Effect of reduced versus usual lipid emulsion dosing on bilirubin neurotoxicity and neurodevelopmental impairment in extremely preterm infants: study protocol for a randomized controlled trial.

BACKGROUND: Bilirubin neurotoxicity (BN) occurs in premature infants at lower total serum bilirubin levels than term infants and causes neurodevelopmental impairment. Usual dose lipid infusions in preterm infants may increase free fatty acids sufficiently to cause bilirubin displacement from albumin, increasing passage of unbound bilirubin (UB) into the brain leading to BN and neurodevelopmental impairment not reliably identifiable in infancy. These risks may be influenced by whether cycled or continuous phototherapy is used to control bilirubin levels. OBJECTIVE: To assess differences in wave V latency measured by brainstem auditory evoked responses (BAER) at 34-36 weeks gestational age in infants born ≤ 750 g or < 27 weeks' gestational age randomized to receive usual or reduced dose lipid emulsion (half of the usual dose) irrespective of whether cycled or continuous phototherapy is administered. METHODS: Pilot factorial randomized controlled trial (RCT) of lipid dosing (usual and reduced) with treatment groups balanced between cycled or continuous phototherapy assignment. Eligible infants are born at ≤ 750 g or < 27 weeks' gestational age enrolled in the NICHD Neonatal Research Network RCT of cycled or continuous phototherapy. Infants will randomize 1:1 to reduced or usual dose lipid assignment during the first 2 weeks after birth and stratified by phototherapy assignment. Free fatty acids and UB will be measured daily using a novel probe. BAER testing will be performed at 34-36 weeks postmenstrual age or prior to discharge. Blinded neurodevelopmental assessments will be performed at 22-26 months. Intention-to-treat analyses will be performed with generalized linear mixed models with lipid dose and phototherapy assignments as random effects covariates, and assessment for interactions. Bayesian analyses will be performed as a secondary analysis. DISCUSSION: Pragmatic trials are needed to evaluate whether lipid emulsion dosing modifies the effect of phototherapy on BN. This factorial design presents a unique opportunity to evaluate both therapies and their interaction. This study aims to address basic controversial questions about the relationships between lipid administration, free fatty acids, UB, and BN. Findings suggesting a reduced lipid dose can diminish the risk of BN would support the need for a large multicenter RCT of reduced versus usual lipid dosing. TRIAL REGISTRATION: Clinical Trials.gov, NCT04584983, Registered 14 October 2020, https://clinicaltrials.gov/ct2/show/NCT04584983 Protocol version: Version 3.2 (10/5/2022).

Effect of Reduced Versus Usual Lipid Emulsion Dosing on Bilirubin Neurotoxicity and Neurodevelopmental Impairment in Extremely Preterm Infants: Study Protocol for a Randomized Controlled Trial.

