Long-term Effects of Early Exposure to Stress, Pain, Opioids and Anaesthetics on Pain Sensitivity and Neurocognition.

Background Experimental studies have shown that neonatal exposure to stress, pain, opioids and anaesthetics may cause histologic and morphologic changes in the central nervous system with associated functional and behavioural changes in the long term. An important question is whether this holds true for humans also - and in particular for sick neonates who often are exposed to pain and receive anaesthetics and sedatives. Methods In this narrative review, we evaluate the effects of neonatal exposure to stress, pain, opioids and anaesthetics in infancy and childhood in animals and in preterm born and term born humans on pain sensitivity, brain morphology, cognition and behaviour later in life. Results In animals, neonatal exposure to stress, pain, opioids and early exposure to anaesthetics are associated with neurodegeneration and cognitive problems later in life. Human studies mainly focus on pain sensitivity, cognition and behaviour and find contradictory outcomes. Dramatic long-term effects found in animal studies could not be confirmed in human. Conclusion While studies in animals suggest neurotoxic effects of early exposure to stress, pain, opioids and anaesthetics, these effects seem clinically less relevant in humans. A possible reason is that the latter often receive opioids in the presence of pain and opioids and anaesthetics in balanced therapeutic dosages and with adequate monitoring of physiological parameters, in contrast to animal studies.

The CLOSED trial; CLOnidine compared with midazolam for SEDation of paediatric patients in the intensive care unit: study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Sedation is an essential part of paediatric critical care. Midazolam, often in combination with opioids, is the current gold standard drug. However, as it is a far-from-ideal agent, clonidine is increasingly being used in children. This drug is prescribed off-label for this indication, as many drugs in paediatrics are. Therefore, the CLOSED trial aims to provide data on the pharmacokinetics, safety and efficacy of clonidine for the sedation of mechanically ventilated patients in order to obtain a paediatric-use marketing authorisation. METHODS AND ANALYSIS: The CLOSED study is a multicentre, double-blind, randomised, active-controlled non-inferiority trial with a 1:1 randomisation between clonidine and midazolam. Both treatment groups are stratified according to age in three groups with the same size: <28 days (n=100), 28 days to <2 years (n=100) and 2-18 years (n=100). The primary end point is defined as the occurrence of sedation failure within the study period. Secondary end points include a pharmacokinetic/pharmacodynamic relationship, pharmacogenetics, occurrence of delirium and withdrawal syndrome, opioid consumption and neurodevelopment in the neonatal age group. Logistic regression will be used for the primary end point, appropriate statistics will be used for the secondary end points. ETHICS: Written informed consent will be obtained from the parents/caregivers. Verbal or deferred consent will be used in the sites where national legislation allows. The study has institutional review board approval at recruiting sites. The results will be published in a peer-reviewed journal and shared with the worldwide medical community. TRIAL REGISTRATION: EudraCT: 2014-003582-24; Clinicaltrials.gov: NCT02509273; pre-results.