Impact of secondary sepsis on mortality in adult intensive care unit patients.

RATIONALE: Septic patients admitted to the intensive care unit (ICU) suffer from immune dysregulation, potentially leading to a secondary sepsis episode. This study aims to (i) assess the secondary sepsis rate, (ii) compare the second with the first episodes in terms of demographics, clinical and laboratory characteristics, and outcomes, and iii) evaluate the outcome of secondary sepsis. METHODS: A single-center, retrospective study (2014-2017) was conducted in a Greek ICU, including consecutive cases of adult patients admitted to the ICU for at least 48 h with a principal admission diagnosis of sepsis and stayed for at least 48 h. We searched for a secondary episode of sepsis following the primary-one. We performed survival analyses with Cox proportional hazard, Fine-Gray, and multistate models. RESULTS: In this study, 121 patients that fulfilled the eligibility criteria were included. The secondary sepsis group included 28 (23.1 %) patients, with episode onset, median (interquartile range), 9.5 (7.7-16.2) days after ICU admission, who had less frequently had a medical admission diagnosis, a microbiologically confirmed first episode, and the C-reactive protein was lower. The overall ICU mortality of the cohort was 44.6 %. The group that developed secondary sepsis had higher mortality, but significance was lost in Cox regression [Hazard ratio (95 % CI) 0.59(0.31-1.16)]. However, after multistate modeling adjustment, the attributable mortality was estimated at 43.9 % (95 %CI ± 14.8 %). CONCLUSION: Secondary sepsis was evident in a quarter of the study participants and may be associated with an increased risk of death.

Immunogenicity and Safety of the BNT162b2 mRNA COVID-19 Vaccine in Patients with Melanoma Treated with Immunotherapy.

The BNT162b2 vaccine against SARS-CoV-2 has a proven efficacy and a favorable safety profile. In cancer patients under immunotherapy in the form of immune-checkpoint inhibitors (ICIs), the efficacy of the vaccine has not been thoroughly studied, while a theoretical concern has also been raised about triggering immune-related adverse events (irAEs) by the vaccine. We conducted a prospective, non-interventional study on the immunogenicity and safety of the BNT162b2 vaccine in patients with advanced or metastatic melanoma treated with ICIs. Blood samples were obtained 0-4 days before the first dose and 12-21 days after the second dose of the vaccine for the quantification of the SARS-CoV-2 anti-spike antibody using an ELISA and immunophenotyping of the T and myeloid cell subpopulations. The active recording of AEs for a two-month period was conducted. Forty patients were included in the study. All but one (97.3%) achieved seroconversion after two doses of the vaccine and no correlations of the antibody titers with any of the studied parameters (age, gender, stage and duration of the disease, type of ICI, previous treatment, etc.) were found. Moreover, no differences in the subpopulations of the T cells (including the T-regulatory cells) or the myeloid cells were found pre- and post-vaccination. All AEs were low-grade, while one case of arthritis exacerbation was noted. The seroconversion rate in the studied population was high and was comparable to that of healthy subjects, while no major safety issues were raised during the safety follow-up. Finally, no derangements in the subpopulations of T cells or myeloid cells were noted. This is the first study focusing on the immunogenicity, safety, and effect of anti-SARS-CoV-2 vaccines on the blood-cell immunophenotype status of patients with melanoma treated with ICIs.

Current Perspectives on the Diagnosis and Management of Healthcare-Associated Ventriculitis and Meningitis.

