Proven infection-related sepsis induces a differential stress response early after ICU admission

Abstract

Introduction: Neuropeptides arginine-vasopressin (AVP), apelin (APL), and stromal-derived factor-1α (SDF-1α) are involved in the dysfunction of the corticotropic axis observed in septic ICU patients. Study aims were: (i) to portray a distinctive stress-related neuro-corticotropic systemic profile of early sepsis, (ii) to propose a combination data score, for aiding ICU physicians in diagnosing sepsis on admission.

Methods: This prospective one-center observational study was carried out in a medical intensive care unit (MICU), tertiary teaching hospital. Seventy-four out of 112 critically ill patients exhibiting systemic inflammatory response syndrome (SIRS) were divided into two groups: proven sepsis and non sepsis, based on post hoc analysis of microbiological criteria and final diagnosis, and compared to healthy volunteers (n = 14). A single blood sampling was performed on admission for measurements of AVP, copeptin, APL, SDF-1α, adrenocorticotropic hormone (ACTH), cortisol baseline and post-stimulation, and procalcitonin (PCT).

Results: Blood baseline ACTH/cortisol ratio was lower and copeptin higher in septic vs. nonseptic patients. SDF-1α was further increased in septic patients vs. normal patients. Cortisol baseline, ACTH, PCT, APACHE II and sepsis scores, and shock on admission, were independent predictors of sepsis diagnosis upon admission. Using the three first aforementioned categorical bio-parameters, a probability score for predicting sepsis yielded an area under the Receiver Operating Curve (ROC) curves better than sepsis score or PCT alone (0.903 vs 0.727 and 0.726: P = 0.005 and P < 0.04, respectively).

Conclusions: The stress response of early admitted ICU patients is different in septic vs. non-septic conditions. A proposed combination of variable score analyses will tentatively help in refining bedside diagnostic tools to efficiently diagnose sepsis after further validation.

Figure 1

Study design. Grouping process of studied patients and volunteers.

Figure 2

On ICU-admission blood concentrations of cortisol; ACTH; ACTH-to-cortisol and cortisol-to-albumin ratios. Three groups were compared: normal volunteers (white bars, n = 14), non-septic ICU patients (light grey bars, n = 37), septic ICU patients (dark grey bars, n = 37). Graphs represent analysis (median, box 25^th to 75^th percentile range; error bars 10th to 90^th percentile range) of (a) cortisol baseline (nMol/L), (b) ACTH (nMol/L), (c) ACTH-to-cortisol ratio, (d) cortisol-to-albumin. The Y axis is shown in logarithmic scale. P is indicative of significant difference(s) between groups: *: P ≤ 0.05, **: P ≤ 0.01, ***: P ≤ 0.001.

Figure 3

On ICU-admission blood concentrations of arginine-vasopressin (AVP); copeptin; copeptin-to-AVP ratio, and apelin (APL). The three groups were compared in bar charts as described in Figure 1, and represent (a) AVP (pMol/L), (b) copeptin (pMol/L), (c) copeptin-to-AVP ratio, (d) apelin (APL, pMol/L). The Y axis is shown in logarithmic scale except for panel F which is linear. P is indicative of significant difference(s) between groups: *: P ≤ 0.05, **: P ≤ 0.01.

Figure 4

On ICU-admission blood concentrations of SDF-1α(CXCL-12) and expression of its receptor (CXCR4) in adrenal gland. The three groups were compared in bar charts as described in Figure 1, and represent (a) SDF-1α (pMol/L) in studied groups. The Y axis is in logarithmic scale. P are indicative of significant difference(s) between groups: **: P < 0.01, ***: P < 0.001. (b) low magnification of a human adrenal gland (× 40) stained with H&E; and after CP450-21-hydroxylase label (red), showing dominant specific expression in the zona fasciculata, (c) sparse expression of the SDF-1α receptor CXCR4 (green labeling, white arrows) by CP450-21-hydroxylase expressing cells of a human adrenal gland cortex (zona fasciculata, red labeling, magnification × 400) (upper panel), and dominant expression of CXCR4 (green labeling) by adrenal vascular wall cells, surrounded by CP450-21-hydroxylase expressing clusters in zona fasciculata (red labeling, magnification × 400) (lower panel).

Figure 5

On ICU-admission blood concentrations of procalcitonin (PCT). The three groups were compared in bar charts as described in Figure 1, representing PCT (ng/mL) in studied groups. The Y axis is in logarithmic scale. P are indicative of significant difference(s) between groups: *: P ≤ 0.05, ***: P ≤ 0.001.

Figure 6

Correlation between blood SDF-1α and cortisol baseline. The overall studied population sample (including normal subjects) is shown included in the main panel: r = 0.2827 (95% CI: 0.06899 to 0.4717). The insert shows the strongest association between these two parameters found in healthy volunteers after subgroup analyses: r = 0.6220, (95% CI: -0.1191 to 0.8709).

Figure 7

Correlation between blood AVP and cortisol baseline. The strongest association between these two parameters is shown in the non-septic ICU patient group: r = 0.5765 (95% CI: 0.2917 to 0.7674).

Figure 8

Comparative Receiver operating characteristic curves for early sepsis diagnosis. The curves relate the different models of logistic regression detailed in Table 4: M1: sepsis score >7; ACTH ≤ 233 nM/L; cortisol ≥ 450 nM/L, M2: PCT >2 ng/mL; ACTH ≤ 233 nM/L; cortisol ≥ 450 nM/L, M3: ACTH ≤ 233 nM/L; cortisol ≥ 450 nM/L, M4: PCT >2 ng/mL, M5: sepsis score >7. Sepsis score is a recommended clinico-biological multiple variable score [17,18], ACTH and cortisol baseline are a combination of two HPA biological stress parameters, and blood PCT is a gold standard biological marker of sepsis [13,50]. Respective AUC values are expressed in Table 4. The three combination panels including the two selected gold standards: sepsis score or PCT (in M1 and M2), performed for the best and similarly and offered added-value to each selected gold standard individually (that is, sepsis score (in M5) or PCT (in M4)): P = 0.005 and P < 0.001, respectively. On the other hand, adding sepsis score or PCT to the two combinations of stress parameters (ACTH, cortisol baseline) also optimized the prediction vs. ACTH and cortisol baseline: P = 0.037 and P = 0.036, respectively. Vertical axis represents the number of true positive values (sensitivity) and horizontal axis the number of false positive values (1-specificity), with the diagonal segments produced by ties.