Nonseptic Critical Illness Research Articles

Elevated Midkine Serum Levels Are Associated with Long-Term Survival in Critically Ill Patients.

Midkine (Mdk) is a multifunctional protein involved in inflammatory processes. Hence, circulating Mdk is increased in sepsis and has been previously suggested as a potential biomarker in these patients. The aim of this study was to elucidate the role of Mdk serum concentrations in critical illness and sepsis and to verify its value as a prognostic biomarker. Thus, we analyzed the Mdk serum concentrations of 192 critically ill patients on admission to the medical intensive care unit (ICU). While the serum levels of Mdk at admission were similar in septic and nonseptic critical illness (362 vs. 337 ng/L, p = 0.727), we found several interesting correlations of Mdk to laboratory and clinical markers associated with ischemia or hypoxia, e.g., to renal failure and hepatic injury. Mdk serum concentrations at admission did not differ between various causes of sepsis or other critical illness. Most noticeable, we observed upregulated Mdk serum concentrations at admission in patients surviving in the long-term, which was only seen in nonseptic critical illness but not in sepsis. Our study suggests a relevant role of Mdk in critically ill patients in general and highlights the possible protective features of Mdk in critical illness.

Circulating extracellular vesicles are associated with the clinical outcomes of sepsis.

Sepsis is associated with endothelial cell (EC) dysfunction, increased vascular permeability and organ injury, which may lead to mortality, acute respiratory distress syndrome (ARDS) and acute renal failure (ARF). There are no reliable biomarkers to predict these sepsis complications at present. Recent evidence suggests that circulating extracellular vesicles (EVs) and their content caspase-1 and miR-126 may play a critical role in modulating vascular injury in sepsis; however, the association between circulating EVs and sepsis outcomes remains largely unknown. We obtained plasma samples from septic patients (n=96) within 24 hours of hospital admission and from healthy controls (n=45). Total, monocyte- or EC-derived EVs were isolated from the plasma samples. Transendothelial electrical resistance (TEER) was used as an indicator of EC dysfunction. Caspase-1 activity in EVs was detected and their association with sepsis outcomes including mortality, ARDS and ARF was analyzed. In another set of experiments, total EVs were isolated from plasma samples of 12 septic patients and 12 non-septic critical illness controls on days 1, and 3 after hospital admission. RNAs were isolated from these EVs and Next-generation sequencing was performed. The association between miR-126 levels and sepsis outcomes such as mortality, ARDS and ARF was analyzed. Septic patients with circulating EVs that induced EC injury (lower transendothelial electrical resistance) were more likely to experience ARDS (p<0.05). Higher caspase-1 activity in total EVs, monocyte- or EC-derived EVs was significantly associated with the development of ARDS (p<0.05). MiR-126-3p levels in EC EVs were significantly decreased in ARDS patients compared with healthy controls (p<0.05). Moreover, a decline in miR-126-5p levels from day 1 to day 3 was associated with increased mortality, ARDS and ARF; while decline in miR-126-3p levels from day 1 to day 3 was associated with ARDS development. Enhanced caspase-1 activity and declining miR-126 levels in circulating EVs are associated with sepsis-related organ failure and mortality. Extracellular vesicular contents may serve as novel prognostic biomarkers and/or targets for future therapeutic approaches in sepsis.

Integrated machine learning approaches for flow cytometric quantification of myeloid-derived suppressor cells in acute sepsis.

Highly heterogeneous cell populations require multiple flow cytometric markers for appropriate phenotypic characterization. This exponentially increases the complexity of 2D scatter plot analyses and exacerbates human errors due to variations in manual gating of flow data. We describe a semi-automated workflow, based entirely on the Flowjo Graphical User Interface (GUI), that involves the stepwise integration of several, newly available machine learning tools for the analysis of myeloid-derived suppressor cells (MDSCs) in septic and non-septic critical illness. Supervised clustering of flow cytometric data showed correlation with, but significantly different numbers of, MDSCs as compared with the cell numbers obtained by manual gating. Neither quantification method predicted 30-day clinical outcomes in a cohort of 16 critically ill and septic patients and 5 critically ill and non-septic patients. Machine learning identified a significant decrease in the proportion of PMN-MDSC in critically ill and septic patients as compared with healthy controls. There was no difference between the proportion of these MDSCs in septic and non-septic critical illness.

