The Fetus Can Teach Us: Oxygen and the Pulmonary Vasculature

Abstract

Neonates suffering from pulmonary hypertension of the newborn (PPHN) continue to represent an important proportion of patients requiring intensive neonatal care, and have an increased risk of morbidity and mortality. The human fetus has evolved to maintain a high pulmonary vascular resistance (PVR) in utero to allow the majority of the fetal circulation to bypass the lungs, which do not participate in gas exchange, towards the low resistance placenta. At birth, oxygen plays a major role in decreasing PVR to enhance pulmonary blood flow and establish the lungs as the organ of gas exchange. The failure of PVR to fall following birth results in PPHN, and oxygen remains the mainstay therapeutic intervention in the management of PPHN. Knowledge gaps on what constitutes the optimal oxygenation target leads to a wide variation in practices, and often leads to excessive oxygen use. Owing to the risk of oxygen toxicity, avoiding hyperoxemia is as important as avoiding hypoxemia in the management of PPHN. Current evidence supports maintaining arterial oxygen tension in the range of 50-80 mm Hg, and oxygen saturation between 90-97% in term infants with hypoxemic respiratory failure. Clinical studies evaluating the optimal oxygenation in the treatment of PPHN will be enthusiastically awaited.

Keywords: fetal circulation; oxygen saturation; oxygen target; pulmonary hypertension of the newborn.

Figure 1

Fetal circulation. The placenta serves as a major buffer in reducing oxygen exposure to the fetus. The partial oxygen tension (PO₂) in the maternal uterine artery is 90–100 mm Hg compared to 32–35 mm Hg in the fetal umbilical vein (UV). The relatively higher oxygenated UV blood does not completely mix with the blood returning from the fetal body in the inferior vena cava (IVC), and is preferentially streamed towards the left atrium (through the foramen ovale). As the lungs do not participate in gas exchange in utero, the fetal pulmonary vascular resistance is very high, and the pulmonary circulation only receives 16–21% of the combined ventricular cardiac output (by phase-contrast MRI and Doppler studies) in the near-term human fetus. As a result, there is only a small amount of desaturated blood from the pulmonary veins draining into the left atrium, maintaining a relatively high PO₂ in the left heart. Therefore, the blood pumped into the aorta supplying the brain and coronaries contains the highest fetal PO₂ (25–28 mm Hg: saturation 58% in human fetus and 65% in fetal lambs). Desaturated blood returning from the brain and the body into the right heart is pumped through the pulmonary artery and is mostly diverted through the ductus arteriosus to supply the rest of the body. Approximately 29–30% of the combined ventricular cardiac output circulates to the placenta. SO₂: oxyhemoglobin saturation (Copyright Satyan Lakshminrusimha).

Figure 2

Fetal adaptation to maternal hypoxia and hyperoxia. The pulmonary circulation plays an important role in maintaining stable oxygen delivery to the brain. Exposing the mother to supraphysiologic levels of oxygen only slightly raises fetal umbilical venous (UV) partial oxygen tension (PO₂). The higher fetal PO₂ increases blood flow towards the lungs, resulting in more desaturated blood draining into the left atrium from the pulmonary veins, thus lowering the PO₂ in the left heart supplying the brain. With more blood flowing to the lungs, there is decreased blood flow to the brain, effectively counterbalancing the higher UV PO₂ and maintaining constant oxygen delivery to the brain. Other protective mechanisms to avoid oxygen toxicity are highlighted in the red boxes. Conversely, exposing the mother to a hypoxic environment leads to a decrease in UV PO₂ causing increased pulmonary vascular resistance and less blood shunting to the lungs, therefore limiting the amount of desaturated blood returning to the left atrium from the pulmonary veins. Increased umbilical flow, dilation of the ductus venosus, and cerebral vasodilation increase blood flow to the brain to counteract the lower PO₂ to maintain oxygen delivery (Copyright Satyan Lakshminrusimha).

Figure 3

Umbilical venous partial pressure of oxygen and fetal hemoglobin during gestation. There is a linear decrease in the partial oxygen tension (PO₂) with a concomitant rise in fetal hemoglobin as gestation progresses, which maintains the oxygen content in the blood constant throughout gestation. In addition, replacing fetal hemoglobin with adult hemoglobin packed red cells increases fetal PO₂ by 4.8 mm Hg and maintains similar oxygen content. HbA: adult hemoglobin; HbF: fetal hemoglobin; PRBC: packed red blood cell. Data from [29] (Copyright Satyan Lakshminrusimha).

Figure 4

Oxygen hemoglobin dissociation curves and oxygen supply. The higher oxygen affinity of fetal hemoglobin (purple curve) shifts the oxygen dissociation curve to the left, which results in a greater release in oxygen at lower arterial partial oxygen tension (PO₂) compared to adult hemoglobin (red curve). In the adult, a decrease in PO₂ from 97 mm Hg (level present in arterial blood) to 40 mm Hg (level in venous blood) results in a release of oxygen amounting to ≈5 mL/dL (area shaded in red). For the fetus, the difference between the umbilical venous PO₂ (35 mm Hg) and the umbilical arterial PO₂ (25 mm Hg) results in a similar release of oxygen to the tissues of ≈4 mL/dL (area shaded in blue). AVDO₂: arterio-venous difference in oxygen content. Data from [20] (Copyright Satyan Lakshminrusimha).

Figure 5

Relationship between oxygen delivery and consumption. O₂ delivery is a product of blood flow and arterial O₂ content. When O₂ delivery decreases below a critical point, O₂ consumption is compromised leading to anaerobic metabolism and lactic acidosis. The driving force for O₂ into mitochondria is PO₂. Increased mitochondrial PO₂ can lead to reactive oxygen species formation, while hypoxia can exacerbate pulmonary vasoconstriction. The optimal target range encompasses oxygenation that guarantees an oxygen delivery higher than the critical point so that oxygen consumption is not dependent on delivery, while also avoiding oxygen toxicity. Hb: hemoglobin; SaO₂: arterial oxyhemoglobin saturation (Copyright Satyan Lakshminrusimha).