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Plasma Cytokine and Endotoxin Levels Correlate with Survival in Patients with the Sepsis Syndrome

Larry C. Casey, MD, PhD; Robert A. Balk, MD; and Roger C. Bone, MD
[+] Article and Author Information

From Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois. Requests for Reprints: Larry C. Casey, MD, PhD, Rush-Presbyterian-St. Luke's Medical Center, Department of Pulmonary and Critical Care Medicine, 1725 West Harrison Street, Suite 306, Chicago, IL 60612.


Copyright 2004 by the American College of Physicians


Ann Intern Med. 1993;119(8):771-778. doi:10.7326/0003-4819-119-8-199310150-00001
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Objective: To determine whether plasma tumor necrosis factor- (TNF-), interleukin-1 (IL-1 ), interleukin-6 (IL-6), and lipopolysaccharide are detectable in patients when they first present with the sepsis syndrome and to determine whether levels correlate with patient survival.

Design: Prospective study comparing patients with the sepsis syndrome, critically ill patients without sepsis, and normal healthy volunteers.

Setting: Tertiary care hospital affiliated with a medical school.

Patients: The study included 97 consecutive patients on a medical service who met the criteria for the sepsis syndrome; 20 critically ill patients without sepsis who were in the medical intensive care unit; and 20 healthy volunteers who served as comparison groups.

Measurements: Plasma tumor necrosis factor-, IL-1 , interleukin-6, and endotoxin (lipopolysaccharide) levels were measured when a patient was first identified as having the sepsis syndrome. Survival was defined as being alive 30 days after the sepsis syndrome was diagnosed.

Results: Fifty-four percent of patients with the sepsis syndrome had detectable levels of TNF- (median, 26 pg/mL; range, nondetectable to 1000 pg/mL); 37% had detectable levels of IL-1 (median, 20 pg/mL; range, nondetectable to 2850 pg/mL); 80% had detectable levels of IL-6 (median, 415 pg/mL; range, nondetectable to 2380 pg/mL); and 89% had detectable levels of lipopolysaccharide (median, 2.6; range, nondetectable to 12.5 endotoxin units [EU]/mL). In all cases, levels were higher than those in critically ill patients without sepsis and normal healthy controls (P < 0.001 for all comparisons). Plasma levels of TNF-, IL-1 , IL-6, and lipopolysaccharide were detectable in patients regardless of culture status. The IL-6 level was 69% (95% CI, 30% to 108%) higher in patients who died compared with those who survived. The scores for the individual levels of TNF-, IL-1 , IL-6, and lipopolysaccharide were summed to arrive at a total lipopolysaccharide-cytokine score, and mortality increased with lipopolysaccharide-cytokine score (P < 0.001).

Conclusions: Patients with the sepsis syndrome have detectable levels of circulating TNF-, IL-1, IL-6, and lipopolysaccharide independent of culture-documented infection. Lipopolysaccharide and cytokines may play a pathogenic role in sepsis, and the combination of several elevated factors may be important in determining patient survival.

Figures

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Figure 1.
Comparison of plasma lipopolysaccharide, tumor necrosis factor-, interleukin-1 , and interleukin-6 levels in patients with the sepsis syndrome (n = 97), patients in medical intensive care who did not have sepsis (n = 20), and normal healthy controls (n = 20).PPP

Plasma samples were obtained immediately after the identification of patients with the sepsis syndrome and critically ill patients without sepsis who were in medical intensive care (MICU). The three groups differed regarding plasma levels of tumor necrosis factor- (TNF), interleukin-1 (IL-1 ), interleukin-6 (IL-6), and lipopolysaccharide (LPS) ( < 0.001 for all comparisons). Plasma TNF, IL-1 , IL-6, and lipopolysaccharide levels were elevated in patients with sepsis as compared with both critically ill patients without sepsis ( < 0.01 for all comparisons) and normal controls ( < 0.001 for all comparisons).

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Figure 2.
Plasma tumor necrosis factor-, interleukin-1 , interleukin-6, and lipopolysaccharide levels in patients with the sepsis syndrome who survived or died.PP

Plasma interleukin-6 (IL-6) was elevated in patients who died ( < 0.01). No differences were observed in plasma tumor necrosis factor- (TNF), interleukin-1 (IL-1), or lipopolysaccharide (LPS) levels between patients who survived and those who died ( > 0.2).

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Figure 3.
Relations between categorized levels of tumor necrosis factor- (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6), and lipopolysaccharide (LPS) (seeTable 1and mortality from the sepsis syndrome.PPPP

Mortality increased with increasing categorized plasma levels of TNF- [ = 0.047], IL-1 ( < 0.01), and IL-6 ( < 0.01) but not with lipopolysaccharide level ( > 0.2). The number of patients in each category is indicated at the top of each bar.

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Figure 4.
Relation between lipopolysaccharide-cytokine score and mortality from the sepsis syndrome.P

A unit increase in the lipopolysaccharide-cytokine score was associated with a 5% increase in mortality ( < 0.001). The numbers under the points represent the number of patients with that score.

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