Endotoxemia and mortality prediction in ICU and other settings: underlying risk and co-detection of gram negative bacteremia are confounders

Abstract

IntroductionThe interdependence between endotoxemia, gram negative (GN) bacteremia and mortality has been extensively studied. Underlying patient risk and GN bacteremia types are possible confounders of the relationship.MethodsPublished studies with ≥10 patients in either ICU or non-ICU settings, endotoxemia detection by limulus assay, reporting mortality proportions and ≥1 GN bacteremia were included. Summary odds ratios (OR) for mortality were derived across all studies by meta-analysis for the following contrasts: sub-groups with either endotoxemia (group three), GN bacteremia (group two) or both (group one) each versus the group with neither detected (group four; reference group). The mortality proportion for group four is the proxy measure of study level risk within L'Abbé plots.ResultsThirty-five studies were found. Among nine studies in an ICU setting, the OR for mortality was borderline (OR <2) or non-significantly increased for groups two (GN bacteremia alone) and three (endotoxemia alone) and patient group one (GN bacteremia and endotoxemia co-detected) each versus patient group four (neither endotoxemia nor GN bacteremia detected). The ORs were markedly higher for group one versus group four (OR 6.9; 95% confidence interval (CI), 4.4 -to 11.0 when derived from non-ICU studies. The distributions of Pseudomonas aeruginosa and Escherichia coli bacteremias among groups one versus two are significantly unequal.ConclusionsThe co-detection of GN bacteremia and endotoxemia is predictive of increased mortality risk versus the detection of neither but only in studies undertaken in a non-ICU setting. Variation in GN bacteremia species types and underlying risk are likely unrecognized confounders in the individual studies.

Prognostic Value of Endotoxemia in Patients with Gram-Negative Bacteremia Is Bacterial Species Dependent

“…This search was supplemented by a hand search for studies reporting mortality outcome data in relation to endotoxemia detection and detection of GN bacteremia with blood culture for patient groups at risk of GN bacteremia. This search has been performed and repeatedly updated [21,29] between 1993 and April 2012 as detailed previously [4] and a call for data was issued [30]. Additional data was obtained through correspondence with authors of potentially eligible studies.…”

“…On the other hand, larger studies of sepsis in which the type of GN bacteremias were not restricted to any specific GN species type [10,11,12,13,14,15,16,17,18,19,20], have generated findings that were contradictory. In aggregate, the results from these studies indicate that endotoxemia detection is a borderline predictor of mortality risk (odds ratio <2) [4,21]. …”

“…However, among large clinical studies, the predictive value of endotoxemia detection remains unclear [4] and a disconnect with animal models exists [5,6]. On the one hand, studies of patients with plague [7,8], or meningococcemia [9], have found a quantitative correlation between the level of endotoxemia and the degree of organ dysfunction or mortality.…”

“…Clarification might also help to reconcile conflicting observations in the clinical literature especially given the variable prevalence of different GN bacteremia species types in different studies [4]. …”

History and current status of polymyxin B‐immobilized fiber column for treatment of severe sepsis and septic shock

“…Endotoxins appeared to play a major role in the pathogenesis of Gram‐negative bacterial infections and in triggering toxic symptoms in patients with sepsis and septic shock. A recent review has shown that co‐detection of Gram‐negative bacteria and endotoxemia is predictive of an increased risk of mortality compared to the detection of neither 1. It is, therefore, reasonable to detect and remove circulating endotoxins in the blood of patients with Gram‐negative bacterial infections.…”