Outcomes of Two Trials of Oxygen-Saturation Targets in Preterm Infants.

BACKGROUND: The safest ranges of oxygen saturation in preterm infants have been the subject of debate. METHODS: In two trials, conducted in Australia and the United Kingdom, infants born before 28 weeks' gestation were randomly assigned to either a lower (85 to 89%) or a higher (91 to 95%) oxygen-saturation range. During enrollment, the oximeters were revised to correct a calibration-algorithm artifact. The primary outcome was death or disability at a corrected gestational age of 2 years; this outcome was evaluated among infants whose oxygen saturation was measured with any study oximeter in the Australian trial and those whose oxygen saturation was measured with a revised oximeter in the U.K. trial. RESULTS: After 1135 infants in Australia and 973 infants in the United Kingdom had been enrolled in the trial, an interim analysis showed increased mortality at a corrected gestational age of 36 weeks, and enrollment was stopped. Death or disability in the Australian trial (with all oximeters included) occurred in 247 of 549 infants (45.0%) in the lower-target group versus 217 of 545 infants (39.8%) in the higher-target group (adjusted relative risk, 1.12; 95% confidence interval [CI], 0.98 to 1.27; P=0.10); death or disability in the U.K. trial (with only revised oximeters included) occurred in 185 of 366 infants (50.5%) in the lower-target group versus 164 of 357 infants (45.9%) in the higher-target group (adjusted relative risk, 1.10; 95% CI, 0.97 to 1.24; P=0.15). In post hoc combined, unadjusted analyses that included all oximeters, death or disability occurred in 492 of 1022 infants (48.1%) in the lower-target group versus 437 of 1013 infants (43.1%) in the higher-target group (relative risk, 1.11; 95% CI, 1.01 to 1.23; P=0.02), and death occurred in 222 of 1045 infants (21.2%) in the lower-target group versus 185 of 1045 infants (17.7%) in the higher-target group (relative risk, 1.20; 95% CI, 1.01 to 1.43; P=0.04). In the group in which revised oximeters were used, death or disability occurred in 287 of 580 infants (49.5%) in the lower-target group versus 248 of 563 infants (44.0%) in the higher-target group (relative risk, 1.12; 95% CI, 0.99 to 1.27; P=0.07), and death occurred in 144 of 587 infants (24.5%) versus 99 of 586 infants (16.9%) (relative risk, 1.45; 95% CI, 1.16 to 1.82; P=0.001). CONCLUSIONS: Use of an oxygen-saturation target range of 85 to 89% versus 91 to 95% resulted in nonsignificantly higher rates of death or disability at 2 years in each trial but in significantly increased risks of this combined outcome and of death alone in post hoc combined analyses. (Funded by the Australian National Health and Medical Research Council and others; BOOST-II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry number, ACTRN12605000055606.).

Association Between Oxygen Saturation Targeting and Death or Disability in Extremely Preterm Infants in the Neonatal Oxygenation Prospective Meta-analysis Collaboration.

