Factors to Consider to Study Preductal Oxygen Saturation Targets in Neonatal Pulmonary Hypertension

Abstract

There are potential benefits and risks to the infant with higher and lower oxygen saturation (SpO2) targets, and the ideal range for infants with pulmonary hypertension (PH) remains unknown. Targeting high SpO2 can promote pulmonary vasodilation but cause oxygen toxicity. Targeting lower SpO2 may increase pulmonary vascular resistance, especially in the presence of acidosis and hypothermia. We will conduct a randomized pilot trial to compare two ranges of target preductal SpO2 in late-preterm and term infants with hypoxic respiratory failure (HRF) and acute pulmonary hypertension (aPH) of the newborn. We will assess the reliability of a newly created HRF/PH score that could be used in larger trials. We will assess trial feasibility and obtain preliminary estimates of outcomes. Our primary hypothesis is that in neonates with PH and HRF, targeting preductal SpO2 of 95-99% (intervention) will result in lower pulmonary vascular resistance and pulmonary arterial pressures, and lower the need for pulmonary vasodilators (inhaled nitric oxide-iNO, milrinone and sildenafil) compared to targeting SpO2 at 91-95% (standard). We also speculate that a higher SpO2 target can potentially induce oxidative stress and decrease response to iNO (oxygenation and pulmonary vasodilation) for those patients that still require iNO in this range. We present considerations in planning this trial as well as some of the details of the protocol design (Clinicaltrials.gov (NCT04938167)).

Keywords: hypoxic respiratory failure; oxygen saturation; persistent pulmonary hypertension of the newborn (PPHN); pulmonary vascular resistance; randomized trial; study protocol.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1

Oxygen saturations targets (SpO2), fraction inspired oxygen (FiO2), pulmonary vascular resistance (PVR), pulmonary blood flow (Qp), preductal partial arterial oxygen tension (PaO2) and achieved SpO2 (interquartile range—IQR) in lambs with meconium aspiration. The horizontal axis demonstrates the achieved preductal SpO2 ranges and interquartile ranges (IQR) closest to the figure and then the target SpO2 range just below the achieved ranges. Modified from Lakshminrusimha S., Keszler M., Chapter 34, Diagnosis and management of persistent pulmonary hypertension in assisted ventilation of the neonate, 7th edition, 2021. Copyright Satyan Lakshminrusimha.

Figure 2

Speculation regarding the basis for increased incidence of morbidities associated with hypoxia among black neonates and those associated with hyperoxia among white infants. Copyright Satyan Lakshminrusimha.

Figure 3

Hemoglobin–oxygen dissociation curve shifts to the left in hypothermia (Afzal et al., 2019). PaO2 = partial arterial oxygen tension, SpO2 = oxygen saturation. To achieve the clinically accepted range of PaO2 50–80 mmHg, SpO2 target is in the low-to-mid 90 s during normothermia but in the high 90 s during whole body hypothermia. Copyright Satyan Lakshminrusimha.

Figure 4

Benefits and risks associated with targeting lower (left panel) and higher (right panel) oxygen targets. Lower targets may be associated with lower alveolar oxygen tension (PAO2), possibly less pulmonary vasodilation especially in the presence of hypothermia and acidosis resulting in exacerbation of hypoxic pulmonary vasoconstriction and high right ventricular (RV) afterload. However, inhaled nitric oxide (iNO) may be more effective due to less inactivation by superoxide anions (O2−) and there may be less oxidative stress and improved cerebral blood flow. Higher oxygen target may be associated with need for higher FiO2, higher PAO2 and enhanced pulmonary vasodilation decreasing RV afterload and right-to-left (R → L) shunts. However, higher inspired oxygen can lead to increased superoxide anion formation that may interact with nitric oxide to form peroxynitrite (OONO−), a toxic substance that can inactivate surfactant, cause inflammation and pulmonary vasoconstriction. Copyright Satyan Lakshminrusimha.

Figure 5

Hypoxic Respiratory Failure and Pulmonary Hypertension Score (HRF/PH). (a) Oxygenation component of score. (b) Echocardiographic portion of score for PH. (c) Total HRF/PH score = Oxygenation score + Echocardiogram Score. CPAP = continuous positive airway pressure, NIPPV = non-invasive positive pressure ventilation, LPM = liters per minute, FiO2 = fraction of inspired oxygen, OSI = oxygen saturation index, OI = oxygenation index (if both OI and OSI are available, OI will preferentially be used), SpO2 = pulse oximetry oxygen saturation, MAP = mean airway pressure, PaO2 = partial pressure of arterial oxygen, RVsP = right ventricular systolic pressure, RV DYSFxN = right ventricular dysfunction, TAPSE = tricuspid annular plane systolic excursion, mm = millimeters. Copyright Avni Bhatt.

Figure 6

Overview of study design and objectives. Copyright Satyan Lakshminrusimha.

Figure 7

Study events following consent. CDH = congenital diaphragmatic hernia, FiO2 = fraction inspired oxygen, SpO2 = oxygen saturation, iNO = inhaled nitric oxide. Copyright Satyan Lakshminrusimha.

Figure 8

Oxygen saturation target and alarm limits for standard arm and intervention arm. Copyright Satyan Lakshminrusimha.