The Integration of qSOFA with Clinical Variables and Serum Biomarkers Improves the Prognostic Value of qSOFA Alone in Patients with Suspected or Confirmed Sepsis at ED Admission.

BACKGROUND: The prognostic value of quick sepsis-related organ failure assessment (qSOFA) outside intensive care units has been criticized. Therefore, we aimed to improve its ability in predicting 30-day all-cause mortality, and in ruling out the cases at high risk of death among patients with suspected or confirmed sepsis at emergency department (ED) admission. METHODS: This study is a secondary analysis of a prospective multicenter study. We built three predictive models combining qSOFA with the clinical variables and serum biomarkers that resulted in an independent association with 30-day mortality, in both 848 undifferentiated patients (Group 1) and in 545 patients definitively diagnosed with sepsis (Group 2). The models reaching the highest negative predictive value (NPV) with the minimum expenditure of biomarkers in Group 1 and in Group 2 were validated in two cohorts of patients initially held out due to missing data. RESULTS: In terms of the area under the receiver-operating characteristic curve, all six models significantly exceeded qSOFA in predicting prognosis. An "extended" qSOFA (eqSOFA1) in Group 1 and an eqSOFA2 integrated with C-reactive protein and mid-regional proadrenomedullin (eqSOFA2+CRP+MR-proADM) in Group 2 reached the best NPV (0.94 and 0.93, respectively) and ease of use. eqSOFA1 and eqSOFA2+CRP+MR-proADM performed equally well in both the inception and validation cohorts. CONCLUSIONS: We have derived and validated two prognostic models that outweigh qSOFA in predicting mortality and in identifying the low risk of death among patients with suspected or confirmed sepsis at ED admission.

Subclinical Contrast-Induced Acute Kidney Injury in Patients Undergoing Cerebral Computed Tomography.

INTRODUCTION: The nephrotoxicity of modern contrast media remains controversial. Novel biomarkers of kidney damage may help in identifying a subclinical structural renal injury not revealed by widely used markers of kidney function. OBJECTIVE: The aim of this study was to investigate clinical (contrast-induced acute kidney injury [CI-AKI]) and subclinical CI-AKI (SCI-AKI) after intra-arterial administration of Iodixanol and Iopamidol in patients with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2. METHODS: This is a prospective observational monocentric study. Urinary sample was collected at 4-8 h after contrast medium exposure to measure neutrophil gelatinase associated lipocalin (NGAL) and the product tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 ([TIMP-2] × [IGFBP7]), while blood samples were collected at 24 and 48 h after exposure to measure serum creatinine. RESULTS: One hundred patients were enrolled, of whom 53 were exposed to Iodixanol and 47 to Iopamidol. Patients in Iodixanol and Iopamidol groups were comparable in terms of demographics, pre-procedural and procedural data. No patient developed CI-AKI according KDIGO criteria, while 13 patients reported SCI-AKI after exposure to iodine-based medium contrast (3 patients in Iodixanol group and 10 patients in Iopamidol group), defined by positive results of NGAL and/or [TIMP-2] × [IGFBP7]. A positive correlation was found between NGAL and [TIMP-2] × [IGFBP7] in the analysed population (Spearman's rho 0.49, p < 0.001). In logistic regression analysis, Iopamidol exposure showed higher risk for SCI-AKI compared to Iodixanol (OR 4.5 [95% CI 1.16-17.52], p = 0.030), even after controlling for eGFR and volume of contrast medium used. CONCLUSIONS: This study showed that intra-arterial modern contrast media administration may have a nephrotoxic effect in a population without pre-existing chronic kidney disease. Further investigations on larger scale are warranted to confirm if Iopamidol exposed patients to increased risk of SCI-AKI compared to Iodixanol.

Plasma Lipopolysaccharide Concentrations in Cardiorenal Syndrome Type 1.