Importance: There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more vs less supplemental oxygen. Objective: To compare the effects of different target ranges for oxygen saturation as measured by pulse oximetry (Spo2) on death or major morbidity. Design, Setting, and Participants: Prospectively planned meta-analysis of individual participant data from 5 randomized clinical trials (conducted from 2005-2014) enrolling infants born before 28 weeks' gestation. Exposures: Spo2 target range that was lower (85%-89%) vs higher (91%-95%). Main Outcomes and Measures: The primary outcome was a composite of death or major disability (bilateral blindness, deafness, cerebral palsy diagnosed as ≥2 level on the Gross Motor Function Classification System, or Bayley-III cognitive or language score <85) at a corrected age of 18 to 24 months. There were 16 secondary outcomes including the components of the primary outcome and other major morbidities. Results: A total of 4965 infants were randomized (2480 to the lower Spo2 target range and 2485 to the higher Spo2 range) and had a median gestational age of 26 weeks (interquartile range, 25-27 weeks) and a mean birth weight of 832 g (SD, 190 g). The primary outcome occurred in 1191 of 2228 infants (53.5%) in the lower Spo2 target group and 1150 of 2229 infants (51.6%) in the higher Spo2 target group (risk difference, 1.7% [95% CI, -1.3% to 4.6%]; relative risk [RR], 1.04 [95% CI, 0.98 to 1.09], P = .21). Of the 16 secondary outcomes, 11 were null, 2 significantly favored the lower Spo2 target group, and 3 significantly favored the higher Spo2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower Spo2 target group and 418 of 2440 infants (17.1%) in the higher Spo2 target group (risk difference, 2.8% [95% CI, 0.6% to 5.0%]; RR, 1.17 [95% CI, 1.04 to 1.31], P = .01). Treatment for retinopathy of prematurity was administered to 220 of 2020 infants (10.9%) in the lower Spo2 target group and 308 of 2065 infants (14.9%) in the higher Spo2 target group (risk difference, -4.0% [95% CI, -6.1% to -2.0%]; RR, 0.74 [95% CI, 0.63 to 0.86], P < .001). Severe necrotizing enterocolitis occurred in 227 of 2464 infants (9.2%) in the lower Spo2 target group and 170 of 2465 infants (6.9%) in the higher Spo2 target group (risk difference, 2.3% [95% CI, 0.8% to 3.8%]; RR, 1.33 [95% CI, 1.10 to 1.61], P = .003). Conclusions and Relevance: In this prospectively planned meta-analysis of individual participant data from extremely preterm infants, there was no significant difference between a lower Spo2 target range compared with a higher Spo2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower Spo2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.

Oxygen saturation and outcomes in preterm infants.

BACKGROUND: The clinically appropriate range for oxygen saturation in preterm infants is unknown. Previous studies have shown that infants had reduced rates of retinopathy of prematurity when lower targets of oxygen saturation were used. METHODS: In three international randomized, controlled trials, we evaluated the effects of targeting an oxygen saturation of 85 to 89%, as compared with a range of 91 to 95%, on disability-free survival at 2 years in infants born before 28 weeks' gestation. Halfway through the trials, the oximeter-calibration algorithm was revised. Recruitment was stopped early when an interim analysis showed an increased rate of death at 36 weeks in the group with a lower oxygen saturation. We analyzed pooled data from patients and now report hospital-discharge outcomes. RESULTS: A total of 2448 infants were recruited. Among the 1187 infants whose treatment used the revised oximeter-calibration algorithm, the rate of death was significantly higher in the lower-target group than in the higher-target group (23.1% vs. 15.9%; relative risk in the lower-target group, 1.45; 95% confidence interval [CI], 1.15 to 1.84; P=0.002). There was heterogeneity for mortality between the original algorithm and the revised algorithm (P=0.006) but not for other outcomes. In all 2448 infants, those in the lower-target group for oxygen saturation had a reduced rate of retinopathy of prematurity (10.6% vs. 13.5%; relative risk, 0.79; 95% CI, 0.63 to 1.00; P=0.045) and an increased rate of necrotizing enterocolitis (10.4% vs. 8.0%; relative risk, 1.31; 95% CI, 1.02 to 1.68; P=0.04). There were no significant between-group differences in rates of other outcomes or adverse events. CONCLUSIONS: Targeting an oxygen saturation below 90% with the use of current oximeters in extremely preterm infants was associated with an increased risk of death. (Funded by the Australian National Health and Medical Research Council and others; BOOST II Current Controlled Trials number, ISRCTN00842661, and Australian New Zealand Clinical Trials Registry numbers, ACTRN12605000055606 and ACTRN12605000253606.).

Automated control of inspired oxygen in ventilated preterm infants: crossover physiological study.

