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Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome
Abstract
To determine whether plasma tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and lipopolysaccharide are detectable in patients when they first present with the sepsis syndrome and to determine whether levels correlate with patient survival.
Prospective study comparing patients with the sepsis syndrome, critically ill patients without sepsis, and normal healthy volunteers.
Tertiary care hospital affiliated with a medical school.
The study included 97 consecutive patients on a medical service who met the criteria for the sepsis syndrome; 20 critically ill patients without sepsis who were in the medical intensive care unit; and 20 healthy volunteers who served as comparison groups.
Plasma tumor necrosis factor-alpha, IL-1 beta, interleukin-6, and endotoxin (lipopolysaccharide) levels were measured when a patient was first identified as having the sepsis syndrome. Survival was defined as being alive 30 days after the sepsis syndrome was diagnosed.
Fifty-four percent of patients with the sepsis syndrome had detectable levels of TNF-alpha (median, 26 pg/mL; range, nondetectable to 1000 pg/mL); 37% had detectable levels of IL-1 (median, 20 pg/mL; range, nondetectable to 2850 pg/mL); 80% had detectable levels of IL-6 (median, 415 pg/mL; range, nondetectable to 2380 pg/mL); and 89% had detectable levels of lipopolysaccharide (median, 2.6; range, nondetectable to 12.5 endotoxin units [EU]/mL). In all cases levels were higher than those in critically ill patients without sepsis and normal healthy controls (P < 0.001 for all comparisons). Plasma levels of TNF-alpha, IL-1 beta, IL-6, and lipopolysaccharide were detectable in patients regardless of culture status. The IL-6 level was 69% (95% CI, 30% to 108%) higher in patients who died compared with those who survived. The scores for the individual levels of TNF-alpha, IL-1 beta, IL-6, and lipopolysaccharide were summed to arrive at a total lipopolysaccharide-cytokine score, and mortality increased with lipopolysaccharide-cytokine score (P < 0.001).
Patients with the sepsis syndrome have detectable levels of circulating TNF-alpha, IL-1, IL-6, and lipopolysaccharide independent of culture-documented infection. Lipopolysaccharide and cytokines may play a pathogenic role in sepsis, and the combination of several elevated factors may be important in determining patient survival.
... Significant elevations of plasma IL-1β have been detected in healthy humans injected with lipopolysaccharide (LPS) and in patients with septic shock and burns (Cannon et al., 1992). Correlations have been found between plasma IL-1β levels and severity of acute attacks of rheumatoid arthritis, thermal burns, and mortality in septic shock (Casey et al., 1993). ...
... Agents that reduce the production and activity of IL-1β are likely to have an impact on clinical applications. In fact, IL-1Ra, a blocker of IL-1β transduction, has been administered to patients with septic shock, rheumatoid arthritis, steroid resistant graft-versus-host disease, acute myeloid leukemia, chronic myelogenous leukemia and so on (Casey et al., 1993). ...
... Correlations have been found between plasma IL-1β levels and severity of acute attacks of rheumatoid arthritis (RA), thermal burns, and mortality in septic shock (Casey et al., 1993). ...
Procalcitonin (PCT) is a 116 amino acid peptide with a sequence identical to that of prohormone of calcitonin but devoid of hormonal activity. The aim of this study was to determine Procalcitonin and it using as a new prognostic proinflammatory marker in burn patients & determine the role of procalcitonin level as mortality indicator in survival and non-survival burn patients. The burn patients in this study was divided into four groups according to the percentage of total body surface area (TBSA%) burned carry out on (50) burn patients admitted to burn unit in West Erbil Emergency Hospital (WEEH) in Erbil governorate and (20) apparently healthy non burn individuals who regarded as healthy control group (HC) in this study from February 2012 - April 2012. Out of 50 burnt patients 20 patients were secondly sampled to follow-up their immune profile.
... Several studies have found that the presence of increased plasma concentrations of endotoxin as an initiator of the inflammatory response, or of cytokines as mediators of the response, is not consistent enough to be helpful in the identification of impending sepsis, as will be discussed. Even in patients with severe SIRS, microbiological evidence of infection may be absent, excluding this as a possible predictive tool (Bone et al, 1989;Casey et al, 1993). Since part of the systemic response to trauma and infection involves the production of acute phase proteins by the liver, these proteins have been studied as possible early markers of sepsis. ...
... Evidence of the central role of endotoxin in gram-negative sepsis includes the effects of infusing endotoxin experimentally (Michie et al, 1988;Natanson et al, 1989;Sufifredini et al, 1989a;, the detection of endotoxin in the bloodstream of animals (Wessels et al, 1988, Quezado et al, 1993 and humans (Van Deventer et al, 1998;Brandtzaeg et al, 1989;Danner et al, 1991;Schedel et al, 1991;Wortel et al, 1992;Casey et al, 1993) infected with gram-negative organisms, and the protective effect of anti-endotoxin antibodies {vide infra). Whilst there is little doubt about the clinical and biochemical effects of endotoxin administration, the clinical significance of circulating endotoxin is more controversial (Hofl&nan and . ...
... Whilst there is little doubt about the clinical and biochemical effects of endotoxin administration, the clinical significance of circulating endotoxin is more controversial (Hofl&nan and . For example, not all patients with proven gram-negative bacteraemia have detectable endotoxin in the bloodstream (Danner et al, 1991;Wortel et al, 1992;Casey et al, 1993). In addition, circulating endotoxin may be detected in patients without gram-negative bacterial infections (Danner et al, 1991;Wortel et al, 1992;Casey et al, 1993). ...
The cytokines tumour necrosis factor-α (TNFα), interleukin-1β (IL-1β) and interleukin-6 (IL-6) are considered central to the pathophysiology of sepsis, which is a major cause of morbidity and mortality in the Intensive Care Unit (ICU). Gram- negative endotoxin (lipopolysaccharide) is a potent initiator of cytokine production experimentally, and may play a part in clinical sepsis. Therapies for sepsis under development include antibodies against endotoxin or specific cytokines. One consequence of antibody therapy is formation of immune complexes, which may themselves affect cytokine production. Experiments were performed which suggested modulation of the endotoxin-induced cytokine response in whole blood by presentation of endotoxin within immune complexes containing polyvalent IgG (Sandoglobulin; Sandoz Products Ltd.) or a human monoclonal IgM directed against endotoxin (HA-1A (Centoxin); Centocor). This modulation was related to complement activation, especially for IgG/endotoxin complexes. The cytokine response to IgG immune complexes without endotoxin was also complement-dependant. It was found that HA-1A was recognised by antiserum to mouse IgG, suggesting a further possible mechanism of immune complex formation in patients with heterophile antibodies. Increased IL-6 concentrations occurred in whole blood from certain ICU patients following incubation with HA-1A; this response was associated with increased mortality. Evidence was found for spontaneous production of IL-6 in vitro in blood from certain other patients. The possibility that certain patients might be "primed" for subsequent cytokine production was investigated using flow cytometry. Certain ICU patients exhibited bright staining for cytoplasmic IL-1β in peripheral blood mononuclear cells (PBMCs), but this was unrelated to clinical condition or outcome. These results suggest that immune complexes may be important in sepsis. HA-1A may induce cytokine production in vitro. Certain ICU patients appear to be "primed" for cytokine production. Use of flow cytometry to detect cytoplasmic IL-1β in PBMCs might identify "primed" ICU patients but this is of no clinical value as a predictor of clinical course.
... Heterozygous MORG1 +/− deletion is associated with reduced plasma IL-6 levels in LPS treated mice Since it has already been shown that plasma cytokine levels of IL-6 correlate with survival as well as endotoxin levels in patients with septic syndrome [29], we measured the plasma concentrations of IL-6 and IFNγ. We found that LPS administration sharply elevated the plasma levels of IL-6 (p < 0.05) in MORG1 +/+ mice (Fig. 5a) as previously shown [29]. ...
... Heterozygous MORG1 +/− deletion is associated with reduced plasma IL-6 levels in LPS treated mice Since it has already been shown that plasma cytokine levels of IL-6 correlate with survival as well as endotoxin levels in patients with septic syndrome [29], we measured the plasma concentrations of IL-6 and IFNγ. We found that LPS administration sharply elevated the plasma levels of IL-6 (p < 0.05) in MORG1 +/+ mice (Fig. 5a) as previously shown [29]. However, the IL-6 plasma concentrations in endotoxemic MORG1 +/− mice were significantly (p < 0.05) lower than in MORG1 +/+ mice (Fig. 5a). ...
... Or it is possible that in those conditions PHD3 is regulated via HIF-α independent mechanism. Furthermore, our data confirmed that endotoxemia increased the plasma levels of the pro-inflammatory cytokine IL-6 in plasma and the TNF-α renal expression in wild type MORG1 +/+ mice [29,40] while in contrast IL-6 and TNF-α induction were significantly reduced in MORG1 +/− mice. This finding open the question whether MORG1 heterozygosity could play a role not only in the HIFs pathway, but as well in the NF-κB signalling path, that is activated through LPS/ TLR4 signalling. ...
Background
The MAPK-organizer 1 (MORG1) play a scaffold function in the MAPK and/or the PHD3 signalling paths. Recently, we reported that MORG1+/− mice are protected from renal injury induced by systemic hypoxia and acute renal ischemia-reperfusion injury via increased hypoxia-inducible factors (HIFs). Here, we explore whether MORG1 heterozygosity could attenuate renal injury in a murine model of lipopolysaccharide (LPS) induced endotoxemia. Methods
Endotoxemia was induced in mice by an intraperitoneal (i.p) application of 5 mg/kg BW LPS. The renal damage was estimated by periodic acid Schiff’s staining; renal injury was evaluated by detection of urinary and plasma levels of neutrophil gelatinase-associated lipocalin and albumin/creatinine ratio via ELISAs. Renal mRNA expression was assessed by real-time PCR, whereas the protein expression was determined by immunohistochemistry or Western blotting. ResultsLPS administration increased tubular injury, microalbuminuria, IL-6 plasma levels and renal TNF-α expression in MORG1 +/+ mice. This was accompanied with enhanced infiltration of the inflammatory T-cells in renal tissue and activation of the NF-κB transcription factors. In contrast, endotoxemic MORG1 +/− showed significantly less tubular injury, reduced plasma IL-6 levels, significantly decreased renal TNF-α expression and T-cells infiltration. In support, the renal levels of activated caspase-3 were lower in endotoxemic MORG1 +/− mice compared with endotoxemic MORG1 +/+ mice. Interestingly, LPS application induced a significantly higher accumulation of renal HIF-2α in the kidneys of MORG1+/− mice than in wild-type mice, accompanied with a diminished phosphorylation of IκB-α and IKK α,β and decreased iNOS mRNA in the renal tissues of the LPS-challenged MORG1+/− mice, indicating an inhibition of the NF-κB transcriptional activation. ConclusionsMORG1 heterozygosity protects against histological renal damage and shows anti-inflammatory effects in a murine endotoxemia model through modulation of HIF-2α stabilisation and/or simultaneous inhibition of the NF-κB signalling. Here, we show for the first time that MORG1 scaffold could represent the missing link between innate immunity and inflammation.
... LPS has been shown to cause an oxidative burst in murine neutrophils, but only when used at concentrations several log scales above concentrations observed in patients with severe sepsis and probably not present in the assays. (195,(210)(211)(212) When using LPS at lower concentrations that also occur in gram-negative The use of human anti-meningococcal antibodies would be necessary to control for this. However, it should be considered that human anti-meningococcal antibodies were investigated in the context of phagocytosis and did not show significant effects in the absence of complement. ...
