How Do We Monitor Oxygenation During The Management of PPHN? Alveolar, Arterial, Mixed Oxygen Tension or Peripheral Saturation?

Oxygen is a pulmonary vasodilator and plays an important role in mediating circulatory transition from fetal and postnatal period. Alveolar oxygen tension (PAO2) and pulmonary arterial PO2 are the main factors that influence hypoxic pulmonary vasoconstriction (HPV). Inability to achieve adequate pulmonary vasodilation at birth leads to persistent pulmonary hypertension of the newborn (PPHN). Supplemental oxygen is the mainstay of PPHN management. However, optimal monitoring of oxygenation to achieve low pulmonary vascular resistance (PVR) and optimize oxygen delivery to vital organs is not known. Noninvasive pulse oximetry measures peripheral saturations (SpO2) and ranges 91-95% are recommended during acute PPHN management. However, for a given SpO2, there is wide variability in arterial oxygen tension, especially with variations in hemoglobin type (transfusions), pH and body temperature. This review evaluates the role of alveolar, preductal, postductal, and mixed venous oxygen tension and SpO2 in the management of PPHN. Translation and clinical studies suggest maintaining an arterial oxygen tension of 50-80 mmHg to help decrease PVR and optimize pulmonary vasodilator management. Nevertheless, there are no randomized clinical trials evaluating outcomes in PPHN based on targeting SpO2 or PO2. However, most critically ill patients have umbilical arterial catheters and postductal arterial oxygenation may not be an accurate assessment of oxygen delivery to vital organs or factors influencing HPV. The mixed venous oxygen tension from umbilical venous catheter blood gas may assess pulmonary arterial PO2 and potentially predict HPV. It is crucial to conduct randomized controlled studies with different PO2/SpO2 ranges and compare outcomes in PPHN.


Introduction:
Persistent pulmonary hypertension of the newborn (PPHN) occurs when there is impaired pulmonary vascular transition during birth due to disruption of pulmonary vasodilator mechanisms. Impaired transition from fetal to neonatal circulation leads to elevated pulmonary vascular resistance (PVR), right-to-left shunts at patent foramen ovale (PFO) and/or patent ductus arteriosus (PDA) leading to hypoxemia [1]. Both term and preterm neonates are at risk for PPHN [2][3][4][5]. The course of preterm neonates in the neonatal intensive care unit (NICU) is further complicated by the development of bronchopulmonary dysplasia (BPD) and can potentially be associated with pulmonary hypertension (PHT) [6][7][8]. The incidence of PPHN in neonates are often underestimated but is thought to be around 1.8 to 2/1000 live births [1,5,9]. In infants with PPHN, several studies report poor long-term neurodevelopment outcomes and higher early mortality rates despite pulmonary vasodilator therapies [1,10,11]. At birth, with the initiation of spontaneous breathing or with positive pressure ventilation (PPV) and with adequate lung inflation, the pulmonary blood flow (PBF) increases by 8 to 10-fold along with a decrease in PVR. As the fetus grows in a relatively hypoxemic environment, increase in oxygen tension seems to play a significant role in decreasing PVR at birth [12]. Optimal oxygenation is necessary to meet tissue demand, especially in vital organs such as brain and heart and to prevent hypoxic pulmonary vasoconstriction (HPV). This review intends to discuss the role of oxygen tension (PO2) and pulse oximetry (SpO2) during the management of PPHN. With lack of clinical evidence on optimal oxygenation in PPHN, this review discusses data from both term and preterm translational models associated with high PVR in the perinatal period.

Discussion:
Understanding the relationship of fetal oxygenation, PVR, PBF in both the fetus and newborn is critical to managing a neonate with PPHN.