Background : Bilirubin neurotoxicity ( BN ) occurs in premature infants at lower total serum bilirubin levels than term infants and causes neurodevelopmental impairment. Usual dose lipid infusions in preterm infants may increase free fatty acids sufficiently to cause bilirubin displacement from albumin, increasing passage of unbound bilirubin ( UB ) into the brain leading to BN and neurodevelopmental impairment not reliably identifiable in infancy. These risks may be influenced by whether cycled or continuous phototherapy is used to control bilirubin levels. Objective : To assess differences in wave V latency measured by brainstem auditory evoked responses ( BAER ) at 34-36 weeks gestational age in infants born ≤750 g or <27 weeks' gestational age randomized to receive usual or reduced dose lipid emulsion (half of the usual dose) irrespective of whether cycled or continuous phototherapy is administered. Methods : Pilot factorial randomized controlled trial ( RCT ) of lipid dosing (usual and reduced) with treatment groups balanced between cycled or continuous phototherapy assignment. Eligible infants are born at ≤750 g or <27 weeks' gestational age enrolled in the NICHD Neonatal Research Network RCT of cycled or continuous phototherapy. Infants will randomize 1:1 to reduced or usual dose lipid assignment during the first 2 weeks after birth and stratified by phototherapy assignment. Free fatty acids and UB will be measured daily using a novel probe. BAER testing will be performed at 34-36 weeks postmenstrual age or prior to discharge. Blinded neurodevelopmental assessments will be performed at 22-26 months. Intention-to-treat analyses will be performed with generalized linear mixed models with lipid dose and phototherapy assignments as random effects covariates, and assessment for interactions. Bayesian analyses will be performed as a secondary analysis. Discussion : Pragmatic trials are needed to evaluate whether lipid emulsion dosing modifies the effect of phototherapy on BN. This factorial design presents a unique opportunity to evaluate both therapies and their interaction. This study aims to address basic controversial questions about the relationships between lipid administration, free fatty acids, UB, and BN. Findings suggesting a reduced lipid dose can diminish the risk of BN would support the need for a large multicenter RCT of reduced versus usual lipid dosing. Trial Registration : Clinical Trials.gov, NCT04584983, Registered 14 October 2020, https://clinicaltrials.gov/ct2/show/NCT04584983 Protocol Version : Version 3.2 (10/5/2022).

Increasing early exposure to mother's own milk in premature newborns.

OBJECTIVE: Increase the proportion of ≤33 weeks newborns exposed to mother's own milk (MOM) oral care by 12 h of age by 20% over 2 years to support a healthier microbiome. STUDY DESIGN: We implemented interventions to support early expression of colostrum and reliable delivery of resultant MOM to premature newborns. Statistical process control charts were used to track progress and provide feedback to staff. Proportions of newborns exposed to MOM by 12 h were compared relative to baseline. RESULTS: There were 46, 66, and 46 newborns in the baseline, implementation, and sustainability periods, respectively. The primary outcome improved from 48% to 61% in the implementation period (relative change 1.27, 95% CI 0.89, 1.81, p = 0.2), to 69% in sustainability period (relative to baseline 1.45, 95% CI 1.02, 2.08, p = 0.03). CONCLUSION: An interdisciplinary team-based, multicycle, quality improvement intervention resulted in increased rates of early exposure to MOM.

Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning.

T-cell-redirecting bispecific antibodies have emerged as a new class of therapeutic agents designed to simultaneously bind to T cells via CD3 and to tumor cells via tumor-cell-specific antigens (TSA), inducing T-cell-mediated killing of tumor cells. The promising preclinical and clinical efficacy of TSAxCD3 antibodies is often accompanied by toxicities such as cytokine release syndrome due to T-cell activation. How the efficacy and toxicity profile of the TSAxCD3 bispecific antibodies depends on the binding affinity to CD3 remains unclear. Here, we evaluate bispecific antibodies that were engineered to have a range of CD3 affinities, while retaining the same binding affinity for the selected tumor antigen. These agents were tested for their ability to kill tumor cells in vitro, and their biodistribution, serum half-life, and anti-tumor activity in vivo. Remarkably, by altering the binding affinity for CD3 alone, we can generate bispecific antibodies that maintain potent killing of TSA + tumor cells but display differential patterns of cytokine release, pharmacokinetics, and biodistribution. Therefore, tuning CD3 affinity is a promising method to improve the therapeutic index of T-cell-engaging bispecific antibodies.

Evaluation of Thawing and Stress Restoration Method for Artificial Frozen Sandy Soils Using Sensors.

