Neonatal target oxygen levels for preterm infants

INTRODUCTION — Oxygen supplementation is an important component of neonatal intensive care for the preterm infant. Ideally, oxygen administration provides adequate oxygenation for the metabolic needs of the neonate while avoiding the consequences of both hypoxemia and hyperoxia.

Neonatal target oxygen levels for the preterm infant is discussed here. Oxygen delivery and monitoring and mechanical ventilation in the newborn are discussed separately. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn" and "Approach to mechanical ventilation in very preterm neonates".)

SpO2 AND PaO2 — Normal values for hemoglobin oxygen saturation (SpO₂) reach or exceed 80 percent within 10 minutes of birth in term and healthy preterm infants without supplemented oxygen [1]. In general, arterial partial pressure of oxygen (PaO₂) values of 50 to 80 mmHg are adequate to meet metabolic demands of the neonate in part due to the greater proportion of fetal hemoglobin (HbF).

Use of SpO2 for targeting oxygen levels — For neonates receiving supplemental oxygen therapy, target oxygen levels are based on peripheral oxygen saturation (SpO₂) measured noninvasively with continuous pulse oximetry. Arterial blood gas (ABG) samples, which measure arterial oxygen tension (PaO₂), may be obtained periodically to correlate with pulse oximetry measurements and further assess the neonate's ventilatory status (eg, pH and carbon dioxide level).

However, ABG measurements require blood sampling, either through indwelling catheters or percutaneous puncture of a palpable artery. ABG measurements may change during percutaneous punctures as the infant responds to the procedure. Clinicians should be mindful of this when interpreting the results. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Pulse oximetry' and "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn", section on 'Arterial blood gas measurement'.)

Correlation between PaO2 and SpO2 — In neonates, SpO₂ levels between 85 and 95 percent generally correlate to PaO₂ levels between 45 and 65 mmHg (figure 1) [2,3]. However, pulse oximetry measurements are less reliable for detecting hyperoxemia or severe hypoxemia. For example, at saturations >96 percent, PaO₂ values can continue to increase with little or no further corresponding change in SpO₂.

Neonates have increased levels of HbF which has a high affinity for oxygen. This is an important factor to consider when setting SpO₂ targets. HbF shifts the oxygen dissociation curve to the left, which may result in high oxygen saturation (eg, 85 percent) at PaO₂ levels below 45 mmHg (figure 1). The proportion of HbF increases with decreasing gestational age (GA) so that the concentration of HbF in an infant born at 28 weeks gestation is approximately 90 percent.

Because of these complex interactions, preterm infants at high risk for hyperoxemia or severe hypoxemia, as well as those with rapidly changing cardiopulmonary status, require periodic ABG determination. (See "Anemia of prematurity (AOP)", section on 'Physiologic consequences'.)

OXYGEN TARGET LEVELS

Goals — The goals of supplemental oxygen therapy in preterm infants are to:

●Meet the metabolic needs of the infant.

●Avoid hyperoxia and high concentrations of oxygen, which contribute to bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP). (See "Retinopathy of prematurity (ROP): Risk factors, classification, and screening", section on 'Risk factors' and "Bronchopulmonary dysplasia (BPD): Clinical features and diagnosis", section on 'Oxygen toxicity'.)

●Avoid hypoxemia, which is associated with increased risk of mortality and neurodevelopmental impairment. (See 'Supporting evidence' below.)

Targets during delivery room resuscitation — SpO₂ targets for neonates undergoing resuscitation in the delivery room are summarized in the table (table 1) and discussed in detail separately. (See "Neonatal resuscitation in the delivery room", section on 'Pulse oximetry'.)

Targets for neonates requiring ongoing respiratory support — For preterm neonates requiring ongoing oxygen therapy in the neonatal intensive care unit (NICU), our suggested approach to setting target ranges for SpO₂ according to gestational age (GA) is as follows:

●Extremely preterm (EPT) infants (GA <28 weeks) – We recommend a SpO₂ target range of 90 to 95 percent for EPT infants during the first few weeks after birth [4,5]. EPT infants are most vulnerable to the effects of both high and low oxygenation levels. This target range minimizes both the low and high extreme oxygenation levels that are associated with adverse outcomes, and it is supported by the clinical trial data described below. (See 'Supporting evidence' below.)