AIM: To evaluate the efficacy of automated control of the fraction of inspired oxygen (FiO2 ) in comparison with manual FiO2 control in maintaining target pulse oxygen saturation (SpO2 ) range. METHODS: Crossover physiological study involving preterm infants requiring mechanical ventilation and supplemental oxygen. Each infant was studied for two consecutive 12 hours in a random sequence. Outcome measures included the proportion of time with SpO2 within and outside the target range of 90-95%, extreme hypoxaemia (< 80%) and hyperoxaemia (≥ 98%). RESULTS: Complete data set was available in 27 infants. The percentage of time (median, IQR) within the target range was higher during automated control 72.8 (58.8-82.6) compared to manual control 59.6 (49.3-73.3), p = 0.031. Corresponding reduction in per cent time below the target range was 18.1 (12.7-23.6) versus 25.9 (17.8-30.7), p = 0.028, and above the target range 4.8 (3-16) versus 10.1 (6.4-22.5), p = 0.026. Median (IQR) per cent time spent with severe hypoxaemia (SpO2 < 80%) and severe hyperoxaemia (SpO2 ≥ 98%) was 1.3 (0.1-2.9) versus 3.2 (1.4-6.1), p = 0.022 and 0.08 (0.05-0.36) versus 1.7 (0.7-6.8), p = 0.001, respectively. Median number of manual adjustments of FiO2 per 12 hour was 0 and 63, respectively. CONCLUSION: Automated control of FiO2 significantly improved compliance of oxygen saturation targeting and significantly reduced exposure to hypoxaemia as well as hyperoxaemia.

Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity.

CONTEXT: Very preterm infants are prone to apnea and have an increased risk of death or disability. Caffeine therapy for apnea of prematurity reduces the rates of cerebral palsy and cognitive delay at 18 months of age. OBJECTIVE: To determine whether neonatal caffeine therapy has lasting benefits or newly apparent risks at early school age. DESIGN, SETTING, AND PARTICIPANTS: Five-year follow-up from 2005 to 2011 in 31 of 35 academic hospitals in Canada, Australia, Europe, and Israel, where 1932 of 2006 participants (96.3%) had been enrolled in the randomized, placebo-controlled Caffeine for Apnea of Prematurity trial between 1999 and 2004. A total of 1640 children (84.9%) with birth weights of 500 to 1250 g had adequate data for the main outcome at 5 years. MAIN OUTCOME MEASURES: Combined outcome of death or survival to 5 years with 1 or more of motor impairment (defined as a Gross Motor Function Classification System level of 3 to 5), cognitive impairment (defined as a Full Scale IQ<70), behavior problems, poor general health, deafness, and blindness. RESULTS: The combined outcome of death or disability was not significantly different for the 833 children assigned to caffeine from that for the 807 children assigned to placebo (21.1% vs 24.8%; odds ratio adjusted for center, 0.82; 95% CI, 0.65-1.03; P = .09). The rates of death, motor impairment, behavior problems, poor general health, deafness, and blindness did not differ significantly between the 2 groups. The incidence of cognitive impairment was lower at 5 years than at 18 months and similar in the 2 groups (4.9% vs 5.1%; odds ratio adjusted for center, 0.97; 95% CI, 0.61-1.55; P = .89). CONCLUSION: Neonatal caffeine therapy was no longer associated with a significantly improved rate of survival without disability in children with very low birth weights who were assessed at 5 years.

Long-term effects of caffeine therapy for apnea of prematurity.

BACKGROUND: Methylxanthine therapy is commonly used for apnea of prematurity but in the absence of adequate data on its efficacy and safety. It is uncertain whether methylxanthines have long-term effects on neurodevelopment and growth. METHODS: We randomly assigned 2006 infants with birth weights of 500 to 1250 g to receive either caffeine or placebo until therapy for apnea of prematurity was no longer needed. The primary outcome was a composite of death, cerebral palsy, cognitive delay (defined as a Mental Development Index score of <85 on the Bayley Scales of Infant Development), deafness, or blindness at a corrected age of 18 to 21 months. RESULTS: Of the 937 infants assigned to caffeine for whom adequate data on the primary outcome were available, 377 (40.2%) died or survived with a neurodevelopmental disability, as compared with 431 of the 932 infants (46.2%) assigned to placebo for whom adequate data on the primary outcome were available (odds ratio adjusted for center, 0.77; 95% confidence interval [CI], 0.64 to 0.93; P=0.008). Treatment with caffeine as compared with placebo reduced the incidence of cerebral palsy (4.4% vs. 7.3%; adjusted odds ratio, 0.58; 95% CI, 0.39 to 0.87; P=0.009) and of cognitive delay (33.8% vs. 38.3%; adjusted odds ratio, 0.81; 95% CI, 0.66 to 0.99; P=0.04). The rates of death, deafness, and blindness and the mean percentiles for height, weight, and head circumference at follow-up did not differ significantly between the two groups. CONCLUSIONS: Caffeine therapy for apnea of prematurity improves the rate of survival without neurodevelopmental disability at 18 to 21 months in infants with very low birth weight. (ClinicalTrials.gov number, NCT00182312 [ClinicalTrials.gov].).

