Objective: The developing hypothalamic--pituitary--adrenal axis (HPAA) may be immature and not yet fully functional in preterm infants. This may result in an inappropriate adrenal response to stress. Little is known about the pituitary--adrenal response to corticotrophin-releasing hormone (CRH) stimulation during the early neonatal period in preterm infants born before 32 weeks of gestation. Therefore, in a first study we investigated the pituitary--adrenal response to 1 microg/kg CRH i.v. in 13 preterm infants born less-than-or-equal 32 weeks of gestation. In addition, in a randomized placebo-controlled study we compared the pituitary--adrenal response of 1 microg/kg CRH to placebo and stimulation with 2 microg/kg CRH.
Results: In the first study, the level of ACTH increased from 6.9 +/-2.1 to 11.6 +/- 5.1 pmol/l (P < 0.01) and cortisol increased from 350 plus minus 115 to 582 +/- 201 nmol/l (P < 0.05). Thirty-eight percent of the studied infants showed a maximal level of ACTH < 9 pmol/l, and 15% showed a maximal level of cortisol < 360 nmol/l. In the randomized study, infants in the 1 microg/kg and in the 2 microg/kg CRH group, but not in the placebo group, showed a significant increase in cortisol and ACTH after stimulation (P < 0.01). Stimulated levels of ACTH and cortisol were significantly higher in the 2 microg/kg group compared with the placebo and the 1 microg/kg group. No differences were found for plasma ACTH and cortisol levels in the 1 microg/kg group compared with the placebo group. Basal levels of cortisol and ACTH obtained from the first and from the randomized study correlated significantly (n = 29; r = 0.42, P < 0.03). In addition, in infants stimulated with 1 microg/kg CRH a lower cortisol response correlated with a longer stay in hospital (n = 13; r = --0.57, P < 0.05).
Conclusions: In this study we show that a 1 microg/kg CRH stimulation test in preterm infants results more often in an inappropriate adrenal response while stimulation with 2 microg/kg CRH gives rise to an appropriate response in all studied infants. Furthermore, stimulation with 2 microg/kg CRH results in higher levels of ACTH and cortisol compared to placebo and 1 microg/kg CRH. We conclude that in preterm infants the ability of the pituitary to respond adequately to CRH stimulation depends on the dose of CRH used and may also be dependent on the maturity of the pituitary--adrenal axis.