Relation of PO2 and fetal PVR:
The fetus develops with placenta serving as an organ of gas exchange.
The highest PO2 within the fetal circulation is approximately 32-35 mmHg in the umbilical vein. There is a further decrease in PO2 to 25-28 mmHg in the ascending aorta supplying the developing brain and myocardium [13][14][15]. The placenta protects the fetus from maternal hyperoxia and hypoxia [14,15]. As observed in translation studies, during maternal hyperoxia/hypoxia, the distribution of blood in the placenta, channeling of blood to and from the fetal liver by ductus venosus, and alteration of PVR (increase/decrease) avoids excessive fluctuations in fetal PO2 [16]. The relationship of fetal PVR to PO2 is dependent on the gestational age of the fetus [17]. At term gestation, PVR changes dramatically in response to fetal PO2 [18].

Gestational age, fetal PVR, and PO2:
The changes in PVR to PO2 in relation to gestational age (GA) were studied in fetal ovine model [19]. Ovine fetuses at different gestational ages of 0.6 (103-104/term ~150d), 0.74 (112-119d), 0.80 (121-130d, and 0.90 (132-138d) were exposed to hypoxia or hyperoxia by adjusting the oxygen exposure to the ewe. Pulmonary vasoconstriction and vasodilation were observed at term gestation when exposed to low and high PO2. Hypoxia and hyperoxia did not have a significant effect on PVR at 0.6 and 0.74 gestation. In humans, maternal hyperoxia did not alter fetal PBF at 20-26 weeks GA but increased PBF and reduced atrial and ductal shunting at 31 to 36 weeks [20]. Extrapolating from these findings, the pulmonary vascular response to PO2 seems to increase with advancing gestational age.

Effect of PO2 on PVR at birth:
During the normal transition, spontaneous breath initiated by the newborn infant ventilates the lung and increases alveolar oxygen tension, which increases PBF reducing PVR, successfully switching from fetal to neonatal circulation [21]. Multiple factors such as mode of delivery (vaginal delivery results in more rapid reduction in PVR compared to an elective cesarean section), maturity, antenatal glucocorticoids, temperature (hypothermia increases PVR), mode of cord clamping and asphyxia (related to higher PVR), could affect transition at birth [22].
These factors affect the balance between the vasoconstrictors (endothelin-1, thromboxane), and vasodilators (prostacyclin and endothelium derived nitric oxide), which exert their effects on the pulmonary artery smooth muscle cells (PASMC). Despite these factors, oxygen (O2) seems to play a greater role in the regulation of PVR by having a direct effect on PASMC. Oxygen stimulates the increased production of pulmonary endothelial nitric oxide (NO), which is a potent pulmonary vasodilator birth [22].

Oxygen and hypoxic pulmonary vasoconstriction (HPV):
A fundamental difference between pulmonary blood vessels and systemic vessels is their ability to constrict in response to hypoxia [23].
Regional HPV diverts blood away from underventilated alveoli and promotes ventilation-perfusion (V/Q) matching. HPV is mediated by PO2 surrounding the precapillary pulmonary arteriole ( figure   1) and is influenced both by mixed venous (pulmonary arterial) PVO2 and alveolar PAO2 [24]. The stimulus for HPV is dictated by the equation P(stimulus)O2 = PVO2 0.375 X PAO2 0.626 . Based on this equation, it is clear that alveolar PAO2 is the predominant factor determining the severity of HPV.

Supplemental oxygen and PO2 during the transition:
Oxygen supplementation is the most common resuscitative measure for newborns in the delivery room. American Academy of Pediatrics Neonatal Resuscitation Program (AAP NRP), recommend that supplemental O2 be started at concentrations of 21% O2 in term and 21-30% O2 in preterm neonates and to titrate based on prespecified preductal saturations [25]. Given the ease and universal use of pulse oximetry, preductal oxygen saturations (SpO2) could be the most efficient way of targeting oxygenation in the delivery room and the neonatal intensive care unit (NICU). However, for a given saturation range, the achieved PO2 could vary widely and the extremes of SpO2 have low accuracy [26]. In a newborn, requiring resuscitation, hypoperfusion could also decrease the accuracy of SpO2.