Caffeine for Apnea of Prematurity trial: benefits may vary in subgroups.

OBJECTIVE: To determine whether the benefits of caffeine vary in three subgroups of 2006 participants in the Caffeine for Apnea of Prematurity (CAP) trial. STUDY DESIGN: Post-hoc subgroup analyses were performed on the basis of: (1) indication for commencement of study drug: treat apnea, prevent apnea, or facilitate extubation; (2) positive pressure ventilation (PPV) at randomization: endotracheal tube (ETT), noninvasive ventilation, or none; and (3) timing of commencement of study drug: early or late (< or =3 versus >3 days). Outcomes assessed were those showing treatment effects in the original analyses. We investigated the consistency of caffeine effects by using regression models that incorporated treatment/subgroup factor interactions. RESULTS: There was little evidence of a differential treatment effect of caffeine in subgroups defined by the clinical indication for starting study drug. The size and direction of the caffeine effect on death or disability differed depending on PPV at randomization (P = .03). Odds ratios (95% CI) were: no support, 1.32 (0.81-2.14); noninvasive support, 0.73 (0.52-1.03); and ETT, 0.73 (0.57-0.94). Adjustment for baseline factors strengthened this effect (P = .02). Starting caffeine early resulted in larger reductions in days of respiratory support. Postmenstrual age at time of discontinuing PPV was shorter with earlier treatment (P = .01). Mean differences (95% CI) were: early, 1.35 weeks (0.90-1.81); and late 0.55 weeks (-0.11-0.99). Adjustment for baseline factors weakened this effect (P = .03). CONCLUSIONS: There is evidence of variable beneficial effects of caffeine. Infants receiving respiratory support appeared to derive more neurodevelopmental benefits from caffeine than infants not receiving support. Earlier initiation of caffeine may be associated with a greater reduction in time on ventilation.

Caffeine therapy for apnea of prematurity.

BACKGROUND: Methylxanthines reduce the frequency of apnea of prematurity and the need for mechanical ventilation during the first seven days of therapy. It is uncertain whether methylxanthines have other short- and long-term benefits or risks in infants with very low birth weight. METHODS: We randomly assigned 2006 infants with birth weights of 500 to 1250 g during the first 10 days of life to receive either caffeine or placebo, until drug therapy for apnea of prematurity was no longer needed. We evaluated the short-term outcomes before the first discharge home. RESULTS: Of 963 infants who were assigned to caffeine and who remained alive at a postmenstrual age of 36 weeks, 350 (36 percent) received supplemental oxygen, as did 447 of the 954 infants (47 percent) assigned to placebo (adjusted odds ratio, 0.63; 95 percent confidence interval, 0.52 to 0.76; P<0.001). Positive airway pressure was discontinued one week earlier in the infants assigned to caffeine (median postmenstrual age, 31.0 weeks; interquartile range, 29.4 to 33.0) than in the infants in the placebo group (median postmenstrual age, 32.0 weeks; interquartile range, 30.3 to 34.0; P<0.001). Caffeine reduced weight gain temporarily. The mean difference in weight gain between the group receiving caffeine and the group receiving placebo was greatest after two weeks (mean difference, -23 g; 95 percent confidence interval, -32 to -13; P<0.001). The rates of death, ultrasonographic signs of brain injury, and necrotizing enterocolitis did not differ significantly between the two groups. CONCLUSIONS: Caffeine therapy for apnea of prematurity reduces the rate of bronchopulmonary dysplasia in infants with very low birth weight. (ClinicalTrials.gov number, NCT00182312.).