Ventriculitis or post-neurosurgical meningitis or healthcare-associated ventriculitis and meningitis (VM) is a severe infection that complicates central nervous system operations or is related to the use of neurosurgical devices or drainage catheters. It can further deteriorate patients who have already presented significant neurologic injury and is associated with high morbidity, mortality, and poor functional outcome. VM can be difficult to distinguish from aseptic meningitis, inflammation that follows hemorrhagic strokes and neurosurgical operations. The associated microorganisms can be either skin flora or nosocomial pathogens, most commonly, Gram-negative bacteria. Classical microbiology can fail to isolate the culprit pathogen. Novel cerebrospinal fluid (CSF) biomarkers and molecular microbiology can fill the diagnostic gap and expedite pathogen identification and treatment. The pathogens may demonstrate significant resistant patterns and their antibiotic treatment can be difficult, as many important drug classes, including the beta-lactams and the glycopeptides, hardly penetrate to the CSF, and do not achieve therapeutic levels at the site of the infection. Treatment modifications, such as higher daily dose and prolonged or continuous administration, might increase antibiotic levels in the site of infection and facilitate pathogens clearance. However, in the case of therapeutic failure or infection due to difficult-to-treat bacteria, the direct antibiotic instillation into the CSF, in addition to the intravenous antibiotic delivery, may help in the resolution of infection. However, intraventricular antibiotic therapy may result in aseptic meningitis and seizures, concerning the administration of aminoglycosides, polymyxins, and vancomycin. Meanwhile, bacteria form biofilms on the catheter or the device that should routinely be removed. Novel neurosurgical treatment modalities comprise endoscopic evacuation of debris and irrigation of the ventricles. VM prevention includes perioperative antibiotics, antimicrobial impregnated catheters, and the implementation of standardized protocols, regarding catheter insertion and manipulation.

ICU-Associated Gram-Negative Bloodstream Infection: Risk Factors Affecting the Outcome Following the Emergence of Colistin-Resistant Isolates in a Regional Greek Hospital.

Intensive care unit patients may present infections by difficult-to-treat-resistant Gram-negative microorganisms. Colistin resurfaced as a last resort antibiotic for the treatment of multi-drug-resistant Gram-negative bacteria. However, colistin might not improve survival, particularly after the emergence of colistin-resistant isolates. We aimed to (1) examine the first Gram-negative-associated-bloodstream infection (GN-BSI) effect on 28-day mortality and (2) distinguish mortality risk factors. From 1 January 2018 to 31 December 2019, we retrospectively studied all adult patients admitted for more than 48 h in the critical care department of a regional Greek hospital, with prevalent difficult-to-treat Gram-negative pathogens. We examined the patient records for the first GN-BSI. The local laboratory used broth microdilution to evaluate bacterial susceptibility to colistin. Seventy-eight patients fulfilled the entry criteria: adult and first GN-BSI. They developed GN-BSI on day 10 (6-18), while the overall mortality was 26.9%. Thirty-two and 46 individuals comprised the respective colistin-resistant and colistin-sensitive groups. The admission Acute Physiology Assessment and Chronic Health Evaluation II score was associated with acquiring colistin-resistant GN-BSI in the multivariable logistic regression analysis (οdds ratio (CI), 1.11 (1.03-1.21)). Regarding mortality, the index day sequential organ failure assessment score was solely associated with the outcome (hazard-ratio (CI), 1.23 (1.03-1.48), Cox proportional hazard analysis). GN-BSI was often caused by colistin-resistant bacteria. Concerning our data, sepsis severity was the independent predictor of mortality regardless of the colistin-resistance phenotype or empirical colistin treatment.

Type I Interferon Signature in Primary Antiphospholipid Syndrome: Clinical and Laboratory Associations.