BACKGROUND: Cardiorenal syndrome (CRS) type 1 is characterized by a rapid worsening of cardiac function that leads to acute kidney injury (AKI). This study evaluated the role of lipopolysaccharide (LPS) in the development of AKI in patients with acute heart failure (AHF) and its relationship with renal parameters, to enable a better comprehension of the pathophysiology of CRS type 1. METHODS: We enrolled 32 AHF patients, 15 of whom were classified as having CRS type 1. Eight of these 15 exhibited AKI at the time of admission (caused by AHF) and the other 7 developed AKI during their stay in hospital (in the first 48 h). We evaluated the plasmatic LPS concentrations as well as conventional (serum creatinine [sCr] and urea) and unconventional (neutrophil gelatinase-associated lipocalin [NGAL] and cystatin C) renal markers. RESULTS: LPS levels were significantly higher in the CRS type 1 patients. No significant difference in LPS level was found in patients who were admitted with AKI and those developed AKI in hospital, but there was a tendency towards a higher level of LPS in CRS type 1 patients admitted with AKI. The LPS concentrations at admission were similar in CRS type 1 survivors (n = 12) and nonsurvivors (n = 3) (p = 0.22). We observed a positive correlation between LPS level and NGAL, Scr at admission and peak Scr during hospitalization and urea at admission. CONCLUSION: CRS type 1 patients present with an increased level of LPS and there is a direct correlation between LPS and renal parameters. This pilot research is the first study to explore the premise of LPS as novel pathophysiological factor in CRS type 1.

Lipopolysaccharide in systemic circulation induces activation of inflammatory response and oxidative stress in cardiorenal syndrome type 1.

BACKGROUND: Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury. In this study, we evaluate the role of lipopolysaccharide (LPS) and various inflammatory markers in the developing acute kidney injury (AKI) in acute heart failure (AHF) patients. METHODS: We enrolled 31 AHF patients and 20 CRS type 1 (the cause of AKI was presumed to be related to cardiac dysfunction) and 17 healthy volunteers without AHF, AKI or CKD, as control group (CTR). We assessed levels of LPS, proinflammatory cytokines (TNF-α, IL-6, IL-18), and oxidative stress marker (myeloperoxidase, MPO). RESULTS: We observed a significant increase in LPS, TNF-α, IL-6, IL-18 and MPO levels in CRS type 1 and AHF group compared to CTR. LPS levels resulted significantly higher in CRS type 1 patients compared with AHF (118.2 pg/mL, IQR 77.8-217.6 versus 13.5 pg/mL, IQR 12.0-17.0, p = 0.008). We found a cytokines and oxidative stress dysregulation in CRS type 1 patients compared with AHF. Furthermore, we observed a strong positive significant correlation between LPS levels and IL-6 (Spearman's rho = 0.79, p < 0.001), and IL-18 (Spearman's rho = 0.77, p < 0.001) and MPO (Spearman's rho = 0.80, p < 0.001), all confirm by simple linear regression analysis. CONCLUSION: CRS type 1 patients presented an increased level of LPS, pro-inflammatory cytokines, and MPO. Furthermore, there is a direct correlation between LPS and pro-inflammatory cytokines and stress oxidative marker. LPS may play a role in the pathophysiology of CRS type 1 inducing inflammation, oxidative stress and finally kidney damage.

Tissue inhibitor metalloproteinase-2 (TIMP-2) • IGF-binding protein-7 (IGFBP7) levels are associated with adverse outcomes in patients in the intensive care unit with acute kidney injury.

The G1 cell cycle inhibitors tissue inhibitor metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been identified as novel biomarkers for the prediction of moderate to severe acute kidney injury (AKI) risk. However, the prognostic value of [TIMP-2]•[IGFBP7] in predicting adverse outcomes in intensive care unit (ICU) patients with AKI was not previously described. To evaluate this, we conducted a cohort study, measuring [TIMP2]•[IGFBP7] levels in critically ill patients admitted to the ICU and classified the patients as NephroCheck (NC) (+) or NC (-) according to [TIMP-2]•[IGFBP7] values and AKI (+) or AKI (-) according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We then evaluated the incidence of continuous renal replacement therapy initiation, all-cause mortality and a composite endpoint of both in the four groups. Baseline [TIMP-2]•[IGFBP7] values were available for 719 patients, of whom 239 developed AKI and 151 met the composite endpoint. Compared to NC (-)/AKI (+) patients, NC (+)/AKI (+) patients had a significant risk of ICU mortality and the composite endpoint. Kaplan-Meier curves showed that the survival estimate for the composite endpoint of NC (+)/AKI (+) patients was 34.4%; significantly worse than NC (-)/AKI (+) patients (67.4%). Multivariate analyses showed strong association between NC positivity and the composite endpoint. The inflammatory marker, procalcitonin, was an additional prognostic biomarker to compare and confirm the incremental value of NephroCheck. No association between procalcitonin and the composite endpoint was found, especially in patients with AKI, suggesting that NephroCheck may be more kidney specific. Thus, the [TIMP-2]•[IGFBP7] values can serve to identify patients with AKI at increased risk for adverse outcomes in the ICU.

