Cell‐Based Microfluidic Platform – Showing A Cure For Sepsis?

Associations of coagulation function indicators and intestinal function impairment markers with clinical outcomes in septic patients with gastrointestinal dysfunction.

Comparative Safety of Atorvastatin 80 mg Versus 10 mg Derived from Analysis of 49 Completed Trials in 14,236 Patients

We sought to examine the interrelationship between statin use, inflammation, and outcome of high-risk patients with advanced atherosclerosis. We prospectively studied 515 patients with severe peripheral artery disease (median age 70 years, 296 males). The cardiovascular risk profile and laboratory parameters of inflammation (high-sensitivity C-reactive protein [hs-CRP], serum amyloid A [SAA], fibrinogen, serum albumin, neutrophil counts) were obtained, and patients were followed for a median of 21 months (interquartile range 12-25) for the occurrence of myocardial infarction (MI) and death. We observed 19 MIs (5 fatal and 14 nonfatal) and 65 deaths. Cumulative survival and event-free survival rates (freedom from death and MI) at 6, 12, and 24 months were 97%, 95%, and 89%, and 96%, 93% and 87%, respectively. Patients receiving statin therapy (n=269, 52%) had a lower level of inflammation (hs-CRP p<0.001, SAA p=0.001, fibrinogen p=0.007, albumin p<0.001, neutrophils p=0.049) and better survival (adjusted hazard ratio [HR] 0.52, p=0.022) and event-free survival rates (adjusted HR 0.48, p=0.004) than patients not treated with statins. However, patients with low inflammatory activity (hs-CRP < or =0.42 mg/dl) had no significant benefit from statin therapy (p=0.74 for survival; p=0.83 for event-free survival), whereas in patients with high hs-CRP (>0.42 mg/dl) statin therapy was associated with a significantly reduced risk for mortality (adjusted HR 0.58, p=0.046) and the composite of myocardial infarction and death (adjusted HR 0.46, p=0.016). Statin therapy is associated with a substantially improved intermediate-term survival of patients with severe peripheral artery disease and a high inflammatory activity, whereas in patients with low hs-CRP no survival benefit was observed.

The multicenter study conducted by Lorente and coworkers - published in the previous issue of Critical Care - suggests that levels of tissue inhibitor of metalloproteinase (TIMP)-1 in association with the 372 T/C genetic polymorphism of TIMP-1 are promising markers to predict the clinical outcome of septic patients. TIMPs bind to active matrix metalloproteinases and, amongst other effects, inhibit their proteolytic activity of the extracellular matrix. Previous clinical studies showed increased plasma levels of TIMP-1 in nonsurvivors of sepsis, and showed associations between the 372 T/C genetic polymorphism of TIMP-1 and increased risk of developing certain diseases. In recent years, there has been great interest in understanding whether genetic determinants of the host response to systemic infections are associated with poor outcome. Furthermore, the pharmacogenomics of sepsis may allow us to target immune-modulating therapies. Measurement of TIMP-1 protein levels and TIMP-1 polymorphism 372 T/C in the intensive care setting could therefore be an attractive noninvasive tool to determine the outcome of septic patients, and might help to select patients potentially benefitting from a target-specific immune-modulatory therapy directed to matrix metalloproteinase/TIMP homeostasis.

