Outcomes of Two Trials of Oxygen-Saturation Targets in Preterm Infants.

BACKGROUND: The safest ranges of oxygen saturation in preterm infants have been the subject of debate. METHODS: In two trials, conducted in Australia and the United Kingdom, infants born before 28 weeks' gestation were randomly assigned to either a lower (85 to 89%) or a higher (91 to 95%) oxygen-saturation range. During enrollment, the oximeters were revised to correct a calibration-algorithm artifact. The primary outcome was death or disability at a corrected gestational age of 2 years; this outcome was evaluated among infants whose oxygen saturation was measured with any study oximeter in the Australian trial and those whose oxygen saturation was measured with a revised oximeter in the U.K. trial. RESULTS: After 1135 infants in Australia and 973 infants in the United Kingdom had been enrolled in the trial, an interim analysis showed increased mortality at a corrected gestational age of 36 weeks, and enrollment was stopped. Death or disability in the Australian trial (with all oximeters included) occurred in 247 of 549 infants (45.0%) in the lower-target group versus 217 of 545 infants (39.8%) in the higher-target group (adjusted relative risk, 1.12; 95% confidence interval [CI], 0.98 to 1.27; P=0.10); death or disability in the U.K. trial (with only revised oximeters included) occurred in 185 of 366 infants (50.5%) in the lower-target group versus 164 of 357 infants (45.9%) in the higher-target group (adjusted relative risk, 1.10; 95% CI, 0.97 to 1.24; P=0.15). In post hoc combined, unadjusted analyses that included all oximeters, death or disability occurred in 492 of 1022 infants (48.1%) in the lower-target group versus 437 of 1013 infants (43.1%) in the higher-target group (relative risk, 1.11; 95% CI, 1.01 to 1.23; P=0.02), and death occurred in 222 of 1045 infants (21.2%) in the lower-target group versus 185 of 1045 infants (17.7%) in the higher-target group (relative risk, 1.20; 95% CI, 1.01 to 1.43; P=0.04). In the group in which revised oximeters were used, death or disability occurred in 287 of 580 infants (49.5%) in the lower-target group versus 248 of 563 infants (44.0%) in the higher-target group (relative risk, 1.12; 95% CI, 0.99 to 1.27; P=0.07), and death occurred in 144 of 587 infants (24.5%) versus 99 of 586 infants (16.9%) (relative risk, 1.45; 95% CI, 1.16 to 1.82; P=0.001). CONCLUSIONS: Use of an oxygen-saturation target range of 85 to 89% versus 91 to 95% resulted in nonsignificantly higher rates of death or disability at 2 years in each trial but in significantly increased risks of this combined outcome and of death alone in post hoc combined analyses. (Funded by the Australian National Health and Medical Research Council and others; BOOST-II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry number, ACTRN12605000055606.).

Oxygen saturation and outcomes in preterm infants.

BACKGROUND: The clinically appropriate range for oxygen saturation in preterm infants is unknown. Previous studies have shown that infants had reduced rates of retinopathy of prematurity when lower targets of oxygen saturation were used. METHODS: In three international randomized, controlled trials, we evaluated the effects of targeting an oxygen saturation of 85 to 89%, as compared with a range of 91 to 95%, on disability-free survival at 2 years in infants born before 28 weeks' gestation. Halfway through the trials, the oximeter-calibration algorithm was revised. Recruitment was stopped early when an interim analysis showed an increased rate of death at 36 weeks in the group with a lower oxygen saturation. We analyzed pooled data from patients and now report hospital-discharge outcomes. RESULTS: A total of 2448 infants were recruited. Among the 1187 infants whose treatment used the revised oximeter-calibration algorithm, the rate of death was significantly higher in the lower-target group than in the higher-target group (23.1% vs. 15.9%; relative risk in the lower-target group, 1.45; 95% confidence interval [CI], 1.15 to 1.84; P=0.002). There was heterogeneity for mortality between the original algorithm and the revised algorithm (P=0.006) but not for other outcomes. In all 2448 infants, those in the lower-target group for oxygen saturation had a reduced rate of retinopathy of prematurity (10.6% vs. 13.5%; relative risk, 0.79; 95% CI, 0.63 to 1.00; P=0.045) and an increased rate of necrotizing enterocolitis (10.4% vs. 8.0%; relative risk, 1.31; 95% CI, 1.02 to 1.68; P=0.04). There were no significant between-group differences in rates of other outcomes or adverse events. CONCLUSIONS: Targeting an oxygen saturation below 90% with the use of current oximeters in extremely preterm infants was associated with an increased risk of death. (Funded by the Australian National Health and Medical Research Council and others; BOOST II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry numbers, ACTRN12605000055606 and ACTRN12605000253606.).

