Making a choice: initial fraction of inspired oxygen for resuscitation at birth of a premature infant less than 32 weeks gestational age

Dear editor

As briefly noted by Abdel-Hady and Nasef in their 2012 publication in Research and Reports in Neonatology,¹ the best initial fraction of inspired oxygen (FiO₂) to use during resuscitation of preterm neonates <32 weeks gestational age (GA) has not been clearly elucidated. Most recent neonatal resuscitation guidelines leave the difficult choice of the actual FiO₂ in the hands of individual physicians. We believe that this letter, through review and discussion of the recent published literature, will aid physicians in this choice and confirm that, as per the opinion of Abdel-Hady and Nasef, the best present evidence-based choice for the initial FiO₂ for resuscitating preterm infants <32 weeks GA appears to be 30%. However, determination of the ideal initial resuscitation gas requires further research assessing both short-term and long-term outcomes.

The common clinical scenario of attending the birth of a premature infant brings up an important clinical question: in an infant born at <32 weeks GA (population), does the use of a low level of oxygen (≤30%, intervention) instead of a high level of oxygen (≥90%, comparison) as the initial FiO₂ for resuscitation result in adequate stabilization (outcome)? In order to answer this question, we sought recent randomized controlled trials (RCTs) examining the desired patient population, intervention, comparison, and outcome. We performed a PubMed search covering January 2008 until October 2013 using the following keywords: “oxygen” AND “resuscitation” AND “premature infant”. Limits were: human species, English language, and age from birth to 23 months. Publications prior to January 2008 were excluded because of redundancy, lack of applicability, or outdated information being likely in these publications. We examined personal files and reference listings of the full-text articles for any additional publications. Our search yielded a total of 141 titles. We reviewed 44 abstracts and retrieved 21 full-text articles or conference proceedings for detailed review. We found four relevant RCTs^2–5 from the search and one additional RCT from our gray search⁶ (Table 1).