When a calorie isn't just a calorie: a revised look at nutrition in critically ill patients with sepsis and acute kidney injury.

To discuss how nutritional management could be optimized to promote protective metabolism in sepsis and associated acute kidney injury. Recent evidence suggests that sepsis is a metabolically distinct critical illness and that certain metabolic alterations, such as activation of fasting metabolism, may be protective in bacterial sepsis. These findings may explain the lack of survival benefit in recent randomized controlled trials of nutrition therapy for critical illness. These trials are limited by cohort heterogeneity, combining both septic and nonseptic critical illness, and the use of inaccurate caloric estimates to determine energy requirements. These energy estimates are also unable to provide information on specific substrate preferences or the capacity for substrate utilization. As a result, high protein feeding beyond the capacity for protein synthesis could cause harm in septic patients. Excess glucose and insulin exposures suppress fatty acid oxidation, ketogenesis and autophagy, of which emerging evidence suggest are protective against sepsis associated organ damage such as acute kidney injury. Distinguishing pathogenic and protective sepsis-related metabolic changes are critical to enhancing and individualizing nutrition management for critically ill patients.

Elevated Interleukin-6 Levels within 72 Hours Post Admission Are Associated with Disease Progression in Nonseptic Critically Ill Children.

It has been established that the innate and adaptive immune suppression was heterogeneous in septic and nonseptic critically ill patients, while the value of immune function in pediatric patients with nonseptic critical illness is limited. We conducted a single-center retrospective study to explore this issue. A total of 65 children with nonseptic illnesses were studied for lymphocyte subpopulations, immunoglobulin concentrations, complement concentrations, and cytokines in peripheral blood in the next 72 hours after admission to our Pediatric Intensive Care Unit (PICU). When compared to clinically recovered patients, patients with disease progression had a numerically lower but not significantly different median pediatric critical illness score and longer PICU median stays. The analysis of serum immunoglobulin (IgG, IgM, and IgA), serum complement (C3, C4) concentrations, and lymphocyte subpopulations showed no significantly difference between patients with and without relieved clinical symptoms by day 4. For the cytokine analysis, the level of IL-6 was significantly higher in patients with disease progression than that in patients who clinically recovered (p = 0.046). In the univariate Cox regression analysis, plasma IL-6 levels were associated with outcome. Multivariate analysis evidenced that the level of plasma IL-6 was one of the factors determining the length of hospital stays. In conclusions, our results demonstrate that increased IL-6 levels in the initial 72 hours post admission are associated with prolonged stays and disease progression in nonseptic critically ill children in the PICU.

Total and high-affinity corticosteroid-binding globulin depletion in septic shock is associated with mortality.

Corticosteroid-binding globulin (CBG) and albumin transport circulating cortisol. Cleavage of high-affinity CBG (haCBG) by neutrophil elastase at inflammatory sites causes cortisol release into tissues, facilitating immunomodulatory effects. To determine whether depletion of haCBG is related to mortality in septic shock. A single-center prospective observational cohort study of patients recruited with critical illness or septic shock, using serum samples collected at 0, 8, 24, 48 and 72hours. Serum total and haCBG, and total and free cortisol were assayed directly. Glucocorticoid treatment was an exclusion criterion. Mortality was assessed at 28days from Intensive Care Unit admission. Thirty septic shock (SS) and 42 nonseptic critical illness (CI) patients provided 195 serum samples. SS/CI patients had lower total CBG, haCBG and low-affinity CBG (laCBG) than controls. Total CBG and haCBG were significantly lower in septic shock patients who died than in those that survived (P<0.009, P=0.021, respectively). Total and free cortisol were higher in septic than nonseptic individuals. Free/total cortisol fractions were higher in those with low haCBG as observed in septic shock. However, cortisol levels were not associated with mortality. Albumin levels fell in sepsis but were not related to mortality. Low circulating haCBG concentrations are associated with mortality in septic shock. These results are consistent with an important physiological role for haCBG in cortisol tissue delivery in septic shock.

Long-term (10-year) mortality of younger previously healthy patients with severe sepsis/septic shock is worse than that of patients with nonseptic critical illness and of the general population.