Cerebral fractional oxygen extraction is inversely correlated with oxygen delivery in the sick, newborn, preterm infant.

Cerebral blood flow (CBF) is known to be low in newborn infants, but this has not been shown to be damaging. The purpose of this study was to investigate the relationships between cerebral haemoglobin flow, blood flow, oxygen delivery, oxygen consumption, venous saturation, and fractional oxygen extraction (OEF) in newborn, preterm infants. Measurements were made by near-infrared spectroscopy in 13 very preterm, extremely low birth weight infants (median gestation 25 weeks) during the first 3 days after birth. There was a negative correlation between cerebral oxygen delivery and OEF (n=13, r=-0.5, P=0.03), which implies that when there is a reduction in cerebral oxygen delivery in sick preterm infants, increased cerebral oxygen extraction may be responsible for maintaining oxygen availability to the brain. During the first 3 days after birth CBF (n=13, r=0.7, P=0.01), oxygen delivery (n=13, r=0.5, P=0.03), and oxygen consumption (n=13, r=0.7, P=0.004) all increased. This increase in oxygen consumption indicates increased cerebral metabolic activity after birth, which is likely to be a normal adaptation to extrauterine life. The increases in blood flow and oxygen delivery may also be normal adaptations that facilitate this increase in metabolic activity. There was a decrease (P=0.04) in mean (+/-s.d.) cerebral OEF between day 1 (0.37+/-0.10) and day 2 (0.29+/-0.09), with no change between day 2 and day 3. Taking into account the negative correlation between OEF and oxygen delivery, this decrease in OEF may be because of increased oxygen delivery during this time.

Postnatal changes in cerebral oxygen extraction in the preterm infant are associated with intraventricular hemorrhage and hemorrhagic parenchymal infarction but not periventricular leukomalacia.

Fluctuations in cerebral hemodynamics have been implicated in the pathogenesis of acquired brain damage in babies born prematurely. This study examined the changes in cerebral fractional oxygen extraction (FOE) over the first 3 d after birth in 25 very-low-birth-weight preterm infants. Twelve infants had no major cerebral injury and 13 had acquired brain injury; cystic periventricular leukomalacia (PVL) was present in 4 and intraventricular hemorrhage (IVH) in 9, of whom 2 also had hemorrhagic parenchymal infarction (HPI). Normal values (median, 5(th)-95(th) centiles) for cerebral FOE in very-low-birth-weight infants with no cerebral injury were 0.38 (0.23-0.53) on d 1, 0.31 (0.18-0.45) on d 2, and 0.28 (0.17-0.38) on d 3. Infants who developed cystic PVL had no significant change in cerebral FOE during the first 3 d after birth. By contrast, cerebral FOE fluctuated in infants with IVH over the 3 d of measurement, decreasing from d 1 to d 2 (p = 0.03) and increasing from d 2 to d 3 (p = 0.02). The highest cerebral FOE values were seen in the two infants with HPI. The different patterns of change in cerebral FOE with HPI and cystic PVL provide additional evidence that the pathogenesis of these two conditions is different. Because high cerebral FOE is likely to be a consequence of low cerebral oxygen delivery, probably because of low cerebral blood flow, our results indicate that fluctuations in cerebral blood flow may occur when there is IVH or HPI.

Cerebral fractional oxygen extraction in very low birth weight infants is high when there is low left ventricular output and hypocarbia but is unaffected by hypotension.

This study examined the relationships between cerebral fractional oxygen extraction (FOE), mean arterial blood pressure (MABP), left ventricular output (LVO), blood gases, and other physiologic variables in 36 very-low-birth-weight preterm infants during the first 3 d after birth. There was a decrease in cerebral FOE (p = 0.008), and rises in LVO (p < 0.0001) and MABP (p = 0.02) during the 3 d. Between d 1 and 2, cerebral FOE decreased (p = 0.007) and LVO increased (p < 0.0001). There was no relationship between MABP and cerebral FOE. LVO correlated negatively with cerebral FOE on d 1 (p = 0.01), but not on d 2 (p = 0.07). On d 1, median pressure of arterial CO(2) was lower in infants with low LVO (<5(th) centile) and high cerebral FOE (>95(th) centile) than in infants with low LVO (<5(th) centile) but normal cerebral FOE (5(th)-95(th) centile) (p = 0.03). These findings suggest that cerebral FOE was increased only when LVO was low and there was hypocarbia. MABP had no demonstrable effect. It is likely that increased cerebral FOE is a normal physiologic response to maintain an adequate oxygen supply to the cerebral tissues when LVO is low and hypocarbia has caused vasoconstriction. It is possible that the cerebral hemispheres are low-priority vascular beds in the preterm infant, and that the high cerebral FOE is a result of reduced hemispheric blood flow to maintain MABP in the presence of low LVO.