... Under these conditions, PMNs responsiveness to Nme is reduced dramatically due to overactivation by the C5a/C5aR1 axis and other pro-inflammatory mediators such as LPS. (198,211,232) Therefore, supportive therapies in addition to antibiotics that restore neutrophil functions and removal of bacteria from the circulation seem promising to improve outcome of IMD. Blockade of C5a signalling via C5aR1 and C5aR2 has demonstrated mortality reductions in animal models and merits further research to test the application in humans. ...
The gram-negative diplococcus Neisseria meningitidis (Nme) is a frequent human-specific, commensal bacterium of the upper respiratory tract. Under certain conditions especially in infants, meningococci can translocate into the bloodstream and cause invasive meningococcal disease (IMD) manifesting as meningitis or sepsis or a combination of both. IMD is feared for its rapid progression and high fatality rate if it remains untreated. IMD affects up to one million people annually causing substantial morbidity and mortality worldwide. It is well-established that the complement system is an important protective factor in meningococcal disease through opsonization of bacteria with C3b and the lytic activity of the membrane attack complex although the inflammatory C5a/C5aR1 axis can aggravate IMD. The role of neutrophil granulocytes in meningococcal infection is less clear despite their abundant recruitment throughout the course of disease. This study aimed to characterize neutrophil responses to Nme in vitro and the influence of complement on these responses. In infection assays with whole blood and isolated PMNs, effective binding, internalization and killing of Nme by neutrophils was demonstrated. A significant complement-dependence of neutrophil phagocytosis and oxidative burst was observed. The opsonizing and lytic pathway of the complement cascade were found to be most relevant for these responses since blockade of C3 using inhibitor Compstatin Cp20 reduced phagocytosis and oxidative burst significantly more than the blockade of the inflammatory branch with C5aR1-antagonist PMX53. Opsonization with specific antibodies could not replicate the effect of complement activation indicating that engagement of neutrophil complement receptors, particularly complement receptor 3, is involved. Other neutrophil effector functions such as degranulation and IL-8 release were activated in a complement-independent manner implying activation by other inflammatory signals. Considering existing evidence on the overall protective effect of PMNs, further studies investigating the contribution of each neutrophil effector function to infection survival in vivo are required. Ideally, this should be studied in a murine meningitis or sepsis model in the context of complement activation.
... The increasing information in the literature on the pathophysiological role of cytokines in septic shock has increased the efforts to control their synthesis and their action in clinical conditions. TNF plays an important role in the pathogenesis of sepsis and septic shock 19 . Suppression of the biosynthesis of TNF as an adjuvant therapy might therefore be one of the strategies in the management of sepsis 20,21 . ...
... Lauterbach et al 14 found that PTX significantly affects the synthesis of TNF and IL-6, in addition to reducing the mortality rate in premature infants diagnosed with sepsis. In another study, Casey et al. did not find any difference between the groups receiving PTX and not-receiving PTX, in terms of leukocyte count and the levels of serum TNF alpha and IL-6, CRP 19 . We also did not find any statistical difference in neutrophil count or procalcitonin levels at the time of diagnosis and on the 3 rd day of diagnosis between groups. ...
Amaç: Nozokomiyal sepsis, hastane kaynaklı kazanılmış infeksiyonlar arasında en sık olanıdır. Uygun antibiyotik tedavisine rağmen sepsisin mortalitesi ve morbiditesi hala yüksektir. Bu nedenle diğer tedavi yöntemleri hala aranmaktadır. Yenidoğan yoğun bakım ünitesinde yatan prematüre bebeklerde pentoksifilinin neonatal nozokomiyal sepsisin prognozu üzerine etkisini değerlendirmeyi amaçladık.Gereç ve Yöntem: Bu çalışmaya nozokomiyal sepsis tanısı konan 80 yenidoğan dahil edildi. Bunların 40'ı antibiyotiklere ek olarak pentoksifilin tedavisi alırken, diğer 40'ı almadı ve kontrol grubunu oluşturdu. Gebelik yaşı, doğum ağırlığı, 1. ve 5. dakikadaki Apgar skorları, doğum şekli, cinsiyeti, surfaktan tedavisi, ventilatör tedavisi ve erken başlangıçlı sepsis varlığı vaka grubuyla kontrol arasında karşılaştırıldı.Bulgular: Gruplar arasında tanı anında gebelik haftası, cinsiyet, doğum ağırlığı, mortalite, nötrofil sayısı veya prokalsitonin düzeylerine göre istatistiksel bir fark yoktu. Ayrıca, hastanede kalış süresi, bronkopulmonerdisplazi veya nekrotizan enterokolit gelişmesine göre de gruplar arasında istatistiksel bir fark yoktu.Sonuç: Pentoksifilin, preterm nozokomiyal sepsisin mortalitesi ve morbiditesi üzerinde önemli bir etkiye sahip değildir.
... Endotoxins, also referred to as lipopolysaccharides (LPS), have been regarded as the most important pathogenic factor in gram-negative bacterial sepsis [5]. LPS are released from bacteria during cell division, cell death, or antibiotic treatment [6]. ...
... Two hundred microliters of DiD-labeled M-Lipo was injected into six-week-old female BALB/c mice through the tail vein (n = 3). Blood samples were collected into heparin-rinsed tubes at various time points (1,5,15, and 30 min and 1, 4, 8, 12, and 24 h). Plasma was obtained by centrifugation at 4000 rpm for 5 min. ...
... The frequent association of MODS/MOF with sepsis, SIRS, ARDS, and other inflammatory processes suggests that there may be a causal link to the complex pathophysiologic processes that are characteristic of SIRS. [18][19][20][21][22][23] , Recent evidence has suggested that the SIRS response is rapidly followed in most patients by a compensatory anti-inflammatory response limit the SIRS response so that it is not counterproductive 10 . The subsequent balance between the proinflammatory(SIRS) and anti-inflammatory (CARS) response has been referred to as the mixed antagonistic response syndrome or MARS 10 .Typically, this delicate balance is difficult to achieve and there is a predominance of either the inflammatory response or the anti-inflammatory response. ...
... There are a variety of potential mediators for the injury process seen in sepsis and other causes of SIRS 5,17,18,21,[23][24][25][26][27][28][29][30][31] . A number of the potential humoral, cellular, and exogenous mediators are listed below: The humoral mediators include components of the complement system, products of arachidonic acid metabolism (both lipoxygenase and cyclooxygenase metabolites), tumor necrosis factor (TNF), interleukins (IL 1-15), various growth factors, adhesion molecules, platelet activating factor (PAF), nitric oxide, procoagulants, fibronectin and opsonins, toxic oxygen free radicals, endogenous opiods (endorphins), vasoactive polypeptides and amines, bradykinin and other kinins, neuroendocrine factors, myocardial depressant factor, and coagulation factors and their degradation products. ...
Objective: To review multiple organ dysfunction syndrome with respect to: 1) clinical and preclinical measurement systems; 2) Interventions/ Model system used 3) pathophysiology and 4) Various therapeutic implications. Methods: The Medline, Pubmed, Pubmed Central and Science Direct, conference proceedings, bibliographies of review articles were searched for relevant articles. Key index words were multiple organ failure, multiple system organ dysfunctions, sepsis, septic shock, shock, systemic inflammatory response syndrome. Outcomes prospectively defined were death and physiological reversal of end organ failure. Results: Multiple organ dysfunction/failure (MODS) is very colloquial cause for death in intensive care units. With early resuscitation, it was possible to save life otherwise it would have been hard to save one. It occurs due to the unconstrained systemic inflammation and varied etiologies. As of now, there is no therapy which can prevent or improve MODS with dramatic favourable outcomes. Conclusion: Multiple organ dysfunctionmay serve as a useful way to check disease severity for improved quality of care and therapy. Shock patient streated by Anesthesiologists will take into consideration subsequent development of MODS in the critical care unit and may be required to provide anesthetic support to these patients. Keywords: Aberrant Cellular Signalling, Multiple Organ Failure
... Moreover, the transmigrated immune cells aggravate the inflammatory responses by producing more cytokines, thereby creating a continuous cycle between endothelial cells and immune cells (Fig. 1). Excessive cytokine production and immune cell adhesion to the sites of lesion are two important contributors to the development of inflammatory disorders, including atherosclerosis (Ross, 1999) and sepsis (Casey et al., 1993;Paulus et al., 2011). Endogenous cytokines produced by endothelial and/or immune cells enhance the inflammatory response and initiate tissue damage. ...
... The levels of TNFα, interleukin-6 (IL-6) and LPS are regarded as diagnostic markers in inflammatory diseases (Czepiel et al., 2014;Palladino et al., 2003). However, the therapeutic potential of neutralizing antibodies for these cytokines failed to diminish the outcome of inflammatory diseases (Casey et al., 1993;Glauser, 1996;Palladino et al., 2003). Therefore, new efficient drugs to prevent, combat and cure inflammatory diseases are needed. ...
In the gastro-intestinal tract, short chain fatty acids (SCFAs) have protective effects on epithelial cells. However, their effects on inflammatory cytokine production by endothelial and immune cells and the recruitment of immune cells and their trans-migration across the endothelial layer remain controversial. Both cell types are associated with the initiation and development of inflammatory diseases, such as atherosclerosis and sepsis. SCFAs modulate immune and inflammatory responses via activation of free fatty acid (FFA) receptors type 2 and 3 (FFA2 and FFA3 receptors), G protein-coupled receptor 109A (GPR109A) and inhibition of histone deacetylases (HDACs). This review will focus on the effects of SCFAs on lipopolysaccharide (LPS)- or tumor necrosis factor-alpha (TNFα)-induced inflammatory response on endothelial and immune cells function, and an overview is presented on the underlying mechanisms of the effects of SCFAs on both immune and endothelial cells, including HDACs, FFA2 and FFA3 receptors and GPR109A regulation of nuclear factor-kappa B (NF-κB) activation and mitogen-activated protein kinase (MAPK) signaling pathways.
... While Taudorf et al. (2007) administered 0.3 ng kg −1 of endotoxin as a bolus and a continuous infusion, the cytokine concentrations were notably lower than those from a larger dose (Janum et al., 2016;Krabbe et al., 2001) and near or below reported concentrations in septic patients (Berg et al., 2012;Casey et al., 1993;Wu et al., 2009). Torres et al. (2022 suggested that most patients are likely in the immunosuppressive stage of sepsis upon hospital admittance, so we suspect initial inflammation levels could be higher than reported in sepsis studies. ...
Endotoxin administration is commonly used to study the inflammatory response, and though traditionally given as a bolus injection, it can be administered as a continuous infusion over multiple hours. Several studies hypothesize that the latter better represents the prolonged and pronounced inflammation observed in conditions like sepsis. Yet very few experimental studies have administered endotoxin using both strategies, leaving significant gaps in determining the underlying mechanisms responsible for their differing immune responses. We used mathematical modelling to analyse cytokine data from two studies administering a 2 ng kg⁻¹ dose of endotoxin, one as a bolus and the other as a continuous infusion over 4 h. Using our model, we simulated the dynamics of mean and subject‐specific cytokine responses as well as the response to long‐term endotoxin administration. Cytokine measurements revealed that the bolus injection led to significantly higher peaks for interleukin (IL)‐8, while IL‐10 reaches higher peaks during continuous administration. Moreover, the peak timing of all measured cytokines occurred later with continuous infusion. We identified three model parameters that significantly differed between the two administration methods. Monocyte activation of IL‐10 was greater during the continuous infusion, while tumour necrosis factor α$ {\alpha} $ and IL‐8 recovery rates were faster for the bolus injection. This suggests that a continuous infusion elicits a stronger, longer‐lasting systemic reaction through increased stimulation of monocyte anti‐inflammatory mediator production and decreased recovery of pro‐inflammatory catalysts. Furthermore, the continuous infusion model exhibited prolonged inflammation with recurrent peaks resolving within 2 days during long‐term (20–32 h) endotoxin administration.
