Project description:During recent years, a rising incidence of invasive pulmonary aspergillosis (IPA) in non-neutropenic critically ill patients has been reported. Critically ill patients are prone to develop disturbances in immunoregulation during their stay in the ICU, which render them more vulnerable for fungal infections. Risk factors such as chronic obstructive pulmonary disease (COPD), prolonged use of steroids, advanced liver disease, chronic renal replacement therapy, near-drowning and diabetes mellitus have been described. Diagnosis of IPA may be difficult and obtaining histo- or cytopathological demonstration of the fungus in order to meet the gold standard for IPA is not always feasible in these patients. Laboratory markers used as a non-invasive diagnostic tool, such as the galactomannan antigen test (GM), 1,3-beta-glucan, and Aspergillus PCR, show varying results. Antifungal therapy might be considered in patients with persistent pulmonary infection who exhibit risk factors together with positive cultures or sequentially positive GM and Aspergillus PCR in serum, in whom voriconazole is the drug of choice. The benefit of combination antifungal therapy lacks sufficient evidence so far, but this treatment might be considered in patients with breakthrough infections or refractory disease.
Project description:Pulmonary infections in critically ill patients are common and are associated with high morbidity and mortality. Piperacillin-tazobactam is a frequently used therapy in critically ill patients with pulmonary infection. Antibiotic concentrations in the lung reflect target-site antibiotic concentrations in patients with pneumonia. The aim of this study was to assess the plasma and intrapulmonary pharmacokinetics (PK) of piperacillin-tazobactam in critically ill patients administered standard piperacillin-tazobactam regimens. A population PK model was developed to describe plasma and intrapulmonary piperacillin and tazobactam concentrations. The probability of piperacillin exposures reaching pharmacodynamic end points and the impact of pulmonary permeability on piperacillin and tazobactam pulmonary penetration was explored. The median piperacillin and tazobactam pulmonary penetration ratios were 49.3 and 121.2%, respectively. Pulmonary piperacillin and tazobactam concentrations were unpredictable and negatively correlated with pulmonary permeability. Current piperacillin-tazobactam regimens may be insufficient to treat pneumonia caused by piperacillin-tazobactam-susceptible organisms in some critically ill patients.
Project description:Evaluation of the functional outcomes of patients undergoing an early rehabilitation protocol for critically ill patients from admission to discharge from the intensive care unit.A retrospective cross-sectional study was conducted that included 463 adult patients with clinical and/or surgical diagnosis undergoing an early rehabilitation protocol. The overall muscle strength was evaluated at admission to the intensive care unit using the Medical Research Council scale. Patients were allocated to one of four intervention plans according to the Medical Research Council score, the suitability of the plan's parameters, and the increasing scale of the plan expressing improved functional status. Uncooperative patients were allocated to intervention plans based on their functional status. The overall muscle strength and/or functional status were reevaluated upon discharge from the intensive care unit by comparison between the Intervention Plans upon admission (Planinitial) and discharge (Planfinal). Patients were classified into three groups according to the improvement of their functional status or not: responsive 1 (Planfinal > Planinitial), responsive 2 (Planfinal = Planinitial) and unresponsive (Planfinal < Planinitial).In total, 432 (93.3%) of 463 patients undergoing the protocol responded positively to the intervention strategy, showing maintenance and/or improvement of the initial functional status. Clinical patients classified as unresponsive were older (74.3 ± 15.1 years of age; p = 0.03) and had longer lengths of intensive care unit (11.6 ± 14.2 days; p = 0.047) and hospital (34.5 ± 34.1 days; p = 0.002) stays.The maintenance and/or improvement of the admission functional status were associated with shorter lengths of intensive care unit and hospital stays. The results suggest that the type of diagnosis, clinical or surgical, fails to define the positive response to an early rehabilitation protocol.
