In many newborns with life threatening heart defects, a specialized fetal blood vessel – the ductus arteriosus – plays a crucial role.
In many newborns with life threatening heart defects, a specialized fetal blood vessel – the ductus arteriosus – plays a crucial role. This large blood vessel, that serves to bypass the lungs during fetal life, normally constricts and closes within a few hours of birth. Paradoxically in many infants with heart defects its continued opening is vital to survival. In these "ductus dependent" babies, normal closure is fatal. Flavio Coceani and I, working at Toronto's Hospital for Sick Children, demonstrated that prostaglandins (fatty acid components of cell membranes) were essential to normal ductus opening.
Our "milestone" was to apply this experimental observation to newborns with ductus dependent heart defects. In 1975, we treated our first patient, a three day old "blue baby", dying, because of insufficient oxygenation of his blood. Within a few minutes of starting a continuous arterial infusion of prostaglandins, the baby was transformed. His colour became a normal pink, he gained vigour and made it obvious he was hungry and ready to be fed. This dramatic and gratifying response went far beyond our wildest expectations. Subsequent similar experiences in other babies allowed us to publish our initial clinical results in Circulation in 1976.
The experiments that resulted in this clinical breakthrough were started some five years earlier. Our concepts were founded on observations by other researchers, especially experiments showing the role of oxygen in closure of the ductus (done in the 1940's) and on expanding knowledge of the prostaglandins. Our original experiments, first described in 1973, stimulated others to pursue similar ideas and ultimately to help construct a much more complete picture of the role of prostaglandins in the ductus arteriosus. Traditionally, much of our knowledge of fetal physiology has derived from experiments on fetal sheep. Our own work depended heavily on sheep experiments in which fetal age was accurately known.
Prostaglandin infusion is now an established part of the initial care of newborns with heart disease in all developed countries. With its use, dying infants can be stabilized, transported to tertiary care centres, and prepared for surgery. Prostaglandins have enabled surgery that was previously undertaken under unfavourable emergency conditions to be done semi-electively in much more favourable circumstances.
Our experimental work also inspired the use of Indomethacin to induce closure of the ductus arteriosus in premature infants, who often experience severe circulatory problems because the ductus fails to close normally. Indomethacin blocks the formation of prostaglandins and causes closure of the ductus in about 80% of the infants in whom it is tried. This simple, relatively safe alternative to a surgical operation has been used in many thousands of Canadian babies in the last 15 years. The reduction in severity of illness and in the need for surgery is a significant economic consequence of our work.
It is a pleasure to acknowledge the team component of this research and the contributions of many technicians and trainees. We enjoyed generous support from the Heart and Stroke Foundation of Canada, the Upjohn Company and from the Medical Research Council of Canada.