... It plays an important role in the development of an effective, early inflammatory response. Increased systemic TNF-␣ concentrations, however, have been correlated with mortality rates for septic shock in both adults and children (3,28). TNF-␣ can induce hypotension, tissue injury, and death in animals and is felt to be the major mediator of endotoxin-induced shock (31). ...
Group B streptococci (GBS) are a major cause of severe infection in newborns, pregnant females, and other immunocompromised hosts. Infection often includes septicemia, shock, pneumonia, and respiratory failure. In previous studies, we have reported that GBS induce marked production of tumor necrosis factor alpha (TNF-α) by human mononuclear cells. The present study was designed to measure the production of TNF-α as well as additional cytokines, including interleukin 1β (IL-1β), IL-6, IL-8, IL-12, and gamma interferon (IFN-γ) but also to determine from what cells and at what time point during incubation with GBS that these cytokines are produced. Mixed mononuclear cells were incubated with heat-killed GBS, media alone, or 1 μg of Escherichia coli lipopolysaccharide (LPS). Brefeldin A was added to each sample prior to staining, which prevented the export of cytokines by the Golgi apparatus. The cells were then stained with the appropriate conjugated antibodies and analyzed by using a flow cytometer. Results indicate that intracellular cytokines appear, in almost all cases, simultaneous to or before secreted proteins are detected. In contrast to the response to LPS, where TNF-α, IL-1β, IL-6, and IL-8 appear almost simultaneously, the human monocyte response to GBS results in the production of TNF-α but delayed appearance of IL-1β, IL-6, and IL-8. The lymphocyte response to GBS was also strikingly different from that to LPS in that both secreted IFN-γ and IL-12 was detected, while LPS failed to induce production of these critical cytokines. This suggests an important role for TNF-α, IFN-γ, and IL-12 in GBS pathogenesis and/or immunity.
... the LAL assay detected no difference between the same two samples 16 . In addition, circulating inhibitors of the limulus reaction have been described with published reports showing considerable variability in the prevalence of endotoxemia or its association with Gram-negative infection [17][18][19][20][21] . Therefore, it is strongly recommended to abandon the LAL assay in favor of the more reliable EAA assay. ...
Blood purification as an adjunctive therapy has been studied for several decades. In this review, we will focus on the most recent studies, particularly on adsorption techniques. These include hemofilters with adsorptive membranes, both endotoxin-specific and non-specific. In addition, we will discuss sorbents that target endotoxins, as well as devices that non-selectively capture viruses and bacteria. For each technique, we will also explore the reasons why blood purification methods have thus far failed to improve survival. Conventionally, reasons for the lack of success in blood purification techniques have been attributed to the need for better patient stratification through bedside measurements of interleukins and endotoxins. The choice of assay is also crucial, with endotoxin activity assays being preferable to other forms of limulus amoebocyte lysate assays. Another critical factor is timing, as administering blood purification at the wrong moment can potentially harm the patient. Mechanistic studies are still lacking for most devices, leaving us to treat patients blindly, except in endotoxin cases. In the context of viruses, especially COVID-19, we require a deeper understanding of the complexities involved in viral replication, as this could significantly impact the efficacy of blood purification techniques. The failures highlighted for each device should be viewed as potential areas for improvement. Despite the challenges, we remain hopeful that these techniques will eventually succeed and prove beneficial in the future.
... Only a few studies administer large endotoxin doses (such as 2 ng/kg as used here) as both a bolus and a continuous infusion. While Taudorf et al. (2007) administers 0.3 ng/kg of endotoxin as a bolus and a continuous infusion, the cytokine concentrations are notably lower than those from a larger dose (Krabbe et al., 2001;Janum et al., 2016) and near or below reported concentrations in septic patients (Casey et al., 1993;Wu et al., 2009;Berg et al., 2012). Torres et al. (2022) suggests that most patients are likely in the immunosuppressive stage of sepsis upon hospital admittance, so we suspect initial inflammation levels could be higher than reported in sepsis studies. ...
Endotoxin administration is commonly used to study the inflammatory response, and though traditionally given as a bolus injection, it can be administered as a continuous infusion over multiple hours. Several studies hypothesize that the latter better represents the prolonged and pronounced inflammation observed in conditions like sepsis. Yet, very few experimental studies have administered endotoxin using both strategies, leaving significant gaps in determining the underlying mechanisms responsible for their differing immune responses. We use mathematical modeling to analyze cytokine data from two studies administering a 2 ng/kg dose of endotoxin, one as a bolus and the other as a continuous infusion over four hours. Using our model, we simulate the dynamics of mean and subject-specific cytokine responses as well as the response to long-term endotoxin administration. Cytokine measurements reveal that the bolus injection leads to significantly higher peaks for IL-8, while IL-10 reaches significantly higher peaks during continuous administration. Moreover, the peak timing of all measured cytokines occurs later in the continuous infusion. We identify three model parameters that significantly differ between the two administration methods. Monocyte activation of IL-10 is greater during the continuous infusion, while recovery rates of IL-8 is faster for the bolus injection. This suggests that a continuous infusion elicits a stronger, longer-lasting systemic reaction through increased stimulation of monocyte anti-inflammatory mediator production and decreased recovery of pro-inflammatory catalysts. Furthermore, our continuous infusion model exhibits prolonged inflammation with recurrent peaks resolving within two days during long-term (20-32 hours) endotoxin administration.
... In this study, the increased conductance and FITC-dextran permeation were observed mostly in the jejunum and not in the ileum, suggesting that EHS-induced mucosal injury being confined mostly to the leaky regions of the small intestine such as the jejunum. A large body of evidence implies that circulating markers and indicators of the innate immune response (i.e., cytokines and chemokines) are directly related to increases in gut permeability and subsequently the severity of injury in critical illness (Casey et al., 1993;Clark & Coopersmith, 2007;Yin et al., 2016). Here, we show differences in gut permeability as measured by changes in conductance (Figure 2A,B) and FITC-dextran permeation ( Figure 2C,D) between treatment groups at 30 min recovery without changes in the innate immune response or markers of organ damage, suggesting that widespread systemic inflammation is not specifically derived from the gut following EHS. ...
Increased gut permeability is implicated in the initiation and extent of the cytokine inflammatory response associated with exertional heat stroke (EHS). The primary objective of this study was to determine if a five amino acid oral rehydration solution (5AAS), specifically designed for the protection of the gastrointestinal lining, would prolong time to EHS, maintain gut function and dampen the systemic inflammatory response (SIR) measured during EHS recovery. Male C57/BL6J mice instrumented with radiotelemetry were gavaged with 150 μL of 5AAS or H2 O, and ≈12 h later were either exposed to an EHS protocol where mice exercised in a 37.5°C environmental chamber to a self-limiting maximum core temperature (Tc,max) or performed the exercise control (EXC) protocol (25°C). 5AAS pretreatment attenuated hypothermia depth and length (p < 0.005), which are indicators of EHS severity during recovery, without any effect on physical performance or thermoregulatory responses in the heat as determined by percent body weight lost (≈9%), max speed (≈6 m/min), distance (≈700 m), time to Tc,max (≈160 min), thermal area (≈550°C∙min), and Tc,max (42.2°C). EHS groups treated with 5AAS showed a significant decrease in gut transepithelial conductance, decreased paracellular permeability, increased villus height, increased electrolyte absorption and changes in tight junction protein expression pattern suggestive of improved barrier integrity (p < 0.05). No differences were witnessed between EHS groups in acute phase response markers of liver, circulating SIR markers, or indicators of organ damage during recovery. These results suggest that a 5AAS improves Tc regulation during EHS recovery through maintaining mucosal function and integrity.
... found that inflammatory cytokines, such as IL1b, IL6, and TNF-alpha, can suppress the thyroid function at different levels via direct or indirect pathways, 8,9 and production of pro-inflammatory cytokines is more pronounced in Sepsis than that in other types of critical illness. 10,11 which goes in favor of our findings. ...
Background: Patients suffering from various critical illness admitted to the Intensive Care Unit (ICU) exhibit alterations in their thyroid hormone levels, collectively termed as "EUTHYROID SICK SYNDROME" or "NON THYROIDAL ILLNESS SYNDROME (NTIS). "It is characterized by low serum levels of free and total triiodothyronine (T3) and high levels of reverse T3 (rT3) accompanied by normal or low levels of thyroxine (T4) and thyroid-stimulating hormone (TSH). NTIS is caused because of alterations in the regulation of H-P-T AXIS and thyroid hormone transport and peripheral metabolism which are thought to be influenced by various inflammatory mediators released in critical care patients secondary to the underlying non-thyroidal illness. Our study was undertaken to determine the correlation between these altered thyroid hormone levels and outcomes in critical care patients Materials and Methods: It is a cross-section study done in a tertiary care hospital. A total of 100 patients of age above 18yrs, of both sexes, were admitted to intensive care units with the following diseases, namely Septicemia, AKI, Respiratory failure, CCF, MI, DKA, STROKE with no previous history of thyroid disorder were included in the study. Relevant hematological and radiological examinations were done. Venous samples were obtained at the time of admission and tested for TotalT3,TotalT4 and TSH values. Need for ventilation and mortality were taken as primary outcomes, and we analyzed the ability of thyroid profile to predict the primary outcomes in the participants. Results: Out of a totalof 100 Patients included in the study, 60 patients (60%) had low T3 level, 26 patients (26%) had low T4, and TSH was low in 15 patients (15%). Our study showed low T3 (54%) is the commonest abnormality in ICU admitted patients. Out of 100 patients included in the study, the need for ventilation was seen in 54 (54%) patients, and 26 (26%) patients succumbed to death. There is a significant relation present between T3 and mortality (p value-0.003) and need for ventilation (p value 0.001),between T4 and outcome, namely mortality (p-value 0.01) and need for ventilation (p-value 0.01). A significant correlation was also noted between TSH and outcome (p-value 0.001). Conclusion: we observed low T3 was the commonest finding in critical care patients and the thyroid profile was the strongest predictor of ICU mortality and need for ventilation with a significant p value (<0.05)
... The term "Chronic Critical Illness" (CCI) describes patients with ICU course lasting >7 days, requiring complex medical care, and becoming dependent of one or more life support techniques, causing functional dependence and poor long-term survival (16,17). High levels of IL-6 is one of hallmarks of sepsis and augments the production of reactive oxygen species (ROS), compromising deiodinase function and altering the peripheral T3/T4 activation/inactivation process (18). The use of n-acetylcysteine (NAC), an antioxidant that replenishes glutathione (GSH)/thiols, conteracts the effects of IL-6 on deiodinase mediated T4 to T3 conversion, thereby indicating that IL-6 inhibits the function of deiodinases by increasing cellular ROS, which subsequently reduces the levels of GSH or a GSH-like endogenous cofactor (19). ...
