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Adjudication committee
- First opponent: Associate Professor Raul Chavez-Valdez, Johns Hopkins University School of Medicine, USA
- Second opponent: Professor Henrik Hagberg, University of Gothenburg, Sweden
- Third member and chair of the evaluation committee: Professor Anne Cathrine Staff, University of Oslo
Chair of the Defence
Professor Anne Spurkland, University of Oslo
Principal Supervisor
Professor Emeritus Marianne Thoresen, University of Oslo
Summary
Less than 50 years ago, surgical operations without adequate anaesthesia were routinely performed in premature newborn infants. This practice was based on the misconception that the these infants could not perceive pain due to the immaturity of their central nervous system (K. J. S. Anand 2000). Since then, our understanding of nociception and the impact of neonatal stress has evolved. Today, clinicians recognise the importance of administering adequate sedation and analgesia (SA) to infants in the neonatal intensive care unit (NICU).
Perinatal asphyxia is caused by disruption of placental blood flow to the infant around the time of birth. Severe asphyxia can manifest with metabolic and neurological symptoms consistent with cerebral dysfunction, termed hypoxic- ischemic encephalopathy (HIE). The pathogenesis of HIE is multifactorial and progressive over time. Currently, therapeutic hypothermia (TH) is the only clinically approved treatment which reduces mortality and disability after HIE. During TH, infants are exposed to various stressors, such as the discomfort from cooling, mechanical ventilation and invasive procedures. Opioids are frequently administered during TH for SA. However, the effects of these various stressors and opioids on the vulnerable injured brain are not fully explored.
Experimental animal models have been fundamental in establishing TH as the standard of care after HIE. Furthermore, historical experiments are often able to provide insights beyond their initial research questions. Therefore, in this thesis we have undertaken an analysis of historical animal experiments in rats (Paper II, Paper III) and pigs (Paper IV), in addition to a clinical prospective study (Paper I), to explore the effects of various stressors, sedation, and anaesthesia on HI brain injury and neuroprotection from TH.
Our findings demonstrate that stress responses, whether acute or chronic, significantly alter susceptibility to HI injury and neuroprotection from TH. Stress responses may introduce unpredictable effects from TH, potentially abolishing neuroprotection completely. In the clinical cohort, we find no evidence to suggest that opioids administered for SA during TH and rewarming impair cognitive, language or motor function at 18-24 months of age. Our findings support that adequate SA during TH is necessary to sustain predictable and effective neuroprotection.
Additional information
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