Table 1 Summary of findings in the five relevant randomized controlled trials

Reference	Population	Study type	Intervention	Titration method	Key outcomes	Results
Escrig et al^Table Footnote2,Table Footnote*	Preterm neonates ≤28 weeks GA requiring resuscitation	Prospective, randomized controlled trial; blinded	LOG (30%, n= 19) versus HOG (90%, n=23)	FiO2 increased/decreased by 10% every 60–90 seconds based on HR and SpO2 Goals: HR > 100 at all times and a preductal SpO2 rising towards 85% over first 10 minutes of life	Preductal SpO2 at 10 minutes after birth Difference in preductal SpO2 at 1, 2, 3, 4, 5, 10, 15, and 20 minutes after birth Ventilatory support in delivery room (eg, CPAP, intubation) FiO2 in first 3 minutes of life FiO2 after first 3 minutes of life	No significant difference between LOG (86.9%±2.5%) and HOG (88.7%±2.5%) No significant differences between LOG and HOG No significant difference between LOG and HOG Significantly higher in HOG versus LOG (P<0.01) No significant difference between LOG and HOG
Wang et al^Citation3	Preterm neonates <31 weeks GA requiring resuscitation	Prospective, randomized controlled trial; nonblinded	LOG (21%, n= 18) versus HOG (100% for initial 5 minutes, n=23)	LOG: FiO2 increased to 50% if preductal SpO2 <70% at 3 minutes or <85% at 5 minutes; FiO2 then increased by 25% every 30 seconds to reach target SpO2 HOG: FiO2 kept at 100% for the first 5 minutes, then weaned if preductal SpO2 >95% Treatment failure: preductal SpO2 <70% at 3 minutes of life, requiring an increase in FiO2	LOG requirement of an increase in FiO2 at or before 3 minutes of life Preductal SpO2 at 2, 3, 4, 5, and 10 minutes of life Heart rate in first 10 minutes of life FiO2 administered at 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 minutes of life Percent of neonates with preductal SpO2 of >95% at 5 minutes	100% of infants required an increase in FiO2 because all failed to meet the target with room air as the initial FiO2 Significantly higher SpO2 at all time points (P<0.01) in HOG although by 10 minutes of life, the mean SpO2 in both groups was >85% No significant differences between LOG and HOG Significantly lower at all time points (P<0.01) up to 7 minutes in LOG; no significant differences between LOG and HOG at 8, 9, or 10 minutes HOG ~57% versus LOG ~17% (P<0.05)
Vento et al^Citation4	Preterm neonates ≤28 weeks GA requiring resuscitation	Prospective, randomized controlled trial; nonblinded	LOG (30%, n=37) versus HOG (90%, n=41)	FiO2 increased/decreased by 10% every 60–90 seconds based on HR and SpO2 Goals: preductal SpO2 of 75% at 5 minutes and 85% at 10 minutes	Percent of neonates reaching target preductal SpO2 values of 75% at 5 minutes and 85% at 10 minutes FiO2 administered at 2, 3, 4, 5, and 10 minutes of life Heart rate in first 10 minutes of life Preductal SpO2 at 2, 3, 4, 5, and 10 minutes of life On FiO2 of 21% on arrival at NICU	No significant differences between LOG and HOG; both groups reached the targets Significantly lower at all time points (P<0.01) up to 4 minutes in LOG; no significant differences between LOG and HOG at 5 or 10 minutes No significant differences between LOG and HOG No significant differences between LOG and HOG Significantly higher in LOG (76%) versus HOG (56%, P<0.05)
Rabi et al^Citation5	Preterm neonates ≤32 weeks GA requiring resuscitation	Prospective, randomized controlled trial; blinded	LOG (21%, n=34) versus HOG (100%, n=34)	FiO2 increased/decreased by 20% every 15 seconds based on HR and SpO2 Goals: target preductal SpO2 of 85%–92% Treatment failure: HR <100 beats per minute for >30 seconds	Proportion of resuscitation time spent in target SpO2 range^** Time to reach target SpO2 of 85%–92% Proportion of infants in target SpO2 range at 10 minutes Proportion of infants with SpO2 above 92% at 10 minutes Proportion of infants meeting treatment failure criteria	No significant difference between LOG (16%) and HOG (21%) No significant difference between LOG and HOG (P=0.56); mean SpO2 for each group was >85% by 5 minutes No significant difference between LOG (38%) and HOG (38%); there was also no significant difference at 5 minutes No significant difference between LOG (33%) and HOG (34%); there was also no significant difference at 5 minutes No significant difference between LOG (24%) and HOG (9%)
Kapadia et al^Citation6	Preterm neonates ≤34 weeks GA requiring resuscitation	Prospective, randomized controlled trial; nonblinded	LOG (21%, n=44) versus HOG (100%, n=44)	FiO2 increased/decreased by 10% every 30 seconds based on HR and SpO2 Goals: target preductal SpO2 of NRP-recommended transitional goal saturations^Citation7 Treatment failure: HR <60 beats per minute despite 30 seconds of effective PPV	Proportion of infants in LOG requiring an increase in FiO2 to meet target SpO2 range Preductal SpO2 at 2, 3, 4, 5, 6, 7, 8, 9, and 10 minutes of life Proportion of infants with SpO2 above 94% at 2, 3, 4, 5, 6, 7, 8, 9 and 10 minutes of life Proportion of infants with SpO2 below lower limit of target SpO2 range at 2, 3, 4, 5, 6, 7, 8, 9, and 10 minutes of life Proportion of infants meeting treatment failure criteria	All infants in LOG required an increase in FiO2 Significantly higher SpO2 at 3–6 minutes of life (P<0.05) in HOG Significantly higher at 2–10 minutes of life (P<0.05) in HOG Significantly higher at 3–6 minutes of life (P<0.05) in LOG No significant difference between LOG (0%) and HOG (0%)

Notes:

* The population in this study makes up a portion of the infants in the study by Vento et al.⁴ The reported findings from this study provide readers with different clinical data of importance

** study was powered based on this primary outcome. No other study was specifically powered to assess any of their clinical outcomes.