Background: Low T3 syndrome occurs frequently in patients with sepsis. Type 3 deiodinase (Dio3) is present in immune cells but there is no description of its presence in this patients. Here we aimed to determine the prognostic impact of thyroid hormones levels (TH) measured on ICU admission on mortality and on evolution to chronic critical illness (CCI) and the presence of D3 in white cells. Methods: Prospective cohort study with a follow-up for 28 days or deceased. Results: Low T3 levels at admission were present in 86.5% of the patients. Dio3 was 55% induced in immune cells. The cut-off value of 60 pg/mL for T3 displayed a sensitivity and specificity of 81% and 64% for predicting death, odds ratio of 4.89. Lower T3 yielded an area under the receiver operating characteristic curve of 0.76 and 0.75 for mortality and evolution to CCI, respectively, thus displaying better performance than commonly used prognostic scores. Conclusions: We advance in the pathophysiology of low T3 showing induced D3 in immune cells during sepsis. Low T3 levels independently predicted a progression to CCI and mortality within 28 days in sepsis and septic shock.
... 12,13 In sepsis, the increase in the production of pro-inflammatory cytokines is more pronounced than that in other types of critical illness. 14,15 In this respect, baseline levels of thyroid hormones, including T4, T3, and TSH, can be substantially lower in septic patients than in non-septic patients with critical illness of similar severity. 11 The role of the thyroid hormone abnormalities as predictors of outcome of septic patients on top of the known risk prognostic scoring systems warrants also further evaluation. ...
Background: The thyroid gland produces two related hormones, tetraiodothyronine (T4) and triiodothyronine (T3) play a critical role in cell differentiation during development and maintain thermogenic and metabolic homeostasis in the adult. Critically ill patients have been defined as those that by dysfunction or failure of one or more organ system depend on survival from advanced instruments monitoring and therapy. The objective was to study the thyroid dysfunction in critically ill patients admitted in intensive care units and its relation to the mortality and severity of disease.Methods: This is a cross sectional study carried out in Dr. Pinnamaneni Siddhartha institute of medical sciences and research foundation, Chinoutpalli, Andhra Pradesh from 1st January 2022 to 30th September 2022 involving 100 patients. Patients of age above 18 years, both sexes, admitted to intensive care units with critical illness were analyzed and approved by institutional ethics committee of Dr. PSIMS and RF data were entered in MS-excel and analyzed in SPSS V22 software. Descriptive statistics, Mann-Whitney U test, logistic regression, ROC curves were applied. P values were reported for all statistical tests and a value of<0.05 was considered to be significant.Results: Out of 100 critically ill patients out of which 17 patients had sepsis, 18 had acute renal failure, 19 patients had acute respiratory failure, 19 patients had diabetic ketoacidosis, 16 patients had congestive cardiac failure, and 11 patients had stroke and their correlation with t3 hormone decrement showed positive correlation.Conclusions: Thyroid profile can be used in predicting the mortality in ICU patients.
... IL-6, as a multifunctional cytokine, plays an important role in the acute in ammatory responses. Sustained elevation of IL-6 in plasma and BALF in ARDS patients has been shown to be inversely associated with disease outcome and patient survival 22,23 . Christian et al con rms that IL-6 mediates neutrophil in ltration and pulmonary edema 24 . ...
Background
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), are important causes of morbidity and mortality in critically ill patients. Gastric contents aspiration is one of the most common causes of ALI/ARDS. To date, there are still no specific and effective pharmacological treatments for ALI/ARDS. Polyvinylalcohol-carbazate (PVAC), a polymer that has the ability to bind endogenous aldehydes, neutralize oxidative stress and inhibit inflammatory factors, may be a potential treatment for ALI/ARDS.
Methods
A hydrochloric acid (HCl) induced mouse model were employed to assess the effect of PVAC. The changes of lung mechanics, pulmonary edema, histology and immune cells, cytokines, and lipid mediators in bronchioalveolar lavage fluid (BALF) were investigated in HCl-challenged mice.
Results
In the HCl model, PVAC administration alleviated airway hyperresponsiveness and improved pulmonary edema and damage. In addition, it decreased the recruitment of neutrophils to the lung, and inhibited the increase of IL-6, TNF-α and leukotriene B4.
Conclusions
PVAC is a potential treatment for ALI/ARDS caused by inhalation of gastric acid.
... Effector immune cells participate in the progression of SIRS and impair both innate and acquired immune responses to an infection via excessive synthesis and secretion of chemokines and proinflammatory cytokines [36]. Consistent with the fact that the upregulated production and release of cytokines and chemokines contribute to sepsis and organ dysfunction, such as TNF-α, IL-6, and IL-1β, are positively related to multiple organ dysfunction syndrome (MODS) and mortality [37][38][39]. In addition, the stress response induced by major procedures during the perioperative period could also damage the immune system by an excessive pro-inflammatory response [40]. ...
Systemic inflammatory response syndrome (SIRS) is a sepsis-associated inflammatory state and a self-defense mechanism against specific and nonspecific stimuli. Ketamine influences many key processes that are altered during sepsis. However, the underlying mechanisms remain incompletely understood. In this study, TNF-α-treated mice, as well as HT-29 and L929 cell models, were applied to characterize TNF-α-induced systemic and local cecal tissue inflammatory responses. Behavioral, biochemical, histological, and molecular biological approaches were applied to illustrate the related processes. Mice with TNF-α-induced SIRS showed systemic and local cecal tissue inflammatory responses, as indicated by increased levels of high mobility group box 1 protein (HMGB1), chemokines (C-X-C motif) ligand 10 (CXCL10), interleukin-6 (IL-6), and IL-10, as well as high mortality. Ketamine pretreatment alleviated death rates, symptoms, and the production of inflammatory cytokines induced by TNF-α in mice. Moreover, ketamine also protected the mice from TNF-α-induced cecal damage by suppressing the phosphorylation of receptor-interacting serine/threonine-protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL). In addition, our results showed that ketamine efficiently inhibited TNF-α-induced necroptosis in HT-29 and L929 cells. Furthermore, we explored the mechanism using different L929 cell lines. The results displayed that ketamine inhibited TNF-α-induced necroptosis by enhancing RIP1 ubiquitination and reducing the RIP1-RIP3 and RIP3-MLKL interactions, as well as the formation of necrosomes. Thus, our study may provide a new theoretical and experimental basis for treating diseases characterized by SIRS-associated inflammatory factor storms. Moreover, our exploration may provide potential molecular mechanisms and targets for therapeutic intervention and clinical application of ketamine.
... Inflammation has been demonstrated to play an important role on pathological processes such as metabolic [7] and cardiac disorders [8,9], in which the levels of several pro-inflammatory molecules, such as cytokines and Toll-like receptors (TLR's), are increased in either plasma and tissues [10]. Patients with sepsis syndrome present detectable serum levels of lipopolysaccharide (LPS), an agonist of TLR4 [11]. Many investigations have correlated the up-regulation of the TLR4 signaling pathway with cardiac diseases such as: (i) doxorubicin-induced cardiac dysfunction [12]; (ii) myocardial infarction [13]; and (iii) cardiac ischemia/reperfusion injury [14]. ...
Cardiac arrhythmias are one of the main causes of death worldwide. Several studies have shown that inflammation plays a key role in different cardiac diseases and Toll like receptors (TLR’s) play an important role in cardiac complications. In the present study, we investigated whether the activation of TLR4 induces cardiac electrical remodeling and arrhythmias. Also the signaling pathway involved in these phenomena was studied. Action potentials, the presence of cardiac arrhythmias and transient outward K ⁺ current (I to ) were recorded in Wistar rat’s hearts after 24 h exposure to the TLR4 agonist ultrapure Lipopolysaccharide (LPS - 1μg/ml). TLR4 stimulation in vitro promotes a cardiac electrical remodeling that leads to cardiac action potential prolongation which evokes arrhythmic events such as delayed after depolarization (DAD's) and triggered activity. The perfusion of LPS (1μg/ml) during 30 minutes did not modify I to . Conversely, after 24 h of LPS incubation I to was reduced, with no changes in the biophysical properties of the current. Major changes in Ca ²⁺ cycling were not observed in ventricular myocytes after 24 h exposure to LPS; however, extrasystolic activity was present in a considerable number of cells (25%). Neither the blockade of Interleulink-1 receptor-associated kinase 4 nor nuclear factor kappa B (NF-kB) prevented the LPS effect on I to . However, interferon regulatory factor 3 (IRF3) inhibition prevented the effect of TLR4 activation on I to . Activation of TLR4 induced extrasystolic activity, longer AP duration and evoked DAD's and triggered activity because of a reduction in I to . The mechanism involved is MyD88-independent and IRF3-dependent.
... The findings of our study are consistent with those of Endo et al. [68] because TNF-a levels of patients with septic shock were significantly higher than those of patients with sepsis upon admission to the ICU (Table 2). Casey et al. [72] showed that TNF-a, Il-1b, and Il-6 levels in patients with sepsis may have been higher compared to those in non-sepsis ICU patients, but TNF-a levels alone had no predictive value in terms of mortality. In other studies, elevated TNF-a concentrations were associated with a worse prognosis in patients with sepsis [64,73]. ...
Although coagulation disorders and immune/inflammatory response have been associated with the final outcome of patients with sepsis, their link with thetemporaryclinical deterioration or improvement of patients is unknown. We aimed to investigate this link. We prospectively included consecutive patients admitted to the intensive care unit (ICU) with a suspected diagnosis of infection and evaluated within the first 24 h from admission. Blood levels of many cytokines and inflammatory and coagulation factors were measured and their predictive value was assessed by calculating the Area Under the Receiver Operating Characteristic (AUROC) curves. Patients (n = 102) were allocated in five groups, i.e., sepsis (n = 14), severe sepsis (n = 17), septic shock (n = 28), Systemic Inflammatory Response Syndrome (SIRS) without infection (n = 17), and trauma/surgery without SIRS or infection (n = 26). In septic shock, coagulation factors FVII and FIX and Protein C had AUROCs 0.67–0.78. In severe sepsis, Antithrombin III, Protein C, C-reactive protein, Procalcitonin and Thrombopoietin had AUROCs 0.73–0.75. In sepsis, Tumor Necrosis Factor a, and Interleukins 1β and 10 had AUROCs 0.66–0.72. In patients admitted to the ICU with a suspected diagnosis of infection, coagulation factors and inhibitors, as well as cytokine and inflammatory marker levels, have substantial predictive value in distinct groups of septic patients.
... La elevación persistente de TNF-alfa después de 12 horas, en pacientes con falla multiorgánica sugiere una relación entre los niveles de TNF-alfa y la disfunción orgánica, aunque los niveles de TNF-alfa no son considerados por algunos autores un buen predictor de mortalidad. Se reportan niveles más altos de TNF-alfa, IL-1 beta y de IL-6 en el plasma de pacientes sépticos en UCI (9). Aunque ni el TNF-alfa ni la IL-6 son considerados específicos de infección, concentraciones elevadas de ellos han sido encontrados en pacientes con choque séptico al compararlos con choque no séptico (10). ...
... The bacteria themselves and their metabolites can elicit an exorbitant inflammatory response and lead to profound release of inflammatory mediators, such as TNF-α, IL-6, and IL-1β. The overreleased cytokines positively impact the evolvement of sepsis and even result in organ damage and finally lead to death [31]. Our data demonstrated that the concentrations of proinflammatory cytokines were indeed elevated in the CLP+DMSO group compared with those in the sham groups in both serum and hippocampus homogenates. ...
