William D. Rhine

Response of premature infants with severe respiratory failure to inhaled nitric oxide

Elevated pulmonary vascular resistance is seen in premature infants with severe respiratory distress syndrome (RDS). Inhaled nitric oxide (NO) has been shown to decrease pulmonary vascular resistance and to improve oxygenation in some patients with respiratory failure. The purpose of this study was to determine whether premature infants with severe RDS would respond to inhaled NO with an improvement in oxygenation. Eleven premature infants (mean gestational age 29.8 weeks) with severe respiratory failure caused by RDS were treated with NO in four concentrations [1, 5, 10, 20 parts per million (ppm) NO] and with placebo (0 ppm NO). Arterial blood gas measurements were drawn immediately before and at the end of each of the 15‐minute treatments and were used to determine the arterial/alveolar oxygen ratio (Pao2/PAo2).

Combining hand techniques with electric pumping increases milk production in mothers of preterm infants.

Objective:Pump-dependent mothers of preterm infants commonly experience insufficient production. We observed additional milk could be expressed following pumping using hand techniques. We explored the effect on production of hand expression of colostrum and hands-on pumping (HOP) of mature milk.Study Design:A total of 67 mothers of infants <31 weeks gestation were enrolled and instructed on pumping, hand expression of colostrum and HOP. Expression records for 8 weeks and medical records were used to assess production variables.Result:Seventy-eight percent of the mothers completed the study. Mean daily volumes (MDV) rose to 820 ml per day by week 8 and 955 ml per day in mothers who hand expressed >5 per day in the first 3 days. Week 2 and/or week 8 MDV related to hand expression (P<0.005), maternal age, gestational age, pumping frequency, duration, longest interval between pumpings and HOP (P<0.003). Mothers taught HOP increased MDV (48%) despite pumping less.Conclusion:Mothers of preterm infants may avoid insufficient production by combining hand techniques with pumping.

A Cluster-Randomized Trial of Benchmarking and Multimodal Quality Improvement to Improve Rates of Survival Free of Bronchopulmonary Dysplasia for Infants With Birth Weights of Less Than 1250 Grams

OBJECTIVE. We tested whether NICU teams trained in benchmarking and quality improvement would change practices and improve rates of survival without bronchopulmonary dysplasia in inborn neonates with birth weights of <1250 g. METHODS. A cluster-randomized trial enrolled 4093 inborn neonates with birth weights of <1250 g at 17 centers of the National Institute of Child Health and Human Development Neonatal Research Network. Three centers were selected as best performers, and the remaining 14 centers were randomized to intervention or control. Changes in rates of survival free of bronchopulmonary dysplasia were compared between study year 1 and year 3. RESULTS. Intervention centers implemented potentially better practices successfully; changes included reduced oxygen saturation targets and reduced exposure to mechanical ventilation. Five of 7 intervention centers and 2 of 7 control centers implemented use of high-saturation alarms to reduce oxygen exposure. Lower oxygen saturation targets reduced oxygen levels in the first week of life. Despite these changes, rates of survival free of bronchopulmonary dysplasia were all similar between intervention and control groups and remained significantly less than the rate achieved in the best-performing centers (73.3%). CONCLUSIONS. In this cluster-randomized trial, benchmarking and multimodal quality improvement changed practices but did not reduce bronchopulmonary dysplasia rates.

Improved outcomes with a standardized feeding protocol for very low birth weight infants.

Objective:The objective of this study was to evaluate the impact of a standardized enteral feeding protocol for very low birth weight (VLBW) infants on nutritional, clinical and growth outcomes.Study Design:Retrospective analysis of VLBW cohorts 9 months before and after initiation of a standardized feeding protocol consisting of 6–8 days of trophic feedings, followed by an increase of 20 ml/kg/day. The primary outcome was days to reach full enteral feeds defined as 160 ml/kg/day. Secondary outcomes included rates of necrotizing enterocolitis and culture-proven sepsis, days of parenteral nutrition and growth end points.Result:Data were analyzed on 147 VLBW infants who received enteral feedings, 83 before (‘Before’) and 64 subsequent to (‘After’) feeding protocol initiation. Extremely low birth weight (ELBW) infants in the After group attained enteral volumes of 120 ml/kg/day (43.9 days Before vs 32.8 days After, P=0.02) and 160 ml/kg/day (48.5 days Before vs 35.8 days After, P=0.02) significantly faster and received significantly fewer days of parenteral nutrition (46.2 days Before vs 31.3 days After, P=0.01). Necrotizing enterocolitis decreased in the After group among VLBW (15/83, 18% Before vs 2/64, 3% After, P=0.005) and ELBW infants (11/31, 35% Before vs 2/26, 8% After, P=0.01). Late-onset sepsis decreased significantly in the After group (26/83, 31% Before vs 6/64, 9% After, P=0.001). Excluding those with weight <3rd percentile at birth, the proportion with weight <3rd percentile at discharge decreased significantly after protocol initiation (35% Before vs 17% After, P=0.03).Conclusion:These data suggest that implementation of a standardized feeding protocol for VLBW infants results in earlier successful enteral feeding without increased rates of major morbidities.