A randomized controlled trial of post-extubation bubble continuous positive airway pressure versus Infant Flow Driver continuous positive airway pressure in preterm infants with respiratory distress syndrome.

OBJECTIVE: To compare the efficacy and safety of bubble continuous positive airway pressure (CPAP) and Infant Flow Driver (IFD) CPAP for the post-extubation management of preterm infants with respiratory distress syndrome (RDS). STUDY DESIGN: A total of 140 preterm infants at 24 to 29 weeks' gestation or with a birth weight of 600 to 1500 g who were ventilated at birth for RDS were randomized to receive either IFD CPAP (a variable-flow device) or bubble CPAP (a continuous-flow device). A standardized protocol was used for extubation and CPAP. No crossover was allowed. The primary outcome was successful extubation maintained for at least 72 hours. Secondary outcomes included successful extubation maintained for 7 days, total duration of CPAP support, chronic lung disease, and complications of prematurity. RESULTS: Seventy-one infants were randomized to bubble CPAP, and 69 were randomized to IFD CPAP. Mean gestational age and birth weight were similar in the 2 groups, as were the proportions of infants who achieved successful extubation for 72 hours and for 7 days. However, the median duration of CPAP support was 50% shorter in the infants on bubble CPAP. Moreover, in the subset of infants who were ventilated for less than 14 days, the infants on bubble CPAP had a significantly lower extubation failure rate. There was no difference in the incidence of chronic lung disease or other complications between the 2 study groups. CONCLUSIONS: Bubble CPAP is as effective as IFD CPAP in the post-extubation management of infants with RDS; however, in infants ventilated for < or = 14 days, bubble CPAP is associated with a significantly higher rate of successful extubation. Bubble CPAP also is associated with a significantly reduced duration of CPAP support.

Adjunctive therapies in chronic lung disease: examining the evidence.

Chronic lung disease (CLD) or bronchopulmonary dysplasia (BPD) is one of the most common long-term complications in very premature infants. The incidence of CLD has been increasing over the past two decades in parallel with an improvement in the survival of this population. We have witnessed a revolution in the therapies that are used, either to manage these infants' respiratory distress syndrome (RDS) with an aim to prevent CLD or to manage the established condition. Several devices and strategies have been developed to provide respiratory support with minimal risk of lung injuries. Multiple adjunctive agents have also been used either to reduce the risk of CLD or to mitigate its course. There is considerable evidence supporting the use of exogenous surfactant, but unfortunately many other therapies currently used for CLD, either preventative or as a treatment, are based on very little or no evidence. The gold standard to assess a given therapy is the randomised controlled trial (RCT), designed to look at clinically meaningful outcomes and long-term safety. In this context, we discuss the support - or lack thereof - for the adjunctive therapies used in relation to CLD. Many of the therapies have been examined as systematic reviews by the Cochrane Neonatal Review Group. These reviews are noted in the references and can be easily accessed at the following website sponsored by the National Institute of Child Health and Human Development: www.nichd.nih.gov/cochrane/default.cfm.

Neurobehavioral Outcomes 11 Years After Neonatal Caffeine Therapy for Apnea of Prematurity.

BACKGROUND AND OBJECTIVES: Caffeine is effective in the treatment of apnea of prematurity. Although caffeine therapy has a benefit on gross motor skills in school-aged children, effects on neurobehavioral outcomes are not fully understood. We aimed to investigate effects of neonatal caffeine therapy in very low birth weight (500-1250 g) infants on neurobehavioral outcomes in 11-year-old participants of the Caffeine for Apnea of Prematurity trial. METHODS: Thirteen academic hospitals in Canada, Australia, Great Britain, and Sweden participated in this part of the 11-year follow-up of the double-blind, randomized, placebo-controlled trial. Measures of general intelligence, attention, executive function, visuomotor integration and perception, and behavior were obtained in up to 870 children. The effects of caffeine therapy were assessed by using regression models. RESULTS: Neurobehavioral outcomes were generally similar for both the caffeine and placebo group. The caffeine group performed better than the placebo group in fine motor coordination (mean difference [MD] = 2.9; 95% confidence interval [CI]: 0.7 to 5.1; P = .01), visuomotor integration (MD = 1.8; 95% CI: 0.0 to 3.7; P < .05), visual perception (MD = 2.0; 95% CI: 0.3 to 3.8; P = .02), and visuospatial organization (MD = 1.2; 95% CI: 0.4 to 2.0; P = .003). CONCLUSIONS: Neonatal caffeine therapy for apnea of prematurity improved visuomotor, visuoperceptual, and visuospatial abilities at age 11 years. General intelligence, attention, and behavior were not adversely affected by caffeine, which highlights the long-term safety of caffeine therapy for apnea of prematurity in very low birth weight neonates.

