Reduced ACTH-driven cortisol secretion during critical illness

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 41-52-HPA Axis & Disease States
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-50
Eva Boonen*1, Philippe Meersseman1, Hilke Vervenne1, Geert Meyfroidt1, Johannes D Veldhuis2 and Greet Van den Berghe1
1KU Leuven, Leuven, Belgium, 2Mayo Clinic, Rochester, MN
Background: We recently documented that reduced cortisol metabolism, via suppressed expression and activity of A-ring reductases and 11b-HSD2, substantially contributes to hypercortisolism during critical illness, and that morning ACTH levels are low (1). We hypothesized that reduced cortisol breakdown elevates circulating cortisol, which could suppress pulsatile ACTH secretion via negative-feedback, in turn suppressing pulsatile cortisol release. To test this hypothesis, we compared the dynamics of nocturnal ACTH and cortisol time series in critically ill patients and demographically matched healthy controls.

Methods: Blood was sampled every 10 minutes between 21:00h and 06:00h from 40 critically ill patients and 8 healthy controls, after excluding interfering drugs and pre-existing risk factors for HPA-axis dysfunction. Plasma ACTH and cortisol concentrations were quantified by radioimmunoassay.  ACTH and cortisol secretion profiles were constructed by multiple parameter deconvolution analysis, using cortisol half-lives as previously determined (1). In addition, approximate entropy (ApEn), an estimation of secretory irregularity, Cross ApEn, a quantitation of ACTH and cortisol synchrony, and the ACTH-cortisol dose-response relationships were calculated.

Results: Mean nocturnal plasma cortisol levels were 2.6-fold higher in patients than controls (P<0.0001) while mean nocturnal plasma ACTH levels were comparable (P=0.42). Deconvolution analysis revealed a reduced pulsatile ACTH secretion in critically ill patients to 69% of normal (P=0.03) explained by a decreased ACTH mass per burst to 72% of normal (P=0.02) while ACTH pulse frequency (P=0.50) and ACTH basal secretion (P=0.80) remained unaltered. Deconvolution analysis of the cortisol time series also revealed a reduced pulsatile cortisol secretion in patients to 46% of controls (P=0.005) explained by a reduced cortisol mass per burst to 60% of normal (P=0.03) with a comparable number of cortisol pulses (P=0.35) and a similar cortisol basal secretion (P=0.80).
Approximate entropy of the ACTH and cortisol time series was higher in patients than controls (P<0.03), indicating more irregularity in the secretory patterns. ACTH/cortisol crossApEns were also higher in patients than controls (P≤0.001) suggesting reduced synchrony between both hormones. Dose-response estimates were overall similar in patients and controls.

Conclusions: In the presence of reduced cortisol breakdown, pulsatile ACTH-driven cortisol secretion was found to be suppressed during critical illness, in line with negative feedback inhibition brought about by elevated circulating cortisol. Furthermore, the increased irregularity and the reduced synchrony between ACTH and cortisol secretory patterns support non ACTH-dependent mechanisms active during critical illness, which should be further investigated.

(1) Boonen E, Vervenne H, Meersseman Ph et al. Reduced Cortisol Metabolism during Critical Illness. in press

Nothing to Disclose: EB, PM, HV, GM, JDV, GV

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