If the infant still requires supplemental oxygen when the corrected postmenstrual age (PMA) is >32 weeks, the target the SpO₂ target can be increased to >95 percent. There is a paucity of data regarding oxygen target ranges as the EPT infant advances in age. The rationale for using a higher target at this age is that by two to three weeks postnatal age, the risk of intermittent hypoxia increases, which may aggravate ROP by enhancing retinal proliferation [6]. (See "Retinopathy of prematurity (ROP): Risk factors, classification, and screening", section on 'Vascularization in retinopathy of prematurity'.)

●Very preterm (VPT) and moderate preterm infants (GA 28 to <34 weeks) – We also suggest a SpO₂ target range of 90 to 95 percent for preterm infants <34 weeks GA. Although data are lacking in more mature infants, indirect data from trials in EPT infants support this practice and this target range appears to be safe for preterm infants ≥28 weeks GA.

●Late preterm infants (GA 34 to <37 weeks) – In late preterm infants, the risk of ROP is very low, and the upper limit of the target range can be increased to 97 percent [7].

●Conditions that require individualized SpO₂ targets – For infants with the following conditions, the SpO₂ target should be individualized based upon the clinical status of the neonate:

•BPD (see "Bronchopulmonary dysplasia (BPD): Management and outcome", section on 'Supplemental oxygen')

•Cyanotic congenital heart disease (see "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'General supportive care')

•Persistent pulmonary hypertension of the newborn (see "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome", section on 'Gas exchange targets')

Supporting evidence — The efficacy of using an intermediate SpO₂ target range (ie, 90 to 95 percent) relative to higher (>95 percent) or lower (85 to 89 percent) ranges has been demonstrated in clinical trials and meta-analyses [8-15].

●Intermediate versus higher SpO₂ target – The STOP-ROP (Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity) trial established the efficacy of an intermediate SpO₂ target relative to a higher target. The trial enrolled 649 infants who were randomly assigned to a SpO₂ target range of 89 to 94 percent or 96 to 99 percent [8]. Infants in the lower target group had lower rates of BPD and shorter duration of hospitalization compared with those in the higher target group. This trial is described in greater detail separately. (See "Retinopathy of prematurity (ROP): Treatment and prognosis", section on 'Prevention'.)

●Intermediate versus lower SpO₂ t_arget – Several clinical trials have evaluated the impact of targeting an intermediate SpO₂ (91 to 95) versus a lower target (85 to 89) [9-16]. In a meta-analysis of five trials (>4500 neonates), mortality was lower among neonates assigned to the intermediate SpO₂ target compared with the lower target (17 versus 20 percent; relative risk [RR] 0.86, 95% CI 0.76-0.97) [12]. Rates of major disability at 18 to 24 months corrected age were similar in both groups (38 versus 39 percent). Fewer patients in the intermediate target group developed necrotizing enterocolitis (9 versus 11 percent; RR 0.81, 95% CI 0.68-0.95). However, rates of ROP were higher in the intermediate target group (15 versus 11 percent; RR 1.39, 95% CI 1.18-1.64). Similar findings were noted in three other meta-analyses of the same five trials [13-15].

There have been several follow-up publications of these trials that include the following:

•A post-hoc analysis of one of the trials (Canadian Oxygen Trial [COT]) evaluated the impact of profound desaturation episodes on mortality and long-term neurodevelopment [17]. The analysis found that prolonged hypoxemic episodes (defined as SpO₂ <80 percent for ≥1 minute) during the first two to three months after birth were associated with late mortality or neurodevelopmental impairment at 18 months corrected age. Of note, the association between exposure to prolonged hypoxemic episodes and the primary outcome of death and neurodevelopmental impairment was stronger for infants randomly assigned to the high oxygen saturation target range (91 to 95 percent) than for those assigned to the low target range (85 to 89 percent). The authors speculated that these episodes of prolonged hypoxemia in infants assigned to the high oxygen target levels represented greater drops of saturations from baseline values resulting in more severe disturbance of oxygen homeostasis.

