The blood circulation in a fetus is markedly different compared to adult circulation. It is structured with three vital shunts so that fetal blood can pick up vital nutrients from placenta and avoid the lungs to deliver oxygen to organs.
Deoxygenated blood from the fetus flows through two umbilical arteries to the placenta1. Here oxygen and nutrients are taken up from the maternal blood while waste products are passed on. Oxygenated blood then enters the fetal heart through umbilical vein, ductus venosus (DV) and inferior vena cava. DV helps blood bypass the liver since the placenta can perform many of the roles of the liver2. On reaching the right atrium the blood is divided into two streams by crista dividens at the interatrial septum3.The large stream is directed through the foramen ovale (FO) to the Left atrium (LA). The smaller stream enters the right ventricles where it is mixed with deoxygenated blood from other parts of the body3.
The ductus arteriosus (DA) connects the pulmonary trunk to the aorta4. The increased pulmonary vascular resistance (PVR) as a result of dysfunctional lungs aid shunting of the blood from pulmonary trunk to aorta through the DA. Note that DA is located after the carotid arteries to ensure that vital organs in the upper part of the body such as the brain receive well oxygenated blood4. The route of fetal circulation is well illustrated on a diagram in Appendix.
At birth several cardiopulmonary changes take place to accommodate for the gas exchange being transferred from placenta to the lungs. Clamping of umbilical vessels at birth and overall cessation of blood flow causes the DV to close5.As the lung expands with first breath the PVR falls and causes a reduction in hypoxic pulmonary vasoconstriction4. LA pressure is raised above that of the right atria through4:
Decreased PVR leading to more blood flow to lungs and therefore LA
Decreased blood flow to right atrium by occlusion of umbilical vein
Increased resistance to left ventricular output by occlusion of umbilical arteries
These factors cause the reversal of the pressure gradient in the atria leading to the closure of FO. Although this closure happens between minute to hours after birth, anatomical closure by tissue proliferation takes several days to happen3. The fall in pulmonary arterial pressure and the higher partial pressure of oxygen causes the DA to constrict and close within 1-2 days of birth4, becoming the ligamentum arteriosum2.
Along with the factors mentioned above fetal circulation has other quality that benefits the fetus. The fetus has a high concentration of fetal haemoglobin F which is composed of 2 alpha (?) and 2 gamma (Y) chains. The inability of 2,3-BPG to bind to Y chain and the higher oxygen affinity ensures that oxygen transport is efficient in the fetus6,7. The Y chain is replaced to a ? chains at around 3-6 months of age6. Additionally at the placenta there is a double Bohr Effect whereby release of CO2 by fetal haemoglobin causes a leftward shift in fetal oxyhaemoglobin dissociation curve and the CO2 binding to maternal haemoglobin causes rightward shift of maternal haemoglobin. Overall, the affinity of fetal haemoglobin chain for oxygen is enhanced.
Surfactant and CPAP
Surfactant, secreted by pneumocytes, prevents alveolar collapse through alveolar interdependence where interaction between adjacent alveoli means that collapsing alveoli can pull adjacent alveoli preventing further collapse8. Furthermore, it reduces the work of breathing by reducing transmural pressure needed to expand the alveoli8. Surface tension also has the property of pulling fluids from the capillaries into the alveoli leading to pulmonary oedema. By lowering the surface tension, surfactant prevents this phenomenon4,8. The fetus will start producing surfactant around 26-28th week of gestation thus premature babies are prone to Respiratory Distress Syndrome (RDS) where there is inadequate production of surfactant which leads to increased respiratory work and inadequate exchange of gasses. The alveoli collapse can also lead to accumulation of damaged cells called hayaline membranes making it even harder to breathe.
Surfactant contains proteins, notability Sp-A and Sp-D, which play a role in defending the host4. The most abundant of these is Sp-A which enhances alveolar macrophage activity through opsonisation4,9.
RDS in neonates can lead to difficulty in breathing which is often rapid and laboured with expiratory grunt, chest wall retraction, cyanosis and nasal flaring10. The surfactant deficient lung can collapse leading to well perfused but poorly ventilated areas, resulting in ventilation perfusion mismatch with hypoxaemia and hypercapnia (causing acidosis as result)10.It is not unusual to find RDS accompanied by various metabolic disorders and complications. Pulmonary and cerebral haemorrhage are not uncommon and there is also the possibility of chronic complications such as bronchopulmonary dysplasia where the use of ventilation causes lung tissue to become scarred affecting their development11.12.