Undisturbed frozen samples can be efficiently obtained using the artificial ground freezing method. Thereafter, the restoration of in situ conditions, such as stress and density after thawing, is critical for laboratory testing. This study aims to experimentally explore the effects of thawing and the in situ stress restoration process on the geomechanical properties of sandy soils. Specimens were prepared at a relative density of 60% and frozen at -20 °C under the vertical stress of 100 kPa. After freezing, the specimens placed in the triaxial cell underwent thawing and consolidation phases with various drainage and confining stress conditions, followed by the shear phase. The elastic wave signals and axial deformation were measured during the entire protocol; the shear strength was evaluated from the triaxial compression test. Monotonic and cyclic simple shear tests were conducted to determine the packing density effect on liquefaction resistance. The results show that axial deformation, stiffness, and strength are minimized for a specimen undergoing drained thawing, restoring the initial stress during the consolidation phase, and that denser specimens are less susceptible to liquefaction. Results highlight that the thawing and stress restoration process should be considered to prevent the overestimation of stiffness, strength, and liquefaction resistance of sandy soils.

Cycled Phototherapy Dose-Finding Study for Extremely Low-Birth-Weight Infants: A Randomized Clinical Trial.

Importance: Cycled (intermittent) phototherapy (PT) might adequately control peak total serum bilirubin (TSB) level and avoid mortality associated with usual care (continuous PT) among extremely low-birth-weight (ELBW) infants (401-1000 g). Objective: To identify a cycled PT regimen that substantially reduces PT exposure, with an increase in mean peak TSB level lower than 1.5 mg/dL in ELBW infants. Design, Setting, and Participants: This dose-finding randomized clinical trial of cycled PT vs continuous PT among 305 ELBW infants in 6 US newborn intensive care units was conducted from March 12, 2014, to November 14, 2018. Interventions: Two cycled PT regimens (≥15 min/h and ≥30 min/h) were provided using a simple, commercially available timer to titrate PT minutes per hour against TSB level. The comparator arm was usual care (continuous PT). Main Outcomes and Measures: Mean peak TSB level and total PT hours through day 14 in all 6 centers and predischarge brainstem auditory-evoked response wave V latency in 1 center. Mortality and major morbidities were secondary outcomes despite limited power. Results: Consent was requested for 452 eligible infants and obtained for 305 (all enrolled) (mean [SD] birth weight, 749 [152] g; gestational age, 25.7 [1.9] weeks; 81 infants [27%] were multiple births; 137 infants [45%] were male; 112 [37%] were black infants; and 107 [35%] were Hispanic infants). Clinical and demographic characteristics of the groups were similar at baseline. After a preplanned interim analysis of 100 infants, the regimen of 30 min/h or more was discontinued, and the study proceeded with 2 arms. Comparing 128 infants receiving PT of 15 min/h or more with 128 infants receiving continuous PT among those surviving to 14 days, mean peak TSB levels were 7.1 vs 6.4 mg/dL (adjusted difference, 0.7; 95% CI, 0.4-1.1 mg/dL) and mean total PT hours were 34 vs 72 (adjusted difference, -39; 95% CI, -45 to -32). Wave V latency adjusted for postmenstrual age was similar in 37 infants receiving 15 min/h or more of PT and 33 infants receiving continuous PT: 7.42 vs 7.32 milliseconds (difference, 0.10; 95% CI, -0.11 to 0.30 millisecond). The relative risk for death was 0.79 (95% CI, 0.40-1.54), with a risk difference of -4.5% (95% CI, -10.9 to 2.0). Morbidities did not differ between groups. Conclusions and Relevance: Cycled PT can substantially reduce total PT with little increase in peak TSB level. A large, randomized trial is needed to assess whether cycled PT would increase survival and survival without impairment in small, preterm infants. Trial Registration: ClinicalTrials.gov Identifier: NCT01944696.

An Ethnography of Parents' Perceptions of Patient Safety in the Neonatal Intensive Care Unit.

