Proefschrift Kerklaan

Introduction

Immunologic and metabolic response The metabolic response is hypercatabolism. To guarantee substrate delivery to vital tissues, free amino acids and fatty acids (FFA) are mobilised by muscle protein breakdown and lipolysis, caused by elevated levels of cortisol and other counter-regulatory hormones (catecholamines and glucagon) 19,22,23 . This results in increased triglycerides levels and reduced high- and low- density-lipoproteins, especially in children with sepsis 24 . Hyperglycaemia develops due to increased endogenous glucose production and peripheral insulin resistance 25 . Hypercata- bolism in the acute phase is primarily induced by inflammation and is more pronounced in multiorgan failure 26 . After the initial cytokine release, other markers of immune cell activation become apparent, such as acute phase CD64 + expression on neutrophils and monocytes 27 . When comparing measured to predicted resting energy expenditure (REE), different metabolic patterns appear to interchange within the child during the clinical course of severe illness 28-32 . This might be explained by the varying and often opposing effects of the different components of the acute phase response on metabolic rate. Duration of the stress response This first phase can take hours to days after an event (such as trauma, sepsis or surgery) and, based on circumstantial evidence, might last shorter in surviving critically ill children than in critically ill adults. In the majority of children with meningococcal disease, blood glucose, cortisol and ACTH levels normalise within 48 hours suggesting an early resolution of the stress response concerning counter-regulatory hormones and glucose metabolism 33,34 . In critically ill and post-surgical neonates, the plasma levels of catecholamines, thyroid hormones and IGF-1 return to baseline even faster than in older children 35,36 , with the earliest return of anabolic protein metabolism found after acute injury in preterm neonates 37 . Nutrient administration in the acute phase of critical illness The acute stress response is affected by nutrition. However, in contrast to previous ideas, hypercatabolism and subsequent muscle atrophy are not reversed with increased provision of nutrients during this phase 26,38 . Recent high-quality trials in adults have extensively investigated the provision of artificial nutrition during this phase 11,12 , and showed no beneficial effects of early initiation of parenteral nutrition 39-41 . Nutrient restriction early in critical illness enhanced the central and peripheral neuro-endocrine response by further lowering T3, thyroxine (T4) and TSH levels as well as the T3 (active thyroid hormone)/reverseT3 (inactive thyroid hormone) ratio. The T3/rT3 ratio was also further reduced by the application of a tight glucose control protocol in critically ill children 42 . This decrease in T3/rT3 ratio was associated with a better outcome both in critically ill adults and children 42,43 , possibly indicating that changing the peripheral conversion of T4 frommetabolically active T3 to inactive rT3 during the first days of critical illness is adaptive and beneficial for recovery 42 .

1

13