Robin K. Whyte

Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy An Updated Systematic Review and Meta-analysis

OBJECTIVE To establish the evidence of therapeutic hypothermia for newborns with hypoxic ischemic encephalopathy(HIE). DATA SOURCES Cochrane Central Register of Controlled Trials, Oxford Database of Perinatal Trials, MEDLINE, EMBASE, and previous reviews. STUDY SELECTION Randomized controlled trials that compared therapeutic hypothermia to normothermia for newborns with HIE. INTERVENTION Therapeutic hypothermia. MAIN OUTCOME MEASURES Death or major neurodevelopmental disability at 18 months. RESULTS Seven trials including 1214 newborns were identified. Therapeutic hypothermia resulted in a reduction in the risk of death or major neurodevelopmental disability(risk ratio [RR], 0.76; 95% CI, 0.69-0.84) and increase in the rate of survival with normal neurological function (1.63; 1.36-1.95) at age 18 months. Hypothermia reduced the risk of death or major neurodevelopmental disability at age 18 months in newborns with moderate HIE (RR, 0.67; 95% CI, 0.56-0.81) and in newborns with severe HIE (0.83; 0.74-0.92). Both total body cooling and selective head cooling resulted in reduction in the risk of death or major neurodevelopmental disability(RR, 0.75; 95% CI, 0.66-0.85 and 0.77; 0.65-0.93,respectively). CONCLUSION Hypothermia improves survival and neurodevelopment in newborns with moderate to severe HIE.Total body cooling and selective head cooling are effective methods in treating newborns with HIE. Clinicians should consider offering therapeutic hypothermia as part of routine clinical care to these newborns.

Effects of Targeting Higher vs Lower Arterial Oxygen Saturations on Death or Disability in Extremely Preterm Infants: A Randomized Clinical Trial

IMPORTANCE The goal of oxygen therapy is to deliver sufficient oxygen to the tissues while minimizing oxygen toxicity and oxidative stress. It remains uncertain what values of arterial oxygen saturations achieve this balance in preterm infants. OBJECTIVE To compare the effects of targeting lower or higher arterial oxygen saturations on the rate of death or disability in extremely preterm infants. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind trial in 25 hospitals in Canada, the United States, Argentina, Finland, Germany, and Israel in which 1201 infants with gestational ages of 23 weeks 0 days through 27 weeks 6 days were enrolled within 24 hours after birth between December 2006 and August 2010. Follow-up assessments began in October 2008 and ended in August 2012. INTERVENTIONS Study participants were monitored until postmenstrual ages of 36 to 40 weeks with pulse oximeters that displayed saturations of either 3% above or below the true values. Caregivers adjusted the concentration of oxygen to achieve saturations between 88% and 92%, which produced 2 treatment groups with true target saturations of 85% to 89% (n = 602) or 91% to 95% (n = 599). Alarms were triggered when displayed saturations decreased to 86% or increased to 94%. MAIN OUTCOMES AND MEASURES The primary outcome was a composite of death, gross motor disability, cognitive or language delay, severe hearing loss, or bilateral blindness at a corrected age of 18 months. Secondary outcomes included retinopathy of prematurity and brain injury. RESULTS Of the 578 infants with adequate data for the primary outcome who were assigned to the lower target range, 298 (51.6%) died or survived with disability compared with 283 of the 569 infants (49.7%) assigned to the higher target range (odds ratio adjusted for center, 1.08; 95% CI, 0.85 to 1.37; P = .52). The rates of death were 16.6% for those in the 85% to 89% group and 15.3% for those in the 91% to 95% group (adjusted odds ratio, 1.11; 95% CI, 0.80 to 1.54; P = .54). Targeting lower saturations reduced the postmenstrual age at last use of oxygen therapy (adjusted mean difference, -0.8 weeks; 95% CI, -1.5 to -0.1; P = .03) but did not alter any other outcomes. CONCLUSION AND RELEVANCE In extremely preterm infants, targeting oxygen saturations of 85% to 89% compared with 91% to 95% had no significant effect on the rate of death or disability at 18 months. These results may help determine the optimal target oxygen saturation. TRIAL REGISTRATIONS ISRCTN Identifier: 62491227; ClinicalTrials.gov Identifier: NCT00637169.