Extracorporeal techniques for the treatment of critically ill patients with sepsis beyond conventional blood purification therapy: the promises and the pitfalls.

Sepsis is one of the leading causes of morbidity and mortality worldwide. It is characterized by a dysregulated immune response to infections that results in life-threatening organ dysfunction and even death. Bacterial cell wall components (endotoxin or lipopolysaccharide), known as pathogen-associated molecular patterns (PAMPs), as well as damage-associated molecular patterns (DAMPs) released by host injured cells, are well-recognized triggers resulting in the elevation of both pro-inflammatory and anti-inflammatory cytokines. Understanding this complex pathophysiology has led to the development of therapeutic strategies aimed at restoring a balanced immune response by eliminating/deactivating these inflammatory mediators. Different extracorporeal techniques have been studied in recent years in the hope of maximizing the effect of renal replacement therapy in modulating the exaggerated host inflammatory response, including the use of high volume hemofiltration (HVHF), high cut-off (HCO) membranes, adsorption alone, and coupled plasma filtration adsorption (CPFA). These strategies are not widely utilized in practice, depending on resources and local expertise. The literature examining their use in septic patients is growing, but the evidence to support their use at this stage is considered of low level. Our aim is to provide a comprehensive overview of the technical aspects, clinical applications, and associated side effects of these techniques.

Levels of Proinflammatory Cytokines, Oxidative Stress, and Tissue Damage Markers in Patients with Acute Heart Failure with and without Cardiorenal Syndrome Type 1.

BACKGROUND: Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Inflammation and oxidative stress seem to play a pivotal role in its pathophysiology. In this in vivo study, we examined the putative role of inflammation and humoral markers in the pathogenesis of the CRS type 1. METHODS: We enrolled 53 patients with acute heart failure (AHF); 17 of them developed AKI (CRS type 1). The cause of AKI was presumed to be related to cardiac dysfunction after having excluded other causes. We assessed the plasma levels of proinflammatory cytokines (TNF-α, IL-6, IL-18, sICAM, RANTES, GMCSF), oxidative stress marker (myeloperoxidase, MPO), brain natriuretic peptide (BNP), and neutrophil gelatinase-associated lipocalin (NGAL) in AHF and CRS type 1 patients. RESULTS: We observed a significant increase in IL-6, IL-18, and MPO levels in CRS type 1 group compared to AHF (p < 0.001). We found higher NGAL at admission in the CRS type 1 group compared to the AHF group (p = 0.008) and a positive correlation between NGAL and IL-6 (Spearman's rho = 0.45, p = 0.003) and between IL-6 and BNP (Spearman's rho = 0.43, p = 0.004). We observed lower hemoglobin levels in CRS type 1 patients compared to AHF patients (p < 0.05) and inverse correlation between hemoglobin and cytokines (IL-6: Spearman's rho = -0.38, p = 0.005; IL-18: Spearman's rho = -0.32, p = 0.02). CONCLUSION: Patients affected by CRS type 1 present increased levels of proinflammatory cytokines and oxidative stress markers, increased levels of tissue damage markers, and lower hemoglobin levels. All these factors may be implicated in the pathophysiology of CRS type 1 syndrome.

Determinants of Monocyte Apoptosis in Cardiorenal Syndrome Type 1.

BACKGROUND: Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Its pathophysiology is complex and not completely understood. In this study, we examined the role of apoptosis and the caspase pathways involved. MATERIAL AND METHODS: We enrolled 40 acute heart failure (AHF) patients, 11 of whom developed AKI characterizing CRS type 1. We exposed the human cell line U937 to plasma from the CRS type 1 and AHF groups and then we evaluated apoptotic activity by annexin-V evaluation, determination of caspase-3, -8 and -9 levels, and BAX, BAD, and FAS gene expression. RESULTS: We observed significant upregulation of apoptosis in monocytes exposed to CRS type 1 plasma compared to AHF, with increased levels of caspase-3 (p < 0.01), caspase-9 (p < 0.01), and caspase-8 (p < 0.03) showing activation of both intrinsic and extrinsic pathways. Furthermore, monocytes exposed to CRS type 1 plasma had increased gene expression of BAX and BAD (intrinsic pathways) (p = 0.010 for both). Furthermore, strong significant correlations between the caspase-9 levels and BAD and BAX gene expression were observed (Spearman ρ = - 0.76, p = 0.011, and ρ = - 0.72, p = 0.011). CONCLUSION: CRS type 1 induces dual apoptotic pathway activation in monocytes; the two pathways converged on caspase-3. Many factors may induce activation of both intrinsic and extrinsic apoptotic pathways in CRS type 1 patients, such as upregulation of proinflammatory cytokines and hypoxia/ischemia. Further investigations are necessary to corroborate the present findings, and to better understand the pathophysiological mechanism and consequent therapeutic and prognostic implications for CRS type 1.

