Ritchie Centre for Baby Health Research

Respiratory fetal & neonatal physiology

Lung disease in premature infants

With improvements in neonatal intensive care, the percentage of infants surviving premature birth has increased dramatically over the last two decades. However, improved survival has come at the price of a steadily rising number of preterm infants who develop chronic lung disease (CLD), a severe respiratory condition that afflicts approximately 2% of the children born each year. Premature infants with CLD have increased mortality and a constellation of morbidities, including poor growth, delayed development of fine and gross motor skill, neuro-developmental delay and recurrent respiratory morbidity for which home oxygen therapy and hospital readmission are often required. NIH estimates the overall costs of treating infants with CLD in the United States at 2.4 billion USD, an amount second only to that for treating asthma and far greater than the cost of treating cystic fibrosis.

Inflammation is increasingly recognised as the mainstay in the development of CLD. The Ritchie Centre has a program that is for the first time systematically probing the molecular causes, and identifying therapeutic strategies, for this major disease entity, with the ultimate goal of initiating clinical trials of new therapies to reduce the impact of lung disease in the newborn.

Causes and consequences of unstable breathing patterns in preterm infants
Despite intensive study over many years, the reasons for the appearance of sleep disordered breathing in infants between one week and six months of age and its disappearance thereafter remain largely unknown. Clinically the importance of repetitive breathing pauses, or apneas, is that they can give rise to a precipitous fall in arterial O₂ level that could endanger the function of vital organs. Considerable evidence suggests that repetitive apneas, and the profound loss of arterial and tissue oxygenation they cause, play an important role in brain injury, delayed development and poor neuro-cognitive function that are common in the 20,000 infants delivered preterm each year in Australia.

Our goal is to clarify the mechanisms underlying apnea in preterm infants and to identify the factors that lead to rapid loss of O₂ saturation during apnea. We address these issues using both mathematical and experimental models to examine the importance of abnormal factors known to exist in the newborn infant, including diffusion limitation, low venous oxygen levels, low haemoglobin and high metabolic rate. In both the mathematical and animal models we seek to provide for the first time an understanding of the implications of apnea for the delivery of oxygen to the tissues, the key determinant of tissue wellbeing.

Maturation of motor activity during fetal life
In early prenatal life the spontaneous activity patterns generated by the fetus of animals and man undergo a dramatic change that we have shown depends upon the action of the brain on spinal cord circuits. At this time, cycles of synchronised activation of all the muscles of the body, followed by their synchronised inactivation, are replaced by a pattern in which there is independent activation of individual muscles. This seminal event in development of motor control represents the first known instance of the brain exerting control over the spinal cord. It is also an essential step for the generation of complex behaviours on which life depends, such as feeding and breathing, since these behaviours involve movements of high spatial and temporal precision that require selective recruitment of individual muscles.

The abrupt imposition of brainstem control over the pattern generators of the spinal cord provides us with a unique opportunity to identify the neurons and neurotransmitters through which brainstem regulation of spinal activity is achieved, and to examine how its loss as a result of spinal cord injury affects the function of spinal circuits, leading to hyperreflexia in both the autonomic and somatic nervous systems. Accordingly this study has the potential to improve our understanding of the severe episodic hypertension that can result in fatal stroke in patients with spinal cord injury and to suggest pharmacological means for treating the condition.