•A post-hoc analysis of another trial (Surfactant, Positive Pressure, and Oxygenation Randomized Trial [SUPPORT]) evaluated the impact of intermediate versus lower oxygen targets according to whether the infant was small for gestational age (SGA) or appropriate for gestational age (AGA). Overall, hospital mortality was higher among SGA infants (38 versus 16 percent) [18]. For the subgroup of SGA infants, mortality was lower for the infants assigned to the intermediate SpO₂ target compared with the lower target (26 versus 56 percent, respectively), whereas for the subgroup of AGA infants, mortality was similar in both arms (18 versus 15 percent). This subgroup effect was also seen in other trials, although the difference was less dramatic in a pooled analysis of all five trials [15]. Mortality was highest among SGA infants with a high number of hypoxic events lasting >20 seconds in the first three days after birth [19].

•In a follow-up study of SUPPORT, growth measurements during the hospitalization (birth to 36 weeks postmenstrual age [PMA]) and at 18 to 22 months corrected age were similar in both the intermediate and lower target oxygen groups [20].

Challenges adhering to oxygen targets — Maintaining infants within the targeted range remains challenging, as illustrated by the following [21-24]:

●In a prospective Australian study of 45 preterm infants (mean GA 30 weeks) receiving continuous positive airway pressure (CPAP) and supplemental oxygen, continuous pulse oximetry monitoring over a 24-hour period demonstrated that infants were in the target SpO₂ range for only 31 percent of the total recording time [23]. There were 48 episodes of severe hyperoxia (defined as SpO₂ ≥98 percent) and 9 episodes of severe hypoxemia (defined as SpO₂ <80 percent). On average, infants required 25 adjustments in the fraction of inspired oxygen (FiO₂) during the 24-hour study period.

●In another multicenter cohort study involving 84 infants manages at 12 NICUs, centers maintained infants within their intended range 16 to 64 percent of the time but they were above range 20 to 73 percent of the time [24].

These findings highlight the difficulty of keeping infants in the desired target range. Guidelines and institutional protocols for oxygen therapy in preterm neonates should acknowledge these challenges and should aim for a safe SpO₂ range that can reliably be achieved in the real world practice setting.

Novel technology using automated systems with closed loop feedback may enhance consistency of adhering to oxygen saturation targets compared with the current method of manual control of FiO₂ [25-30]. Although encouraging, data are only from short-term observational studies and do not provide information on the impact of these new systems on patient outcomes [31].

CEREBRAL OXIMETRY — We do not use cerebral oximetry monitors routinely in neonatal practice since the available evidence suggests they do not improve outcomes [32-34]. However, cerebral oximetry may be used in select circumstances such as neonates undergoing major surgery.

Monitoring cerebral oxygenation has been proposed as a means of identifying neonates with inadequate oxygen delivery, which can occur as a consequence of hypoxemia from respiratory disease, poor perfusion from cardiovascular compromise, excessive metabolic demand (eg, fever, seizure), or a combination of these factors. Cerebral oximetry monitors use near-infrared spectroscopy (NIRS) to provide noninvasive continuous monitoring of cerebral oxygenation. A persistently low reading is associated with increased risk of mortality and other adverse outcomes (necrotizing enterocolitis, neurologic injury, and neurodevelopmental impairment later in childhood) [35-39]. Thus, it has been proposed that cerebral oximetry monitoring may be useful in neonatal practice since low values may signal the need for intervention to improve oxygen delivery (eg, optimizing respiratory support, improving perfusion with a fluid bolus or vasopressor, increasing oxygen carrying capacity with a red blood cell transfusion, or reducing oxygen demand with sedation).

