Resuscitation from birth asphyxia

The most common cause of newborn failure to transition at birth is perinatal asphyxia. Asphyxia is a multi-causal condition of simultaneous hypoxia and hypercapnia that leads to acideamia. Severely asphyxiated newborn infants are born bradycardic and apneic and require resuscitation to establish pulmonary gas exchange and restore cardiac function after birth. However, as there is a lack of evidence to support any specific resuscitation regime, there is currently no globally accepted resuscitation strategy for asphyxiated newborns. The evidence-base for current neonatal resuscitation guidelines remains low and data is extrapolated largely from adult or animal resuscitation studies. Most animal studies have been conducted in adult models or newborn animals that were hours or days into postnatal life, which is not reflective of the newborn circulation. This is because the fetal shunts (ductus arterious and foreman ovale) are functionally closed in these models, thus the circulation is more reflective of an adult as opposed to the newborn. Therefore, most of the information from these studies is of limited applicability to neonatal delivery room resuscitation. In my thesis, I have utilised for the first time a relevant animal model where near-term lambs are asphyxiated immediately after delivery. This almost exactly mimics that which occurs in the neonatal intensive care unit, and for the first time examines the pulmonary and cerebral circulatory response to different ventilation and cardiopulmonary resuscitation strategies. Therefore, the global aim of my thesis is to determine the effects of different resuscitation strategies on the cardiorespiratory transition in an appropriate animal model of asphyxia immediately after birth. The outcomes from these studies provide a better understanding of the critical relationship between initial respiratory support in the delivery room and cardiorespiratory haemodynamics in asphyxiated newborns. A cornerstone of neonatal resuscitation teaching describes a rapid vagal-mediated bradycardic response to asphyxia and is one of the first signs of perinatal compromise. As such, heart rate is the primary parameter used to assess the well-being of the newborn. This understanding is based primarily on fetal studies. The first aim of this thesis was to investigate the heart rate response to asphyxia depending upon whether lambs were in utero or ex utero (Chapter 3). Heart rate response to asphyxia was markedly different depending upon whether the lamb was in utero or ex utero. Heart rates in in utero lambs rapidly decreased, while heart rates in ex utero lambs initially increased following cord occlusion before they started to decrease. Mean arterial pressure initially increased then decreased in both groups. This data indicates that our current understanding of the cardiovascular responses that indicate the stage and severity of a perinatal asphyxic event may not be as accurate as previously assumed. International neonatal resuscitation guidelines vaguely state that shorter or longer inflation times to can be used to establish initial lung inflation in apnoeic newborn infants. The second aim of this thesis was to compare three different ventilation strategies immediately after delivery asphyxiated near-term lambs on the cardiovascular and respiratory transition at birth (Chapter 4). Immediately after asphyxia, animals were either resuscitated with i) immediate start of ventilation with inflation times of 0.5 s at a rate of 60 inflations per minute (conventional ventilation) ii) five initial inflations of 3 s duration (European approach) or iii) one long inflation of 30 s duration (experimental approach). A single sustained inflation of 30 s duration improved speed of circulatory recovery and lung compliance in this near-term lamb asphyxia model. However, the restoration in heart rate and blood pressure was so rapid that the resulting increase in cerebral blood flow may induce or enhance brain pathology. Therefore, ventilation with an initial single 30 s SI improves circulatory recovery, but is also associated with a rapid increase in cerebral blood flow, which may exacerbate brain injury suffered by asphyxiated newborns. The use an initial 30 s SI was found to rapidly improve circulatory recovery in asphyxiated lambs Chapter 4. The mechanism of this dramatic response in heart rate is unknown. It is known that aeration of the lungs is associated with a rapid increase in pulmonary blood flow (PBF). The third aim of this thesis was to determine if the entry of gas into the lungs was the major mechanism driving the cardiopulmonary transition in asphyxiated newborns (Chapter 5). It was found that an SI using nitrogen did not increase heart rate or PBF. Therefore, oxygen content during an SI is important in increasing heart rate in asphyxiated lambs. The increase in heart rate is likely driven by the increase in PBF and venous return to the heart. Chest compressions (CC) and adrenaline administration are recommended in asphyxiated newborns that have persistent bradycardia despite effective ventilation. Although this improves circulatory recovery in adults and infants, the effects of CC on cerebral blood flow in newborns at birth, when ductal shunts are patent, is unknown. The final aim of this thesis was to determine the effects of CC, with or without adrenaline administration on the return of spontaneous circulation, carotid blood flow (CBF) and carotid arterial pressure in asphyxiated near-term lambs (Chapter 6). We found that CC with adrenaline administration was required to increase CBF and restore spontaneous circulation in asphyxiated lambs. We also found the presence of a low CBF and retrograde diastolic CBF during CC, which was only abolished when adrenaline was administered, leading to the return in spontaneous circulation. In conclusion, the studies contained in this thesis increase our understanding of the effects of different resuscitation strategies on the cardiovascular transition at birth in an appropriate model of perinatal asphyxia. The knowledge of how these strategies influences cardiovascular and cerebrovascular haemodynamics will benefit the future design of ventilation strategies that aerate the lungs without compromising cardiac output