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

Abstract

Introduction: The 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.

Methods: Published 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.

Results: Thirty-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.

Conclusions: The 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.

Figure 1

Flow diagram of study selection within the meta-analysis.

Figure 2

Forest plot of odds ratios for mortality for Groups 1 (Endotoxemia and GN bacteremia detected) versus groups 4 (neither detected). Study specific and summary odds ratios (and 95% confidence intervals) derived from all 35 studies with studies sorted into those conducted in an ICU or non-ICU setting. Arrowheads indicate 95% confidence intervals that extend out of range. GN, gram negative.

Figure 3

Forest plot of odds ratios for mortality for Groups 2 (GN bacteremia alone) versus groups 4 (neither detected). Study specific and summary odds ratios (and 95% confidence intervals) derived from all 35 studies with studies sorted into those conducted in an ICU or non-ICU setting. Arrowheads indicate 95% confidence intervals that extend out of range. GN, gram negative.

Figure 4

Forest plot of odds ratios for mortality for Groups 3 (Endotoxemia alone) versus groups 4 (neither detected). Study specific and summary odds ratios (and 95% confidence intervals) derived from all 35 studies with studies sorted into those conducted in an ICU or non-ICU setting. Arrowheads indicate 95% confidence intervals that extend out of range.

Figure 5

L'Abbé plots of study specific mortality rates. Each figure shows mortality rates for studies undertaken in an ICU (triangles) or non-ICU (circles) setting with symbols proportional to group size with the line of no difference (y = x; dotted line) shown for visual reference purposes. Shown are Groups 1 (endotoxemia and GN bacteremia detected) versus groups 4 (neither detected) (Figure 5a - top), Groups 2 (GN bacteremia alone) versus groups 4 (neither detected) (Figure 5b - middle), and Groups 3 (endotoxemia alone) versus groups 4 (neither detected) (Figure 5c - bottom). GN, gram negative.