Cerebral oximetry has been studied in various clinical settings, including neonates undergoing cardiac surgery [40,41], neonates with septic shock [42], neonates at risk for intraventricular hemorrhage (ie, extremely preterm [EPT] neonates) [32], and neonates with established cerebral injury including hypoxic-ischemic encephalopathy [43-45]. Based on the available clinical trial data, routine use of cerebral oximetry in preterm neonates does not appear to improve outcomes [32-34]. In the largest trial, which involved 1579 EPT infants randomly assigned to treatment guided by cerebral oximetry or standard care without cerebral oximetry during the first 72 hours after birth, mortality was similar in both groups (21 versus 20 percent, respectively) as was the risk of severe brain injury (24 percent in both groups) [32]. Further studies are needed to identify whether there are clinical settings wherein this tool may improve neonatal outcomes.

The use of NIRS monitoring in neonates with shock or intraventricular hemorrhage is discussed separately. (See "Neonatal shock: Management", section on 'Monitoring' and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Monitoring'.)

SUMMARY AND RECOMMENDATIONS

●Monitoring oxygenation using SpO₂ – For neonates receiving supplemental oxygen, target levels are based on peripheral oxygen saturation (SpO₂) measured noninvasively with pulse oximetry. Arterial blood gas (ABG) samples, which measure arterial oxygen tension (PaO₂), may be obtained periodically to correlate with pulse oximetry measurements and further assess the neonate's ventilatory status (eg, pH and carbon dioxide level). (See 'Use of SpO2 for targeting oxygen levels' above.)

●Correlation between PaO₂ and SpO₂ – In neonates, SpO₂ levels between 85 and 95 percent generally correlate to PaO₂ levels between 45 and 65 mmHg (figure 1). However, pulse oximetry measurements are less reliable for detecting hyperoxemia or severe hypoxemia. Neonates have an increased concentration of fetal hemoglobin (HbF), which has a high affinity for oxygen (ie, it shifts the oxygen dissociation curve to the left). This must be considered when interpreting SpO₂ levels in neonates; HbF levels increase with decreasing gestational age (GA). (See 'Correlation between PaO2 and SpO2' above.)

●SpO₂ target levels – An optimal target SpO₂ range provides adequate oxygenation that meets the metabolic needs of the neonate while avoiding high concentrations of oxygen, hyperoxia, and hypoxia. (See 'Goals' above.)

Our suggested approach to setting target ranges for SpO₂ is as follows (see 'Oxygen target levels' above):

•During delivery room resuscitation – SpO₂ targets for neonates undergoing resuscitation in the delivery room are summarized in the table (table 1) and discussed in detail separately. (See "Neonatal resuscitation in the delivery room", section on 'Pulse oximetry'.)

•Neonates <28 weeks gestation – For most extremely preterm (EPT) neonates who require oxygen therapy, we recommend a SpO₂ target range of 90 to 95 percent during the first few weeks after birth rather than higher or lower levels (Grade 1B). This target range minimizes both the low and high extreme oxygenation levels that have been associated with adverse outcomes, and it is supported by clinical trial data. If the infant still requires supplemental oxygen when the corrected postmenstrual age (PMA) is >32 weeks, the SpO₂ target can be raised to >95 percent. (See 'Targets for neonates requiring ongoing respiratory support' above and 'Supporting evidence' above.)

•Neonates 28 to <34 weeks gestation – We also suggest a SpO₂ target range of 90 to 95 percent for preterm infants 28 to <34 weeks GA (Grade 2C). Although data are lacking in more mature infants, indirect data from trials in EPT infants support this practice and this target range appears to be safe for preterm infants ≥28 weeks gestation. (See 'Targets for neonates requiring ongoing respiratory support' above.)

•Neonates 34 to <37 weeks gestation – For late preterm infants, we suggest a SpO₂ target range of 90 to 97 percent (Grade 2C). A more liberal range is reasonable in these infants since they are at low risk of bronchopulmonary dysplasia and retinopathy of prematurity. (See 'Targets for neonates requiring ongoing respiratory support' above.)

●Adherence – Maintaining infants within the targeted range is challenging. As a result, guidelines and institutional protocols for oxygen therapy in preterm neonates should aim for a safe SpO₂ range that can reliably be achieved in the real world practice setting. (See 'Challenges adhering to oxygen targets' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges James Adams, Jr., MD, who contributed to an earlier version of this topic review.