Optimal Oxygen Targets in Term Lambs with Meconium Aspiration Syndrome and Pulmonary Hypertension

Abstract

Optimal oxygen saturation as measured by pulse oximetry (Sp_O2) in neonatal lung injury, such as meconium aspiration syndrome (MAS) and persistent pulmonary hypertension of newborn (PPHN), is not known. Our goal was to determine the Sp_O2 range in lambs with MAS and PPHN that results in the highest brain oxygen delivery (bDO₂) and pulmonary blood flow (Qp) and the lowest pulmonary vascular resistance and oxidative stress. Meconium was instilled into endotracheal tubes in 25 near-term gestation lambs, and the umbilical cord was occluded to induce asphyxia and gasping, causing MAS and PPHN. Lambs were randomized into four groups and ventilated for 6 hours with fixed fraction of inspired oxygen (Fi_O2) = 1.0 irrespective of Sp_O2, and three groups had Fi_O2 titrated to keep preductal Sp_O2 between 85% and 89%, 90% and 94%, and 95% and 99%, respectively. Tissues were collected to measure nitric oxide synthase activity, 3-nitrotyrosine, and 8-isoprostanes. Throughout the 6-hour exposure period, lambs in the 95-99% Sp_O2 target group had the highest Qp, lowest pulmonary vascular resistance, and highest bDO₂ but were exposed to higher Fi_O2 (0.5 ± 0.21 vs. 0.29 ± 0.17) with higher lung 3-nitrotyrosine (0.67 [interquartile range (IQR), 0.43-0.73] ng/mcg protein vs. 0.1 [IQR, 0.09-0.2] ng/mcg protein) and lower lung nitric oxide synthase activity (196 [IQR, 192-201] mMol nitrite/mg protein vs. 270 [IQR, 227-280] mMol nitrite/mg protein) compared with the 90-94% target group. Brain 3-nitrotyrosine was lower in the 85-89% target group, and brain/lung 8-isoprostane levels were not significantly different. In term lambs with MAS and PPHN, Qp and bDO₂ through the first 6 hours are higher with target Sp_O2 in the 95-99% range. However, the 90-94% target range is associated with significantly lower Fi_O2 and lung oxidative stress. Clinical trials comparing the 90-94% versus the 95-99% Sp_O2 target range in term infants with PPHN are warranted.

Keywords: PPHN; lung injury; oxygen saturation.

Figure 1.

Oxygenation. (A) Box plot showing oxygen saturations achieved in the three target saturations groups and fixed 100% inspired oxygen from 15 minutes to 6 hours of postnatal age. Horizontal colored bars reflect the desired target oxygen saturation (Sp_O2) range. There was overlap in oxygen saturations between the three target Sp_O2 groups. However, the saturations achieved by the three target groups were different (P < 0.0001). In addition, the 100% fixed inspired oxygen group achieved significantly higher Sp_O2 compared with the 85–89% target (P < 0.001) and 90–94% target groups (P = 0.0022). There was no significant difference between the 95–99% target group and the fixed Fi_O2 = 1.0 group. (B) Changes in preductal oxygen saturations during different time points in the lambs ventilated with inspired oxygen to target saturations in the 85–89% range (solid green triangle), the 90–94% range (blue cross), and the 95–99% range (open black square). The lambs ventilated with fixed 100% inspired oxygen are shown in open red diamonds. The three target saturation ranges were different by repeated-measures ANOVA (P = 0.005). (C) Inspired oxygen to maintain target saturations in the three Sp_O2 target groups. The inspired oxygen required to maintain saturations in the 95–99% target range was higher than that in the 90–94% (P < 0.0001) and 85–89% ranges (P = 0.0017) by repeated-measures ANOVA. (D) Partial pressure of oxygen in preductal (right carotid arterial) blood (Pa_O2) in the four groups. Lambs ventilated with fixed 100% inspired oxygen had higher Pa_O2 than the three target saturation groups. Pa_O2 in the 85–89% group was lower than in the 90–94% (P = 0.02) and 95–99% groups (P = 0.01). There was no difference between the 90–94% and 95–99% target Sp_O2 groups.

Figure 2.

Ventilation parameters. (A and B) The changes in ventilator rate (A) and mean airway pressure (B) during 6 hours of postresuscitation phase are shown. (C) Changes in the Pa_CO2 during asphyxiation and 6 hours of postresuscitation phase. There were no significant differences between the four groups (100% fixed inspired oxygen [open red diamonds], 85–89% target Sp_O2 [solid green triangles], 90–94% target Sp_O2 [blue crosses], and 95–99% target Sp_O2 [open black squares]). Pa_CO2 = arterial carbon dioxide pressure.

Figure 3.

Systemic hemodynamics. (A–C) Changes in heart rate (A), mean systemic blood pressure (B), and left carotid blood flow (C) during asphyxiation and 6 hours of postresuscitation phase are shown. The lambs ventilated to maintain target oxygen saturation in the 85–89% range (solid green triangles) had lower heart rates than those in the 90–94% (P = 0.03) (blue crosses) and 95–99% (P = 0.01) (open black squares) groups. Similarly, lambs ventilated with fixed 100% inspired oxygen (open red diamonds) also had lower heart rates than 90–94% (P = 0.03) and 95–99% (P = 0.008) oxygen saturation groups. The mean blood pressure was lower in the 85–89% target group compared with the 90–94% (P = 0.014) and 95–99% (P = 0.05) target groups. There carotid artery blood flows (C) were similar between the groups. *Significantly different from the 90–94% and 95–99% target groups. BPM = beats per minute.

Figure 4.

Pulmonary hemodynamics. (A–C) Changes in left pulmonary arterial blood flow (A), mean pulmonary arterial blood pressure (B), and left pulmonary vascular resistance (C) during asphyxiation and 6 hours of postresuscitation phase are shown. (A) Pulmonary blood flow was lower in the lambs randomized to the 85–89% (solid green triangles) target oxygen saturation range compared with those randomized to the 90–94% (P = 0.0007) (blue crosses) and 95–99% (P = 0.0023) (open black squares) ranges. Lambs ventilated with fixed 100% inspired oxygen (red diamonds) also had lower pulmonary blood flow than the 90–94% (P = 0.012) and 95–99% target groups (P = 0.04). (B) Mean pulmonary artery pressure was not significantly different between the groups. (C) Pulmonary vascular resistance was lower in the 95–99% target group compared with the 85–89% (P = 0.05) and 90–94% (P = 0.05) target groups. The pulmonary vascular resistance of the fixed 100% inspired oxygen group was lower than that of the 85–89% (P = 0.05) and 90–94% (P = 0.04) target groups. *Significantly different from the 90–94% and 95–99% target groups. ^†Significantly different from the 85–89% and 90–94% target groups.