Evidence-based use of adjunctive therapies to ventilation.

Respiratory distress is the most common reason for admission to newborn intensive care units. Over the past two decades, we have witnessed a revolution in the therapies that are used to manage neonates who have pulmonary disorders. Multiple adjunctive agents have also been used in an attempt to mitigate the course of neonatal lung disease. The disorders we discuss include respiratory distress syndrome, chronic lung disease/bronchopulmonary dysplasia, persistent pulmonary hypertension of the newborn, meconium aspiration syndrome, and transient tachypnea of the newborn. We review the evidence that either supports or refutes the use of adjunctive therapies for these disorders.

Academic Performance, Motor Function, and Behavior 11 Years After Neonatal Caffeine Citrate Therapy for Apnea of Prematurity: An 11-Year Follow-up of the CAP Randomized Clinical Trial.

Importance: Caffeine citrate therapy for apnea of prematurity reduces the rates of bronchopulmonary dysplasia, severe retinopathy, and neurodevelopmental disability at 18 months and may improve motor function at 5 years. Objective: To evaluate whether neonatal caffeine therapy is associated with improved functional outcomes 11 years later. Design, Setting, and Participants: A follow-up study was conducted at 14 academic hospitals in Canada, Australia, and the United Kingdom from May 7, 2011, to May 27, 2016, of English- or French-speaking children who had been enrolled in the randomized, placebo-controlled Caffeine for Apnea of Prematurity trial between October 11, 1999, and October 22, 2004. A total of 1202 children with birth weights of 500 to 1250 g were eligible for this study; 920 (76.5%) had adequate data for the main outcome. Interventions: Caffeine citrate or placebo until drug therapy for apnea of prematurity was no longer needed. Main Outcomes and Measures: Functional impairment was a composite of poor academic performance (defined as at least 1 standard score greater than 2 SD below the mean on the Wide Range Achievement Test-4), motor impairment (defined as a percentile rank of ≤5 on the Movement Assessment Battery for Children-Second Edition), and behavior problems (defined as a Total Problem T score ≥2 SD above the mean on the Child Behavior Checklist). Results: Among the 920 children (444 females and 476 males; median age, 11.4 years [interquartile range, 11.1-11.8 years]), the combined rates of functional impairment were not significantly different between the 457 children assigned to receive caffeine compared with the 463 children assigned to receive placebo (145 [31.7%] vs 174 [37.6%]; adjusted odds ratio, 0.78; 95% CI, 0.59-1.02; P = .07). With all available data, including those from up to 24 Swedish trial participants, the rates of poor academic performance on 1 or more of 4 subtests (66 of 458 [14.4%] vs 61 of 462 [13.2%]; adjusted odds ratio, 1.11; 95% CI, 0.77-1.61; P = .58) and behavior problems (52 of 476 [10.9%] vs 40 of 481 [8.3%]; adjusted odds ratio, 1.32; 95% CI, 0.85-2.07; P = .22) were broadly similar between the group that received caffeine and the group that received placebo. However, caffeine therapy was associated with a reduced risk of motor impairment compared with placebo (90 of 457 [19.7%] vs 130 of 473 [27.5%]; adjusted odds ratio, 0.66; 95% CI, 0.48-0.90; P = .009). Conclusions and Relevance: Caffeine therapy for apnea of prematurity did not significantly reduce the combined rate of academic, motor, and behavioral impairments but was associated with a reduced risk of motor impairment in 11-year-old children with very low birth weight. At the doses used in this trial, neonatal caffeine therapy is effective and safe into middle school age. Trial Registration: clinicaltrials.gov Identifier: NCT00182312; isrctn.org Identifier: ISRCTN44364365.