Neurodevelopmental outcome of extremely low birth weight infants randomly assigned to restrictive or liberal hemoglobin thresholds for blood transfusion

BACKGROUND AND OBJECTIVE. Extremely low birth weight infants frequently receive red cell transfusions. We sought to determine whether a restrictive versus liberal hemoglobin transfusion threshold results in differences in death or adverse neurodevelopmental outcomes of extremely low birth weight infants. PATIENTS AND METHODS. Extremely low birth weight infants previously enrolled in the Preterm Infants in Need of Transfusion Trial, a randomized, controlled trial of low versus high hemoglobin transfusion thresholds, were followed up at 18 to 21 months’ corrected age. Erythrocyte transfusion was determined by an algorithm of low (restrictive) or high (liberal) hemoglobin transfusion thresholds, differing by 10 to 20 g/L and maintained until first hospital discharge. The primary composite outcome was death or the presence of cerebral palsy, cognitive delay, or severe visual or hearing impairment. RESULTS. Of 451 enrolled infants, the primary outcome was available in 430. There was no statistically significant difference in the primary outcome, found in 94 (45%) of 208 in the restrictive group and 82 (38%) of 213 in the liberal group. There were no statistically significant differences in preplanned secondary outcomes. However, the difference in cognitive delay (Mental Development Index score < 70) approached statistical significance. A posthoc analysis with cognitive delay redefined (Mental Development Index score < 85) showed a significant difference favoring the liberal threshold group. CONCLUSIONS. Maintaining the hemoglobin of extremely low birth weight infants at these restrictive rather than liberal transfusion thresholds did not result in a statistically significant difference in combined death or severe adverse neurodevelopmental outcome.

Improving the quality of care for infants: a cluster randomized controlled trial.

Background: We developed and tested a new method, called the Evidence-based Practice for Improving Quality method, for continuous quality improvement. Methods: We used cluster randomization to assign 6 neonatal intensive care units (ICUs) to reduce nosocomial infection (infection group) and 6 ICUs to reduce bronchopulmonary dysplasia (pulmonary group). We included all infants born at 32 or fewer weeks gestation. We collected baseline data for 1 year. Practice change interventions were implemented using rapid-change cycles for 2 years. Results: The difference in incidence trends (slopes of trend lines) between the ICUs in the infection and pulmonary groups was − 0.0020 (95% confidence interval [CI] − 0.0007 to 0.0004) for nosocomial infection and − 0.0006 (95% CI − 0.0011 to − 0.0001) for bronchopulmonary dysplasia. Interpretation: The results suggest that the Evidence-based Practice for Improving Quality method reduced bronchopulmonary dysplasia in the neonatal ICU and that it may reduce nosocomial infection.

Low versus high haemoglobin concentration threshold for blood transfusion for preventing morbidity and mortality in very low birth weight infants

BACKGROUND Infants of very low birth weight often receive multiple transfusions of red blood cells, usually in response to predetermined haemoglobin or haematocrit thresholds. In the absence of better indices, haemoglobin levels are imperfect but necessary guides to the need for transfusion. Chronic anaemia in premature infants may, if severe, cause apnoea, poor neurodevelopmental outcomes or poor weight gain.On the other hand, red blood cell transfusion may result in transmission of infections, circulatory or iron overload, or dysfunctional oxygen carriage and delivery. OBJECTIVES To determine if erythrocyte transfusion administered to maintain low as compared to high haemoglobin thresholds reduces mortality or morbidity in very low birth weight infants enrolled within three days of birth. SEARCH METHODS Two review authors independently searched the Cochrane Central Register of Controlled Trials (The Cochrane Library) , MEDLINE,EMBASE, and conference proceedings through June 2010. SELECTION CRITERIA We selected randomised controlled trials (RCTs) comparing the effects of early versus late, or restrictive versus liberal erythrocyte transfusion regimes in low birth weight infants applied within three days of birth, with mortality or major morbidity as outcomes.