Cardiovascular disease is the primary cause of death in the US. Controlling dyslipidemia, particularly elevated low-density lipoprotein-cholesterol (LDL-C), is considered a primary strategy to reduce cardiovascular risk. HMG-CoA reductase inhibitors (statins) are the most effective agents available to lower LDL-C. Moreover, evidence from numerous prospective clinical trials has shown that statins reduce both cardiovascular disease morbidity and mortality in patients with dyslipidemia. Newer evidence has resulted in updated consensus guidelines that list reducing LDL-C values to a greater degree than has previously been recommended as therapeutic options for certain at-risk populations. Despite these conclusive benefits, most patients at risk for cardiovascular disease have LDL-C values that are above recommended goal values. Observational studies have identified several problems in managing dyslipidemia. These include infrequent screening for dyslipidemia by measuring fasting lipid panels, not prescribing statin therapy in high-risk individuals, incomplete monitoring in patients receiving statin therapy, and a general inability to attain recommended LDL-C goal values in patients receiving statin therapy. This gap between efficacy from clinical trials and treatment in clinical practice is particularly important to managed care organizations because statin therapy can reduce cardiovascular risk and may result in reduced overall healthcare costs. Many drug-based and system-based strategies can be implemented by managed care organizations to reduce this gap. Using high-potency statins, selecting appropriate initial statin doses based on the degree of LDL-C reduction that is required, and combination therapy (e.g. a statin with ezetimibe, bile acid sequestrants, niacin, or fibric acid derivatives) can result in greater LDL-C lowering than by simply using the lowest starting dose of any given statin. System-based models that utilize specific disease state management clinics, therapeutic intervention programs that target population-based improvements in LDL-C goal attainment, and judicious formulary management that includes therapeutic conversion initiatives have all been successfully implemented in managed care environments.

Association between statin therapy and amputation-free survival in patients with critical limb ischemia in the CRITISCH registry

ABSTRACTStatins are the first line of pharmacologic treatment for the management of hypercholesterolemia in patients at risk for atherosclerotic cardiovascular (CV) disease. In recent years, several randomized, controlled trials (RCTs) and observational studies have reported increased risk for new-onset type 2 diabetes mellitus (T2D) with statin treatment, particularly with use of high-intensity statins that reduce low-density lipoprotein cholesterol (LDL-C) by 50% or more. This paper summarizes the data from RCTs and observational studies for statin-associated T2D risk, and puts into perspective this evidence, weighed against the established benefits of statin therapy for CV risk reduction. In RCTs, the increase in T2D risk with statin therapy appears to be attributable mainly to those with major T2D risk factors. The increase in incidence of T2D in those with major risk is approximately 25% for statin use, compared to placebo, and for intensive statin therapy compared to moderate-intensity statin therapy. However, in those with major T2D risk factors, the number of CV disease events prevented for each excess case of T2D is close to or greater than one, indicating that the risk-benefit ratio still strongly favors use of statin therapy, or intensive statin therapy, for patients with sufficient CV disease risk to warrant cholesterol-lowering drug therapy. Recommendations are summarized for evaluation of the T2D risk factor profile before initiation of and during statin therapy. In addition, the importance of lifestyle management and other preventive measures is emphasized for management of risks for both T2D and CV disease events in patients receiving statin therapy.

Malnutrition is a critical concern in ICU settings. It is associated with increased morbidity and mortality, yet its prevalence and impact on clinical outcomes in patients with stroke and traumatic brain injury (TBI) remain underexplored. To evaluate the prevalence and impact of malnutrition risk on clinical outcomes in ICU patients with TBI, ischemic stroke, and hemorrhagic stroke, and to identify key risk factors associated with malnutrition risk. This retrospective cohort study utilized electronic health records encompassing ICU admissions from 2017 to 2023. Patients with either stroke or TBI were included, with malnutrition risk assessed using the prognostic nutritional index. Data were extracted and analyzed to determine patient characteristics, clinical and laboratory parameters, and outcomes. This study included 1352 patients (267 TBI, 825 ischemic stroke, and 260 hemorrhagic stroke patients, >30% with pneumonia at admission). Severe malnutrition risk at admission was observed in over 60% of patients. Stroke patients, particularly those with hemorrhagic stroke, exhibited a higher risk of malnutrition compared to TBI patients. Malnutrition risk was associated with significantly higher hospital mortality and increased need for mechanical ventilation. Predictive factors for malnutrition risk included advanced age, higher SOFA scores, lower FOUR and GCS scores, and the presence of pneumonia at admission. Risk of malnutrition is highly prevalent among ICU patients with TBI, ischemic, and hemorrhagic stroke, significantly impacting mortality and other clinical outcomes. Identifying and managing malnutrition early in the ICU setting is crucial for improving patient outcomes. Further prospective, multicenter studies are needed to validate these findings and develop effective interventions.