Principles of pulse oximetry and its clinical application in neonatal medicine.

Pulse oximetry is one of the most commonly used monitoring devices in clinical medicine. It was first introduced to neonatal medicine in the mid-1980s to monitor oxygenation and guide therapy, and it is now used widely in the delivery room during resuscitation. More recently, it is utilized to screen for congenital heart disease. Pulse oximetry is based on the variation in the ratio of the light absorbances of tissues during systole and diastole. It has become the mainstay of non-invasive continuous oxygen monitoring but with a wide variation in clinical practices and without good research evidence. This article provides a brief historical overview of pulse oximetry development, its principles, advantages and limitations, and the clinical applications in neonatal medicine.

[Oxidative Stress Derived from Airborne Fine and Ultrafine Particles and the Effects on Brain-Nervous System: Part 2].

Traffic-related air pollution is a major contributor to urban air pollution. Diesel exhaust (DE) is its most important component of near-road and urban air pollutions and is commonly used as a surrogate model of air pollution in health effects studies. In particular, diesel exhaust particles (DEPs) and nanoparticles in DEPs are the components considered hazardous for health. It is widely known that exposure to DEPs is associated with mortality caused by respiratory and cardiovascular diseases. Recently, evidence has been accumulating showing that DEPs and nanoparticles may cause neurodegenerative disorders. Here, we introduce evidence suggesting their association with these disorders. The chemical components and the translocation of DEPs and nanoparticles to the brain are described in part 1. In part 2, we introduce the mechanism of development of neurodegenerative diseases such as stroke, Alzheimer's disease, and Parkinson's disease via oxidative stress and inflammatory events. Furthermore, there are many lines of epidemiological evidence showing that the particulates impair cognitive function and ability of memory through oxidative and inflammatory events in the brain. These lines of evidences are supported by many animal experiments on neurological disorders.

Predicting severe motor impairment in preterm children at age 5 years.

OBJECTIVE: To determine whether the ability to predict severe motor impairment at age 5 years improves between birth and 18 months. DESIGN: Ancillary study of the Caffeine for Apnea of Prematurity Trial. SETTING AND PATIENTS: International cohort of very low birth weight children who were assessed sequentially from birth to 5 years. OUTCOME MEASURES: Severe motor impairment was defined as a score <5th percentile on the Movement Assessment Battery of Children (MABC), or inability to complete the MABC because of cerebral palsy. Multivariable logistic regression cumulative risk models used four sets of predictor variables: early neonatal risk factors, risk factors at 36 weeks' postmenstrual age, risk factors at a corrected age of 18 months, and sociodemographic variables. A receiver operating characteristic curve (ROC) was generated for each model, and the four ROC curves were compared to determine if the addition of the new set of predictors significantly increased the area under the curve (AUC). RESULTS: Of 1469 children, 291 (19.8%) had a severe motor impairment at 5 years. The AUC increased from 0.650 soon after birth, to 0.718 (p<0.001) at 36 weeks' postmenstrual age, and to 0.797 at 18 months (p<0.001). Sociodemographic variables did not significantly improve the AUC (AUC=0.806; p=0.07). CONCLUSIONS: Prediction of severe motor impairment at 5 years of age using a cumulative risk model improves significantly from birth to 18 months of age in children with birth weights between 500 g and 1250 g. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number NCT00182312.

Urinary NAG as an early indicator of renal damage in Russell's viper bite envenomation.