99mTc Annexin V Imaging of Neonatal Hypoxic Brain Injury

Background and Purpose— Delayed cell loss in neonates after cerebral hypoxic-ischemic injury (HII) is believed to be a major cause of cerebral palsy. In this study, we used radiolabeled annexin V, a marker of delayed cell loss (apoptosis), to image neonatal rabbits suffering from HII. Methods Twenty-two neonatal New Zealand White rabbits had ligation of the right common carotid artery with reduction of inspired oxygen concentration to induce HII. Experimental animals (n=17) were exposed to hypoxia until an ipsilateral hemispheric decrease in the average diffusion coefficient occurred. After reversal of hypoxia and normalization of average diffusion coefficient values, experimental animals were injected with 99mTc annexin V. Radionuclide images were recorded 2 hours later. Results Experimental animals showed no MR evidence of blood-brain barrier breakdown or perfusion abnormalities after hypoxia. Annexin images demonstrated multifocal brain uptake in both hemispheres of experimental but not control animals. Histology of the brains from experimental animals demonstrated scattered pyknotic cortical and hippocampal neurons with cytoplasmic vacuolization of glial cells without evidence of apoptotic nuclei by terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling (TUNEL) staining. Double staining with markers of cell type and exogenous annexin V revealed that annexin V was localized in the cytoplasm of scattered neurons and astrocytes in experimental and, less commonly, control brains in the presence of an intact blood-brain barrier. Conclusions Apoptosis may develop after HII even in brains that appear normal on diffusion-weighted and perfusion MR. These data suggest a role of radiolabeled annexin V screening of neonates at risk for the development of cerebral palsy.

A quality improvement project to increase breast milk use in very low birth weight infants.

OBJECTIVE: To evaluate a multihospital collaborative designed to increase breast milk feeding in premature infants. METHODS: Eleven NICUs in the California Perinatal Quality of Care Collaborative participated in an Institute for Healthcare Improvement–style collaborative to increase NICU breast milk feeding rates. Multiple interventions were recommended with participating sites implementing a self-selected combination of these interventions. Breast milk feeding rates were compared between baseline (October 2008–September 2009), implementation (October 2009–September 2010), and sustainability periods (October 2010–March 2011). Secondary outcome measures included necrotizing enterocolitis (NEC) rates and lengths of stay. California Perinatal Quality of Care Collaborative hospitals not participating in the project served as a control population. RESULTS: The breast milk feeding rate in the intervention sites improved from baseline (54.6%) to intervention period (61.7%; P = .005) with sustained improvement over 6 months postintervention (64.0%; P = .003). NEC rates decreased from baseline (7.0%) to intervention period (4.3%; P = .022) to sustainability period (2.4%; P < .0001). Length of stay increased during the intervention but returned to baseline levels in the sustainability period. Control hospitals had higher rates of breast milk feeding at baseline (64.2% control vs 54.6% participants, P < .0001), but over the course of the implementation (65.7% vs 61.7%, P = .049) and sustainability periods (67.7% vs 64.0%, P = .199), participants improved to similar rates as the control group. CONCLUSIONS: Implementation of a breast milk/nutrition change package by an 11-site collaborative resulted in an increase in breast milk feeding and decrease in NEC that was sustained over an 18-month period.

A quality improvement project to improve admission temperatures in very low birth weight infants

Objective: To review the results of a quality improvement (QI) project to improve admission temperatures of very low birth weight inborn infants.Study Design: The neonatal intensive care unit at Lucile Packard Childrens Hospital underwent a QI project to address hypothermic preterm newborns by staff education and implementing processes such as polyethylene wraps and chemical warming mattresses. We performed retrospective chart review of all inborn infants with birth weight <1500 g during the 18 months prior to (n=134) and 15 months after (n=170) the implementation period. Temperatures were compared between periods. Multivariable logistic regression was used to account for potential confounding variables. We compared mortality rates and grade 3 or 4 intraventricular hemorrhage rates between periods.Result: The mean temperature rose from 35.4 to 36.2 °C (P<0.0001) after the QI project. The improvement was consistent and persisted over a 15-month period. After risk adjustment, the strongest predictor of hypothermia was being born in the period before implementation of the QI project (odds ratio 8.12, 95% confidence interval 4.63, 14.22). Although cesarean delivery was a strong risk factor for hypothermia prior to the project, it was no longer significant after the project. There was no significant difference in death or intraventricular hemorrhage detected between periods.Conclusion: There was a significant improvement in admission temperatures after a QI project, which persisted beyond the initial implementation period. Although there was no difference in mortality or intraventricular hemorrhage rates, we did not have sufficient power to detect small differences in these outcomes.