Long-term (1- to 10-year) outcomes after severe sepsis in previously healthy persons are unknown. We aimed to determine the 1- to 10-year mortality rates of previously healthy patients with severe sepsis and compare these to mortality rates of patients with nonseptic critical illness and the general population. A prospective cohort study of 2,289 patients from one mixed medical-surgical ICU and one cardiovascular surgery ICU. Age- and gender-comparable general British Columbia population was used as comparison. Patients were followed from the date of admission to the ICU to January 31, 2013. Provincial vital statistics were used to determine the patients' date of death. For the general population comparison, expected survival was obtained from life tables of the population of British Columbia, Canada. A quaternary-level provincial referral hospital in Vancouver, British Columbia, Canada. Two thousand two hundred eighty-nine patients from one mixed medical-surgical ICU and one cardiovascular surgery ICU. Age- and gender-comparable general British Columbia population was used for comparison. None. Patients with severe sepsis without comorbidities had higher mortality from 1 to 10 years than general British Columbia population (p < 0.01). Younger patients with severe sepsis (< 60 yr) had the worst 1- to 5-year and 5- to 10-year mortality (hazard ratio [95% CI], 17.8 [13.4-24.8] and 6.0 [4-9]) compared with the general population. Patients with severe sepsis had significantly poorer 1- to 10-year mortality rates (30.5%) compared with patients with nonseptic critical illness (22.1%) and patients who have undergone cardiovascular surgery (15.9%). Patients with sepsis had higher mortality rates from 1-5 years and 5-10 years than the general British Columbia population (hazard ratio [95% CI], 4.5 [2.2-9.1] and 2.2 [0.9-14.7]). Previously healthy patients suffering an episode of severe sepsis have increased long-term mortality compared with patients with nonseptic critical illness and a general population.

Steroidogenesis in the adrenal dysfunction of critical illness: impact of etomidate

IntroductionThis study was aimed at characterizing basal and adrenocorticotropic hormone (ACTH)-induced steroidogenesis in sepsis and nonsepsis patients with a suspicion of critical illness-related corticosteroid insufficiency (CIRCI), taking the use of etomidate-inhibiting 11β-hydroxylase into account.MethodThis was a prospective study in a mixed surgical/medical intensive care unit (ICU) of a university hospital. The patients were 62 critically ill patients with a clinical suspicion of CIRCI. The patients underwent a 250-μg ACTH test (n = 67). ACTH, adrenal steroids, substrates, and precursors (modified tandem mass spectrometry) also were measured. Clinical characteristics including use of etomidate to facilitate intubation (n = 14 within 72 hours of ACTH testing) were recorded.ResultsAt the time of ACTH testing, patients had septic (n = 43) or nonseptic critical illness (n = 24). Baseline cortisol directly related to sepsis and endogenous ACTH, independent of etomidate use. Etomidate was associated with a lower baseline cortisol and cortisol/11β-deoxycortisol ratio as well as higher 11β-deoxycortisol, reflecting greater 11β-hydroxylase inhibition in nonsepsis than in sepsis. Cortisol increases < 250 mM in exogenous ACTH were associated with relatively low baseline (HDL-) cholesterol, and high endogenous ACTH with low cortisol/ACTH ratio, independent of etomidate. Although cortisol increases with exogenous ACTH, levels were lower in sepsis than in nonsepsis patients, and etomidate was associated with diminished increases in cortisol with exogenous ACTH, so that its use increased, albeit nonsignificantly, low cortisol increases to exogenous ACTH from 38% to 57%, in both conditions.ConclusionsA single dose of etomidate may attenuate stimulated more than basal cortisol synthesis. However, it may only partly contribute, particularly in the stressed sepsis patient, to the adrenal dysfunction of CIRCI, in addition to substrate deficiency.