Oxygen tension in spontaneous air breathing infants: The concept of normoxemia in a transitioning
newborn is not well defined. A healthy newborn, who transitioned from placenta to lungs as an organ of gas exchange, sees a rise in arterial oxygen tension (PaO2) by 30 -40 mmHg from fetal values. The higher alveolar and arterial PaO2 along with ventilation plays a greater role in decreasing PVR and increase in PBF. In a study using transitional ovine model (near term gestation comparable to human term neonates), the use 21% O2 lead to PaO2 values of 50 -60 mmHg [12]. The observed decrease in PVR (0.24 -0.0013 mmHg/ml/kg/min) from fetal life occurred at a PaO2 of 52.5 ± 1.7 mmHg, also known as the change point [12]. In human neonates, who were spontaneously breathing room air, 176 samples of arterial blood gas were analyzed [27]. The analysis showed that 80% of the PaO2 was between 40 -80 mmHg and the average PaO2 was 64 mmHg. A recent study, defined normoxemia with a PaO2 range of 50 -80 mmHg [28]. Based on these observations, the PaO2 in normal neonates mostly ranges between 50 -80 mmHg.

Oxygen tension and PPHN:
In a neonate with PPHN secondary to failed transition or underlying lung pathology, the elevated pulmonary pressures often lead to shunting of blood from pulmonary to the systemic circulation, leading to profound and labile hypoxemia despite PPV and supplemental oxygen. Adequate oxygenation remains the cornerstone of PPHN management in both term and preterm neonates.

Alveolar PO2 and its effect on PPHN:
The alveolar PO2 (PAO2), which takes into account the inspired O2 concentration and arterial oxygenation and carbon dioxide tension, is a major determinant of HPV [29]. In the presence of parenchymal lung injury and or immature lungs, alveolar hypoxia could exacerbate pulmonary vasoconstriction. Studies done four decades ago, using ovine models, have shown that alveolar hypoxia leads to significant HPV leading to redistribution of pulmonary circulation to both lungs exacerbating ventilation-perfusion mismatch [30].  [31]. One concern with alveolar PAO2 is that it is calculated using mathematical equations and in heterogenous lung disease, different areas of the lung may have different PAO2 values. In a meconium aspiration model of ovine PPHN, increase in PaO2 and PAO2 were necessary to achieve adequate decrease in PVR.

Arterial oxygen tension and its effect on PPHN:
Preductal arterial oxygenation (PaO2) is typically used to assess the severity (based on oxygenation index), management, and response to therapy of PPHN.  [17].
Similarly, the change point for preductal PaO2 was 45 ± 0.1 mmHg in a model of asphyxia with meconium aspiration syndrome. Recently, we have shown that in a model of asphyxia and meconium aspiration with PPHN, within the first 6 hours post-resuscitation, targeting a preductal SpO2 of 95-99%, with a corresponding PaO2 of 58±19 mmHg was associated with the lowest PVR (0.55±0.15 mmHg/ml/kg/min), with an inspired oxygen requirement of 68±18 % [32]. In this study, the SpO2 range of 90-94 % had a similar PaO2 (56±11 mmHg), but the corresponding PVR was much higher with a significantly lower inspired oxygen requirement (30±17 %) [32]. These results shown in figure 2 outline the importance of alveolar PAO2 in addition to arterial PaO2 in mediating lower PVR. While the PaO2 in the 90-94% target SPO2 group and 95-99% target SpO2 group were identical, the difference in FiO2 contributed to the drop in PVR were different (Figure 1).
With the available data, preductal PaO2 has a high utility in neonate PPHN as it dictates the amount of oxygen delivered to the brain and coronary circulation. In summary, targeting preductal arterial oxygenation in the clinically accepted range of normoxemia (50-80 mmHg), could help in managing PPHN by optimizing oxygen delivery, but is not the only factor determining PVR. Providing adequate FiO2 to maintain optimal alveolar PAO2 is also important in mediating pulmonary vasodilation. Avoiding extremely high PaO2 (> 100 mmHg) and PAO2 (> 300 mmHg) may potentially facilitate response to other pulmonary vasodilators, reducing high cumulative oxygen and its toxicity [12,29,31]. The optimal PaO2 range during acute phase of PPHN warrants further clinical trials focusing on both short-term and long-term outcomes.