BackgroundThe role of early enteral nutrition (EEN) in septic shock remains unclear. This study aimed to evaluate the association between EEN and clinical outcomes in septic patients requiring vasopressor therapy and invasive mechanical ventilation.MethodsThis retrospective cohort study used the MIMIC-IV database and included adult septic patients receiving vasopressors and mechanical ventilation at ICU admission. EEN was defined as enteral nutrition initiated within 48 hours. The primary outcome was 28-day mortality. Secondary outcomes included ICU and hospital length of stay, and duration of mechanical ventilation. Inverse probability of treatment weighting (IPTW) was used to adjust for baseline confounders. Vasopressor dose was stratified based on the maximum norepinephrine-equivalent dose in the first 48 hours: low (<0.1 micrograms/kg/min), medium (0.1–0.5), and high (>0.5). Multivariable regression models were used to assess associations.ResultsA total of 4,673 patients were included, of whom 997 (21.3%) received EEN. Before weighting, EEN was associated with higher 28-day mortality (21.9% vs. 15.3%). After IPTW adjustment, early feeding remained significantly associated with increased mortality (adjusted odds ratio 1.80; 95% confidence interval, 1.42 to 2.27). In stratified analyses, EEN was associated with increased mortality in the medium-dose (odds ratio 1.66; 95% confidence interval, 1.26 to 2.19, p < 0.001) and high-dose groups (1.90; 1.21 to 2.98, p < 0.001), but not in the low-dose group(1.92, 1.12 to 3.27, p = 0.016).ConclusionsIn critically ill septic patients receiving vasopressors and mechanical ventilation, EEN was associated with increased 28-day mortality, particularly among those receiving medium- or high-dose vasopressor therapy.

BackgroundWhether early dietary fiber intake in septic patients is associated with a better clinical prognosis remains unclear, especially the time and the amount. Therefore, we assessed the association between early dietary fiber intake and clinical outcomes in septic patients by examining an extensive database.MethodsWe conducted a retrospective cohort study using data from the MIMIC IV 2.1 database, focusing on consecutive septic patients requiring mechanical ventilation in medical or mixed medical-surgical ICUs. We collected patient demographics and nutritional data. Dietary fiber amounts were calculated according to enteral nutrition instructions from manufacturers within the first 72 h after admission. After adjusting for covariates, we employed restricted cubic spline (RCS) regression to investigate the relationship between fiber intake (FI) and 28-day mortality. Patients were categorized into three groups based on their fiber index (FI) within 72 h of admission: low fiber index (LFI) group when FI was < 3 g/(%), medium fiber index (MFI) group when FI ranged from 3 to 35 g(%), and high fiber index (HFI) group when FI ≥ 35 g(%). Univariate and multivariate Cox proportional hazards regression models were utilized to assess the association between early FI and 28-day mortality. We ultimately employed Kaplan–Meier (KM) curves and log-rank test visually represent the association between FI and 90-day mortality. The second outcomes include ICU-acquired infections and the hospital and ICU death, length of hospital and ICU stay, and length of mechanical ventilation.ResultsAmong 1057 subjects, 562 (53.2%) were male, with a median age of 64.8 years (IQR 53.4–75.2). We observed a J-shaped relationship between FI and 28-day mortality. The MFI group exhibited the lowest 28-day mortality [adjusted HR 0.64 (0.45–0.91), p = 0.013] and the lowest rate of hospital mortality [adjusted OR 0.60 (0.39–0.93), p = 0.022], with no statistically significant differences noted in the HFI group when compared to the LFI group. Similar patterns were observed for 60-day and 90-day mortality. However, no statistically significant differences were observed in other secondary outcomes after adjusting for covariates.ConclusionEarly medium fiber index intake improved 28-day mortality and lower hospital mortality in septic M/SICU patients on mechanical ventilation.

The early recognition and treatment of severe sepsis and septic shock is the key to a successful outcome. The longer the delay in starting treatment, the worse the prognosis due to persistent tissue hypoperfusion and consequent development and worsening of organ dysfunction. One of the main mechanisms responsible for the development of cellular dysfunction is tissue hypoxia. The adjustments necessary for adequate tissue blood flow and therefore of oxygen supply to metabolic demand according to the assessment of the cardiac index and oxygen extraction rate should be performed during resuscitation period, especially in high complexity patients. New technologies, easily handled at the bedside, and new studies that directly assess the impact of macro-hemodynamic parameter optimization on microcirculation and in the clinical outcome of septic patients, are needed.