Sepsis may lead to sleep deprivation, which will promote the development of neuroinflammation and mediate the progression of sepsis-associated encephalopathy (SAE). Senkyunolide I, an active component derived from an herb medicine, has been shown to provide a sedative effect to improve sleep. However, its role in sepsis is unclear. The present study was performed to investigate whether Senkyunolide I protected against SAE in a murine model of cecal ligation and puncture (CLP). Here, we showed that Senkyunolide I treatment improved the 7-day survival rate and reduced the excessive release of cytokines including TNF-α, IL-6, and IL-1β. A fear conditioning test was performed, and the results showed that Senkyunolide I attenuated CLP-induced cognitive dysfunction. Senkyunolide I treatment also decreased the phosphorylation levels of inflammatory signaling proteins, including p-ERK, p-JNK, p-P38, and p-P65, and the level of inflammatory cytokines, including TNF-α, IL-6, and IL-1β, in the hippocampus homogenate. Sleep deprivation was attenuated by Senkyunolide I administration, as demonstrated by the modification of the BDNF and c-FOS expression. When sleep deprivation was induced manually, the protective effect of Senkyunolide I against inflammatory responses and cognitive dysfunction was reversed. Our data demonstrated that Senkyunolide I could protect against sepsis-associated encephalopathy in a murine model of sepsis via relieving sleep deprivation.
... 27 ACLF patients have high TNF-α and IL-1β, which is similar to patients with Gram-negative septicemia. 28 The high baseline IL-6 and IL-10 is comparable with the study by Claria et al. 29 A dominant rise in IL-6 was seen in the control group due to a higher incidence of infection. 29,30 Omega-3 FAs led to a decrease in endotoxin levels, prevented exacerbated rise in TNF-α, IL-6, and suppressed IL-1β, whereas omega-6 FAs prevented the rise in endotoxin levels, and TNF-α. ...
Background and aim: Sepsis is an important determinant of the outcome of acute-on-chronic
liver failure (ACLF) patients. Omega-3 fatty acids (FAs) are known to suppress inflammation,
reduce morbidity, and mortality in postoperative and critically ill patients.
We aimed to evaluate the effect of intravenous omega-6 and omega-3 FA lipid emulsions in ACLF patients.
Methods: Ninety ACLF patients were randomly allocated to 3 groups- Gr. A- received no lipid emulsions, Gr. B- omega-6 FAs, and Gr. C- omega-3 FAs. The primary and secondary aims were to compare the effects of lipid emulsions on immune modulation, the incidence of bacterial sepsis, and mortality at day-28.
Results: The baseline characteristics of the patients were comparable. Serum endotoxin levels remained suppressed by 22% in Gr. C compared with a 4% and 12% rise in Gr. B and A (p<0.001). Omega-3 FAs also suppressed C-reactive protein levels and neutrophil-to lymphocyte ratio in Gr. C. Compared with Gr.A, omega-3 FAs reduced sepsis by 86% (HR0.14(95%CI, 0.04-0.43; p<0.001). Omega-3 FAs significantly increased the expression of TLR2 and TLR4 on both CD14+ and CD16+ monocytes, and TLR4, on macrophages and neutrophils. There were no serious adverse events, except transient flushing in 20% and 16.6% of patients receiving omega-6 FAs and omega-3 FAs, respectively.
Conclusion: Omega-3 FAs are safe and effective in reducing systemic inflammation,
endotoxemia, and sepsis in patients with ACLF. These lipid emulsions could also be considered as effective sources of immunonutrition in such sick patients.
... Cytokines are regulators of acute or chronic infection and immune response. The pro-inflammatory cytokine Interleukin 6 (IL6) is a potent mediator of sepsis and is associated with an increased risk of organ dysfunction and mortality in patients with abdominal sepsis [15][16][17][18][19][20]. Furthermore, IL6 was shown to reflect overall cytokine cascade activation [21]. ...
Objectives
Open abdomen technique with negative pressure therapy (NPT) is widely used in patients with severe abdominal sepsis. The aim of this study was to evaluate cytokine clearance in serum and peritoneal fluid during NPT.
Methods
This prospective pilot study included six patients with severe abdominal sepsis requiring discontinuity resection and NPT for 48 h followed by planned reoperation. Cytokines (IL6, IL8, IL10, TNFalpha, and IL1beta) were measured in the serum and peritoneal fluid during index operation, on postoperative days 0, 1, and 2.
Results
Concentrations of cytokines in peritoneal fluid were higher than in serum. IL10 showed a clearance both in serum (to 16.6%, p=0.019) and peritoneal fluid (to 40.9%, p=0.014). IL6 cleared only in serum (to 24.7%, p=0.001) with persistently high levels in peritoneal fluid. IL8 remained high in both serum and peritoneal fluid. TNFalpha and IL1beta were both low in serum with wide range of high peritoneal concentrations. Only TNFalpha in peritoneal fluid showed significant differences between patients with ischemia vs. perforation (p=0.006).
Conclusions
The present pilot study suggests that cytokines display distinct patterns of clearance or persistence in the peritoneal fluid and serum over the first 48 h of treatment in severe abdominal sepsis with NPT.
... The bacteria themselves and their metabolites can elicit an exorbitant in ammatory response and lead to profound release of in ammatory mediators, such as TNF-α, IL-6 and IL-1β. The over-released cytokines positively impact the evolvement of sepsis and even result in organ damage, nally lead to death (28). Our data demonstrated that the concentrations of proin ammatory cytokines were obviously elevated in CLP + DMSO group compared to those in the sham groups in both of serum and hippocampus homogenate. ...
Background: Sepsis may lead to sleep deprivation, which will promote the development of neuroinflammation and mediate the progression of sepsis associated encephalopathy (SAE). Senkyunolide I, an active component derived from an herb medicine, has been shown to provide sedative effect to improve sleep. But its role in sepsis is unclear. The present study was performed to investigate whether Senkyunolide I protected against SAE in a murine model of cecal ligation and puncture (CLP).
Methods: The male C57BL/6 mice were used to investigate the effects of Senkyunolide I on SAE. The related protein of the sleep deprivation and inflammatory signaling pathway was detected by western blot. The activation of microglia and the neuronal apoptosis were separately detected by immunofluorescence staining and TUNEL staining.
Results: Here, we showed that Senkyunolide I treatment improved the 7-day survival rate and reduced the excessive release of cytokines including TNF-α, IL-6 and IL-1β. A fear conditioning test was performed and the result showed that Senkyunolide I attenuated CLP-induced cognitive dysfunction. Senkyunolide I treatment also decreased the phosphorylation levels of inflammatory signaling proteins, including p-ERK, p-JNK, p-P38, p-P65, and the level of inflammatory cytokines, including TNF-α, IL-6 and IL-1β, in the hippocampus homogenate. The sleep deprivation was attenuated by Senkyunolide I administration, as demonstrated by the modification of the BDNF and c-FOS expression. When sleep deprivation was induced manually, the protective effect of Senkyunolide I against inflammatory responses and cognitive dysfunction was reversed.
Conclusion: Our data demonstrated that Senkyunolide I could protect against sepsis-associated encephalopathy in a murine model of sepsis via relieving sleep deprivation.
... Extensive basic science research has been carried out to define inflammatory-mediated pathways in ischemia, and animal as well as clinical studies analyzing the effects of aortic occlusion in aortic aneurism repair have been used to characterize the sequalae in IRI. High levels of TNF-a, IL-6, IL-8, and IL-1b have been found during ischemia elicited by aortic occlusion studies (51)(52)(53)(54). Moreover, IL-10 has been implied as a driving factor in the development of systemic inflammatory response syndrome in severe trauma patients (55), while the cytokines released into the systemic circulation were found to activate resident neutrophils in distant sites leading to inflammatory mediated reactions in distant organ systems (54,56). ...
The emerging concept of endovascular resuscitation applies catheter-based techniques in the management of patients in shock to manipulate physiology, optimize hemodynamics and bridge to definitive care. These interventions hope to address an unmet need in the care of severely injured patients, or those with refractory non-traumatic cardiac arrest, who were previously deemed non-survivable. These evolving techniques include Resuscitative Endovascular Balloon Occlusion of Aorta (REBOA), Selective Aortic Arch Perfusion (SAAP) and Extracorporeal Membrane Oxygenation (ECMO) and there is growing literature base behind them. This review presents the up to date techniques and interventions, along with their application, evidence base and controversy within the new era of resuscitation.
... 9 Additionally, serum level of IL-6 instead of TNF-a, IL-1b and IL-12p40 was significantly decreased ª 2020 John Wiley & Sons Ltd, Immunology in NmU-deficient mice after LPS administration, 9 which was considered as an important factor associated with the reduced mortality rate. 9,106 Although NmU/NmUR1 signalling was demonstrated to promote IL-6 production from macrophages in LPS-induced endotoxaemia, the detailed molecular mechanisms were still undetermined. ...
Since the discovery of Neuromedin U (NmU) from porcine spinal cord in 1985, this neuropeptide has been subsequently identified in many other species with multiple physiological and pathophysiological roles detected, ranging from smooth muscle contraction, feeding, energy balance to tumorigenesis. Intriguingly, NmU is also emerging to play pro-inflammatory roles involving immune cell activation and cytokine release in a neuron-dependent or neuron-independent manner. The NmU-mediated inflammatory responses have already been observed in worm infection, sepsis, autoimmune arthritis and allergic animal models. In this review, we focus on the roles of NmU in immunity and inflammation by highlighting the interactions between NmU and immune cells, summarising the signalling mechanism involved in their reactions, and discussing its potential contributions to inflammatory diseases.
... During pyroptosis, the cells extracellularly release proinflammatory cytokines (interleukin (IL)-1β and IL-18) 7) 8) . IL-1β stimulates both local and systemic inflammatory/immune responses 9) , and acts synergistically with other cytokines to cause tissue injury in sepsis 10) . ...
Antimicrobial peptides (AMPs) represent the first line of host defense against invading microorganisms. Cathelicidin family of AMPs has been identified in various mammalian species, and LL-37 is the only cathelicidin identified in humans. In addition to its antimicrobial and lipopolysaccharide (LPS)-neutralizing activities, LL-37 exhibits diverse biological activities, including regulation of inflammatory responses. Recently, we have evaluated the effect of LL-37 on a murine cecal ligation and puncture (CLP) septic model. The results indicated that LL-37 exhibits multiple protective actions on septic mice; firstly, LL-37 improves the survival of CLP mice by suppressing the macrophage pyroptosis that induces the release of pro-inflammatory cytokines (such as IL-1β) and augments inflammatory reactions in sepsis; secondly, LL-37 induces the release of neutrophil extracellular traps (NETs) with potent bactericidal activity, and protects mice from CLP-induced sepsis; thirdly, LL-37 stimulates neutrophils to release antimicrobial microvesicles (ectosomes), thereby improving murine sepsis. These observations suggest that LL-37 protects CLP septic mice through at least three mechanisms, i.e., the suppression of pro-inflammatory macrophage pyroptosis and the release of antimicrobial NETs (induction of NETosis) and ectosomes from neutrophils. Thus, LL-37 can be a promising therapeutic candidate for sepsis because of its multiple functions, including the modulation of cell death (pyroptosis and NETosis) and release of antimicrobial NETs and ectosomes as well as its own bactericidal and LPS-neutralizing activities.
... Evidence o f elevated IL -1 p has been found in the acute phase o f rheumatoid arthritis, heat-bums, septic shock, and Alzheimer's disease (Li et al. 2008;Casey et al. 1993;Lanzrein et al. 1998). IL -ip production also leads to stimulation o f insulin resistance in the obese (Maedler et al. 2009). ...