Septic Shock with Multi Organ Failure Due to Fluoroquinolones Resistant Campylobacter Jejuni.

BACKGROUND Campylobacter jejuni infections are typically self-limited, and severe extra-intestinal complications are uncommon. CASE REPORT We report a case of a man with septic shock due to fluoroquinolones resistant Campylobacter jejuni. CONCLUSIONS This manuscript emphasizes the potential lethality of fluorquinolones resistant Campylobacter jejuni bacteremia.

Inverse relationship between "a body shape index" (ABSI) and fat-free mass in women and men: Insights into mechanisms of sarcopenic obesity.

BACKGROUND & AIMS: Sarcopenic obesity may be defined by a high fat to fat-free mass (FM/FFM) ratio. Skeletal muscle may be negatively influenced by the pro-inflammatory milieu associated with visceral fat, while the loading effect induced by a heavier body mass index (BMI) may enhance muscle anabolism. Recently, a new anthropometric measure based on waist circumference (A Body Shape Index, ABSI) was developed. In this study we have assessed the predictive power of ABSI on the FFM index (FFMI), a surrogate marker of lean mass. METHODS: Standard anthropometric parameters and ABSI as well as body composition data (fat and fat-free mass determined by bioelectrical impedance analysis) were assessed in 111 female and 89 male overweight/obese subjects, with no clinically significant co-morbidities. Groups with higher- or lower-ABSI were identified according to median values of this index. RESULTS: In women and men, ABSI did not correlate with BMI, while multiple linear regression indicated that BMI (ß-coefficients: 0.62 and 0.77, respectively) and ABSI (ß-coefficients: -0.26 and -0.22, respectively) independently predicted FFMI (multiple R: 0.72 and 0.83, respectively, P < 0.001). Men and women with lower-ABSI exhibited significantly greater FFMI than the higher-ABSI groups for comparable values of BMI. In men, ABSI was correlated positively with C-reactive protein (CRP) (R = 0.30; P < 0.05) and negatively with the reciprocal of insulin (R = 0.28; P < 0.05), an index of insulin sensitivity. FM/FFM ratio significantly (P < 0.01) correlated with CRP (R = 0.31) in women only. CONCLUSIONS: ABSI, a recently introduced marker of abdominal adiposity, may contribute to define the risk of sarcopenia in overweight/obese individuals.

Procalcitonin in early rule-in/rule-out of sepsis in SIRS patients admitted to a medical ward.

BACKGROUND: A relevant amount of patients with clinical suspect of sepsis is admitted and treated in medical wards (MW). These patients have a better prognosis but are older and with more comorbidities compared to those admitted to intensive care units (ICU). Procalcitonin (PCT) is extensively used in emergency departments for the diagnosis of sepsis, but its accuracy in the setting of a MW has not been thoroughly investigated. Predicted low PCT levels also call for the comparison of immunomagnetic-chemiluminescent (L-PCT) and time-resolved amplified cryptate emission (TRACE, K-PCT) technologies, in PCT determination. METHODS: In 80 patients with systemic inflammatory response syndrome (SIRS) diagnostic criteria and suspect of sepsis newly admitted to a MW, PCT was determined with L- and K-PCT method. RESULTS: Sixty patients were diagnosed as sepsis (20 microbiologically and 40 clinically proven) and 20 with non-infective SIRS. The sepsis group had significantly higher levels of both PCTs, with no differences between the clinically and microbiologically proven subgroups. The areas under ROC curves for L- and K-PCT were 0.72 and 0.78 (p<0.001 for each), respectively. Based on MW customized cut-off values of 0.150 (L-PCT) and 0.143 ng/mL (K-PCT), overall accuracies were 66.8 (95% CI 58.7-78.9) and 78.2% (69.8-87.2), respectively, compared to the 55% (44.2-66) of 0.5 ng/mL canonical cut-off. Neither PCT-L nor -K held prognostic value on survival. CONCLUSIONS: In MW patients, customized PCT cut-off levels provide better accuracy than customary levels adopted from ICU, and TRACE technology seems to offer a wider analysis range.