenged with LPS to induce caspase-11-mediated lethal septic shock, the efficacy of goitrin had been verified. Those results revealed the effect of goitrin in protective against LPS-induced septic shock via inhibiting caspase-11 non-canonical inflammasome, which provided a new therapeutic strategy for clinical treatment of septic shock.

Synthesis and evaluation of a new class of MIF-inhibitors in activated macrophage cells and in experimental septic shock in mice.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with enzymatic activities. Anti-inflammatory effects of MIF enzyme inhibitors indicate a link between its cytokine- and catalytic activities. Herein the synthesis, docking, and bioactivity of substituted benzylidene-1-indanone and -1-tetralone derivatives as MIF-tautomerase inhibitors is reported. Many of these substituted benzylidene-1-tetralones and -indan-1-ones were potent MIF-tautomerase inhibitors (IC50 < 10 µmol/L), and the most potent inhibitors were the 1-indanone derivatives 16 and 20. Some of these compounds acted as selective enolase or ketonase inhibitors. In addition, compounds 16, 20, 26, 37 and 61 efficiently inhibited NO, TNFα and IL-6 production in lipopolysaccharide-induced macrophages. Compound 20, 37 and 61 also inhibited ROS generation, and compound 26 and 37 abolished activation of NF-κB. Compound 37 significantly augmented hypothermia induced by high dose of lipopolysaccharide in mice. The possible mechanisms of action were explored using molecular modelling and docking, as well as molecular dynamics simulations.

Manganese potentiates lipopolysaccharide-induced innate immune responses and septic shock.

Divalent metal ions such as magnesium (Mg2+), manganese (Mn2+), and zinc (Zn2+) play important roles in regulating innate immune responses. Lipopolysaccharide stimulation led to increased intracellular Mn and Zn in macrophages. However, the effect of those metal ions in regulating lipopolysaccharide-induced innate immune responses remains unclear. Here, we uncovered that both Mn2+ and Zn2+ have immunostimulatory effects, which could potentiate the lipopolysaccharide-induced expression of interferon-stimulated genes (ISGs), cytokines and pro-inflammatory genes in a dose-dependent manner. Enhancement of lipopolysaccharide-induced innate immune gene expression by Mn2+ varies between 10 % and 900 %. Conversely, the chelating of Mn2+ almost totally diminished Mn2+-enhanced lipopolysaccharide-induced gene expression. In addition, Mn2+ exerted its ability to potentiate LPS-induced innate immune gene expression regardless of slight pH changes. Importantly, we found that Mn2+ potentiates lipopolysaccharide-induced immune responses independent of TLR4 but partially relies on cGAS-STING pathway. Further in vivo study showed that colloidal Mn2+ salt (Mn jelly [MnJ]) pretreatment exacerbated lipopolysaccharide-induced septic shock and mice death. In conclusion, we demonstrated that Mn2+ plays an essential role in boosting lipopolysaccharide-induced innate immune responses. These findings greatly expand the current understanding of the immunomodulatory potential of divalent metal Mn2+ and may provide a potential therapeutic target to prevent excessive immune responses.

High-dose vasoactive agents in aeromedical retrievals for septic shock: A role for vasopressin?

OBJECTIVE: To determine the number of patients retrieved by aeromedical teams for septic shock requiring vasopressor support who meet criteria for vasopressin therapy under the Surviving Sepsis Campaign 2021 guidelines. METHODS: Retrospective chart review of patients transferred by LifeFlight Retrieval Medicine on vasopressors over 2 years. RESULTS: One thousand one hundred and fifty-eight patients were retrieved on vasopressor therapy, with 428 requiring infusions for septic shock. One hundred and fifteen of these met criteria for administration of vasopressin under Surviving Sepsis Campaign guidelines. CONCLUSION: A sufficient percentage of patients on vasopressors for septic shock require vasopressin therapy to meet current best treatment guidelines, and the inclusion of vasopressin in retrieval drug kits should be considered by Australian aeromedical services.

The Use of Hydrocortisone, Ascorbic Acid and Thiamine in Patients with Sepsis and Septic Shock - A Systematic Review.