Urinary N-acetyl-beta-D-glucosaminidase (NAG; beta-N-acetylglucosaminidase; EC 3.2.1.30), blood urea, serum creatinine and creatinine clearance were measured in 23 patients bitten by Russell's viper (Daboia russelii siamensis), with systemic envenomation, at different time intervals after the bite during clinical observation for 5 d. Activities of urinary NAG were compared with these indicators of renal function in 3 clinical conditions: non-oliguric acute renal failure (ARF), oliguric ARF not requiring peritoneal dialysis, and oliguric ARF requiring peritoneal dialysis. Cut-off values to identify the 3 conditions were established. When the times of onset of the conditions, indicated by the cut-off values, were compared, urinary NAG was generally found to be the earliest indicator of renal damage. In each type of ARF, the urinary NAG level was abnormal before changes in the values of the other indicators of renal function. It may be possible to predict the types of ARF within 2 h after the bite by measurement of urinary NAG.

Defining neonatal hypoglycaemia: a continuing debate.

Hypoglycaemia is one of the most frequent metabolic problems in neonatal medicine, and maintaining glucose homeostasis is one of the important physiological events during fetal-to-neonatal transition. Although frequently observed transient low blood glucose concentrations in the majority of healthy newborns are the reflections of normal metabolic adaptation processes during this transition, there has been a genuine concern that prolonged or recurrent low blood glucose levels may result in acute systemic effects and long-term neurological and developmental consequences. Hence, it is not surprising that neonatal hypoglycaemia remains one of the most important issues in our day-to-day practice and that we also become obsessed with the numbers and values that we believe are a 'cut-off' for its definition. The aim of this article is to critically appraise some of the available evidence either to support or refute the most widely accepted definition of 'neonatal hypoglycaemia' (blood glucose concentration: <2.6 mmol/l or 47 mg/dl), to highlight our knowledge gaps in defining neonatal hypoglycaemia, and to address the important concept of using an 'operational threshold', rather than focusing too much on a single blood glucose cut-off value, which is often applied to all newborn infants.

Adjunctive drug therapies for treatment of respiratory diseases in the newborn: based on evidence or habit?

Respiratory distress syndrome is a disease of prematurity and is caused by a relative deficiency of endogenous surfactant production. Respiratory distress syndrome is the most common cause of mortality and morbidity in the newborn population and the standard of care is to provide exogenous surfactant therapy. This saves lives and reduces respiratory complications but, despite treatment, a significant proportion of these infants go onto develop chronic lung disease, the severest form of which is bronchopulmonary dysplasia. Once developed, this is a multisystem disease and treatment is mostly supportive by using various therapeutic adjuncts. Some of these have been proven to be safe and effective in large randomized, controlled trials but similar evidence for other drugs is lacking. The aim of this paper is to provide an overview and critically appraise the available scientific evidence for or against their use in routine practice.

15-year follow-up of recurrent "hypoglycemia" in preterm infants.

BACKGROUND: Observational study of 543 infants who weighed <1850 g, published in 1988 reported seriously impaired motor and cognitive development at 18 months in those with recurrent, asymptomatic hypoglycemia (plasma glucose level ≤2.5 mmol/L on ≥3 days). No study has yet replicated this observation. AIM: To quantify disability in a similar cohort of children followed up throughout childhood. POPULATION: All children born at <32 weeks' gestation in the north of England in 1990-1991 and had laboratory blood glucose levels measured daily for the first 10 days of life. RESULTS: Forty-seven index children of the 566 who survived to 2 years had a blood glucose level of ≤2.5 mmol/L on ≥3 days. All of these children and hypoglycemia-free controls, matched for hospital of care, gestation, and birth weight, were assessed at age 2. No differences in developmental progress or physical disability were detected. The families were seen again when the children were 15 years old, and 38 of the index children (81%) and matched controls agreed to detailed psychometric assessment. Findings in the 2 groups were nearly identical (mean full-scale IQ: 80.7 vs 81.2). Findings in the 21 children with a level of ≤2.5 mmol/L on ≥4 days, 7 children with a level this low on 5 days, and 11 children with a level of <2.0 mmol/L on 3 different days did not alter these conclusions. CONCLUSIONS: This study found no evidence to support the belief that recurrent low blood glucose levels (≤2.5 mmol/L) in the first 10 days of life usually pose a hazard to preterm infants.