Background: Increased expression of type I interferon (IFN)-regulated genes has been described in blood and tissue cells from patients with systemic lupus erythematosus (SLE) and other rheumatic disorders. Only isolated studies have examined the type I IFN gene expression in antiphosholipid syndrome (APS), while efforts to evaluate associations with APS-related factors are scarce. Objective: Our aim was to investigate the type I IFN signature in patients with primary APS (PAPS), SLE/APS, and SLE in comparison with healthy controls, and to evaluate associations with disease-related characteristics. Methods: We measured the type I IFN score, derived from relative expressions of three IFN-inducible genes (MX-1, IFIT-1, and IFI-44) in peripheral blood mononuclear cells from 55 patients with PAPS, 34 with SLE/APS, 48 with SLE, and 28 controls. In patients with PAPS, we performed multivariate regression to examine associations of type I IFN score with their clinical, laboratory and treatment characteristics. Results: Type I IFN score was increased in all patient groups vs. controls (p = 0.028, p = 0.027, p = 0.028 for PAPS, SLE/APS, and SLE, respectively). IFI-44 had the most pronounced expression. In patients with PAPS, multivariate linear regression revealed positive associations of type I IFN score with female gender (b-coefficient = 0.49; 95% CI 0.04, 0.94; p = 0.034) and IgG or IgM anti-ß2GPI antibodies (b-coefficient = 0.53; 95% CI 0.10, 0.96; p = 0.017), and negative associations with age (b-coefficient = -0.02/year; 95% CI -0.04, -0.01; p = 0.027) and hydroxychloroquine use (b-coefficient = -0.51; 95% CI-0.96, -0.06; p = 0.027). Conclusion: Type I IFN score is increased in PAPS and correlated positively with anti-ß2GPI antibodies and negatively with hydroxychloroquine use.

The impact of N-acetylcysteine and ascorbic acid in contrast-induced nephropathy in critical care patients: an open-label randomized controlled study.

BACKGROUND: The aim was to investigate whether the use of N-acetylcysteine and ascorbic acid reduce contrast-induced nephropathy incidence in critical care patients. METHODS: This was a one-center, two-arm, prospective, randomized, open-label, controlled trial in the Intensive Care Unit of the University Hospital of Larissa, Greece. Patients with stable renal function, who underwent non urgent contrast-enhanced computed tomography for diagnostic purposes, were included in the study. Patients in the treatment group (NacA, n = 60) received intravenously N-acetylcysteine (1200 mg) and ascorbic acid (2 g) dissolved separately in 100 ml of normal saline 2 hours before, and at 10 hours and 18 hours following the infusion of contrast agent, while control group patients (CG, n = 64) received only normal saline. All patients received additional hydration. Contrast-induced nephropathy was defined as relative increase by 25% of the baseline values of serum creatinine. RESULTS: Contrast-induced nephropathy in NacA and CG were 18.33% and 15.6%, respectively (p = 0.81). The percentage change median (interquartile range (IR)) of serum cystatin-C (mg/L) from baseline in patients who underwent contrast-induced tomography, were 37.23% (28.53) and 93.20% (46.90) in NacA and in CG, respectively (p = 0.03). The 8-isoprostane serum levels in NacA were significantly lower compared to CG at 2 hours (p = 0.012) and 24 hours (p = 0.006) following radiocontrast infusion. Multivariate analysis revealed that contrast-induced nephropathy was independently associated with a higher baseline ratio of serum urea/creatinine (odds ratio, 1.02; 95 CI%, 1.00-1.05) and with the use of nephrotoxic medications (odds ratio, 0.24; 95 CI%, 0.06-0.94). CONCLUSION: Intravenous administration of N-acetylcysteine and ascorbic acid failed to reduce contrast-induced nephropathy in critically ill patients who underwent contrast-enhanced computed tomography, despite a significant reduction of 8-isoprostane levels in treated patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01017796 . Registered on 20 November 2009.

New insights into the mechanisms involved in B-type natriuretic peptide elevation and its prognostic value in septic patients.