INTRODUCTION: This thesis presents a panel of the anti-inflammatory, cytotoxic and antioxidant activities of nine plant species, which have been selected from Thai textbooks, in order to assess the traditional claims about the therapeutic potential and to select plants for further phytochemical research, of active compounds through bioassay-guided fractionation procedures. METHODS: Anti-inflammatory, Nuclear factor-kappa B (NF-κB) inhibitory effects on PMA-induced NF-κB activation in stably tranfected HeLa cells were determined by luciferase assay, and the effects on LPS-induced pro-inflammatory mediators prostaglandin E2 (PGE2), interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)α in primary monocytes were assessed by ELISA. Cytotoxic activities were examined against cervix cancer HeLa cells, human leukaemia CCRF-CEM cells and the multidrug-resistant CEM/ADR5000 cells using the MTT and XTT tests. However, as redox status has been linked with both inflammation and cancer, antioxidant effects were also assessed using the DPPH, lipid-peroxidation, and Folin- Ciocalteau methods. Phytochemical investigation of active compounds from the methanol extract of G. pseudochina var. hispida was carried out using Sephadex LH-20 column chromatography, TLC and HPLC as well as NMR and MS spectroscopic techniques. RESULTS: Among the nine species, the methanol extract of Gynura pseudochina var. hispida and the ethylacetate extract of Oroxylum indicum showed the most promising NF-κB-inhibitory effects with the lowest IC50 values (41.96 and 47.45 μg/ml, respectively). The ethyl acetate and methanol extracts of Muehlenheckia platyclada did not inhibit the NF-κB activation but effectively inhibited the release of IL-6, IL-1β and TNF-α with IC50 values ranging between 0.28 and 8.67 μg/ml. The petroleum ether extract of Pouzolzia indica was the most cytotoxic against CCRF-CEM cells and the multidrug resistant CEM/ADR5000 cells (9.75% and 10.48% viability, at 10 μg/ml, respectively). The ethylacetate extract of Rhinacanthus nasutus showed the most potent cytotoxicity against HeLa cells (IC50 3.63 μg/ml) and the methanol extract of R. nasutus also showed specific cytotoxicity against the multidrug resistant CEM/ADR5000 cells (18.72% viability at 10 μg/ml, p< 0.0001 compared to its cytotoxicity against CCRF-CEM cells). Moreover, the ethylacetate extract of O. indicum showed a high level of antioxidant activity by inhibiting lipid-peroxidation (IC50=0.08 μg/ml). As the most active anti-inflammatory species via the NF-κB signaling pathway, G. pseudochina var. hispida was selected for further investigation of active compounds. Through bioassay guided fractionation and isolation procedures, flavonoid glycosides; quercetin-rutinoside (rutin), dicaffeoylquinic acid derivatives and caffeoylquinic acid were isolated as the active NF-κB inhibitors. CONCLUSIONS: This thesis provides in vitro evidence for the use of the Thai plants, most importantly Gynura pseudochina var. hispida, Oroxyhm indicum and Muehlenheckia platyclada as Thai anti-inflammatory remedies. The active compounds isolated from the methanol extract of G. pseudochina var. hispida: the most potent NF-κB inhibitory extract, were identified as the known compounds quercetin-rutinoside and dicaffeoylquinic acid. Some of the results obtained might support the uses of the plants and are in agreement with previously reported literature, but some are in need of further investigation of either active compounds or their pharmacology. This finding provides a new insight for understanding the anti-inflammatory activities of a panel of traditionally used anti-inflammatory plants. The active compounds isolated from the methanol extract of G. pseudochina var. hispida: the most potent NF-κB inhibitory extract, were identified as the known compounds quercetin-rutinoside, dicaffeoylquinic acid and caffeoylquinic acid derivatives. The active compounds are reported from this genus for the first time.
... Rather than through its direct effect, endotoxin triggers a strong response by stimulating hormonal and chemical mediators. Endotoxemia originating from the intestine is particularly observed in patients with IBD, burns, trauma, liver failure or acute pancreatitis (33). In our study, plasma endotoxin levels were significantly elevated in the rats with induced colitis compared to the control group. ...
Objectives:
In this experimental study, it was aimed to assess the effects of erythropoietin (EPO) on bacterial translocation in a rat model of colitis.
Material and methods:
The rats were randomly assigned into control, colitis and EPO-treated groups (n= 8 in each group). Saline solution (NS) was administered to control rats via rectal route. A trinitrobenzene sulfonic acid and ethanol mixture (TNBS-E) was used to induce colitis in the experiment groups. No treatment was administered to colitis group after induction. Starting at one day after induction of colitis with TNBS-E, EPO (1000 IU/kg) was administered subcutaneously for three days to the rats in the EPO-treated group. Colonic inflammation was assessed by gross and microscopic examination on day five. Blood samples were obtained to evaluate bacterial translocation while hepatic, mesenteric tissue samples and mesenteric lymph node (MLN) samples were collected for tissue culture. Tissue myeloperoxidase (MPO) levels, and tumor necrosis factor alpha (TNF- α) and endotoxin levels in the sera were studied.
Results:
Significant gross and microscopic differences were found in the comparison between colitis and EPO-treated groups (p <0.05). MPO level was significantly lower when compared to the colitis group (p <0.05). Serum TNF-α and plasma endotoxin levels were significantly lower in the EPO-treated group than the colitis group (p <0.05). Bacterial translocation was lower in the liver, spleen, MLNs and systemic blood in the EPO-treated group when compared to the colitis group (p <0.05).
Conclusion:
In TNBS-E-induced rat model of colitis, EPO significantly decreased inflammation and bacterial translocation based on histopathological, biochemical and microbiological parameters.
... Treatment of septic shock remains a major challenge because of the associated high mortality (nearly 40%) and morbidity [1]. In patients with septic shock, endotoxins, which are pathogen-associated molecular patterns, induce inflammatory cytokines such as interleukin-6 (IL-6) in a dose-dependent fashion [2]. An excessive inflammatory response can cause hypotension, shock, organ failure, and death [3]. ...
The aim of this study was to evaluate the effect of prolonged direct hemoperfusion using polymyxin B immobilized fiber cartridges (PMX-DHP) on interleukin-6 (IL-6) concentration in patients with septic shock. A total of 16 patients received a total of 26 sessions of 12-h PMX-DHP (PMX-DHP-12h group) and 7 patients received a total of 11 sessions of 2-h PMX-DHP (PMX-DHP-2h group). We compared serum IL-6 concentrations and other secondary outcomes between the two treatment groups. IL-6 concentrations were measured at 0, 2, 5, 8, and 12 h. The median age was 78 years (interquartile range [IQR] 60–84) in PMX-DHP-12h group and 75 years (IQR 66–81) in PMX-DHP-2h group (P = 0.92). The median acute physiology and chronic health evaluation II score was 23 (IQR 18–31) in the PMX-DHP-12h group and 21 (IQR 17–28) in the PMX-DHP-2h group (P = 0.64). A major source of infection in both groups was the abdomen. The serum IL-6 concentrations in both groups significantly decreased at each time point after 0 h (P < 0.05). However, the decrease in IL-6 concentration did not differ between the groups (P = 0.92). In-hospital mortality was not significantly different in the PMX-DHP-12h group vs. PMX-DHP-2h group (7 patients [44%] vs. 1 patient [14%]; P = 0.35). We could not confirm the additional effect that 12 h of PMX-DHP had on the reduction in serum IL-6 concentrations over that exerted by 2 h of this regimen. UMIN-CTR, UMIN000016654. Registered 3 March 2015
... Что касается ИЛ-8 в сыворотке крови, то обнаружена тенденция к его многократному возрастанию во II группе больных (р>0,05). Имеются сведения о том, что увеличение уровня сывороточного IL-8 связано с неблагоприятным исходом пневмонии у взрослых пациентов, особенно с клиникой сепсиса [29]. ...
... Circulating mononuclear cells from septic patients show reduced caspase-1 activity which is reflected by the diminished ability to secrete IL-1β upon re-stimulation (Munoz et al. 1991a), however this does not apply to IL-18 release (Oberholzer et al. 2000;Giamarellos-Bourboulis et al. 2011). As for the serum levels of those cytokines, most studies reported moderately increased IL-1β (not in all patients) and significantly increased IL-18 concentrations (Cannon et al. 1990;Casey, Balk and Bone 1993;Oberholzer et al. 2001) whereas IL-1α was rarely detected in the plasma of sepsis patients (Munoz et al. 1991a). These observations together with support from animal models led to the clinical trials of the recombinant IL-1Ra in sepsis (Fisher et al. 1994). ...
Despite great efforts and numerous clinical trials, there is still a major need for effective therapies for sepsis. Neutralization or elimination of bacterial toxins remains a promising approach. The understanding of the interaction of the endotoxin (lipopolysaccharide, LPS) of Gram-negative bacteria with its cellular receptor, namely the CD14/TLR4/MD2 complex, was a major breakthrough. Unfortunately, clinical trials for sepsis on the neutralization of LPS or on the inhibition of the TLR4 signaling failed whereas those on LPS removal remain controversial. Recent discoveries of another class of LPS receptors localized within the cytoplasm, namely caspase-11 in mice and caspases-4/5 in human, renew interest in the field. These provide new potential targets for intervention in sepsis pathogenesis. Since cytoplasmic recognition of LPS induces non-canonical inflammasome pathway, a potentially harmful host response, it is conceivable to therapeutically target this mechanism. However, a great deal of care should be used in the translation of research on the non-canonical inflammasome inhibition due to multiple inter-species differences. In this review, we summarize the knowledge on endotoxin sensing in sepsis with special focus on the intracellular sensing. We also highlight the murine versus human differences and discuss potential therapeutic approaches addressing the newly discovered pathways.
... 39 IL-6 is a cytokine released near the onset of infection that correlates well with severity and outcomes in septic patients, where decreasing levels are predictive of survival. 40,41 A recent metaanalysis found the area under receiver operating characteristic curve (AUROC) value for IL-6 to be 0.79, indicating moderate diagnostic sensitivity. 36 CRP is expressed as a response to cytokines like IL-6 (ref. ...
Sepsis is a rapidly progressing, life threatening immune response triggered by infection that affects millions worldwide each year. Current clinical diagnosis relies on broad physiological parameters and time consuming lab-based cell culture. If proper treatment is not provided, cases of sepsis can drastically increase in severity over the course of a few hours. Development of new point of care tools for sepsis has the potential to improve diagnostic speed and accuracy, leading to prompt administration of appropriate therapeutics, thereby reducing healthcare costs and improving patient outcomes. In this review we examine developing and commercially available technologies to assess the feasibility of rapid, accurate sepsis diagnosis, with emphasis on point of care.
... Our results show that the treatment of MaR1 markedly increased the survival rate and alleviated lung and liver injury in CLP-induced septic mice. In addition, our data demonstrate that MaR1 treatment significantly reduced the levels of TNF-α and IL-6 in plasma, which may influence the patients' outcome in critical illness [23]. Korner et al. reported that Omega-3 fatty acids reduced inflammation and improved sepsis survival in mice by stimulating the endogenous production of MaR1 [24]. ...
Maresin1 (MaR1), a new anti-inflammatory and proresolving lipid mediator, has been proven to exert organ-protective effects in septic animal models. However, the potential mechanisms are still not fully elucidated. In this study, we sought to explore the impact of MaR1 on metabolic dysfunction in cecal ligation and puncture- (CLP-) induced septic mice. We found that MaR1 significantly increased the overall survival rate and attenuated lung and liver injuries in septic mice. In addition, MaR1 markedly reduced the levels of proinflammatory cytokines (TNF- α and IL-6) and alleviated mitochondrial damage. Based on a ¹ H NMR-based metabolomics analysis, CLP-induced septic mice had increased levels of acetate, pyruvate, and lactate in serum and decreased levels of alanine, aspartate, glutamate, and fumarate in lungs. However, these metabolic disorders, mainly involving energy and amino acid metabolism, can be recovered by MaR1 treatment. Therefore, our results suggest that the protective effects of MaR1 on sepsis could be related to the recovery of metabolic dysfunction and the alleviation of inflammation and mitochondrial damage.