Abbreviations: LOG, low-oxygen group; HOG, high-oxygen group; NRP, Neonatal Resuscitation Program; NICU, neonatal intensive care unit; CPAP, continuous positive airway pressure; HR, heart rate; GA, gestational age; PPV, positive pressure ventilation; SpO₂, oxygen saturation; FiO₂, fraction of inspired oxygen.

Discussion

Term neonates and premature neonates born at ≥32 weeks GA should be resuscitated with room air in nearly all circumstances,⁷ while there is no consensus on the ideal FiO₂ for resuscitation of preterm infants <32 weeks.^7–10 However, as recently as 2005, virtually all resuscitations for extremely low birth weight infants in the USA used 100% oxygen.⁹

The International Liaison Committee on Resuscitation (ILCOR) has stated that the initial use of room air or 100% oxygen is more likely to result in hypoxemia or hyperoxia, respectively, than initiation of resuscitation with 30% or 90% oxygen for preterm infants <32 weeks GA. ILCOR also recommends that resuscitation be performed with judicious use of blended oxygen and room air, ideally guided by pulse oximetry. Notably, the ILCOR⁸ and American Heart Association recommendations¹¹ did not include the published results of three RCTs found in Table 1^4–6 due to their more recent publication dates. A recent meta-analysis outlines the limitations of the current data around the topic,¹² but does not provide clinicians with a practical conclusion on how to presently manage the use of oxygen in these resuscitations.

The science around this issue is evolving. A high FiO₂ leads to production of free radicals with the potential to extensively damage human cells.¹³ A high FiO₂ may prolong time to spontaneous crying and breathing, increase oxygen consumption, decrease minute ventilation, cause atelectasis, or decrease cerebral blood flow.^13,14 At the same time, an overly low FiO₂ may result in various types of organ dysfunction, including neonatal encephalopathy.¹³ The result of these data is physician uncertainty as to what is best for the premature infant they are resuscitating.

The determination of an appropriate oxygen saturation (SpO₂) target below which oxygen therapy does more good than harm during resuscitation of premature infants remains elusive; the highest safe SpO₂ remains unclear as well.¹⁵ Preterm infants take longer than term infants to reach an SpO₂ of >85%.^16,17 Dawson et al report on SpO₂ levels in term and preterm infants (including 39 infants born at <32 weeks GA) that could guide post-delivery changes in the F_iO₂, but the infants studied were those that required no oxygen or assisted ventilation in the minutes after birth;¹⁸ therefore, the reported SpO₂ levels may not be best for preterm infants of <32 weeks GA who actually require resuscitation. That said, these levels are recommended by the American Academy of Pediatrics’ guideline for use when resuscitating even preterm babies,⁷ and the European Resuscitation Council does not provide clearly recommended saturation targets for the preterm infant <32 weeks GA.^19,20 Based on a review of several publications, Finer and Rich¹⁴ recommend: “initial SpO₂ following delivery can be assumed to be around 50% and increases by 5 to 6% per min for the very preterm infant. This will result in an SpO₂ of 65 to 70% at 3 min, 75 to 80% at 5 min and 85 to 90% by 7 to 8 min of age.” All RCTs we reviewed (Table 1) considered an SpO₂ of ≥85% at 10 minutes acceptable, although one targeted an SpO₂ of ≥85% at 5 minutes in their low-oxygen group while accepting notably higher SpO₂ readings of >95% in the first 5 minutes of life in their high-oxygen group,³ and one targeted an SpO₂ of 85%–92% as soon as SpO₂ readings were available,⁵ which is usually by 1–2 minutes of life. Although the final determination of the ideal SpO₂ targeting remains elusive, an SpO₂ of 85%–94% at 10 minutes seems to be considered acceptable by most experts.

