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Three Part Question

In [newborn babies] is [resuscitation in 21% air superior to 100% oxygen] without causing [adverse neurodevelopmental outcome]?

Clinical Scenario

I am called to the labour ward to resuscitate a term newborn who has apnoea and bradycardia at birth. The resuscitaire has a warning to keep the oxygen blender at 100% Fio2 at all times. I had earlier worked in a unit where term babies were resuscitated in 21% air. I wondered if resuscitation of all babies in 21% air was safe especially in terms of neurodevelopment. I took to appraising the current evidence.

Search Strategy

Primary source: Medline 1966-2004, EMBASE 1974-2004 and CINHAL 1982-2004 using the Dialog Datastar.
Secondary source: The Cochrane library (2004, Issue 1).
Primary Source: The search term [({air OR oxygen} AND {resuscitation}] Filter: controlled clinical trial. Limit to human, newborn and English language. Hits: Medline (321), EMBASE (113) and CINAHL (47).
Secondary Source: The search term 'air AND oxygen AND resuscitation'. Hits: 25, systematic reviews (19) and controlled trials (6).

Search Outcome

6 relevant studies identified

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Vento M et al 2001 Spain	830 asphyxiated newly born term infants who received room air (n = 304) or 100% oxygen (n = 526) for resuscitation	Retrospective review	Time to onset of a regular respiratory pattern	Air= required a shorter time. (Data not available for scrutiny)	Retrospective review
			Morbidity and mortality	No significant differences between the air and oxygen groups. (Data not available for scrutiny)
Vento M et al 2003 Spain	Asphyxiated term newborn infants (n = 106) were randomly resuscitated with room air (n= 51) or 100% oxygen (n = 55).	Prospective, randomized, blinded trial	Time of ventilation	Air=5.3 +/- 1.5 min, Oxygen=6.8 +/- 1.2 min (P <0.05)	The primary outcome measure was hyperoxemia and oxidative stress
			Hyperoxia (PO2)	Air=72.2 + /- 6.8 mm Hg, Oxygen=126.3 +/-21.8 mm Hg
Saugstad et al 2003 Norway	Children who had been resuscitated at birth with either 21% or 100% oxygen (O2) in the Resair 2 study (1998) were followed up at 18 to 24 months for neurological sequelae.	A multicenter, international, controlled study.	Weight, height and head circumference	No difference between air and oxygen groups	Follow up of Resair 2 study. Only 7 out of 10 centers participated (selection bias). 213/323 (66%) of the eligible children available for follow up. The other neurological sequelae are mentioned as not normal (no objective criteria)
			Cerebral palsy	Air=10%, Oxygen=7% (NS)
			Cerebral palsy and/or mental or other delay	Air=11 cases (12%), Oxygen=11 cases (9%), (OR 1.39, 95% CI 0.57-3.36)
			Other neurological sequelae (labelled as not normal)	Air=14 (15%), Oxygen=12 (10%), (OR 1.67, 95% CI 0.73-3.80)
Ramji S et al 2003 India	431 asphyxiated babies weighing > 1000 grams (mean birth weight in grams +/-SD 2400 +/- 563 (air), 2529 +/- 629 (oxygen); mean gestation in weeks +/- SD 37.9 +/- 2.9 (air), 38.1 +/- 2.6 (oxygen) with heart rate < 100 per min and/or apnea, unresponsive to nasopharyngeal suction and tactile stimuli. Asphyxiated neonates born on odd dates were given 100% oxygen (n=221) and those on even dates room air (n=210) for resuscitation	Multicenter, quasi randomized controlled trial.	Heart rates at 1, 5 and 10 mins	1 min [94 (air), 88 bpm (oxygen)], 5 min [131(air), 131 bpm (oxygen)], 10 min [135 bpm, 136 bpm (oxygen)] (NS)	Unblinded, quasi-randomised
			Median apgar scores at 5 and 10 mins	Air=7 and 8, Oxygen=7 and 8 (NS)
			Median time to first breath	Air=1.5 mins, Oxygen=1.5 mins (NS)
			Median time to first cry	Air=2.0 mins, Oxygen=3.0 mins (Significant)
			Median duration of resuscitation	Air=2.0 mins, Oxygen=3 mins (Significant)
			HIE during first seven days of life	Air=35.7%, Oxygen=37.1% (NS)
			Overall and asphyxia related mortality	Air=12.4% and 10.0%, Oxygen=18.1% and 13.6% (NS)
Ramji S et al 1993 India	84 neonates (birth weight > 999 g) with heart rate < 80 and/or apnea at birth were allocated to be resuscitated with either room air (n = 42) or 100% oxygen (n = 42).	Randomised controlled trial	Heart rate at 1, 3, 5, 10 mins	No difference between the air and oxygen groups	Unblinded study. 72/77 surviving neonates were available for follow-up at 28 days.
			Apgar score at 1 mins	No difference between the air and oxygen groups
			Apgar score at 5 mins	Air=8 (7-9), Oxygen=7 (6-8), Median (25th and 75 th percentile) (p=0.03)
			Pao2, PH, BE	No difference between air and oxygen groups
			Assisted ventilation	Air=2.4 (1.5-3.4) min, Oxygen=3.0 (2.0-4.0) min (p = 0.14).
			Median time to first breath	Air=1.5 (1.0-2.0) min, Oxygen=1.5 (1.0-2.0) (p = 0.59)
			Time to first cry	Air=3.0 (2.0-4.0) min, Oxygen=3.5 (2.5-5.5) min (p = 0.19).
			Mortality in the neonatal period	Air= 3, Oxygen=4 (NS)
			Neurologic sequelae at 28 days	Air=0/36, Oxygen=0/36 (NS)
Saugstad OD et al (Resair 2 study) 1998 Norway	609 asphyxiated newborn infants with birth weight > 999 g (median (5 to 95 percentile) gestational ages were 38 (32.0 to 42.0) and 38 (31.1 to 41.5) weeks, and birth weights were 2600 (1320 to 4078) g and 2560 (1303 to 3900) g in the room air and oxygen groups, respectively) were allocated to resuscitation with either room air (n=288) or 100% oxygen (n=321). Those born on even dates were resuscitated with room air and those born on odd dates with 100% oxygen. Entry criterion was apnea or gasping with heart rate <80 beats per minute at birth.	Prospective, international, quasi-randomised controlled multicenter study	Mortality in the first 7 days of life	Air=12.2%, Oxygen=15.0% (adjusted odds ratio (OR) 0.82, 95% confidence intervals (CI) 0.50-1.35)	Informed consent was obtained after the recruitment. The study was not blinded or randomised (not practical). The majority of infants were recruited from centres in the developing countries (selection bias)
			Neonatal mortality	Air=13.9%, Oxygen=19%; (adjusted OR 0. 72, 95% CI 0.45-1.15)
			Death within 7 days of life and/or moderate or severe hypoxic-ischemic encephalopathy (primary outcome measure)	Air=21.2%, Oxygen=23.7% (OR 0.94, 95% CI 0.63-1.40).
			HR at 1 min and 90 sec	Air=90 ± 31, Oxygen=93 ± 33 bpm at 1 minute, Air=110 ± 27, Oxygen113 ± 30 bpm at 90 seconds (mean ± SD)
			Apgar scores at 1 min	Air= (5 [1 to 6.7]), Oxygen= (4 [1 to 7]) (median and 5 to 95 percentiles) (Significant)
			Apgar scores at 5 mins	Air=8 (4 to 9), Oxygen=7 (3 to 9). (NS)
			Apgar scores < 4 at 1 min	Air=32.3%, Oxygen=44.4% (Significant)
			Apgar scores < 7 at 5 mins	Air=24.8%, Oxygen=31.8% (Significant)
			Acid base status and saturations	No difference between air and oxygen groups
			Time to first breath	Air=1.1 (1.0-1.2) mins, Oxygen=1.5 (1.4 to 1.6) mins (Median, 95% CI)

