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This trial involving critically ill adults with multiorgan failure who were receiving mechanical ventilation showed that early provision of glutamine and antioxidants did not improve clinical outcomes. Furthermore, the use of glutamine appeared to increase mortality. Critically ill patients have oxidative stress. The most seriously ill patients in intensive care units (ICUs) have increased mediators of oxidant stress and a higher incidence of multiorgan failure than less seriously ill patients. 1 – 5 Meta-analyses of randomized trials suggest that glutamine and antioxidant supplementation in critically ill patients may be associated with improved survival. 6 , 7 However, recent large studies have not confirmed such an effect. 8 , 9 The objective of the present trial was to evaluate the effect of early glutamine and antioxidant supplementation in critically ill patients. Our a priori hypothesis was that supplementation with these nutrients would reduce . . .

In a phase 1 trial, six healthy male volunteers received 0.1 mg per kilogram of body weight of a superagonistic anti-CD28 monoclonal antibody. Unexpectedly, all six volunteers had a transient critical illness characterized by multiorgan failure. These events give a view of a specific form of the cytokine-release syndrome in the absence of underlying medical disease. Six volunteers who received the anti-CD28 monoclonal antibody had a transient critical illness characterized by multiorgan failure. These events give a view of a specific form of the cytokine-release syndrome in the absence of underlying medical disease. On March 13, 2006, eight healthy male volunteers participated in a double-blind, randomized, placebo-controlled phase 1 study of the safety of TGN1412 (TeGenero), a novel monoclonal antibody. The study drug is a recombinantly expressed, humanized superagonist anti-CD28 monoclonal antibody of the IgG4κ subclass that stimulates and expands T cells independently of the ligation of the T-cell receptor. 1 In contrast to other antibodies in clinical use or in clinical trials, TGN1412 directly stimulates the immune response in vivo. In preclinical models, the stimulation of CD28 with TGN1412 (or with murine-antibody counterparts) preferentially activated and expanded type 2 helper T cells 2 and, . . .

Abstract Rationale Limited data exist about the international burden of severe sepsis in critically ill children. Objectives To characterize the global prevalence, therapies, and outcomes of severe sepsis in pediatric intensive care units to better inform interventional trials. Methods A point prevalence study was conducted on 5 days throughout 2013–2014 at 128 sites in 26 countries. Patients younger than 18 years of age with severe sepsis as defined by consensus criteria were included. Outcomes were severe sepsis point prevalence, therapies used, new or progressive multiorgan dysfunction, ventilator- and vasoactive-free days at Day 28, functional status, and mortality. Measurements and Main Results Of 6,925 patients screened, 569 had severe sepsis (prevalence, 8.2%; 95% confidence interval, 7.6–8.9%). The patients’ median age was 3.0 (interquartile range [IQR], 0.7–11.0) years. The most frequent sites of infection were respiratory (40%) and bloodstream (19%). Common therapies included mechanical ventilation (74% of patients), vasoactive infusions (55%), and corticosteroids (45%). Hospital mortality was 25% and did not differ by age or between developed and resource-limited countries. Median ventilator-free days were 16 (IQR, 0–25), and vasoactive-free days were 23 (IQR, 12–28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. Among survivors, 17% developed at least moderate disability. Sample sizes needed to detect a 5–10% absolute risk reduction in outcomes within interventional trials are estimated between 165 and 1,437 patients per group. Conclusions Pediatric severe sepsis remains a burdensome public health problem, with prevalence, morbidity, and mortality rates similar to those reported in critically ill adult populations. International clinical trials targeting children with severe sepsis are warranted.

The Sequential Organ Failure Assessment (SOFA) score was developed more than 25 years ago to provide a simple method of assessing and monitoring organ dysfunction in critically ill patients. Changes in clinical practice over the last few decades, with new interventions and a greater focus on non-invasive monitoring systems, mean it is time to update the SOFA score. As a first step in this process, we propose some possible new variables that could be included in a SOFA 2.0. By so doing, we hope to stimulate debate and discussion to move toward a new, properly validated score that will be fit for modern practice.