Lymphocyte Phenotyping to Distinguish Septic from Nonseptic Critical Illness

Clinical signs and symptoms of sepsis are nonspecific and often indistinguishable from those of nonseptic critical illness. This ambiguity frequently delays the diagnosis of sepsis until culture results can confirm the presence or absence of an infectious organism. Lymphocyte phenotyping can be conducted rapidly and may provide information on the presence of infection before culture results are available. In this study, we hypothesized that lymphocyte phenotype can distinguish between septic and nonseptic critical illness. C57Bl/6 mice were subjected to either P aeruginosa pneumonia or lipopolysaccharide-induced acute lung injury (ALI). Animals were sacrificed 24 hours postinjury and splenic lymphocytes were harvested. Additionally, 13 patients in a surgical ICU were enrolled in the study. Whole blood was obtained and lymphocytes were isolated by density gradient centrifugation. Lymphocyte phenotype was identified through flow cytometry after labeling lymphocytes for CD3, CD4, CD8, CD20, CD40, CD69, and CD86 with fluorochrome-conjugated antibodies. CD69 expression on B cells and CD8+ splenocytes from septic mice was significantly increased compared with acute lung injury mice (p < 0.001 and p < 0.05, respectively). Similarly, CD4+ and CD8+ lymphocytes from septic patients had a two- to threefold increase in the expression of CD69 compared with nonseptic critically ill patients (p < 0.05). These data indicated that CD69 expression on lymphocytes may be useful in distinguishing between septic and nonseptic critical illness. Continued investigation into the expression of CD69 during sepsis is warranted.

Lymphocyte phenotype distinguishes septic from nonseptic critical illness

Lymphocyte phenotype distinguishes septic from nonseptic critical illness

A Circulating Myocardial Depressant Substance is Associated with Cardiac Dysfunction and Peripheral Hypoperfusion (Lactic Acidemia) in Patients with Septic Shock

Using spontaneously beating rat myocardial cells as an in vitro model of myocardial depression, recent studies demonstrated that septic shock patients' sera frequently contain a myocardial depressant substance (MDS) that is associated with a reversible decrease in left ventricular ejection fraction (LVEF). To further characterize MDS, 50 consecutive patients with possible septic shock were studied serially from shock onset until recovery or death. Thirty-four patients had criteria diagnostic of septic shock, and 16 had a nonseptic critical illness. Of the 34, 14 met strict criteria for circulating MDS, with a mean inhibition of 35 percent (range 20 percent to 62 percent). Compared with those patients not exhibiting significant MDS activity, the 14 MDS-positive patients had a lower mean minimal EF (28 percent vs 39 percent, p less than 0.01), a greater mean decrease in EF (22.1 percent vs 8.8 percent, p = 0.002), a higher pulmonary artery wedge pressure (16.8 vs 11.9 mm Hg, p less than 0.01), greater LV dilatation (162 vs 118 ml/m2, p = 0.02), and a higher circulating mean peak lactic acid (6.9 vs 2.7 mmol/L, p less than 0.01). In the 14 MDS-positive patients, the in vitro myocardial cell depression had a negative correlation with the in vivo EF (r = -060, p less than 0.05). These findings suggest that a circulating MDS is a cause of the myocardial depression frequently accompanying human septic shock.

Neutrophil aggregating activity and septic shock in humans: Neutrophil aggregation by a C5a-like material occurs more frequently than complement component depletion and correlates with depression of systemic vascular resistance

Complement activation frequently accompanies septic shock. Our study goals were to determine the optimal method of complement quantification, and to evaluate complement-generated mediators in the pathogenesis of septic shock cardiovascular dysfunction. Sera from 108 acute episodes of septic and nonseptic critical illness were studied. The 54 episodes of blood culture-positive septic shock had statistically higher neutrophil aggregating activity (by a C5a-like material) compared with 42 episodes of blood culture negative septic shock and 12 episodes of nonseptic shock. In 47 episodes of sepsis-induced adult respiratory distress syndrome, peak neutrophil aggregating activity was higher in nonsurvivors than survivors. A significant negative correlation was found between increased neutrophil aggregating activity and decreased systemic vascular resistance index (SVRI) in culture positive (n = 54, r = −.346, P < .02) and clinical septic shock (n = 42, r = −.30, P < .05). Abnormally elevated neutrophil aggregating activity (increased circulating C5a-like material) was demonstrated more frequently than depletion of either C3, C5, or CH-50 in clinical septic shock. This study suggests that elevated C5a (measured by neutrophil aggregation) is the most frequent manifestation of sepsis-induced complement activation. The negative correlation between neutrophil aggregation and SVRI suggests that complement activation may be important in the pathogenesis of cardiovascular dysfunction in human septic shock.