Ola Didrik Saugstad

European Consensus Guidelines on the Management of Neonatal Respiratory Distress Syndrome in Preterm Infants – 2010 Update

Despite recent advances in the perinatal management of neonatal respiratory distress syndrome (RDS), controversies still exist. We report the updated recommendations of a European panel of expert neonatologists who had developed consensus guidelines after critical examination of the most up-to-date evidence in 2007. These updated guidelines are based upon published evidence up to the end of 2009. Strong evidence exists for the role of a single course of antenatal steroids in RDS prevention, but the potential benefit and long-term safety of repeated courses are unclear. Many practices involved in preterm neonatal stabilisation at birth are not evidence-based, including oxygen administration and positive pressure lung inflation, and they may at times be harmful. Surfactant replacement therapy is crucial in the management of RDS, but the best preparation, optimal dose and timing of administration at different gestations is not always clear. Respiratory support in the form of mechanical ventilation may also be lifesaving, but can cause lung injury, and protocols should be directed at avoiding mechanical ventilation where possible by using nasal continuous positive airways pressure or nasal ventilation. For babies with RDS to have best outcomes, it is essential that they have optimal supportive care, including maintenance of a normal body temperature, proper fluid management, good nutritional support, management of the ductus arteriosus and support of the circulation to maintain adequate tissue perfusion.

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, resulting in ∼1 million deaths and an equal number of serious sequelae annually. It is therefore important to develop new and better ways to treat asphyxia. Resuscitation after birth asphyxia traditionally has been carried out with 100% oxygen, and most guidelines and textbooks recommend this; however, the scientific background for this has never been established. On the contrary, theoretic considerations indicate that resuscitation with high oxygen concentrations could have detrimental 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 thoroughly, we organized a multicenter study and hypothesized that room air is superior to 100% oxygen when asphyxiated newborn infants are resuscitated. 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 resuscitation with either room air or 100% oxygen. The study was not blinded, and the patients were allocated to one of the two treatment groups according to date of birth. Those born on even dates were resuscitated with room air and those born on odd dates with 100% oxygen. Informed consent was not obtained until after the initial resuscitation, an arrangement in agreement with the new proposal of the US Food and Drug Administrations rules governing investigational drugs and medical devices to permit clinical research on emergency care without the consent of subjects. The protocol was approved by the ethical committees at each participating center. Entry criterion was apnea or gasping with heart rate <80 beats per minute at birth necessitating resuscitation. Exclusion criteria were birth weight <1000 g, lethal anomalies, hydrops, cyanotic congenital heart defects, and stillbirths. Primary outcome measures were death within 1 week and/or presence of hypoxic–ischemic encephalopathy, grade II or III, according to a modification of Sarnat and Sarnat. Secondary outcome measures were Apgar score at 5 minutes, heart rate 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 existing routines for resuscitation in each participating unit were followed, and the ventilation techniques described by the American Heart Association were used as guidelines aiming at a frequency of manual ventilation of 40 to 60 breaths per minute. Results. Forms for 703 enrolled infants from 11 centers were received by the steering committee. All 94 patients from one of the centers were excluded because of violation of the inclusion criteria in 86 of these. Therefore, the final number of infants enrolled in the study was 609 (from 10 centers), with 288 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 room air and oxygen groups, respectively; adjusted odds ratio (OR) = 0.82 with 95% confidence intervals (CI) = 0.50–1.35. Neonatal mortality was 13.9% and 19.0%; adjusted OR = 0.72 with 95% CI = 0.45–1.15. Death within 7 days of life and/or moderate or severe hypoxic–ischemic encephalopathy (primary outcome measure) was seen in 21.2% in the room air group 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 point and were (mean ± SD) 90 ± 31 versus 93 ± 33 beats per minute at 1 minute and 110 ± 27 versus 113 ± 30 beats per minute at 90 seconds 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 with very low 1-minute Apgar scores (<4) in the oxygen group (44.4%) than in the room air group (32.3%). There also were significantly more infants with 5-minute Apgar score <7 in the oxygen group (31.8%) than in the room air group (24.8%). There were no differences in acid base status or Sao 2during the observation period between the two groups. Mean (SD) Pao 2 was 31 (17) versus 30 (22) mm Hg in cord blood in the room air and oxygen groups, respectively (NS). At 10 minutes Pao 2 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, respectively. Median (95% CI) time to first breath was 1.1 (1.0–1.2) minutes in the room air group versus 1.5 (1.4 to 1.6) minutes in the oxygen group. Time to the first cry also was in mean 0.4 minute shorter in the room air group compared with the oxygen group. In the room air group, there were 25.7% so-called resuscitation failures (bradycardia and/or central cyanosis after 90 seconds) that were switched to 100% oxygen after 90 seconds. The percentage of resuscitation failures in the oxygen group was 29.8%. Conclusions. This study with patients enrolled primarily from developing countries indicates that asphyxiated newborn infants can be resuscitated with room air as efficiently as with pure oxygen. In fact, time to first breath and first cry was significantly shorter in room air- versus oxygen-resuscitated infants. Resuscitation with 100% oxygen may depress ventilation and therefore delay the first breath. More studies are needed confirming these results before resuscitation guidelines are changed.