Project description:Background: Systemic inflammation is a whole body reaction that can have an infection-positive (i.e. sepsis) or infection-negative origin. It is important to distinguish between septic and non-septic presentations early and reliably, because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on a small number of RNAs expressed in peripheral blood could be discovered that would: 1) determine which patients with systemic inflammation had sepsis; 2) be robust across independent patient cohorts; 3) be insensitive to disease severity; and 4) provide diagnostic utility. The overall goal of this study was to identify and validate such a molecular classifier. Methods and Findings: We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICU). Biomarker discovery was conducted with an Australian cohort (n = 105) consisting of sepsis patients and post -surgical patients with infection-negative systemic inflammation. Using this cohort, a four-gene classifier consisting of a combination of CEACAM4, LAMP1, PLA2G7 and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyte® Lab, was externally validated using RT-qPCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Cohort 1 (n=59) consisted of unambiguous septic cases and infection-negative systemic inflammation controls; SeptiCyte® Lab gave an area under curve (AUC) of 0.96 (95% CI: 0.91-1.00). ROC analysis of a more heterogeneous group of patients (Cohorts 2-5; 249 patients after excluding 37 patients with infection likelihood possible) gave an AUC of 0.89 (95% CI: 0.85-0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or the Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility o f SeptiCyte® Lab was evaluated by comparison to various clinical and laboratory parameters that would be available to a clinician within 24 hours of ICU admission. SeptiCyte® Lab was significantly better at differentiating sepsis from infection-negative systemic inflammation than all tested parameters, both singly and in various logistic combinations. SeptiCyte® Lab more than halved the diagnostic error rate compared to PCT in all tested cohorts or cohort combinations. Conclusions: SeptiCyte® Lab is a rapid molecular assay that may be clinically useful in the management of ICU patients with systemic inflammation. SIRS and Sepsis ICU patients, admission samples Retrospective, mutli-site sutdy using retrospective physician adjudication as a comparator
Project description:The use or misuse of statins in critically ill patients recently attracted the attention of intensive care clinicians. Indeed, statins are probably the most common chronic treatment before critical illness and some recent experimental and clinical data demonstrated their beneficial effects during sepsis, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), or after aneurismal subarachnoidal hemorrhage (aSAH). Due to the heterogeneity of current studies and the lack of well-designed prospective studies, definitive conclusions for systematic and large-scale utilization in intensive care units cannot be drawn from the published evidence. Furthermore, the extent of statins side effects in critically ill patients is still unknown. For the intensive care clinician, it is a matter of individually identifying the patient who can benefit from this therapy according to the current literature. The purpose of this review is to describe the mechanisms of actions of statins and to synthesize the clinical data that underline the relevant effects of statins in the particular setting of critical care, in an attempt to guide the clinician through his daily practice.
Project description:OBJECTIVE:Extremely low gestational age neonates (ELGANs) are at risk for pulmonary hypertension (PH). We hypothesized that PH, defined by echocardiogram at 36 weeks gestational age (GA), would associate with respiratory morbidity, increased oxidant stress, and reduced nitric oxide production. STUDY DESIGN:ELGANs in the Vanderbilt fraction of the Prematurity and Respiratory Outcomes Program (PROP) who had echocardiograms at 36 ± 1 weeks GA were studied. Echocardiogram features of PH were compared with clinical characteristics as well as markers of oxidant stress and components of the nitric oxide pathway. Biomarkers were obtained at enrollment (median day 3), 7, 14, and 28 days of life. RESULTS:Sixty of 172 infants had an echocardiogram at 36 weeks; 11 had evidence of PH. Infants did not differ by PH status in regards to demographics, respiratory morbidity, or oxidant stress. However, odds of more severe PH were significantly higher in infants with higher nitric oxide metabolites (NOx) at enrollment and with a lower citrulline level at day 7. CONCLUSIONS:Respiratory morbidity may not always associate with PH at 36 weeks among ELGANs. However, components of nitric oxide metabolism are potential biologic markers of PH in need of further study.
Project description:RationaleSystemic activation of procoagulant and inflammatory mechanisms has been implicated in the pathogenesis of COVID-19. Knowledge of activation of these host response pathways in the lung compartment of COVID-19 patients is limited.ObjectivesTo evaluate local and systemic activation of coagulation and interconnected inflammatory responses in critically ill COVID-19 patients with persistent acute respiratory distress syndrome.MethodsPaired bronchoalveolar lavage fluid and plasma samples were obtained from 17 patients with COVID-19 related persistent acute respiratory distress syndrome (mechanical ventilation > 7 days) 1 and 2 weeks after start mechanical ventilation and compared with 8 healthy controls. Thirty-four host response biomarkers stratified into five functional domains (coagulation, complement system, cytokines, chemokines and growth factors) were measured.Measurements and main resultsIn all patients, all functional domains were activated, especially in the bronchoalveolar compartment, with significantly increased levels of D-dimers, thrombin-antithrombin complexes, soluble tissue factor, C1-inhibitor antigen and activity levels, tissue type plasminogen activator, plasminogen activator inhibitor type I, soluble CD40 ligand and soluble P-selectin (coagulation), next to activation of C3bc and C4bc (complement) and multiple interrelated cytokines, chemokines and growth factors. In 10 patients in whom follow-up samples were obtained between 3 and 4 weeks after start mechanical ventilation many bronchoalveolar and plasma host response biomarkers had declined.ConclusionsCritically ill, ventilated patients with COVID-19 show strong responses relating to coagulation, the complement system, cytokines, chemokines and growth factors in the bronchoalveolar compartment. These results suggest a local pulmonary rather than a systemic procoagulant and inflammatory "storm" in severe COVID-19.