INTRODUCTION: Elevated plasma B-type natriuretic peptide (BNP) levels in patients with critical sepsis (severe sepsis and septic shock) may indicate septic cardiomyopathy. However, multiple heterogeneous conditions may also be involved in increased BNP level. In addition, the prognostic value of BNP in sepsis remains debatable. In this study, we sought to discover potential independent determinants of BNP elevation in critical sepsis. The prognostic value of BNP was also evaluated. METHODS: In this observational study, we enrolled mechanically ventilated, critically septic patients requiring hemodynamic monitoring through a pulmonary artery catheter. All clinical, laboratory and survival data were prospectively collected. Plasma BNP concentrations were measured daily for five consecutive days. Septic cardiomyopathy was assessed on day 1 on the basis of left and right ventricular ejection fractions (EF) derived from echocardiography and thermodilution, respectively. Mortality was recorded at day 28. RESULTS: A total of 42 patients with severe sepsis (N = 12) and septic shock (N = 30) were ultimately enrolled. Daily BNP levels were significantly elevated in septic shock patients compared with those with severe sepsis (P ≤0.002). Critical illness severity (assessed by Acute Physiology and Chronic Health Evaluation II and maximum Sequential Organ Failure Assessment scores), and peak noradrenaline dose on day 1 were independent determinants of BNP elevation (P <0.05). Biventricular EFs were inversely correlated with longitudinal BNP measurements (P <0.05), but not independently. Pulmonary capillary wedge pressures (PCWP) and volume expansion showed no correlation with BNP. In septic shock, increased central venous pressure (CVP) and CVP/PCWP ratio were independently associated with early BNP values (P <0.05). CONCLUSIONS: The severity of critical illness, rather than septic cardiomyopathy, is probably the major determinant of BNP elevation in patients with critical sepsis. Daily BNP values are of limited prognostic value in predicting 28-day mortality; however, fast BNP decline over time and a decrease in BNP <500 pg/ml may imply a favorable outcome.

Contrast-induced nephropathy in aged critically ill patients.

BACKGROUND: Aging is associated with renal structural changes and functional decline. The attributable risk for renal dysfunction from radiocontrast agents in critically ill older patients has not been well established. METHODS: In this prospective study, we assessed the incidence of contrast-induced nephropathy (CIN) in critically ill patients with stable renal function who underwent computed tomography with intravenous contrast media. Patients were categorized into two age groups: <65 (YG) or ≥ 65 years old (OG). CIN was defined as 25% or greater increase from baseline of serum creatinine or as an absolute increase by 0.5 mg/dL until the 5th day after the infusion of contrast agent. We also evaluated the alterations in oxidative stress by assessing serum 8-isoprostane. RESULTS: CIN occurred in 5 of 13 OG patients (38.46%) whereas no YG patient presented CIN (P = 0.015). Serum creatinine kinetics in older patients demonstrated a rise over five days following contrast infusion time while a decline was observed in the YG (P = 0.005). CONCLUSIONS: Older critically ill patients are more prone to develop renal dysfunction after the intravenous infusion of contrast agent in relation to their younger counterparts.

Expression of Fas (CD95/APO-1) and Fas ligand (FasL) in experimentally-induced acute pancreatitis.

INTRODUCTION: Acinar cell death is a crucial event in acute pancreatitis (AP) and may occur either by apoptosis or necrosis. The aim of this study was to investigate the expression of the apoptosis associated proteins Fas and FasL in experimentally induced severe AP. METHODS: AP was induced in 30 rats by injecting 0.2 ml of 4.5% sodium taurocholate solution into the biliopancreatic duct. Sham operated animals (n = 30) and 10 normal controls were used for comparisons. Animals were killed at 6, 12, 24, 48, 72 hr and 1 week after operation (five animals at each time point) and both serum and pancreatic tissue were obtained. The severity of AP was graded by morphological evaluation and by measuring serum amylase levels. Acinar cell apoptosis was detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. Tissue expressions of Fas and FasL were evaluated by immunohistochemistry. RESULTS: Sodium taurocholate injection resulted in severe acute necrotizing pancreatitis as early as six hr after taurocholate infusion with gradually increasing severity and a peak at 72 hr, and a significant increase of serum amylase at 6 and 12 hr. Apoptotic acinar cells were observed between 48 and 72 hr. The expression of both Fas and FasL in pancreatic tissue was induced in comparison with normal controls. Fas expression in AP was higher and statistically significant at 24 hr whereas FasL expression was consistently lower with a statistical significance observed at 12 hr when compared to sham-operated animals suggesting Fas upregulation and FasL downregulation in this model of AP. CONCLUSIONS: Induction and sequential changes in the expressions of Fas and FasL occur during taurocholate induced severe AP in rats and their temporal modulation might associate with acinar cell death by apoptosis.