Hypoxanthine as an indicator of hypoxia: its role in health and disease through free radical production

Hypoxanthine as an Indicator of Hypoxia: Its Role in Health and Disease through Free Radical Production

Oxidative stress in the newborn : A 30-year perspective

In this review the development of the concept ‘hypoxia-reoxygenation injury’ is outlined. An update of some important factors and mechanisms related to oxidative stress injury in newborn infants is presented, including the metabolism of glutathione, the role of antioxidants, iron and nitric oxide, and how these may influence health and disease in the newborn and contribute to ‘oxygen radical disease of the newborn’. New insight into how hyperoxia and hypoxia may induce changes leading to retinopathy of prematurity by vascular endothelial growth factor acting in concert with insulin-like growth factor is briefly summarized. Inflammation and oxidative stress seem to be two sides of the same coin in newborn babies both contributing to injury partly through similar mechanisms.

Bronchopulmonary dysplasia—oxidative stress and antioxidants

There is increasing evidence that oxidative stress is implicated in the development of bronchopulmonary dysplasia. Several important factors contribute to augmented oxidative stress in the newborn and especially the preterm infant: first, because of its immaturity, the lung of preterm infants is frequently exposed to oxygen therapy and hyperoxia. Second, the antioxidant defense and its ability to be induced during an hyperoxic challenge are impaired. Third, the preterm infant has an increased susceptibility to infection and inflammation, which increases oxidative stress. Fourth, free iron, which catalyzes the production of toxic reactive oxygen species, can be detected in preterm infants. The molecular and cellular mechanisms for free radical-induced injury are now understood in more detail, and it is clear that oxidative stress plays an important role in triggering apoptosis, in serving as second messenger and in signal transduction. This new insight might lead to novel and efficient therapies. So far, there has been no significant breakthrough regarding antioxidant therapies. Care should, however, be exercised in supplementing the preterm infant with antioxidants since this may affect growth and development.

Resuscitation of Newborn Infants with 21% or 100% Oxygen: An Updated Systematic Review and Meta-Analysis

Background: The issue of whether 21% O2 is more effective than 100% O2 for resuscitation of newborn infants remains controversial. Objectives: We have updated the systematic review and meta-analysis including all studies reporting resuscitation of newborn infants with 21 or 100% O2. Methods: Randomized or quasi-randomized studies of depressed newborn infants resuscitated with 21 or 100% O2 with or without masking of treatment were considered for inclusion. The outcomes of interest included neonatal mortality and hypoxic ischemic encephalopathy. Results: Ten studies fulfilled the inclusion criteria. Of these, 6 studies were identified as being strictly randomized. In total, 1,082 infants were allocated to resuscitation with 21% O2 and 1,051 infants with 100% O2. The risk of neonatal mortality was reduced in the 21% O2 group compared to the 100% O2 group both in the analysis of all studies (typical RR 0.69, 95% CI 0.54, 0.88) and in the analysis of strictly randomized studies (typical RR 0.32, 95% CI 0.12, 0.84). A trend toward a decrease in the risk of hypoxic ischemic encephalopathy stage 2 and 3 was noted with resuscitation in 21% O2 in the analysis of all studies (typical RR 0.88, 95% CI 0.72, 1.08). Conclusions: There is a significant reduction in the risk of neonatal mortality and a trend towards a reduction in the risk of severe hypoxic ischemic encephalopathy in newborns resuscitated with 21% O2.

Oxygen Toxicity in the Neonatal Period

ABSTRACT. Oxygen is toxic because it produces oxygen radicals. One important oxygen radical generating system is hypoxanthine‐xanthine oxidase. Hypoxic newborn babies who have elevated concentrations of hypoxanthine in tissues and body fluids and simultaneously are treated with supplementary oxygen, may therefore produce oxygen radicals in excess overwhelming the bodys natural defence systems against free radicals. Further, the capacity of many of these defence systems are probably reduced in the preterm baby. A series of conditions in neonates may, at least partly, be caused by oxygen radicals, e. g. bronchopulmonary dysplasia, retinopathy of prematurity, necro‐tising enterocolitis and patent ductus arteriosus. These conditions may be different facets of one disease; the “Oxygen radical disease in neonatology”. It is speculated that oxygen radicals play a role in regulating the perinatal circulation. This new insight concerning the role of oxygen radicals may have fundamental consequences for treatment and handling of sick newborn babies.

