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The understanding of the endocrine changes in critically ill children is important, as it provides insights in the pathophysiology of the acute stress in children and its differences compared with adults. Furthermore, it delineates prognostic factors for survival and supports the rational use of present and future pharmaceutical interventions. Much more than in critically ill adults, the acute phase of critical illness comes into prominence in critically ill children, as they show a very rapid and fierce course of disease, followed by a quick recovery if they survive. This chapter presents a comprehensive summary of the results of various studies undertaken to evaluate endocrine changes seen during the acute stress response in critically ill children suffering from sepsis or septic shock with purpura (Chapters 2 to 6) or undergoing open-heart surgery (Chapter 7). These studies evaluated three hypothalamic-pituitary-end-organ axes:

I. Hypothalamic-pituitary-adrenal axis (Chapter 2 and Chapter 3) II. Hypothalamic-pituitary-thyroid axis (Chapter 4 and Chapter 5) III. Growth hormone / insulin-like growth factor axis (Chapter 6 and Chapter 7)

Chapter 1 provides a general overview of these hormonal axes and the current knowledge on the changes during the acute phase of critical illness in children and adults.

Chapter 2 describes several aspects of adrenocortical function in relation with disease severity in children with meningococcal sepsis or septic shock on PICU admission. The most severely ill children had more signs of adrenal insufficiency, as depicted by lower median cortisol/ACTH ratios. In contrast with data in critically ill adults, bio-available cortisol levels were not more informative on adrenal function than total cortisol levels. Decreased adrenal function was strongly inversely related to IL-6 levels and at least partly to a decreased 11β-hydroxylase activity, but not to a decreased 21-hydroxylase activity. In addition to IL-6 levels, one single bolus of etomidate during intubation was related to a decreased adrenal function and 11β-hydroxylase activity.

Chapter 3 describes retrospectively the influence of one single bolus of etomidate used for intubation on adrenal function in children with meningococcal sepsis on PICU admission, 12 and 24 hours thereafter. Children who received etomidate had significantly more signs of impaired adrenocortical function, such as lower cortisol, higher ACTH and 11-deoxycortisol levels, than those who did not receive etomidate, independently of intubation. The median dose of the etomidate bolus was significantly higher in children who died compared with those who survived. All, except one, children who died had received etomidate. Within 24 hours cortisol/ACTH ratios increased significantly in children who had received etomidate, resulting in cortisol/ACTH ratios 24 hours after admission which were comparable to

those in the children who had not received etomidate. Our data imply that even one single bolus of etomidate negatively influences adrenal function and thereby might increase risk of death. Therefore, considerable caution should accompany the administration of etomidate in children with septic shock. Future research should elucidate the potential role for concomitant steroid replacement when etomidate remains in use.

Chapter 4 describes several aspects of the thyroid function in relation with disease severity in children with meningococcal sepsis or septic shock on PICU admission. The study shows that all critically ill children with sepsis or septic shock had signs of euthyroid sick syndrome on PICU admission, as depicted by a decreased TT3/rT3 ratio. More signs of euthyroid sick syndrome did not inevitably reflect higher disease severity at the time of PICU admission, indicating that other factors influenced the development of euthyroid sick syndrome in the early initial phase as well. Alterations in peripheral deiodination were related to duration of illness and seemed enacted by a profound induction of type 3 deiodinase rather than down regulation of type 1 deiodinase, suggesting that children who died from meningococcal septic shock lacked the time to develop full-blown euthyroid sick syndrome before PICU admission. Low TT4 levels were related to increased cleavage of TBG by elastase. Dopamine-treated children showed only a reduction of TSH levels and no difference in other thyroid hormone levels compared to the non-dopamine-treated children at the time of PICU admission. Values of TT3/rT3 and TT4 were predictive for mortality, but not more informative than IL-6 levels.

Chapter 5 evaluates thyroid function in relation to length of PICU stay in children who survived septic shock with purpura during the first 48 hours of PICU stay. All children surviving from meningococcal septic shock showed features of the euthyroid sick syndrome. Changes in thyroid function on admission were influenced by the duration of illness prior to admission. Changes in thyroid hormone levels over the first 24h of admission, especially the TT3 drop and the rT3 increment were prognostic for length of PICU stay, in addition to TT4 levels on admission and PRISM score. Thyroid hormone concentrations at PICU discharge were still not normalized in short stay shock-survivors, suggesting that those children had still not fully returned to anabolism at PICU discharge. Dopamine was found to have an influence on the course of thyroid levels.

Chapter 6 describes several aspects of the GH-IGF-I axis in relation with disease severity in children with meningococcal sepsis or septic shock on PICU admission.

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normal range and related positively to total IGF-I, IGFBP-3 and ALS levels, suggesting reduced post-GHR signaling rather than decreased GHR function. IGFBP-1 levels increased with increasing disease severity and correlated inversely with free IGF-I levels, emphasizing its counter-regulatory role in critical illness.

Chapter 7 describes the GH-IGF-I axis in children before and after open-cardiac surgery and determines influencing factors. At start of surgery, IGF-I and IGFBP-3 SD-scores were already low, which might have been related to underweight and compromised clinical status. At the end of surgery GH levels were elevated but IGF-I and IGFBP-3 SD-scores were decreased. GH levels were inversely related to dopamine and glucocorticoid use, whereas the plasma administered influenced IGF-I and IGFBP-3 SD-scores. IGFBP-1 levels at the end of surgery related to disease severity, whereas the inverse relation between IGFBP-1 and insulin levels found at start of surgery was lost at the end of surgery. Glucocorticoid administration during surgery was associated with higher glucose levels. Twenty-four hours after surgery, IGF-I and IGFBP-3 SD-scores and IGFBP-1 levels returned to the initial values at start of surgery.

In Chapter 8 we describe the results of our studies in the context of the literature and elaborate on the implications for clinical practice. We discuss the limitations and recommend future research.