Postductal PaO2 (PDPaO2) and PPHN:
Given the easy access path in neonates, a high umbilical arterial catheter (UAC), with its tip in the thoracic portion of the descending aorta, is the most commonly placed arterial access in the NICU [33]. When blood gas is obtained from the UAC, it usually reflects PDPaO2 unless the ductus arteriosus is closed. Labile hypoxemia, in the presence of shunting from pulmonary to systemic circulation, could present with pre and post ductal PaO2 gradient of 10 -20 mmHg, which often goes in hand with pre and post ductal SpO2 difference and is characteristic of PPHN. In the absence of shunting, a PDPaO2 could reflect preductal PaO2. In a clinical trial comparing the blood gas to saturation values, out of 800 arterial blood gas samples collected, 88% of the samples were postductal, which reflects the extensive use of PDPaO2 to evaluate and guide therapy when supplemental oxygen is needed [27].

Mixed venous oxygen tension (PvO2) and management of PPHN:
The mixed venous PO2 typically refers to oxygen tension in the pulmonary artery [34]. Since umbilical venous catheters (UVC) are commonly placed in the NICU, the blood gas obtained from a UVC is used as a proxy for mixed venous gas [35]. The PVO2 could assess the tissue oxygenation in neonates. In a clinical study

Effect of transfusion, acidity (pH) and temperature on relationship between SpO2 and PaO2 in PPHN:
The influence of transfusion, temperature and acidity (pH) on SpO2 and PaO2 could be explained by oxygen dissociation curve. Oxygen dissociation curve (ODC) explains the relationship between oxygen saturation of the hemoglobin (plotted in y-axis) and oxygen tension (plotted in x-axis), which is essential for oxygen absorption in the lungs and delivery to the tissues [38]. A right shift in the curve is associated with release of O2 to the tissues and a left shift is associated with O2 absorption from the lungs. Fetal hemoglobin (HbF) is the predominant type during fetal and neonatal period.
Secondary to high affinity of HbF to O2 the ODC is shifted to the left in neonates and this could lead to higher oxygen saturation for lower PaO2. Thus for a PaO2 of approximately 40 mmHg, the SpO2 could be between 85 -93% , and for a SpO2 of 97% the PaO2 could be > 100 mm Hg [27]. Factors such as blood transfusions affect the ODC. The packed red blood cell transfusion that predominantly has HbA (adult hemoglobin), could alter the oxygen affinity moving the ODC to the right affecting the relation between SpO2 and PaO2 [38]. PPHN, respiratory failure and carbon dioxide retention with low pH could move the ODC right with lower affinity of Hb to O2, which affects the SpO2 for a given PaO2. Lastly, temperature affects the blood gas analysis unless it is corrected [39].
The solubility of a gas increases with lower temperature and it is important to analyze blood gas with   2). Thus, it is important that blood transfusions, pH and temperature be taken into account while managing an infant with PPHN. Periodically checking arterial blood gases and trying to maintain PaO2 at or slightly above 50 mmHg may also help in the management of PPHN by avoiding HPV.

Conclusion:
In the management of PPHN, arterial oxygen tension plays an essential role in diagnosis, assess severity, guide treatment, facilitate specific pulmonary vasodilator therapy, evaluate the response to therapy, and to escalate care if needed. Since an UAC placement is standard of care, the disadvantage of having PDPaO2 could be a limitation, especially in severe PPHN with labile hypoxemia with ductal shunts. Preductal oxygenation dictates oxygen delivery to brain and heart. Hypoxic pulmonary vasoconstriction is associated with low alveolar oxygen tension and mixed venous oxygen tension.
While SpO2 provides a continuous, non-invasive assessment of preductal oxygenation, periodic blood gas evaluation is warranted especially in the presence of hypothermia or acidosis.