The hypothalamic–pituitary–adrenal axis in critical illness: responses to the low-dose corticotropin (ACTH) stimulation test and human corticotropin-releasing hormone (hCRH)

The objective of this study was to investigate the functional integrity of the hypothalamic–pituitary–adrenal axis in critical illness by stimulating with the low-dose ACTH stimulation test (LDST) and hCRH. The study included 16 (15 male) mechanically ventilated patients, having a mean age of 52 ± 19 years. Underlying diagnoses included major operation (n = 7), multiple trauma (n = 5), stroke (n = 3), and pancreatitis (n = 1). Patients were enrolled in the study 3–14 days after initiation of mechanical ventilation. Median APACHE II and SOFA scores at the study day were 13 (range: 8–23) and 5.5 (range: 4–12), respectively. All patients underwent stimulation first with the LDST (1 μg) and then on the following day with 100 μg hCRH. ACTH and cortisol concentrations were determined from -15 to 120 min after hCRH. Normal cortisol responses to the LDST and hCRH were defined as peak plasma concentrations above 18 μg/dl and 20 μg/dl, respectively. An appropriate ACTH response to hCRH was considered if a twofold increase in ACTH was observed. In the entire patient population, baseline cortisol (mean ± SD) was 15.1 ± 7.1 μg/dl and stimulated cortisol (median) was 21.4 μg/dl following the LDST. Four (25%) of the 16 patients had subnormal stimulated cortisol levels after the LDST. These four patients also had subnormal peak cortisol concentrations following hCRH. Analysis of the individual ACTH responses in the four patients revealed two patterns: in three patients a twofold to eightfold increase in ACTH was noted, whereas one patient failed to augment appropriately ACTH levels (peak ACTH was 1.60 times the baseline value).

In conclusion, a significant (25%) subset of critically ill patients has evidence of diminished cortisol production following dynamic stimulation with the LDST. This disorder is mostly due to primary adrenal dysfunction, but also to hypothalamic–pituitary failure.