Energy balance and nitrogen balance in growing low birthweight infants fed human milk or formula

Summary: Energy and nitrogen balances were measured in growing low birthweight infants fed either mothers expressed breast milk or a 20 kcal per ounce formula to determine whether or not there were differences between the two dietary groups in (1) the partition of energy among excretion, expenditure, and storage and (2) the relation of energy storage and nitrogen retention to weight gain.There were no significant differences between the human milk fed infants and formula fed infants in gross energy intake, metabolizable energy intake, nitrogen intake, or nitrogen retention. Energy expenditure was significantly lower in the human milk fed infants than in formula fed infants (221 kJ/(kg. day) and 244 kJ/(kg. day), respectively). There was no difference in mean energy storage between the two groups.Although weight gains were similar in both dietary groups, the ratio of energy storage to weight gain was significantly greater in infants fed with human milk (15.3 kJ/g, S.D. 2.0) than in infants fed formula (13.2 kJ/g S.D. 1.8). There was no significant difference between the two groups in the ratio of nitrogen stored to weight gain.

Neurodevelopmental outcome of extremely low-birth-weight infants randomly assigned to restrictive or liberal hemoglobin thresholds for blood transfusion

Surviving extremely low-birth-weight infants are at risk of severe neurodevelopmental disability. Transfusion with packed red cells is almost universal in the care of these infants, but the hemoglobin threshold at which these transfusions should be given is unclear. Different clinical trials of restrictive (low hemoglobin) versus liberal (high hemoglobin) thresholds have addressed either neurodevelopmental outcomes at 18-21 months of corrected gestational age or psychological tests and brain imaging at 8-15 years of age. Early follow-up shows differences in cognitive outcome favoring the liberal strategy, but as a post hoc secondary outcome. The childhood studies favor the restrictive strategy, but include major methodological problems of secondary recruitment. No firm conclusion can be reached, other than to report that serious adverse effects may be attributable to one or other of these strategies, that prudent practice is to remain within trial protocols, and that further redesigned clinical trials are required.

Trade-Off between Lower or Higher Oxygen Saturations for Extremely Preterm Infants: The First Benefits of Oxygen Saturation Targeting (BOOST) II Trial Reports Its Primary Outcome

See related article, p range of oxygen saturations that will best accomplish this goal is uncertain. To address this knowledge gap, 5 randomized trials were initiated between 2005 and 2007 to compare oxygen saturation target ranges of 85%-89% vs 91%-95% by continuous pulse oximetry. These 2 narrow ranges were chosen because they were within the “pragmatically determined” and commonly accepted wider range of 85%-95%. The different study teams discussed important aspects of the trial protocols such as target populations, study oximeters, saturation targets, sample sizes, and primary outcomes during several planning meetings and agreed to perform an individual patient data meta-analysis after the completion and publication of all 5 trials. However, each of the 5 trials was individually designed and managed. Until now, only 2 of the 5 trials—the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial (SUPPORT) and the Canadian Oxygen Trial (COT)—have reported long-term outcomes of their study participants. Neurodevelopmental disability was defined differently in these 2 trials; nevertheless, rates for the composite outcome of death or disability at 18 months did not differ between the 2 groups in either trial. The SUPPORT investigators reported increased mortality in infants assigned to the lower target range, and a greatly increased rate of severe retinopathy of prematurity (ROP) in infants assigned to the higher target range, whereas the COT investigators found similar rates for both of these outcomes in the 2 comparison groups. These differences between the SUPPORT and COT results are perplexing because the distributions of true median oxygen saturations in the 2 treatment groups overlapped more in SUPPORT than in COT. Consequently, we would expect to find smaller rather than greater differences between the 2 saturation target groups in SUPPORT than in COT. In this issue of The Journal, the first Benefits Of Oxygen Saturation Targeting (BOOST) II study group reports its primary outcome of death or major disability at age 2 years.

Pulmonary thromboemboli after neonatal asphyxia

Two surviving neonates with pulmonary thromboembolism, diagnosed by ventilation-perfusion lung scan, are described. Both infants had respiratory distress, and one had features consistent with persistent pulmonary hypertension of the neonate. These reports demonstrate that substantive pulmonary emboli can occur in neonates and may not be recognized without an appropriate level of clinical suspicion.

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.