Comment(s)

Traditionally babies have been resuscitated at birth using 100% oxygen. Recent studies have suggested a possibility of oxygen toxicity in infants resuscitated in 100% oxygen. The newborn life support course does not conclusively support the use of air for resuscitation. Therefore there is an urgent need to provide an evidence-based answer to the question. The search yielded a multicentre study (Resair 2) which included 11 centres in 6 countries majority of which were in developing countries. Only two studies reported neurodevelopmental outcome, Resair 2 (1998) at 18 to 24 months and Ramji et al (1993) at 28 days, which did show significant difference between the two groups. All studies included infants more than 1000 g or term. Similar studies in preterm cohort <32 weeks were not available.

Editor Comment

Dr A Tan writes (Cochrane author - see reference 1: We identified a significant higher mortality in the oxygen group with a relative risk of 0.71 [95% CI 0.54 - 0.94]). http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD002273/frame.html

Clinical Bottom Line

Room air is as good as 100% oxygen for resuscitation of term asphyxic newborns without causing adverse neurodevelopment at 2 years. Trials are needed to address the question in preterm infants less than 32 weeks gestation.

References

1. Vento M, Asensi M, Sastre J et al Six years of experience with the use of room air for the resuscitation of asphyxiated newly born term infants Biol-Neonate 2001; 79 (3-4): 261-7
2. Vento M, Asensi M, Sastre J et al Oxidative stress in asphyxiated term infants resuscitated with 100% oxygen J Pediatr 2003; 142 (3): 240-6
3. Saugstad OD, Ramji S, Irani SF et al Resuscitation of newborn infants with 21% or 100% oxygen: follow-up at 18 to 24 months Pediatr 2003; 112 (2): 296-300
4. Ramji S, Rasaily R, Mishra PK et al Resuscitation of asphyxiated newborns with room air or 100% oxygen at birth: a multicentric clinical trial Indian-Pediatr 2003; 40 (6): 510-7
5. Ramji S, Ahuja S, Thirupuram S et al Resuscitation of asphyxic newborn infants with room air or 100% oxygen Pediatr Res 1993; 34: 809-12
6. Saugstad OD, Rootwelt T, Aalen O Resuscitation of asphyxiated newborn infants with room air or oxygen: an international controlled trial: the Resair 2 study Pediatr 1998; 102: e1
7. Tan A, Schulze A, O'Donnell CPF, Davis PG. Air versus oxygen for resuscitation of infants at birth [Meta-analysis]. Cochrane Database of Systematic Reviews 2005, Issue 2 Art. No.: CD002273. DOI: 10.1002/14651858.CD002273.pub3.