BACKGROUND: Parents of neonates are integral components of patient safety in the neonatal intensive care unit (NICU), yet their views are often not considered. By understanding how parents perceive patient safety in the NICU, clinicians can identify appropriate parent-centered strategies to involve them in promoting safe care for their infants. PURPOSE: To determine how parents of neonates conceptualize patient safety in the NICU. METHODS: We conducted qualitative interviews with 22 English-speaking parents of neonates from the NICU and observations of various parent interactions within the NICU over several months. Data were analyzed using thematic content analysis. Findings were critically reviewed through peer debriefing. FINDINGS: Parents perceived safe care through their observations of clinicians being present, intentional, and respectful when adhering to safety practices, interacting with their infant, and communicating with parents in the NICU. They described partnering with clinicians to promote safe care for their infants and factors impacting that partnership. We cultivated a conceptual model highlighting how parent-clinician partnerships can be a core element to promoting NICU patient safety. IMPLICATIONS FOR PRACTICE: Parents' observations of clinician behavior affect their perceptions of safe care for their infants. Assessing what parents observe can be essential to building a partnership of trust between clinicians and parents and promoting safer care in the NICU. IMPLICATIONS FOR RESEARCH: Uncertainty remains about how to measure parent perceptions of safe care, the level at which the clinician-parent partnership affects patient safety, and whether parents' presence and involvement with their infants in the NICU improve patient safety.

Phototherapy and the Risk of Photo-Oxidative Injury in Extremely Low Birth Weight Infants.

Phototherapy has been used to treat newborns with jaundice for more than 50 years with the presumption that it is safe and effective for all infants. In fact, this presumption may not be true for all infants, especially the smallest and most immature. The safety and efficacy of phototherapy have never really been questioned or adequately tested in the latter, yet clinical applications of phototherapy have been further refined as its mechanisms of action have been better understood and alternative light sources have become available. This article addresses what is known about the possible risks of photo-oxidative injury in extremely low birth weight infants.

Phototherapy in ELBW newborns: does it work? Is it safe? The evidence from randomized clinical trials.

Phototherapy is assumed to be both effective and safe for extremely low-birth-weight infants. Our objective was to critically assess the relevant evidence from randomized trials. In the decades-old Collaborative Phototherapy Trial, phototherapy reduced serum bilirubin but not neurodevelopmental impairments. In the recent and larger Neonatal Network Trial, aggressive phototherapy compared to conservative phototherapy reduced both peak serum bilirubin (7.0 vs. 9.8mg/dL) and profound impairment at 18-22 months adjusted age (relative risk = 0.68). However, both trials suggested that phototherapy increased deaths among the smallest infants. Conservative Bayesian analyses of ventilator-treated infants under 751g birth weight in the Network trial identified a 99% probability of increased deaths and 99% probability of reduced profound impairment with aggressive phototherapy. Potential strategies to optimize the risk/benefit ratio in achieving low serum bilirubin levels, e.g., use of lowered irradiance levels, light-emitting diode phototherapy units, cycled phototherapy, and/or porphyrin compounds, deserve rigorous evaluation.

When is waiver of consent appropriate in a neonatal clinical trial?

It is difficult to do scientifically rigorous research on treatments that must be administered urgently or emergently. Therefore, such treatments are often provided without a strong evidence base. Research would be facilitated if it were permissible to waive the requirement for parental consent. However, that raises a different set of concerns. Federal regulations allow waiver of the requirement for consent but only if studies meet certain conditions. Institutional review boards must decide whether those conditions are met. Sometimes, reasonable people disagree. We present and analyze a protocol for which investigators request a waiver of consent.

Outcomes following periviable birth.

This review is presented in three segments: (1) important background concepts, (2) recent reports from regional geographically defined cohorts, and (3) prognosis research from the National Institutes of Health Neonatal Research Network. Extending the use of intensive care to newborns of lower gestational ages will unavoidably result in a higher proportion and a higher absolute number of survivors with morbidity, unless other changes in practice offset the increased risk associated with decreasing gestational age. In geographically defined cohort studies, the proportion of periviable newborns delivered in perinatal centers and the practices around foregoing and withdrawing intensive care are two important determinants of outcomes following periviable birth. It is much easier to quantify the effect of the former than the latter. Decisions regarding comfort care vs. intensive are frequently based on gestational age as the sole predictor variable, although multiple factors can be readily used to more accurately assess the benefits and burdens of intensive care and facilitate better informed parental counseling and decision making.