... Em modelo de sobrevivência de Cox com inclusão de idade e valores sequenciais de SOFA, os níveis de interleucina 3 mensurados na inclusão mantiveram-se independentemente estabelecidos nos anos recentes. (5)(6)(7) Contudo, os ensaios clínicos conduzidos para avaliar a resposta a terapêuticas anti-inflamatórias proporcionaram resultados predominantemente desfavoráveis. (8) Por esta razão, encontram-se atualmente em curso estudos sobre novas fases da cascata inflamatória. ...
Objective:
To evaluate the accuracy of IL-3 to predict the outcome of septic patients.
Methods:
Prospective cohort study with adult patients in an intensive care unit with sepsis or septic shock diagnosed within the previous 48 hours. Circulating IL-3 levels were measured upon inclusion (day 1) and on days 3 and 7. The primary outcome was hospital mortality.
Results:
One hundred and twenty patients were included. Serum levels of IL-3 on day 1 were significantly higher among patients who died than among patients who survived the hospital stay (91.2pg/mL versus 36pg/mL, p = 0.024). In a Cox survival model considering the IL-3 levels at inclusion, age and sequential SOFA, IL-3 values remained independently associated with mortality (HR 1.032; 95%CI 1.010 - 1.055; p = 0.005). An receiver operating characteristic curve was built to further investigate the accuracy of IL-3, with an area under the curve of 0.62 (95%CI 0.51 - 0.73; p = 0.024) for hospital mortality. A cutoff initial IL-3 value above 127.5pg/mL was associated with hospital mortality (OR 2.97; 95%CI: 1.27 - 6.97; p = 0.0019) but with a low performance (82% for specificity, 39% for sensibility, 53% for the positive predictive value, 72% for the negative predictive value, 0.73 for the negative likelihood and 2.16 for the positive likelihood ratio).
Conclusion:
Higher levels of IL-3 are shown to be independently associated with hospital mortality in septic patients but with poor clinical performance.
... Although their specific biological functions may vary, cytokines may be categorized in two general classes, i.e., pro-and 3 of 34 anti-inflammatory [30]. In the host defense against Gram-negative bacterial infections and accompanying endotoxemia, a pivotal role is played by endogenous cytokines such as IL-1β, IL-6, IL-8, TNF-α, and interferon-γ (IFN-γ) [25,[31][32][33][34]. Through complex feedback mechanisms, the excessive production of these mediators triggers immune cells to release anti-inflammatory cytokines (i.e., IL-4, IL-10, IL-13, and transforming growth factor-β (TGF-β)) to combat and down-regulate the pro-inflammatory response and to maintain homeostasis [35][36][37][38][39][40][41][42]. ...
In this study, we evaluated the effects of Cyclosporine A (CsA) on Lipopolysaccharide (LPS)-induced cytokine production in the genital tract of female rabbits. Twelve sexually mature and healthy female rabbits were randomly divided into four groups (n = 3 each). The rabbits in the LPS group were given an intrauterine infusion of Escherichia coli LPS (4 mg/kg body weight (BW)). Rabbits in the CsA group were given CsA (20 mg/kg BW). Rabbits in the LPS + CsA group were given LPS (4 mg/kg BW) and CsA (20 mg/kg BW). The control group received only LPS and CsA carrier. The gene expression and protein levels of pro- and anti-inflammatory cytokines were observed using qRT-PCR and immuno-histochemical (IHC) assay, respectively. Our study showed that IL-1β, IL-6, IL-8, TNF-α, IFN-γ, IL-4, IL-10, IL-13, and TGF-β were expressed in female genital organs. The LPS challenge increased the mRNA expression of IL-6 and TNF-α in the uterine body and IL-1β in the uterotubal junction compared to the control group. CsA increased the basal mRNA expression of anti-inflammatory cytokines (i.e., IL-4 in the uterine body, uterotubal junction, and oviductal ampulla; IL-10 in the cervix, oviductal isthmus, and ampulla; and TGF-β in the uterotubal junction and oviductal ampulla) and pro-inflammatory cytokines (i.e., IL-6 and IL-8 in the cervix; IL-1β in the oviductal isthmus; TNF-α in the oviductal ampulla; and IFN-γ in the uterine body compared to the control group). In addition, CsA inhibited the mRNA expression of pro-inflammatory cytokines, such as IL-6 in the uterine body, uterotubal junction, and oviductal isthmus; TNF-α in the uterine body; and IFN-γ in the uterotubal junction and oviductal isthmus induced by the LPS challenge. The IHC assay showed the LPS-induced increase in protein production of IL-6 in the uterine body and oviductal isthmus. CsA increased the protein production of IL-10 in the cervix, uterine body, oviductal ampulla, and isthmus. Moreover, CsA decreased the protein production of IL-6 in the uterine body and oviductal isthmus induced by LPS.
... In patients with sepsis, systemic inflammation is initiated by an acute release of PAMPS by bacteria and secondary activation of the innate immune system cells. [29][30][31][32] Approximately 40% of patients with ACLF share this pathophysiological mechanism. 1,8,33,34 The second similarity is that patients with ACLF and with severe sepsis develop organ failure(s) and that this correlates closely with prognosis. ...
... Ideen hinter dem Einsatz dieses "Blutwäscheverfahrens" sind die Minderung des Zytokinsturms zu Beginn der septischen Reaktion und die Eindämmung der autodestruktiven Wirkung von "pathogenassociated molecular patterns" (PAMP) und "damage-associated molecular patterns" (DAMP). Von besonderer Bedeutung in diesem Zusammenhang als Surrogatparameter ist Interleukin-6 (IL-6), dessen Plasmaspiegel eng mit der Sterblichkeit in der Sepsis korreliert sind [46]. Im vergangenen Jahr wurde nun eine bereits von 2008 bis 2011 in Deutschland durchgeführte, unverblindete Multizenterstudie publiziert [47]. ...
... 8,9 In sepsis, the increase in the production of pro-inflammatory cytokines is more pronounced than that in other types of critical illness. 10,11 A relationship between serum triiodothyronine (T3) and several markers of inflammation, nutrition and endothelial activation in patients with chronic renal failure (CRF) has been documented. 12, 13 Hu, Yan-Yan et al, showed euthyroid sick syndrome are associated with the severity of DKA. 14 Serum TT3 and TT3/TT4 ratio were lower in severe COPD compared to moderate COPD. ...
Background: Thyroid hormones play a key role in the maintenance of body growth by modulating metabolism and the immune system. These alterations in thyroid hormone levels are referred to as “euthyroid sick syndrome” or “non thyroidal illness syndrome” (NTIS), which is characterized by low serum levels of free and total triiodothyronine (T3) and high levels of reverse T3 (rT3) accompanied by normal or low levels of thyroxine (T4) and thyroid-stimulating hormone (TSH). During critical illness, changes in circulating hormone levels are a common phenomenon. These alterations are correlated with the severity of morbidity and the outcomes of patients in ICU.Methods: This study was carried out at a tertiary care hospital. 100 patients of age above 18yrs, both sexes, admitted to intensive care units with following diseases Septicemia, ARF, Respiratory failure, CCF, DKA, Stroke were taken into the cross-sectional study. Relevant hematological and radiological examination are done. Fasting venous blood samples were collected immediately on admission to ICU from all patients and were subjected for hormone analyses. Samples were tested for total T3, total T4, and TSH. The hormone estimation was done by chemiluminescence assay.Results: Patients (59%) had low T3 level, 41(41%) patients had normal T3, 31 patients (31%) had low T4, 69 patients (69%) had normal T4 level and TSH was low in 11 patients (11%), 76 patients (76%) had normal TSH and 14 patients (14%) slightly high. Our study showed low T3 (59%) is the commonest abnormality in ICU admitted patients. There is a significant relation present between T3 and mortality (p value-0.0001) and need for ventilation (p value 0.004).Conclusions: Our study suggests that low T3 is an important marker of mortality in ICU admitted patients. We suggest that in ICU patients T3 levels should be done and used as a prognostic marker for mortality and need for ventilation.
Background and objectives: Sepsis and septic shock are critical health emergencies with high morbidity and mortality rates, often triggered by infections. The study investigates Polymyxin B-immobilized fiber column hemoperfusion (PMX-HP) as a supplementary therapy, evaluating its efficacy in critically ill patients with sepsis or septic shock, and determining the optimal treatment protocol.
Methods: This study conducted a systematic review across multiple databases, including PubMed, EMBASE, Cochrane Library, Web of Science, and several Chinese databases up to September 21, 2023. We applied strict inclusion and exclusion criteria to filter relevant studies. The evaluation employed a Bayesian random effects model within a network meta-analysis framework, utilizing Stata 17 for statistical analysis.
Results: From a total of 1,669 papers, 35 studies involving 12,844 patients were selected. Assessing the primary outcome of 28-day mortality, all PMX-HP treatments demonstrated a significant reduction in mortality, with a pooled risk ratio (RR) of 1.19 (95% CI: 1.08–1.31). The optimal regimen, based on the surface under the cumulative ranking curve (SUCRA), was PMX-HP for 2 hours twice daily (SUCRA 0.403). Secondary outcomes included changes in the Sequential Organ Failure Assessment (SOFA) score, inotropic score, C-reactive protein (CRP), and ICU-free days. The PMX-HP treatment notably improved SOFA scores in 7 studies (593 patients) with a pooled RR of 2.57 (95% CI: 2.11–3.04). For inotropic support, PMX-HP showed a pooled RR of 16.24 (95% CI: 12.76–19.71). In reducing CRP levels, shorter PMX-HP sessions (2 hours, once or twice daily) significantly reduced CRP, while the 4-hour regimen was preferred when extending treatment duration. Prolonged treatments also increased ICU-free days, with PMX-HP exceeding 4 hours showing the highest efficacy (SUCRA 0.801).
Conclusion: PMX-HP significantly enhances survival among adults with severe infections or sepsis/septic shock. The 2-hour regimen administered twice a day was particularly effective. These findings provide crucial insights for refining PMX-HP treatment strategies, highlighting its potential as a valuable adjunct therapy in managing severe sepsis.
OBJECTIVES
To review, analyze, and synthesize the literature on endothelial dysfunction in critically ill children with multiple organ dysfunction syndrome and to develop a consensus biomarker-based definition and diagnostic criteria.
DATA SOURCES
Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020, using a combination of medical subject heading terms and key words to define concepts of endothelial dysfunction, pediatric critical illness, and outcomes.
STUDY SELECTION
Studies were included if they evaluated critically ill children with endothelial dysfunction, evaluated performance characteristics of assessment/scoring tools to screen for endothelial dysfunction, and assessed outcomes related to mortality, functional status, organ-specific outcomes, or other patient-centered outcomes. Studies of adults or premature infants (≤36 weeks gestational age), animal studies, reviews or commentaries, case series with sample size ≤10, and non-English language studies with the inability to determine eligibility criteria were excluded.
DATA EXTRACTION
Data were abstracted from each eligible study into a standard data extraction form along with risk of bias assessment.
DATA SYNTHESIS
We identified 62 studies involving 84 assessments of endothelial derived biomarkers indirectly linked to endothelial functions including leukocyte recruitment, inflammation, coagulation, and permeability. Nearly all biomarkers studied lacked specificity for vascular segment and organ systems. Quality assessment scores for the collected literature were low.
CONCLUSIONS
The Endothelial Subgroup concludes that there exists no single or combination of biomarkers to diagnose endothelial dysfunction in pediatric multiple organ dysfunction syndrome. Future research should focus on biomarkers more directly linked to endothelial functions and with specificity for vascular segment and organ systems.