Mechanisms of tissue injury by oxygen radicals : implications for neonatal disease

A role of the oxygen radical generating system hypoxanthine‐xanthine oxidase in hypoxia‐reoxygenation injury was proposed 15 years ago. In recent years, however, new understanding of hypoxia‐reoxygenation injury has been achieved and the significance of other oxygen radical generating systems has been acknowledged too. The hypothesis that an oxygen radical disease exists in preterm infants has recently been strengthened; an important observation is that preterm infants have lower activities of erythrocyte Cu/Zn superoxide dismutase compared to term babies. New actions of oxygen radicals have also been emphasized, and recently it has been demonstrated that the degree of protein oxidation of the lung of newborn infants is associated with chronic lung injury. The new insight into the interaction of oxygen radicals with other systems as excitatory amino acids and the NO system also increases the possibility to understand and hence prevent oxygen radical injury in the preterm infant as well as in adults exposed to an increased load of oxygen radicals.

Resuscitation of Asphyxic Newborn Infants with Room Air or 100% Oxygen

ABSTRACT: To test the hypothesis that room air is superior to 100% oxygen when asphyxiated newborns are resuscitated, 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). Serial, unblinded observations of heart rates at 1, 3, 5, and 10 min and Apgar scores at 1 min revealed no significant differences between the two groups. At 5 min, median (25th and 75th percentile) Apgar scores were higher in the room air than in the oxygen group [8 (7–9) versus 7 (6–8), p = 0.03]. After the initial resuscitation, arterial partial pressure of oxygen, pH, and base excess were comparable in the two groups. Assisted ventilation was necessary for 2.4 (1.5–3.4) min in the room air group and 3.0 (2.0–4.0) min in the oxygen group (p = 0.14). The median time to first breath was 1.5 (1.0–2.0) min in both the room air and oxygen groups (p = 0.59), and the time to first cry was 3.0 (2.0–4.0) min and 3.5 (2.5–5.5) min in the room air and oxygen groups, respectively (p = 0.19). Three neonates in the room air group and four in the oxygen group died in the neonatal period. At 28 d, 72 of the 77 surviving neonates were available for follow-up (36 in each group), and none had any neurologic sequelae. This preliminary study did not provide conclusive evidence that room air is superior to 100% oxygen in the resuscitation of asphyxiated newborns, although it indicated that room air is as effective as 100% oxygen. Additional trials with increased numbers of patients are necessary before deciding whether room air or oxygen should be used in clinical practice.

Effect of Supplementing Pregnant and Lactating Mothers With n-3 Very-Long-Chain Fatty Acids on Children's IQ and Body Mass Index at 7 Years of Age

OBJECTIVES. Arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3) are essential for brain growth and cognitive development. We have reported that supplementing pregnant and lactating women with n-3 very-long-chain polyunsaturated fatty acids promotes higher IQ scores at 4 years of age as compared with maternal supplementation with n-6 polyunsaturated fatty acids. In our present study, the children were examined at 7 years of age with the same cognitive tests as at 4 years of age. We also examined the relation between plasma fatty acid pattern and BMI in children, because an association between arachidonic acid and adipose tissue size has been suggested. METHODS. The study was randomized and double-blinded. The mothers took 10 mL of cod liver oil or corn oil from week 18 of pregnancy until 3 months after delivery. Their children were tested with the Kaufman Assessment Battery for Children at 7 years of age, and their height and weight were measured. RESULTS. We did not find any significant differences in scores on the Kaufman Assessment Battery for Children test at 7 years of age between children whose mothers had taken cod liver oil (n = 82) or corn oil (n = 61). We observed, however, that maternal plasma phospholipid concentrations of α-linolenic acid (18:3n-3) and docosahexaenoic acid during pregnancy were correlated to sequential processing at 7 years of age. We observed no correlation between fatty acid status at birth or during the first 3 months of life and BMI at 7 years of age. CONCLUSION. This study suggests that maternal concentration of n-3 very-long-chain polyunsaturated fatty acids during pregnancy might be of importance for later cognitive function, such as sequential processing, although we observed no significant effect of n-3 fatty acid intervention on global IQs. Neonatal fatty acid status had no influence on BMI at 7 years of age.