Background Thrombotic microangiopathy-induced thrombocytopenia-associated multiple organ failure and hyperinflammatory macrophage activation syndrome are important causes of late pediatric sepsis mortality that are often missed or have delayed diagnosis. The National Institutes of General Medical Science sepsis research working group recommendations call for application of new research approaches in extant clinical data sets to improve efficiency of early trials of new sepsis therapies. Our objective is to apply machine learning approaches to derive computable 24-h sepsis phenotypes to facilitate personalized enrollment in early anti-inflammatory trials targeting these conditions. Methods We applied consensus, k -means clustering analysis to our extant PHENOtyping sepsis-induced Multiple organ failure Study (PHENOMS) dataset of 404 children. 24-hour computable phenotypes are derived using 25 available bedside variables including C-reactive protein and ferritin. Results Four computable phenotypes (PedSep-A, B, C, and D) are derived. Compared to all other phenotypes, PedSep-A patients ( n  = 135; 2% mortality) were younger and previously healthy, with the lowest C-reactive protein and ferritin levels, the highest lymphocyte and platelet counts, highest heart rate, and lowest creatinine ( p  < 0.05); PedSep-B patients ( n  = 102; 12% mortality) were most likely to be intubated and had the lowest Glasgow Coma Scale Score ( p  < 0.05); PedSep-C patients ( n  = 110; mortality 10%) had the highest temperature and Glasgow Coma Scale Score, least pulmonary failure, and lowest lymphocyte counts ( p  < 0.05); and PedSep-D patients ( n  = 56, 34% mortality) had the highest creatinine and number of organ failures, including renal, hepatic, and hematologic organ failure, with the lowest platelet counts ( p  < 0.05). PedSep-D had the highest likelihood of developing thrombocytopenia-associated multiple organ failure (Adj OR 47.51 95% CI [18.83–136.83], p  < 0.0001) and macrophage activation syndrome (Adj OR 38.63 95% CI [13.26–137.75], p  < 0.0001). Conclusions Four computable phenotypes are derived, with PedSep-D being optimal for enrollment in early personalized anti-inflammatory trials targeting thrombocytopenia-associated multiple organ failure and macrophage activation syndrome in pediatric sepsis. A computer tool for identification of individual patient membership ( www.pedsepsis.pitt.edu ) is provided. Reproducibility will be assessed at completion of two ongoing pediatric sepsis studies.

ObjectiveIn patients with pancreatitis, early persisting organ failure is believed to be the most important cause of mortality. This study investigates the relation between the timing (onset and duration) of organ failure and mortality and its association with infected pancreatic necrosis in patients with necrotising pancreatitis.DesignWe performed a post hoc analysis of a prospective database of 639 patients with necrotising pancreatitis from 21 hospitals. We evaluated the onset, duration and type of organ failure (ie, respiratory, cardiovascular and renal failure) and its association with mortality and infected pancreatic necrosis.ResultsIn total, 240 of 639 (38%) patients with necrotising pancreatitis developed organ failure. Persistent organ failure (ie, any type or combination) started in the first week in 51% of patients with 42% mortality, in 13% during the second week with 46% mortality and in 36% after the second week with 29% mortality. Mortality in patients with persistent multiple organ failure lasting <1 week, 1–2 weeks, 2–3 weeks or longer than 3 weeks was 43%, 38%, 46% and 52%, respectively (p=0.68). Mortality was higher in patients with organ failure alone than in patients with organ failure and infected pancreatic necrosis (44% vs 29%, p=0.04). However, when excluding patients with very early mortality (within 10 days of admission), patients with organ failure with or without infected pancreatic necrosis had similar mortality rates (28% vs 34%, p=0.33).ConclusionIn patients with necrotising pancreatitis, early persistent organ failure is not associated with increased mortality when compared with persistent organ failure which develops further on during the disease course. Furthermore, no association was found between the duration of organ failure and mortality.

Background Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase I trial was to determine the safety of intravenously infused ascorbic acid in patients with severe sepsis. Methods Twenty-four patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive intravenous infusions every six hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n = 8), or Hi-AscA (200 mg/kg/24 h, n = 8), or Placebo (5% dextrose/water, n = 8). The primary end points were ascorbic acid safety and tolerability, assessed as treatment-related adverse-event frequency and severity. Patients were monitored for worsened arterial hypotension, tachycardia, hypernatremia, and nausea or vomiting. In addition Sequential Organ Failure Assessment (SOFA) scores and plasma levels of ascorbic acid, C-reactive protein, procalcitonin, and thrombomodulin were monitored. Results Mean plasma ascorbic acid levels at entry for the entire cohort were 17.9 ± 2.4 μM (normal range 50-70 μM). Ascorbic acid infusion rapidly and significantly increased plasma ascorbic acid levels. No adverse safety events were observed in ascorbic acid-infused patients. Patients receiving ascorbic acid exhibited prompt reductions in SOFA scores while placebo patients exhibited no such reduction. Ascorbic acid significantly reduced the proinflammatory biomarkers C-reactive protein and procalcitonin. Unlike placebo patients, thrombomodulin in ascorbic acid infused patients exhibited no significant rise, suggesting attenuation of vascular endothelial injury. Conclusions Intravenous ascorbic acid infusion was safe and well tolerated in this study and may positively impact the extent of multiple organ failure and biomarkers of inflammation and endothelial injury. Trial registration ClinicalTrials.gov identifier NCT01434121 .