Table 1 details the few small RCTs that compare commencing with a low FiO₂ (21%–30%) versus high FiO₂ (90%–100%) during resuscitation of preterm infants (particularly those ≤31 weeks GA). One RCT likely had a single 32-week GA infant based on their inclusion of preterm neonates ≤32 weeks and their final population having a mean GA of 29 (95% confidence interval 28–30);⁵ another included infants at 32–34 weeks GA.⁶ Various titration methods were used (see Table 1 for details); of note, sudden F_iO₂ alterations (over 10% every 30 seconds) may result in constriction of the pulmonary vasculature.⁴ In the two RCTs^2,4 comparing 30% versus 90% as the starting FiO₂ in infants ≤28 weeks GA, saturations were similar in both groups at all times, but the high-oxygen group had greater exposure to oxygen,² more signs of oxidative stress, more ventilation days, and prolonged oxygen supplementation,⁴ with no noted benefits from the higher oxygen exposure. Two of the three RCTs comparing room air with 100% oxygen^3,5 had a higher treatment failure rate (as defined by the studies and noted in Table 1) in their room air groups (only statistically significant in one³), suggesting that room air is likely not the best initial FiO₂ choice in this population. The other recent RCT comparing room air with 100% oxygen⁶ demonstrated that all babies initially resuscitated with room air required an increase in FiO₂ to reach the targeted preductal saturations, again suggesting room air is perhaps not the best initial FiO₂ choice. In this study, there was no difference in treatment failure (as defined by the study and noted in Table 1) between the groups, but this may have been due to the inclusion of more mature infants at 32–34 weeks GA; importantly, the study was underpowered, particularly for those infants <29 weeks GA, for any clinical outcomes given that the primary outcome was a laboratory-based measurement of oxidative stress. Several upcoming RCTs are using room air as one of their comparison groups and may help determine if, indeed, it should not be used as the initial gas for resuscitation.¹⁵ Another upcoming RCT will compare 30% and 65% as the initial gas for resuscitation.²¹

We have reviewed the most recent and relevant evidence for clinical oxygen use in the resuscitation of infants born at <32 weeks GA. The heterogeneous outcomes assessed in each respective study hamper any meta-analysis of the RCTs.¹² Based on our review of these few small RCTs, the best approach at the present time seems to be initiating resuscitation with an initial FiO₂ of 30% and titrating oxygen up or down based on the preductal pulse oximetry. The oxygen should also be titrated if the HR remains <100 despite 30 seconds of effective positive-pressure ventilation. The FiO₂ should be titrated to match the current recommended “minute by minute” preductal SpO₂ targets from the American Heart Association^7,11 or the original evidence-based data.^15,18 Additionally, should cardiac output fail to improve (ie, heart rate <60 beats per minute) despite adequate ventilation and chest compressions become necessary, the FiO₂ should immediately be increased to 100% based on current recommendations.⁷

In closing, room air may be acceptable as the initial resuscitation gas, but present data suggest it inadequately stabilizes SpO₂ levels or the heart rate of infants <32 weeks GA. Given the equivalent stabilization of these infants on 30% or 90% FiO₂ as the initial resuscitation gas, an FiO₂ of 30% appears to be the better choice given the risks of high oxygen exposure. Determination of the ideal initial resuscitation gas and SpO₂ targets requires further high quality research assessing both short-term and long-term outcomes.

Disclosure

The authors declare no conflict of interest in this work.

Authors’ replyCorrespondence: Hesham Abdel-Hady, Neonatal Intensive Care Unit, Mansoura University Children’s Hospital, Gomhoria, Street, Mansoura 35516, Egypt, Tel [phone] Fax [phone] Email [email protected]

Dear editor

We compliment Moore and Navabi for their updated report on evidence-based choice of the initial fraction of inspired oxygen (FiO₂) for resuscitation of premature infants <32 weeks gestation. These infants often need respiratory support and oxygen supplementation immediately after birth, and adequate oxygenation is essential because both hypoxia and hyperoxia can have detrimental effects.^1,2

Moore and Navabi correctly point out that studies in preterm infants failed to define the optimal initial FiO₂ during resuscitation. A recent meta-analysis³ of six randomized controlled trials (RCTs)^4–9 concluded that there is not sufficient evidence to affirm that the use of lower or higher initial FiO₂ in the delivery room for preterm babies confers important benefits or harm. Moreover, none of these trials^4–9 was actually powered to evaluate important long-term outcomes such as survival without significant neurodevelopmental disability. Until further evidence becomes available, we still believe that the best approach is to initiate a resuscitation with an FiO₂ of 30%, thereafter, FiO₂ should be titrated according to the pulse oximetry oxygen saturation (SpO₂) readings with changes in 10% intervals performed every 30 seconds to allow babies cardio-respiratory response.