Aim: This study aimed to prove the role of IL-17 on the clinical outcomes of septic patients. Materials and Methods: This study used a systematic review and meta-analysis design. Data were obtained by searching articles published between January 2001 and June 2022 in Pubmed, Science Direct, Scopus, and Medline databases to evaluate Interleukin-17 on clinical outcomes in septic patients. Only human studies were used in this study. Meta-analysis was undertaken using random effects models. Results: Fourteen published studies were eligible, and four studies were included in the meta-analysis. Meta-analysis of the ratio of means (RoM) IL-17 concentration demonstrated a 5.96-fold higher level in non-survivor septic patients compared with survivors (four studies; n = 194 patients; RoM=5.96; 95% CI, 3.51-10.31; p < 0.00001; I2 = 92%). Conclusions: IL-17 levels were significantly elevated in non-survivor and predicted mortality of septic patients.

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

This study evaluated whether statin therapy increases the risk of herpes zoster (HZ) infection in Asia. This retrospective cohort study used the Longitudinal Health Insurance Database (LHID2000). From the LHID2000, patients aged 20years were divided into two cohorts according to their statin use and were matched at a 1:1 ratio according to propensity scores, which were calculated using a logistic regression for estimating the probability of treatment assignment. The primary outcome was HZ infection. All patients were followed from the index date until the date of HZ infection, withdrawal from the insurance system, or the end of 2011. The study included 53,069 patients receiving statin therapy as a statin cohort and 53,069 patients without statin therapy as a nonstatin cohort. The mean follow-up durations for the statin cohort and nonstatin cohort were 4.89 [standard deviation (SD) = 2.86] years and 4.75 (SD = 2.90) years, respectively. The patients in the statin cohort had a 21% higher risk of contracting HZ infection than the patients in the nonstatin cohort [95% confidence interval (CI) = 1.13-1.29]. The incidence of HZ infection increased with the Charlson comorbidity index (CCI) score in both cohorts. A high mean defined daily dose of the six types of statins considered in this study was associated with a significantly increased risk of HZ infection. Statin therapy can increase HZ infection in Asia. More benefit-risk evaluations for statin use are necessary in Asia.

Elevated triglyceride levels have been associated with an elevated risk of cardiovascular disease, even when triglyceride levels are below common guidelines. This elevated risk of cardiovascular disease exists independent of total cholesterol or low-density lipoprotein cholesterol levels. Genetic analyses have demonstrated that elevated remnant lipoprotein, a product of triglyceride-rich lipoprotein, is a factor for coronary heart disease, indicating that the association between elevated triglyceride levels and elevated cardiovascular disease risk is causal rather than correlated. Despite this correlation between triglyceride levels and cardiovascular disease risk, treatments targeted at lowering triglyceride levels in patients receiving statin therapy, such as niacin or fibrates, have not demonstrated reduction in cardiovascular disease risk despite lowering triglyceride levels. In addition, omega-3 fatty acids containing a combination of docosahexaenoic acid plus eicosapentaenoic acid failed to demonstrate significant reductions in cardiovascular events in similar patients. Triglyceride-lowering therapies in development include monoclonal antibodies targeted against angiopoietin-like 3 (ANGPTL3); however, these newer ANGPTL3-targeted agents have not yet demonstrated a reduction in cardiovascular disease risk. In contrast, the landmark REDUCE-IT trial demonstrated significant cardiovascular protective effects for icosapent ethyl (IPE) in high cardiovascular risk patients with hypertriglyceridemia despite statin therapy. The protective effects of IPE may be due to unique mechanisms affecting the metabolism of E-series resolvins that may reduce atherosclerotic plaque. IPE also exhibits antiplatelet, antithrombotic, anti-inflammatory, and anti-oxidant effects, all of which contribute to an overall anti-atherosclerotic effect and an overall reduction in cardiovascular disease risk. As a result, treatment guidelines in the United States, China, and other countries recommend IPE for patients with hypertriglyceridemia that persists despite statin therapy.