Background Sepsis remains a common condition with high mortality when multiple organ failure develops. The evidence for therapeutic plasma exchange (TPE) in this setting is promising but inconclusive. Our study aims to evaluate the efficacy of adjunct TPE for septic shock with multiple organ failure compared to standard therapy alone. Methods A retrospective, observational chart review was performed, evaluating outcomes of patients with catecholamine-resistant septic shock and multiple organ failure in intensive care units at a tertiary care hospital in Winston-Salem, NC, from August 2015 to March 2019. Adult patients with catecholamine-resistant septic shock (≥ 2 vasopressors) and evidence of multiple organ failure were included. Patients who received adjunct TPE were identified and compared to patients who received standard care alone. A propensity score using age, gender, chronic co-morbidities (HTN, DM, CKD, COPD), APACHE II score, SOFA score, lactate level, and number of vasopressors was used to match patients, resulting in 40 patients in each arm. Results The mean baseline APACHE II and SOFA scores were 32.5 and 14.3 in TPE patients versus 32.7 and 13.8 in control patients, respectively. The 28-day mortality rate was 40% in the TPE group versus 65% in the standard care group ( p  = 0.043). Improvements in baseline SOFA scores at 48 h were greater in the TPE group compared to standard care alone ( p  = 0.001), and patients receiving adjunct TPE had a more favorable fluid balance at 48 h ( p  = 0.01). Patients receiving adjunct TPE had longer ICU and hospital lengths of stay ( p  = 0.003 and p  = 0.006, respectively). Conclusions Our retrospective, observational study in adult patients with septic shock and multiple organ failure demonstrated improved 28-day survival with adjunct TPE compared to standard care alone. Hemodynamics, organ dysfunction, and fluid balance all improved with adjunct TPE, while lengths of stay were increased in survivors. The study design does not allow for a generalized statement of support for TPE in all cases of sepsis with multiple organ failure but offers valuable information for a prospective, randomized clinical trial.

Background Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5–148.1 pg/ml]. Initial SOFA score was 7 [IQR 5–10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9–2.9]; adjusted HR 1.6 [CI 1.1–2.5]) and between bio-ADM levels and SOFA score ( p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5–9.8). Conclusions AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration ClinicalTrials.gov, NCT02393781 . Registered on March 19, 2015.

Severe trauma induces a widespread response of the immune system. This \"genomic storm\" can lead to poor outcomes, including Multiple Organ Dysfunction Syndrome (MODS). MODS carries a high mortality and morbidity rate and adversely affects long-term health outcomes. Contemporary management of MODS is entirely supportive, and no specific therapeutics have been shown to be effective in reducing incidence or severity. The pathogenesis of MODS remains unclear, and several models are proposed, such as excessive inflammation, a second-hit insult, or an imbalance between pro- and anti-inflammatory pathways. We postulated that the hyperacute window after trauma may hold the key to understanding how the genomic storm is initiated and may lead to a new understanding of the pathogenesis of MODS. We performed whole blood transcriptome and flow cytometry analyses on a total of 70 critically injured patients (Injury Severity Score [ISS] ≥ 25) at The Royal London Hospital in the hyperacute time period within 2 hours of injury. We compared transcriptome findings in 36 critically injured patients with those of 6 patients with minor injuries (ISS ≤ 4). We then performed flow cytometry analyses in 34 critically injured patients and compared findings with those of 9 healthy volunteers. Immediately after injury, only 1,239 gene transcripts (4%) were differentially expressed in critically injured patients. By 24 hours after injury, 6,294 transcripts (21%) were differentially expressed compared to the hyperacute window. Only 202 (16%) genes differentially expressed in the hyperacute window were still expressed in the same direction at 24 hours postinjury. Pathway analysis showed principally up-regulation of pattern recognition and innate inflammatory pathways, with down-regulation of adaptive responses. Immune deconvolution, flow cytometry, and modular analysis suggested a central role for neutrophils and Natural Killer (NK) cells, with underexpression of T- and B cell responses. In the transcriptome cohort, 20 critically injured patients later developed MODS. Compared with the 16 patients who did not develop MODS (NoMODS), maximal differential expression was seen within the hyperacute window. In MODS versus NoMODS, 363 genes were differentially expressed on admission, compared to only 33 at 24 hours postinjury. MODS transcripts differentially expressed in the hyperacute window showed enrichment among diseases and biological functions associated with cell survival and organismal death rather than inflammatory pathways. There was differential up-regulation of NK cell signalling pathways and markers in patients who would later develop MODS, with down-regulation of neutrophil deconvolution markers. This study is limited by its sample size, precluding more detailed analyses of drivers of the hyperacute response and different MODS phenotypes, and requires validation in other critically injured cohorts. In this study, we showed how the hyperacute postinjury time window contained a focused, specific signature of the response to critical injury that led to widespread genomic activation. A transcriptomic signature for later development of MODS was present in this hyperacute window; it showed a strong signal for cell death and survival pathways and implicated NK cells and neutrophil populations in this differential response.