Safe sleep practices and sudden infant death syndrome risk reduction: NICU and well-baby nursery graduates.

Our primary objective was to compare parents of infants cared for in newborn intensive care units (NICUs) and infants cared for in well-baby ("general") nurseries with regard to knowledge and practice of safe sleep practices/sudden infant death syndrome risk reduction measures and guidelines. Our secondary objective was to obtain qualitative data regarding reasons for noncompliance in both populations. Sixty participants (30 from each population) completed our survey measuring safe sleep knowledge and practice. Parents of NICU infants reported using 2 safe sleep practices-(a) always placing baby in crib to sleep and (b) always placing baby on back to sleep-significantly more frequently than parents of well infants. Additional findings and implications for future studies are discussed.

Sound levels, staff perceptions, and patient outcomes during renovation near the neonatal intensive care unit.

OBJECTIVE: Sound levels, staff perceptions, and patient outcomes were evaluated during a year-long hospital renovation project on the floor above a neonatal intensive care unit (NICU). BACKGROUND: Construction noise may be detrimental to NICU patients and healthcare professionals. There are no comprehensive studies evaluating the impact of hospital construction on sound levels, staff, and patients. METHODS: Prospective observational study comparing sound measures and patient outcomes before, during, and after construction. Staff were surveyed about the construction noise, and hospital employee satisfaction scores are reported. RESULTS: Equivalent sound levels were not significantly higher during construction. Most staff members (89%) perceived the renovation period as louder, and 83% reported interruptions of their work. Patient outcomes were the same or more positive during construction. Very low birth weight (VLBW) infants were less likely to require 24+ hours' mechanical ventilation during construction: 54% vs. 59% before (OR = 1.6, p = 0.018) and 62% after (OR = 1.48, p = 0.065); and they required a shorter total period of mechanical ventilation: 3.6 days vs. 8.0 before (p = 0.011) and 9.5 after (p = 0.001). VLBW newborns' differences in ventilation days were mostly in the upper extremes; medians were similar in all periods: 0.6 days vs. 1 day preconstruction and 2 days postconstruction. CONCLUSIONS: Construction above the NICU did not cause substantially louder sound levels, but staff perceived important changes in noise and work routines. No evidence suggested that patients were negatively affected by the renovation period. Meticulous construction planning remains necessary to avoid interference with patient care and caregiver work environments.

Improving erythropoietin-stimulating agent administration in a multihospital system through quality improvement initiatives: a pre-post comparison study.

INTRODUCTION: : Erythropoietin-stimulating agent (ESA) use is associated with serious adverse events in patients with hemoglobin levels of 12 g/dL or higher at the time of administration. Our aim was to determine whether inappropriate ESA use has changed over time since the implementation of new drug warning alerts and local quality improvement initiatives. MATERIALS AND METHODS: : We performed a retrospective review of ESA administration practices at Memorial Hermann Healthcare System (Houston, Tex). Our primary outcome measure was the proportion of inpatient encounters (one entire inpatient hospital stay) with 1 or more inappropriate uses of ESA (defined as ESA administration for a patient with hemoglobin ≥12 g/dL). We analyzed the potential influence of local and national interventions on ESA utilization patterns. RESULTS: : Between May 1, 2006, and May 31, 2009, 15,642 inpatients were treated with ESAs in our system. We classified inpatients as before intervention (n = 6350) and after intervention (n = 9292) based on the date of implementation of a synchronous alert in the electronic medical record. We found a significant decrease in inappropriate ESA administration before to after intervention (9.03%-6.21%; P < 0.001), which can be translated into a 31.25% (05% CI, 21.93%-40.75%) relative risk reduction. Reduced odds ratios for inappropriate ESA use changed little after controlling for relevant demographic variables and clinical characteristics. CONCLUSIONS: : Following several quality improvement interventions to improve patient safety related to ESA use, we found a significant reduction in inappropriate ESA administration to inpatients in a large health care system.

