Characterisation of the stress response to heart surgery in children

In this PhD thesis, I investigate the importance of inflammatory cytokines for activation of adrenal activity, and couple this with the use of a novel microdialysis system to assess the response of the hypothalamic-pituitary-adrenal axis in children undergoing cardiac surgery. The thesis is structured in three parts. Following the recent demonstration that there is an increased sensitivity of the adrenal cortex to ACTH in adults undergoing cardiac surgery, I investigated whether this could be mediated by cytokines. In the first part of my thesis, I describe a novel co-culture model to investigate the local, immune-adrenal crosstalk and its impact on steroidogenesis. I demonstrate that in the adrenocortical cell line ATC-7 the expression of pro-inflammatory cytokines after LPS stimulation is dependent on the ratio of adrenal and immune cells, that the presence of immune cells can modulate steroidogenesis and that this interaction can be further modulated by ACTH stimulation. In the second part, I discuss the current evidence and knowledge gaps behind the practice of glucocorticoid administration in paediatric heart surgery. I also report the results of a national survey showing a considerable variation in glucocorticoid administration within and between units. The above findings set the scene for the third part of this dissertation, that reports a study protocol for the basic understanding of the HPA axis function in children undergoing paediatric heart surgery the - Peacock Study. By using our novel automated tissue microdialysis system, I successfully measured tissue cortisol and cortisone levels in children of various ages without reducing their circulating blood volume. I also report the preliminary results of the study on 36 children undergoing surgery or catheter procedures. Firstly, I demonstrate that cortisol secretion in children is secreted with a pulsatile pattern, suggesting single-point cortisol testing is obsolete. Furthermore, I found marked changes in the perioperative cortisol to cortisone ratio. Neonates had a distinct response in that they had lower cortisol to cortisone rations presumably related to differential 11 β-HSD isoenzymes activities. Also, I show that the release of CBG and cytokines is dependent on the age of the child, the type of procedure and preoperative oxygen saturation.