Background: Sepsis and septic shock are associated with enormous mortality and health care burden. Since the study of Marik et al suggested mortality benefit, there has been great interest in evaluating the role of hydrocortisone, ascorbic acid and thiamine (HAT therapy) in sepsis and septic shock. Purpose: The objective of this article is to review current literature of using HAT therapy in sepsis and septic shock, and discuss the findings in hospital mortality, change in 72 hr SOFA score, other outcomes, and the study limitations. Research Design: Three databases (PubMed, Embase, and Cochrane) were screened using predefined search terms ascorbic acid, vitamin C, thiamine, vitamin B1, hydrocortisone, sepsis, septic shock. Study Sample: Data extracted from eligible studies include authors, publication year, sample size, study design, intervention, outcome measures and study results. Each study was reviewed critically. Results: Among 11 studies included in this literature review, 3 studies reported HAT therapy was associated with mortality benefit, 1 reported hospital mortality was significantly higher in HAT group and the rest of studies didn't reach statistical significance in mortality analysis. Significant improvement of secondary outcomes, although not consistently, were reported. Conclusions: In conclusion, HAT therapy has demonstrated a good safety profile and potential benefits in management of sepsis and septic shock. Further research is required to confirm these findings.

Analysis of Mortality in Patients Treated With Phenylephrine in Septic Shock.

BACKGROUND: Phenylephrine is a selective α1-receptor agonist used to manage shock. Current guidelines for septic shock recommend limited utilization of phenylephrine due to the lack of evidence available. This deviates from previous guidelines, which had recommendations of when utilization may be appropriate. OBJECTIVE: The primary objective of this study was to evaluate mortality in patients receiving phenylephrine for the management of septic shock. METHODS: This was a retrospective chart review from September 2015 to September 2017 evaluating all adult patients admitted to an intensive care unit (ICU) on vasopressors for management of septic shock. Patients were divided into 2 groups, those treated with phenylephrine and those treated without phenylephrine. The primary outcome was mortality. Secondary objectives included days on vasopressors and ICU length of stay. Two subgroup analyses were performed: 1 for phenylephrine as first-line therapy and 1 for patients with tachycardia at initiation of vasopressors. Patients started on phenylephrine for salvage therapy were excluded from this study. RESULTS: 499 patients enrolled in the study. 148 (32%) were enrolled in the phenylephrine group. Phenylephrine was associated with an increase in mortality (56% vs 41%; p = 0.003). There was no difference in the days on vasopressors or ICU length of stay. Patients who had ongoing tachycardia were associated with increased mortality with phenylephrine (54% vs 36%, p = 0.02). There was no difference in mortality when phenylephrine was started as the initial vasopressor. CONCLUSION: Utilization of phenylephrine in septic shock patients, especially those with ongoing tachycardia, was associated with an increased rate of mortality.

Inhibition of Netosis with PAD Inhibitor Attenuates Endotoxin Shock Induced Systemic Inflammation.

Neutrophils play a pivotal role in innate immunity by releasing neutrophils extracellular traps (NETs). Excessive NETs are detrimental to the local tissue and further exacerbate inflammation. Protein arginine deiminases (PAD) mediate histone citrullination and NET formation that, in turn, exacerbate endotoxin shock damages. In this study, we further investigated the molecular mechanism underlying PAD and NETs in endotoxic stress in mice. The control group mice were injected with solvent, the LPS endotoxic shock group mice were intraperitoneally injected with LPS at 35 mg/kg only, while the LPS and PAD inhibitor YW3-56 treatment group mice were injected with YW3-56 at 10 mg/kg prior to the LPS injection. YW3-56 significantly prolonged the survival time of the LPS-treated mice. NETs, cfDNA, and inflammatory factors were detected by ELISA in serum, paitoneal cavity, and lung at 24 h after LPS administration. Lung injuries were detected by immunostaining, and lung tissue transcriptomes were analyzed by RNA-seq at 24 h after LPS administration. We found that YW3-56 altered neutrophil tissue homeostasis, inhibited NET formation, and significantly decreased cytokines (IL-6, TNFα and IL-1ß) levels, cytokines gene expression, and lung tissue injury. In summary, NET formation inhibition offers a new avenue to manage inflammatory damages under endotoxic stress.