Project description:Objective: COVID19 is caused by the SARS-CoV-2 virus and has been associated with severe inflammation leading to organ dysfunction and mortality. Our aim was to profile the transcriptome in leukocytes from critically ill ICU patients positive for COVID19 vs. those negative for COVID19 to better understand the COVID19 associated host response. Design: Transcriptome profiling of buffy coat cells via ribonucleic acid sequencing (RNAseq) at the time of admission to the ICU. Setting: Tertiary care ICU and academic laboratory. Subjects: All patients admitted to the ICU suspected of being infected with SARS-CoV-2, using standardized hospital screening methodologies, had blood samples collected at the time of admission to the ICU. Interventions: None. Measurement and Main Results: Age- and sex-matched ICU patients that were either COVID19+ (PCR positive, 2 genes) or COVID19- (PCR negative) were enrolled. Cohorts were well-balanced with the exception that COVID19- patients had significantly higher total white blood cell counts and circulating neutrophils and COVID19+ patients were more likely to suffer bilateral pneumonia compared to COVID19- patients. Further, the mortality rate for this cohort of COVID19+ ICU patients was 29%. Transcriptional analysis revealed that when compared to COVID19- patients, the altered transcriptional responses of leukocytes in critically ill COVID19+ ICU patients appeared to be associated with multiple interrelated outcomes, including but not limited to robust interferon (IFN)-associated transcriptional responses, a marked decrease in the transcriptional activity of genes contributing to protein synthesis and the dysregulated expression of genes that contribute to coagulation, platelet activation, Toll-like receptor activation, neurotrophin signaling, and protein SUMOylation/ubiquitination. Conclusions: COVID19+ patients on day 1 of admission to the ICU display a unique leukocyte transcriptional profile that distinguishes them from COVID19- patients. Identification of this profile provides guidance for future targeted studies exploring novel prognostic/therapeutic aspects of COVID19.
Project description:Background: Systemic inflammation is a whole body reaction that can have an infection-positive (i.e. sepsis) or infection-negative origin. It is important to distinguish between septic and non-septic presentations early and reliably, because this has significant therapeutic implications for critically ill patients. We hypothesized that a molecular classifier based on a small number of RNAs expressed in peripheral blood could be discovered that would: 1) determine which patients with systemic inflammation had sepsis; 2) be robust across independent patient cohorts; 3) be insensitive to disease severity; and 4) provide diagnostic utility. The overall goal of this study was to identify and validate such a molecular classifier. Methods and Findings: We conducted an observational, non-interventional study of adult patients recruited from tertiary intensive care units (ICU). Biomarker discovery was conducted with an Australian cohort (n = 105) consisting of sepsis patients and post -surgical patients with infection-negative systemic inflammation. Using this cohort, a four-gene classifier consisting of a combination of CEACAM4, LAMP1, PLA2G7 and PLAC8 RNA biomarkers was identified. This classifier, designated SeptiCyte® Lab, was externally validated using RT-qPCR and receiver operating characteristic (ROC) curve analysis in five cohorts (n = 345) from the Netherlands. Cohort 1 (n=59) consisted of unambiguous septic cases and infection-negative systemic inflammation controls; SeptiCyte® Lab gave an area under curve (AUC) of 0.96 (95% CI: 0.91-1.00). ROC analysis of a more heterogeneous group of patients (Cohorts 2-5; 249 patients after excluding 37 patients with infection likelihood possible) gave an AUC of 0.89 (95% CI: 0.85-0.93). Disease severity, as measured by Sequential Organ Failure Assessment (SOFA) score or the Acute Physiology and Chronic Health Evaluation (APACHE) IV score, was not a significant confounding variable. The diagnostic utility o f SeptiCyte® Lab was evaluated by comparison to various clinical and laboratory parameters that would be available to a clinician within 24 hours of ICU admission. SeptiCyte® Lab was significantly better at differentiating sepsis from infection-negative systemic inflammation than all tested parameters, both singly and in various logistic combinations. SeptiCyte® Lab more than halved the diagnostic error rate compared to PCT in all tested cohorts or cohort combinations. Conclusions: SeptiCyte® Lab is a rapid molecular assay that may be clinically useful in the management of ICU patients with systemic inflammation. SIRS and Sepsis ICU patients, admission samples