CONTEXT
Renal dysfunction is associated with poor outcomes in critically ill children.
OBJECTIVE
To evaluate the current evidence for criteria defining renal dysfunction in critically ill children and association with adverse outcomes. To develop contemporary consensus criteria for renal dysfunction in critically ill children.
DATA SOURCES
PubMed and Embase were searched from January 1992 to January 2020.
STUDY SELECTION
Included studies evaluated critically ill children with renal dysfunction, performance characteristics of assessment tools for renal dysfunction, and outcomes related to mortality, functional status, or organ-specific or other patient-centered outcomes. Studies with adults or premature infants (≤36 weeks' gestational age), animal studies, reviews, case series, and studies not published in English with inability to determine eligibility criteria were excluded.
DATA EXTRACTION
Data were extracted from included studies into a standard data extraction form by task force members.
RESULTS
The systematic review supported the following criteria for renal dysfunction: (1) urine output <0.5 mL/kg per hour for ≥6 hours and serum creatinine increase of 1.5 to 1.9 times baseline or ≥0.3 mg/dL, or (2) urine output <0.5 mL/kg per hour for ≥12 hours, or (3) serum creatinine increase ≥2 times baseline, or (4) estimated glomerular filtration rate <35 mL/minute/1.73 m2, or (5) initiation of renal replacement therapy, or (6) fluid overload ≥20%. Data also support criteria for persistent renal dysfunction and for high risk of renal dysfunction.
LIMITATIONS
All included studies were observational and many were retrospective.
CONCLUSIONS
We present consensus criteria for renal dysfunction in critically ill children.
Hematuria of prostatic origin has multiple etiologies including benign prostatic hyperplasia (BPH), iatrogenic urological trauma, prostate cancer, and radiation therapy. Hematuria secondary to benign prostatic hyperplasia can occur because of the increased vascularity of the primary gland, itself, or because of the vascular re-growth following a transurethral resection of the prostate. Prostatic hematuria usually resolves with conservative measures; however, refractory hematuria of prostatic origin may require hospitalization with treatment with blood transfusions, repeated indwelling urinary catheterization, and continuous bladder irrigation. Prostate artery embolization is an emerging minimally invasive procedural therapy for men with BPH that was originally utilized for the treatment of refractory hematuria of prostatic origin . This article aims to summarize the currently available evidence around prostate artery embolization for the treatment of refractory hematuria of prostatic origin.
L’embolia polmonare è una delle emergenze che capita spesso di dover gestire in Medicina interna. Avendo un ampio spettro di presentazione clinica, da forme asintomatiche o pauci-sintomatiche a forme di elevata gravità fino allo shock, con conseguente ampio spettro di gravità e rischio di mortalità, per la sua gestione è necessario disporre di letti monitorati, più opportunamente di un’area critica, in modo da poter assicurare la corretta assistenza nei suoi diversi gradi di gravità, che possono presentarsi anche in pazienti inizialmente non particolarmente impegnativi.
Critical illness syndromes, including sepsis and the acute respiratory distress syndrome (ARDS), are identified using consensus definitions that are based on broad, clinically available criteria and include patients with heterogeneous biology. This heterogeneity is a barrier to developing and testing effective therapies for these syndromes. Biomarkers identify clinically distinct molecular phenotypes of ARDS and sepsis. These molecular phenotypes are associated with differences in mortality and predict response to several treatments in retrospective analyses of clinical trials. Biomarkers can be used for prognostic and predictive enrichment of clinical trials in critical illness to incorporate precision medicine in critical care.
Although studies with interleukin-1 receptor antagonist (IL-1ra) in animal models have shown that IL-1 contributes to mortality in sepsis, the mechanisms whereby IL-1 mediates lethal effects are not well established. A possible mechanism is that IL-1 enhances the activation and release of other inflammatory mediator systems such as coagulation, fibrinolysis, neutrophils, and secretory-type phospholipase A2 (sPLA2). We investigated this possibility by assessing the effect of intravenously injected recombinant human IL-1 alpha (rhIL-1 alpha) on these plasma parameters in baboons. In addition, we examined the course of these inflammatory parameters in baboons after a challenge with a lethal dose of Escherichia coli and while receiving a 24-hour constant infusion of IL-1ra or placebo. Intravenous administration of IL-1 alpha (10 micrograms/kg) induced the formation of thrombin, as evidenced by the appearance of thrombin-antithrombin III (TAT) complexes into the circulation (peak levels, 188 +/- 92 ng/mL at 2 hours), as well as the activation of fibrinolysis, assessed by circulating plasmin-alpha 2- antiplasmin complexes (PAP complexes; peak levels, 0.4% +/- 0.03% of fully activated plasma at 1 hour), the release of tissue-type plasminogen activator (t-PA; peak levels, 6 +/- 2 ng/mL at 2 hours), and its inhibitor, plasminogen activator inhibitor (PAI; peak levels, 724 +/- 246 ng/mL at 4 hours). Il-1 alpha administration also induced the release of sPLA2 (maximal levels, 336 +/- 185 ng/mL at 8 hours), but not degranulation of neutrophils. In the septic baboons, a significant reduction of the formation of thrombin (peak TAT levels decreased from 582 +/- 78 ng/mL to 219 +/- 106 ng/mL; P < .005), the release of t-PA (peak levels decreased from 37 +/- 11 ng/mL to 17 +/- 2 ng/mL; P < .001), and its inhibitor, PAI (peak levels decreased from 2,639 +/- 974 ng/mL to 1,110 +/- 153 ng/mL; P <.001), was observed in the group receiving IL-1ra compared to that receiving placebo. The release of neutrophilic elastase was also significantly attenuated in IL-1a-treated animals (peak levels, 1,024 +/- 393 and 655 +/- 104 ng/mL in control and treatment groups, respectively; P < .05). The difference between sPLA2 levels in both groups, although higher in the controls (maximal levels, 3,140 +/- 1,435 ng/mL in control v 2,217 +/- 1,375 ng/mL in IL-1ra-treated group), was not significant. Thus, IL-1 contributes to activation of various other mediator systems in severe sepsis in nonhuman primates. We propose that these effects may explain the lethal actions of IL-1 in this sepsis model and suggest a similar role for IL-1 in severe human sepsis.
What we already know about this topic:
Among patients with sepsis or septic shock, a variety of extracorporeal blood purification techniques are availableIndividual existing trials evaluating these options are underpowered to provide clear evidence WHAT THIS PAPER TELLS US THAT IS NEW: Meta-analysis of very low-quality randomized controlled trial evidence demonstrates a potential benefit of hemoperfusion, hemofiltration, or plasmapheresisAdditional high-quality trials demonstrating benefit in modern clinical practice are needed before recommending these therapies BACKGROUND:: Sepsis and septic shock are severe inflammatory conditions related to high morbidity and mortality. We performed a systematic review with meta-analysis of randomized trials to assess whether extracorporeal blood purification reduces mortality in this setting.
Methods:
Electronic databases were searched for pertinent studies up to January 2019. We included randomized controlled trials on the use of hemoperfusion, hemofiltration without a renal replacement purpose, and plasmapheresis as a blood purification technique in comparison to conventional therapy in adult patients with sepsis and septic shock. The primary outcome was mortality at the longest follow-up available. We calculated relative risks and 95% CIs. The grading of recommendations assessment, development and evaluation methodology for the certainty of evidence was used.
Results:
Thirty-seven trials with 2,499 patients were included in the meta-analysis. Hemoperfusion was associated with lower mortality compared to conventional therapy (relative risk = 0.88 [95% CI, 0.78 to 0.98], P = 0.02, very low certainty evidence). Low risk of bias trials on polymyxin B immobilized filter hemoperfusion showed no mortality difference versus control (relative risk = 1.14 [95% CI, 0.96 to 1.36], P = 0.12, moderate certainty evidence), while recent trials found an increased mortality (relative risk = 1.22 [95% CI, 1.03 to 1.45], P = 0.02, low certainty evidence); trials performed in the United States and Europe had no significant difference in mortality (relative risk = 1.13 [95% CI, 0.96 to 1.34], P = 0.15), while trials performed in Asia had a positive treatment effect (relative risk = 0.57 [95% CI, 0.47 to 0.69], P < 0.001). Hemofiltration (relative risk = 0.79 [95% CI, 0.63 to 1.00], P = 0.05, very low certainty evidence) and plasmapheresis (relative risk = 0.63 [95% CI, 0.42 to 0.96], P = 0.03, very low certainty evidence) were associated with a lower mortality.
Conclusions:
Very low-quality randomized evidence demonstrates that the use of hemoperfusion, hemofiltration, or plasmapheresis may reduce mortality in sepsis or septic shock. Existing evidence of moderate quality and certainty does not provide any support for a difference in mortality using polymyxin B hemoperfusion. Further high-quality randomized trials are needed before systematic implementation of these therapies in clinical practice.
Sepsis represents a major health problem worldwide because of high mortality rates and cost‐intensive therapy. Immunomodulatory strategies as a means of controlling overshooting inflammatory responses during sepsis have thus far not been effective, and there is a general paucity of new therapies. Regulatory immune cells have been shown to play important roles in limiting systemic inflammation. However, the signals inducing a regulatory phenotype in myeloid cells during infection are unknown. Here, we report that myeloid cell–intrinsic glycoprotein 130 (gp130) signals constitute a critical element for immune homeostasis during polymicrobial sepsis. We identify an essential role for gp130 signaling in myeloid cells during M2 macrophage polarization in vitro and in vivo. Myeloid cell–specific deletion of gp130 signaling leads to a defective M2 macrophage polarization followed by exacerbated inflammatory responses and increased mortality during sepsis. These data provide new insights into the molecular basis of M1 and M2 phenotypic dichotomy and identify gp130 as a key regulator of immune homeostasis during sepsis. Our study highlights the Janus‐faced role of IL‐6 family cytokines during inflammation, which may explain the failure of IL‐6–targeted anti‐inflammatory approaches in the treatment of sepsis.—Sackett, S. D., Otto, T., Mohs, A., Sander, L. E., Strauch, S., Streetz, K. L., Kroy, D. C., Trautwein, C. Myeloid cells require gp130 signaling for protective antiinflammatory functions during sepsis. FASEB J. 33, 6035–6044 (2019). www.fasebj.org
Single, preexposure, parenteral injection with both recombinant tumor necrosis factor/cachectin (TNF/C) and interleukin-1 (IL-1) prolonged the survival of rats (144 +/- 9 h) in continuous hyperoxia (greater than 99% O2 at 1 atm) when compared with rats injected with boiled TNF/C and boiled IL-1 (61 +/- 2 h), TNF/C alone (61 +/- 2 h), IL-1 alone (62 +/- 2 h), or saline (64 +/- 3 h). After exposure to hyperoxia for 52 h, pleural effusion volume, pulmonary artery pressure, total pulmonary resistance, and lung morphologic damage were decreased in those rats given TNF/C and IL-1 as compared with saline-injected rats. In parallel, ratios of reduced (GSH) to oxidized (GSSG) glutathione were greater (P less than 0.05) in lungs of TNF/C + IL-1-injected rats (91 +/- 20) than of saline-injected rats (30 +/- 4) that had been exposed to hyperoxia for 52 h. No differences were found in superoxide dismutase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase, or catalase activities in lungs of TNF/C + IL-1- or saline-treated, hyperoxia-exposed rats. Our results indicate that pretreatment with TNF/C and IL-1 favorably altered lung glutathione redox status, decreased lung injury, and enhanced survival of rats exposed to hyperoxia.