PredictionEndotoxin activity levels as a prediction tool for risk of deterioration in patients with sepsis not admitted to the intensive care unit: A pilot observational study
Introduction
Sepsis represents a continuum of disease severity with most patients with sepsis cared for outside the intensive care unit (ICU). Still, the early and appropriate management of patients with severe sepsis is associated with large improvements in survival rate [1]. Most of the attributable mortality from sepsis is from the development of multiple organ dysfunction syndrome [2]. The early identification of septic patients at high risk for rapid worsening could be a key to prevent the development of organ dysfunction and shock, and numerous biological markers have been proposed toward this aim [3].
Endotoxin, a complex lipopolysaccharide, which is the major component of the outer membrane gram-negative bacteria, is believed to be one of the principal mediators of the cardiovascular, pulmonary, and renal organ dysfunction observed in patients with sepsis [4]. High levels of endotoxin have been detected in patients with severe sepsis and septic shock admitted to ICU [5]. Indeed, endotoxemia has been also documented in patients with severe infections caused by gram-positive bacteria and in critically ill patients with other nonseptic pathologies (eg, trauma, cardiac surgery, burns) supporting the hypothesis of an extravascular source of endotoxin, such as translocation from the gastrointestinal tract [6]. Whatever the source, endotoxemia is generally associated with increased organ dysfunction and other bad outcomes and, therefore, may be a useful biomarker for identifying other high-risk population with sepsis not admitted to ICU [7]. Moreover, a recent pilot study including 64 patients indicated that endotoxin removal seems to have beneficial effects on organ dysfunction in patients with septic shock of abdominal origin and high likelihood of endotoxemia [8], and therefore, endotoxemia may be a valid direct therapeutic target.
The measurement of endotoxin levels in vivo has been notoriously problematic, and the most commonly used diagnostic test (ie, the chromogenic limulus amebocyte lysate assay) has low specificity due to interferences by circulating inhibitors of the coagulation cascade and by fungal products [4]. An alternative and easier method for the assessment of endotoxin levels in the blood has been recently proposed and validated [5], [9]. This novel method assays the endotoxin activity (EAA) by the chemiluminescence measurement of the enhanced respiratory burst of the neutrophils after priming by complexes of endotoxin and a specific anti-endotoxin antibody. The EAA has been used in recent studies that demonstrated a correlation between high EAA levels and worse outcomes both in adult and pediatric ICU populations [6], [10]. The availability of a reliable measurement of endotoxemia in a short time renders the EAA a promising and useful biomarker for the early recognition of septic patients at high risk for clinical worsening. Unfortunately, most studies published on the relationship between EAA levels and clinical consequences in sepsis deal with patients admitted to ICU.
In this pilot observational study, we aimed to define the prevalence of endotoxemia in patient with sepsis not requiring initial ICU admission early after sepsis diagnosis and to evaluate whether high EAA levels are predictive of the development of new organ dysfunction and clinical worsening.
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Study population
In this prospective pilot study, we enrolled 50 consecutive patients with sepsis and severe sepsis admitted to wards (ie, not requiring ICU admission) of a 780-bed teaching hospital and visited by the sepsis outreach team (see below). Sepsis, severe sepsis, and septic shock were defined according to the 2001 Sepsis Definitions Conference [11]. Patients younger than 18 years; pregnant women; those with neutrophil count less than 1.0 × 109/L, do-not-resuscitate orders, or uncertain diagnosis were
Results
Patient characteristics are described in Table 1. Most patients enrolled in the study at the time of recognition of early sepsis had medical reasons for admission to hospital (74%), such as pneumonia (48%), and, at T0, presented with hypoxemia (40%) and hypotension (56%). Bloodstream infection occurred in 13 patients (26%) (6 E coli; 2 Proteus mirabilis; 2 Streptococcus pneumonia; 2 Staphylococcus aureus; 1 Enterococcus faecalis), and in other 16 patients (32%), an infecting microorganism was
Discussion
This pilot study showed that, in patients with sepsis not initially requiring ICU admission: (i) high EAA levels (≥ 0.6) at the time of sepsis recognition are associated with the risk of development of further organ dysfunction, (ii) patients with worsening of multiple organ dysfunction syndrome during sepsis course have EAA values that are higher than patients without deterioration in clinical state, and (iii) repeated EAA levels less than 0.6 in the first 2 days after sepsis recognition have a
Conclusions
In the early phases of severe sepsis, endotoxemia is frequent in patients not initially requiring ICU admission, and high levels are associated with risk of worsening organ failure. In addition, persistently elevated EAA levels in the first 48 hours after sepsis occurrence further predict a high probability of organ failure deterioration, whereas consistently low levels are reassuring. However, appropriate trials are required to better define the role of EAA monitoring in the management of
Acknowledgments
We are grateful to Giorgia Bertazzoni and Silvia Braccini for their support in data collection and analysis.
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