Variability in vancomycin use in newborn intensive care units determined from data in an electronic medical record.

Data from an electronic medical record were used to demonstrate a large variation in the proportion of patients treated with vancomycin in 56 newborn intensive care units, which ranged from 18% to 70% . Use of oxacillin or nafcillin instead of vancomycin was rare during the first few years of the study period but was routine in 13% of the newborn intensive care units during the last few years of the study period. The use of electronic medical record data for studies of antibiotic use is discussed here.

Decreasing antibiotic overuse in neonatal intensive care units: quality improvement research.

Overutilization of antibiotics and emergence of resistant bacteria are important problems, particularly in intensive care units. To date, reproducible interventions to improve antibiotic utilization in hospitals have not been proven to be effective or safe. Evidence-based medicine, clinical practice guidelines, and health information technology are frequently promoted as means to cross the "quality chasm" described by the Institute of Medicine. This article outlines how these approaches intersect in a strategy for quality improvement research evaluating the safety and effectiveness of clinical practice guidelines designed to improve antibiotic use in neonatal intensive care units.

Improving growth of very low birth weight infants in the first 28 days.

OBJECTIVE: To increase weight gain in the first 28 days after birth for very low birth weight (VLBW) infants by isolating and sharing meaningful process differences between high- and low-weight-gain centers within a neonatal network. DESIGN/METHODS: We identified weight gain as an important target for improvement in 1999 for our national group practice of neonatologists. Site-specific average weight gain during the first 28 days was the primary outcome measure. Our target population was defined as inborn infants who survived and remained in the hospital of birth, whose birth weights were between 401 and 1500 g (VLBW), and who were >22 weeks' estimated gestational age. A team of 6 neonatologists and 1 nurse met, reviewed processes that might influence growth, and developed a structured observation guide for site visits. Weight gain data were obtained from an existing administrative database for the period January 1, 1997, through June 30, 1999. Centers were ranked and divided into upper, middle, and lower thirds. Seven team members visited 1 high- and 1 low-weight-gain center without being informed of the center's performance. Following the site visits, the team isolated 16 meaningful differences between high- and low-weight-gain sites. Meaningful differences were defined as processes observed in all or virtually all (for this project, 6 or 7 of 7 centers) of the high and none or virtually none (for this project, 0 or 1 of 7) of the low centers. The meaningful differences were distributed to our medical directors in August 2000 along with their site-specific weight-gain performance. To document the impact of sharing this material, we compared weight gain in a baseline period of January 1 through December 31, 1999 and a posteducational intervention period of January 1 through September 30, 2001. RESULTS: Compared with neonates admitted to our national neonatal practice in 1999, neonates admitted in 2001 were similar in birth weight, gestational age at birth, exposure to antenatal steroids, and male gender. Average daily weight gain during the first 28 days increased from 10.4 +/- 6 g for neonates cared for in 1999 to 12.5 +/- 6 g for neonates cared for in 2001. Thirty-nine of 51 (76%) units noted improvements, 4 were unchanged and 8 noted a decrease in average weight gain. Despite similar average lengths of stay, the average discharge weight for neonates sent home increased from 2.15 +/- 0.5 kg for 1999 to 2.29 +/- 0.5 kg for 2001. There were no differences in frequencies of mortality or major morbidities, including severe intraventricular hemorrhage, retinopathy, or necrotizing enterocolitis, between the 2 time periods. An increase in the use of continuous positive airway pressure was noted in the post implementation period. CONCLUSIONS: Variation in common processes can alter clinical outcomes. Although temporal trends in weight gain may be, in part, responsible for this trend, it appears that isolation and implementation of meaningful differences in processes can augment our desire to rapidly improve clinical outcomes.