Oxygen blenders and pulse oxygen saturation monitors should be used to achieve the balance of administering the FiO₂ based on the infant’s needs. Using pulse oximetry to guide oxygen therapy in the delivery room is not evidence-based practice. However, the American Heart Association (AHA)¹⁰ and the European Resuscitation Council (ERC)¹¹ guidelines advise preductal SpO₂ targets for the first 10 minutes after birth, without specifying the gestational age. These targets are based on observational studies of healthy infants not requiring any intervention during their resuscitation.¹² The AHA guidelines advise a narrow SpO₂ target range close to the median values for infants who do not require resuscitation (SpO₂ target ranges at 1, 2, 3, 4, 5, and 10 minutes after birth are 60%–65%, 65%–70%, 70%–75%, 75%–80%, 80%–85%, and 85%–95%, respectively), while the ERC guidelines prescribe single value SpO₂ targets (SpO₂ of 60%, 70%, 80%, 85%, and 90% at 2, 3, 4, 5, and 10 minutes after birth, respectively) these values are closer to the 25th percentile. Recently a group of experts have suggested that the use of the 10th and 50th percentile SpO₂ curves of Dawson’s nomograms,¹² as the SpO₂ target range may be more appropriate.¹³ Moreover, Dawson’s nomograms classified by gestational age may be very useful for the resuscitation team as they allow more accurate target SpO₂ to be established according to gestational age.¹² It is worth noting that the available SpO₂ targets are based on observational studies of healthy infants not requiring any intervention during their resuscitation, in a recent study it has been shown that preterm babies and especially females receiving positive pressure and air attain higher saturations earlier than those spontaneously breathing.¹⁴ Meanwhile, resuscitation team must control the SpO₂ adequately, and follow the targets with as little deviation as possible. Recently it was demonstrated that the resuscitation team could effectively maintain SpO₂ values within a specific target range during transition using Transitional Oxygen Targeting System (TOTS) plots which record real-time SpO₂ values in relation to 10th and 50th percentile SpO₂ curves.¹⁵

Further appropriately-sized RCTs are needed to define the best initial FiO₂ and the appropriate SpO₂ range in the delivery room. These trials should measure not only short term but also long-term outcomes. The Targeted Oxygenation in the Resuscitation of Premature Infants and Their Developmental Outcome trial (TO2RPIDO)¹⁶ is recruiting infants at ≤31 weeks’ gestation to compare 100% oxygen and air as the initial gas for resuscitation, using SpO₂ targeting. For the air group, FiO₂ is increased if SpO₂ is <65% by 5 minutes, <80% at 5–10 minutes, and <85% thereafter. In the 100% oxygen group, FiO₂ is decreased when SpO₂ >92%. The Study of Room Air Versus 60% Oxygen for Resuscitation of Premature Infants (PRESOX),¹⁷ will use targeted oxygen saturation levels over the first 15 to 20 minutes of life to compare a low (21%) and a higher initial oxygen (60%) level for the resuscitation of preterm infants <29 weeks gestation, and will be large enough to evaluate short term outcomes of survival without oxygen at 36 weeks and survival without retinopathy of prematurity, and the long term outcome of survival without significant neurodevelopmental impairment at 2 years of age.

To summarize, resuscitation in room-air or 100% oxygen is not recommended for preterm neonates <32 weeks gestation. The FiO₂ of 30% apparently enhances successful transition, lowers the oxygen exposure, and diminishes the risk of oxidative damage. The FiO₂ should be titrated according to SpO₂ values. Further RCTs are needed to define the best initial FiO₂ and the appropriate SpO₂ range in the delivery room for preterm infants. These trials should measure not only short term but also long-term outcomes.

Disclosure

The authors report no conflicts of interest in this communication.