Continuous positive airway pressure (CPAP) applies a pressure greater than atmospheric pressure to deliver lung expansion therapy13. It delivers warmed and humidified air to the patient through nasal prongs or other airway interface14. It is used in babies that can breathe themselves but whose breathing is better and easier if small pressure is applied to prevent alveoli collapse15. Application of CPAP confers physiological benefits such as stabilisation of airway, diaphragm and chest wall, increased lung volume and decreased airway resistance16. The decreased work during CPAP is mainly as result of a decreased pulmonary resistance brought about by CPAP17. Aside from the oxygen given to the baby CPAP also has the ability to raise arterial oxygenation through improved ventilation: perfusion ratio and lowering of the physiological dead space17. Use of CPAP over assisted ventilation can minimise lung injury, while preventing volutrauma due to overdistention and/or atelectasis12. However, it must be noted that many of the studies examining CPAP for RDS were done in the pre-surfactant and pre-antenatal steroid era, which can perhaps render them less relevant to current premature infants.
Haemodynamics and nature of problem in blood flow
The pulmonary to systemic flow ratio can be used as an indicator of haemodynamic disturbances. It can be performed simply using the oxygen saturation level data. The neonate’s pulmonary and systemic blood flows are 0.16584 and 0.24876 respectively. These calculations were performed using Ficks method as illustrated in Appendix A Part 2. The pulmonary to systemic blood flow ratio is 2:3 suggesting that left ventricular output is higher than right ventricular output thus there is right-to-left shunting of blood.
Pulmonary hypertension in a fetus is very beneficial as it allows shunting of blood. However birth brings about several changes that decrease PVR. The first gasp for air causes a decrease in PVR causing an increase in pulmonary blood flow which decreases the pressure in the right ventricles18. It also causes an increase concentration of oxygen which decreases circulating prostaglandins leading to closure of the DA19.In the mean time the increased preload and increased afterload on the left side of the heart increase its pressure. The fetus starts to increase pulmonary expression of (Nitric Oxide) NO syntheses in late gestation in preparation for birth20. NO has vasodilatory effects in the vessels which will decrease vascular resistance. All of this means that in a neonate the pressure in the left side of heart will be higher than the right side causing closure of the FO.
The consequences of RDS such as hypoxia and hypercapnia along with any secondary factor that increases pulmonary vascular resistance can all mean normal decreases in pulmonary vasculature does not happen at birth. Despite the surfactant given, the lungs could still remain stiff increase PVR. This pulmonary hypertension will increase the afterload faced by the right ventricles which will need to generate a greater pressure to overcome the pulmonary hypertension. The right ventricles now have to work harder to push blood into the pulmonary circulation causing the right side of the heart to increase in pressure. Since the FO may not yet have anatomically closed this can favour right-to-left shunting of blood. There is also the possibly the FO may take longer to close on a premature infant aiding the right-to-left shunting of blood. This line of events could take a few days to develop which would explain why the neonate originally got better on CPAP before being diagnosed with an ASD. Right-to-left shunt means that portion of deoxygenated blood in the right atrium is being shunted to the LA. This oxygen poor blood is then pumped by the left ventricles to the rest of the body. The tissues may not get enough oxygen which will cause signs of cyanosis.
Embryology of Heart
The heart is the first functioning organ within an embryo. It forms from two tubes located bilaterally of the trilaminar embryo21. The heart primordium arises from the splanchnic mesoderm in the cardiac region which can be thought of as bilateral fields that merge cranially to form horseshoe-shaped cardiogenic field22,23. The disc-like embryo undergoes a process of folding where the cranial and lateral part of the embryo fold forward and this process can be observed around 20-22 days after conception21,22. The two tubes fuse together forming a single primordial heart tube which has six distinctive regions. Listed in direction of blood flow they are: sinus venosus (later become the atria), primitive atrium and primitive ventricle (which become atria and ventricle respectively), bulbus cordis (later becomes the right ventricle) and truncus arteriosus which forms the pulmonary and aborting trunks carrying blood away from the heart21,22.
The primordial tube goes through a process of looping during fourth week of development to a shape closely that of an adult heart. It first transformation resembles the shape of letter U and then following shape that of S22,24. Thus, at the end of the first month of pregnancy there a single atrium, a single ventricle and a single arterial trunk.
The partitioning of primitive heart occurs between middle of fourth week and end of fifth week23. The dorsal and ventral walls of the heart and produce two protrusions called endocardial cushions which fuse to form the right and left atrioventricular canals21. This fusion divides the common atrioventricular canal into primitive atrium and ventricle. In the lateral walls the atrioventricular canal two endocardial cushions form which would later become the mitral and tricuspid valves.
