Monocyte Tumor Necrosis Factor-α-Converting Enzyme Catalytic Activity and Substrate Shedding in Sepsis and Noninfectious Systemic Inflammation.

OBJECTIVES: To determine the effect of severe sepsis on monocyte tumor necrosis factor-α-converting enzyme baseline and inducible activity profiles. DESIGN: Observational clinical study. SETTING: Mixed surgical/medical teaching hospital ICU. PATIENTS: Sixteen patients with severe sepsis, 15 healthy volunteers, and eight critically ill patients with noninfectious systemic inflammatory response syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Monocyte expression of human leukocyte antigen-D-related peptide, sol-tumor necrosis factor production, tumor necrosis factor-α-converting enzyme expression and catalytic activity, tumor necrosis factor receptor 1 and 2 expression, and shedding at 48-hour intervals from day 0 to day 4, as well as p38-mitogen activated protein kinase expression. Compared with healthy volunteers, both sepsis and systemic inflammatory response syndrome patients' monocytes expressed reduced levels of human leukocyte antigen-D-related peptide and released less sol-tumor necrosis factor on in vitro lipopolysaccharide stimulation, consistent with the term monocyte deactivation. However, patients with sepsis had substantially elevated levels of basal tumor necrosis factor-α-converting enzyme activity that were refractory to lipopolysaccharide stimulation and this was accompanied by similar changes in p38-mitogen activated protein kinase signaling. In patients with systemic inflammatory response syndrome, monocyte basal tumor necrosis factor-α-converting enzyme, and its induction by lipopolysaccharide, appeared similar to healthy controls. Changes in basal tumor necrosis factor-α-converting enzyme activity at day 0 for sepsis patients correlated with Acute Physiology and Chronic Health Evaluation II score and the attenuated tumor necrosis factor-α-converting enzyme response to lipopolysaccharide was associated with increased mortality. Similar changes in monocyte tumor necrosis factor-α-converting enzyme activity could be induced in healthy volunteer monocytes using an in vitro two-hit inflammation model. Patients with sepsis also displayed reduced shedding of monocyte tumor necrosis factor receptors upon stimulation with lipopolysaccharide. CONCLUSIONS: Monocyte tumor necrosis factor-α-converting enzyme catalytic activity appeared altered by sepsis and may result in reduced shedding of tumor necrosis factor receptors. Changes seemed specific to sepsis and correlated with illness severity. A better understanding of how tumor necrosis factor-α-converting enzyme function is altered during sepsis will enhance our understanding of sepsis pathophysiology, which will help in the assessment of patient inflammatory status and ultimately may provide new strategies to treat sepsis.

High-throughput mass spectrometry maps the sepsis plasma proteome and differences in patient response.

Sepsis, the dysregulated host response to infection causing life-threatening organ dysfunction, is a global health challenge requiring better understanding of pathophysiology and new therapeutic approaches. Here, we applied high-throughput tandem mass spectrometry to delineate the plasma proteome for sepsis and comparator groups (noninfected critical illness, postoperative inflammation, and healthy volunteers) involving 2612 samples (from 1611 patients) and 4553 liquid chromatography-mass spectrometry analyses acquired through a single batch of continuous measurements, with a throughput of 100 samples per day. We show how this scale of data can delineate proteins, pathways, and coexpression modules in sepsis and be integrated with paired leukocyte transcriptomic data (837 samples from n = 649 patients). We mapped the plasma proteomic landscape of the host response in sepsis, including changes over time, and identified features relating to etiology, clinical phenotypes (including organ failures), and severity. This work reveals subphenotypes informative for sepsis response state, disease processes, and outcome; identifies potential biomarkers; and advances opportunities for a precision medicine approach to sepsis.

An observational study to determine the effect of delayed admission to the intensive care unit on patient outcome.

INTRODUCTION: Delayed patient admission to the intensive care unit (ICU) due to lack of bed availability is a common problem, but the effect on patient outcome is not fully known. METHODS: A retrospective study was performed using departmental computerised records to determine the effect of delayed ICU admission and temporary management within the operating theatre suite on patient outcome. Emergency surgical and medical patients admitted to the ICU (2003 to 2007) were divided into delay (more than three hours from referral to admission) and no-delay (three or fewer hours from referral to admission) groups. Our primary outcome measure was length of ICU stay. Secondary outcome measures were mortality rates and duration of organ support. RESULTS: A total of 1,609 eligible patients were included and 149 (9.3%) had a delayed admission. The delay and no-delay groups had similar baseline characteristics. Median ICU stay was 5.1 days (delay) and 4.5 days (no-delay) (P = 0.55) and ICU mortality was 26.8% (delay) and 24.2% (no-delay) (P = 0.47). Following adjustment for demographic and baseline characteristics there was no difference in either length of ICU stay or mortality rates between groups. ICU admission delay was associated with both an increased requirement for advanced respiratory support (92.3% delay vs. 76.4% no-delay, P <0.01) and a longer time spent ventilated (median four days delay vs. three days no-delay, P = 0.04). CONCLUSIONS: No significant difference in length of ICU stay or mortality rate was demonstrated between the delay and no-delay cohorts. Patients within the delay group had a significantly greater requirement for advanced respiratory support and spent a longer time ventilated.