Lobar lung transplantation as a treatment for congenital diaphragmatic hernia

The mortality rate for infants severely affected with congenital diaphragmatic hernia (CDH) remains high despite significant advances in surgical and neonatal intensive care including delayed repair and extracorporeal membrane oxygenation (ECMO). Because of the increasingly successful experience with single-lung transplantation in adults; this approach has been suggested as a potential treatment for CDH infants with unsalvageable pulmonary hypoplasia. The authors report on a newborn female infant who was the product of a pregnancy complicated by polyhydramnios. At birth, she was found to have a right-sided CDH and initially was treated with preoperative ECMO, followed by delayed surgical repair. Despite the CDH repair and apparent resolution of pulmonary hypertension, the infants condition deteriorated gradually after decannulation, and escalating ventilator settings were required as well as neuromuscular paralysis and pressor support because of progressive hypoxemia and hypercarbia. A lung transplant was performed 8 days after decannulation, using the right lung obtained from a 6-week-old donor. The right middle lobe was excised because of the size discrepancy between the donor and recipient. After transplantation, the patient was found to have duodenal stenosis and gastroesophageal reflux, which required duodenoduodenostomy and fundoplication. The patient was discharged from the hospital 90 days posttransplantation, at 3 1/2 months of age. Currently she is 24 months old and doing well except for poor growth. This case shows the feasibility of single-lung transplantation for infants with CDH, and the potential use of ECMO as a temporary bridge to transplantation. Lobar lung transplantation allowed for less stringent size constraints for the donor lung.

Brief cognitive–behavioral intervention for maternal depression and trauma in the neonatal intensive care unit: A pilot study†

Parents of hospitalized premature infants are at risk for developing psychological symptoms. This randomized controlled pilot study examined the effectiveness of a brief cognitive-behavioral intervention in reducing traumatic and depressive symptoms in mothers 1 month after their infants discharge from the hospital. Fifty-six mothers were randomly assigned to the intervention or control group. Results showed that mothers experienced high levels of symptoms initially and at follow-up. At follow-up, there was a trend for mothers in the intervention group to report lower levels of depression (p = .06; Cohens f = .318), but levels of traumatic symptoms were similar for both groups. Brief psychological interventions may reduce depressive symptoms in this population. Estimates of the effect sizes can be used to inform future intervention studies.

Bilirubin Toxicity and Differentiation of Cultured Astrocytes

OBJECTIVE:To study the toxicity of bilirubin in primary cultures of newborn rat cerebral cortical astrocytes.STUDY DESIGN:Primary cultures of newborn rat astrocytes were incubated at bilirubin concentrations of 0, 1, 5, 10, 25, 50, 100, 200, and 2000 μM, at a bilirubin:albumin molar ratio of 1.7. Bilirubin toxicity was determined by changes in cellular morphology, trypan blue staining, and lactate dehydrogenase (LDH) release into the culture medium at various times of incubation. To determine if differentiation of astrocytes affects bilirubin toxicity, cultures were treated with dibutyryl cyclic adenosine monophosphate.RESULTS:All three indices of toxicity showed a bilirubin concentration dependence. LDH release in experimental cultures was significantly elevated (p < 0.05) above that of control cultures by 24 hours at bilirubin concentrations of ≥100 μM. The absolute amount of LDH release differed significantly between the 200 and 2000 μM cultures from 1.5 to 24 hours, after which duration of exposure appeared to take over and all cultures approached maximum. LDH release for the lower concentrations all reached maximum by 120 hours, except for the 1 μM cultures, which showed no significant elevation above control throughout the study period. At 100 and 200 μM bilirubin, LDH release by untreated cells was significantly higher (p < 0.05) than release by treated cells by 36 hours.CONCLUSION:Undifferentiated astrocytes appeared to be more sensitive to bilirubin toxicity, which may correlate with the greater susceptibility of newborns to kernicteric injury. Studies with primary astrocyte culture may provide insight into how bilirubin sensitivity changes with brain development as well as the cellular and biochemical mechanisms of bilirubin encephalopathy.