Between the primordial atrium the septum primum grows towards the now fused endocardial cushions. The space between the septum and cushions is known as the foramen primum. Before foramen primum completely closes apoptosis-induced perforations appear in the centre of septum primum which forms an opening called the foramen secundum enabling right-to-left shunting of blood. The septum secundum forms to the right of septum primum gradually overlapping the foramen secundum during fifth and sixth week of development25. This incomplete partition of the atrium forms the foramen ovale which remains open until birth as discussed earlier. Blood can flow from the right atrium through the foramen ovale and foramen secundum to the LA thus forming a right-to-left shunt25. The upper section of septum primum degenerates while the lower part is intact and now called the valve of the foramen ovale which acts as a flap. Before birth the pressure in the right side of the fetus is higher than the left but after birth the pulmonary circulation becomes fully functional as result the pressure is now higher in the left side of the heart than the right. The pressure of blood in the LA pushes the valve of foramen ovale against the muscular septum secundum which closes the passageway and it is normally fused around three months after birth.
The bulbus cordis and truncus arteriosus which form the outflow tracts begin developing ridges which are continuous throughout the outflow tract. As these ridges fuse they create two outflow tracts which become the aorta and pulmonary trunk21. Now the heart has two atria and two ventricles with the aorta forming connections with the left ventricle (i.e FO) and the pulmonary trunk connecting to the aorta (i.e DA).
Dopamine, a catecholamine formed by decarboxylation of 3,4-dihydroxyphenylalanine (DOPA), is a well known neurotransmitter as well as a precursor to noradrenaline26,27. It has potent inotropic and chronotropic effects that increase the force and rate of contraction of the myocardium.
Preterm infants are susceptible to hypotension and dopamine is used to increase blood pressure and CO. Dopamine usually has a dose dependant action whereby lower doses act on dopamine receptors having vasodilatory effects by stimulating the renal and mesenteric vascular beds. This peripheral vasodilatation can reduce the afterload, which will increase stroke volume and therefore CO28. Intermediate doses stimulate ? receptors. Action on ?1 receptors can increase CO while action on ?2 receptors can cause broncholidation and relaxation of airway smooth muscle26. Higher doses activate alpha-adrenergic receptors leading to vasoconstriction and increased systemic vascular resistance. However these dose dependant actions are not always seen in preterm infants as plasma concentrations are dependent on metabolism and clearance rather than infusion rates29. Effects of dopamine can also vary due to gestational age dependant peculiarities of the catecholamine receptors29.
Dopamine binding at ?1 receptors in the heart causes G-protein to convert GTP to GDP which activates adenylyl cyclise to generate the second messenger cyclic AMP30. The second messenger activates protein kinases which increases the affinity of myofilaments for Ca2+ and increases transmembrane flux of Ca2+30. The increase in intracellular Ca2+ causes an increased number of cross-bridge formation leading to greater contractility30.It also has the effect of increasing the uptake of Ca2+ into scarcoplasmic reticulum which shortens systole and lengthens diastole30. Longer diastole means the myocardium has more time to extract blood from the coronary arteries. The extended diastolic relaxation can facilitate adequate left ventricular filling despite the reduction in End Diastolic Volume that occurs as a result of increase in heart rate28. Dopamine’s onset of action is within five minutes of intravenous administration which would explain why it is given to the baby to have a quick effect.
In adults dopamine does not cross the blood-brain-barrier, however in infants intravenous administration can cross the incompletely blood-brain-barrier and is capable of inducing marked changes in cerebral monoamine metabolism31,32.
Flow-metabolism is a feature that sustains cerebral oxygen delivery when cerebral metabolic demands (and therefore cerebral oxygen demand) varies31. This mechanism ensures that the brain is provided with adequate levels of oxygen; too little would lead to hypoxia while too much can cause damage to the premature brain though reactive oxygen species31.The cerebral blood flow is maintained by vasoconstriction/vasodilation of the cerebral vasculature and it is thought that dopamine has a big role of play in controlling vascularture tone. Research published in 2009 suggests that dopamine facilitates flow-metabolism coupling in preterm brain33. The results showed that, just like in the mature brain, infants treated with dopamine the cerebral oxygen consumption correlated with cerebral blood flow33.
In conclusion the management of RDS is not as simple as giving surfactant. The presence of congenital defects and other metabolic problems can influence this process. However the increasing understanding of the disease is aiding in the provision of altruistic care.