RESUSCITATION OF ASPHYXIATED NEWBORN-INFANTS WITH ROOM AIR OR OXYGEN - AN INTERNATIONAL CONTROLLED TRIAL - THE RESAIR-2 STUDY

Objective. Birth asphyxia represents a serious problem worldwide, resu lting in similar to 1 million deaths and an equal number of serious se quelae annually. It is therefore important to develop new and better w ays to treat asphyxia. Resuscitation after birth asphyxia traditionall y has been tarried out with 100% oxygen, and most guidelines and textb ooks recommend this; however, the scientific background for this has n ever been established. On the contrary, theoretic considerations indic ate that resuscitation with high oxygen concentrations could have detr imental effects. We have performed a series of animal studies as well as one pilot study indicating that resuscitation can be performed with room air just as efficiently as with 100% oxygen. To test this more t horoughly, we organized a multicenter study and hypothesized that room air is superior to 100% oxygen when asphyxiated newborn infants are r esuscitated. Methodology. In a prospective, international, controlled multicenter study including 11 centers from six countries, asphyxiated newborn infants with birth weight >999 g were allocated to resuscitat ion with either room air or 100% oxygen. The study was not blinded, an d the patients were allocated to one of the two treatment groups accor ding to date of birth. Those born on even dates were resuscitated with room air and those born on odd dates with 100% oxygen. Informed conse nt was not obtained until after the initial resuscitation, an arrangem ent in agreement with the new proposal of the US Food and Drug Adminis tration's rules governing investigational drugs and medical devices to permit clinical research on emergency care without the consent of sub jects. The protocol was approved by the ethical committees at each par ticipating center. Entry criterion was apnea or gasping with heart rat e <80 beats per minute at birth necessitating resuscitation. Exclusion criteria were birth weight <1000 g,lethal anomalies, hydrops, cyanoti c congenital heart defects, and stillbirths. Primary outcome measures were death within 1 week and/or presence of hypoxic-ischemic encephalo pathy, grade II or III, according to a modification of Sarnat and Sarn at. Secondary outcome measures were Apgar score at 5 minutes, heart ra te at 90 seconds, time to first breath, time to first cry, duration of resuscitation, arterial blood gases and acid base status at 10 and 30 minutes of age, and abnormal neurologic examination at 4 weeks. The e xisting routines for resuscitation in each participating unit were fol lowed, and the ventilation techniques described by the American Heart Association were used as guidelines aiming at a frequency of manual ve ntilation of 40 to 60 breaths per minute. Results. Forms for 703 enrol led infants from 11 centers were received by the steering committee. A ll 94 patients from one of the centers were excluded because of violat ion of the inclusion criteria in 86 of these. Therefore, the final num ber of infants enrolled in the study was 609 (from 10 centers), with 2 88 in the room air group and 321 in the oxygen group. Median (5 to 95 percentile) gestational ages were 38 (32.0 to 42.0) and 38 (31.1 to 41 .5) weeks (NS), and birth weights were 2600 (1320 to 4078) g and 2560 (1303 to 3900) g (NS) in the room air and oxygen groups, respectively. There were 46% girls in the room air and 41% in the oxygen group (NS) . Mortality in the first 7 days of life was 12.2% and 15.0% in the roo m air and oxygen groups, respectively; adjusted odds ratio (OR) = 0.82 with 95% confidence intervals (CI) = 0.50-1.35. Neonatal mortality wa s 13.9% and 19.0%; adjusted OR = 0.72 with 95% CI = 0.45-1.15. Death w ithin 7 days of life and/or moderate or severe hypoxic-ischemic enceph alopathy (primary outcome measure) was seen in 21.2% in the room air g roup and in 23.7% in the oxygen group; OR = 0.94 with 95% CI = 0.63-1. 40. Heart rates did not differ between the two groups at any time poin t and were (mean +/- SD) 90 +/- 31 versus 93 +/- 33 beats per minute a t 1 minute and 110 +/- 27 versus 113 +/- 30 beats per minute at 90 sec onds in the room air and oxygen groups, respectively. Apgar scores at 1 minute (median and 5 to 95 percentiles) were significantly higher in the room air group (5 [1 to 6.7]) than in the oxygen group (4 [1 to 7 ]); however, at 5 minutes there were no significant differences, with 8 (4 to 9) versus 7 (3 to 9). There were significantly more infants wi th very low 1-minute Apgar scores (<4) in the oxygen group (44.4%) tha n in the room air group (32.3%). There also were significantly more in fants with Ei-minute Apgar score <7 in the oxygen group (31.8%) than i n the room air group (24.8%). There were no differences in acid base s tatus or SaO(2) during the observation period between the two groups. Mean (SD) PaO2 was 31(17) versus 30 (22) mm Hg in cord blood in the ro om air and oxygen groups, respectively (NS). At 10 minutes PaO2 was 76 (32) versus 87 (49) mm Hg (NS), and at 30 minutes, the values were 74 (29) versus 89 (42) mm Hg in the room air and oxygen groups, respecti vely. Median (95% CI) time to first breath was 1.1 (1.0-1.2) minutes i n the room air group versus 1.5 (1.4 to 1.6) minutes in the oxygen gro up. Time to the first cry also was in mean 0.4 minute shorter in the r oom air group compared with the oxygen group. In the room air group, t here were 25.7% so-called resuscitation failures (bradycardia and/or c entral cyanosis after 90 seconds) that were switched to 100% oxygen af ter 90 seconds. The percentage of resuscitation failures in the oxygen group was 29.8%. Conclusions. This study with patients enrolled prima rily from developing countries indicates that asphyxiated newborn infa nts can be resuscitated with room air as efficiently as with pure oxyg en. In fact, time to first breath and first cry was significantly shor ter in room air-versus oxygen-resuscitated infants. Resuscitation with 100% oxygen may depress ventilation and therefore delay the first bre ath. More studies are needed confirming these results before resuscita tion guidelines are changed.