Influence of Eat, Sleep, and Console on Infants Pharmacologically Treated for Opioid Withdrawal: A Post Hoc Subgroup Analysis of the ESC-NOW Randomized Clinical Trial.

Importance: The function-based eat, sleep, console (ESC) care approach substantially reduces the proportion of infants who receive pharmacologic treatment for neonatal opioid withdrawal syndrome (NOWS). This reduction has led to concerns for increased postnatal opioid exposure in infants who receive pharmacologic treatment. However, the effect of the ESC care approach on hospital outcomes for infants pharmacologically treated for NOWS is currently unknown. Objective: To evaluate differences in opioid exposure and total length of hospital stay (LOS) for pharmacologically treated infants managed with the ESC care approach vs usual care with the Finnegan tool. Design, Setting, and Participants: This post hoc subgroup analysis involved infants pharmacologically treated in ESC-NOW, a stepped-wedge cluster randomized clinical trial conducted at 26 US hospitals. Hospitals maintained pretrial practices for pharmacologic treatment, including opioid type, scheduled opioid dosing, and use of adjuvant medications. Infants were born at 36 weeks' gestation or later, had evidence of antenatal opioid exposure, and received opioid treatment for NOWS between September 2020 and March 2022. Data were analyzed from November 2022 to January 2024. Exposure: Opioid treatment for NOWS and the ESC care approach. Main Outcomes and Measures: For each outcome (total opioid exposure, peak opioid dose, time from birth to initiation of first opioid dose, length of opioid treatment, and LOS), we used generalized linear mixed models to adjust for the stepped-wedge design and maternal and infant characteristics. Results: In the ESC-NOW trial, 463 of 1305 infants were pharmacologically treated (143/603 [23.7%] in the ESC care approach group and 320/702 [45.6%] in the usual care group). Mean total opioid exposure was lower in the ESC care approach group with an absolute difference of 4.1 morphine milligram equivalents per kilogram (MME/kg) (95% CI, 1.3-7.0) when compared with usual care (4.8 MME/kg vs 8.9 MME/kg, respectively; P = .001). Mean time from birth to initiation of pharmacologic treatment was 22.4 hours (95% CI, 7.1-37.7) longer with the ESC care approach vs usual care (75.4 vs 53.0 hours, respectively; P = .002). No significant difference in mean peak opioid dose was observed between groups (ESC care approach, 0.147 MME/kg, vs usual care, 0.126 MME/kg). The mean length of treatment was 6.3 days shorter (95% CI, 3.0-9.6) in the ESC care approach group vs usual care group (11.8 vs 18.1 days, respectively; P < .001), and mean LOS was 6.2 days shorter (95% CI, 3.0-9.4) with the ESC care approach than with usual care (16.7 vs 22.9 days, respectively; P < .001). Conclusion and Relevance: When compared with usual care, the ESC care approach was associated with less opioid exposure and shorter LOS for infants pharmacologically treated for NOWS. The ESC care approach was not associated with a higher peak opioid dose, although pharmacologic treatment was typically initiated later. Trial Registration: ClinicalTrials.gov Identifier: NCT04057820.

Eat, Sleep, Console Approach or Usual Care for Neonatal Opioid Withdrawal.

BACKGROUND: Although clinicians have traditionally used the Finnegan Neonatal Abstinence Scoring Tool to assess the severity of neonatal opioid withdrawal, a newer function-based approach - the Eat, Sleep, Console care approach - is increasing in use. Whether the new approach can safely reduce the time until infants are medically ready for discharge when it is applied broadly across diverse sites is unknown. METHODS: In this cluster-randomized, controlled trial at 26 U.S. hospitals, we enrolled infants with neonatal opioid withdrawal syndrome who had been born at 36 weeks' gestation or more. At a randomly assigned time, hospitals transitioned from usual care that used the Finnegan tool to the Eat, Sleep, Console approach. During a 3-month transition period, staff members at each hospital were trained to use the new approach. The primary outcome was the time from birth until medical readiness for discharge as defined by the trial. Composite safety outcomes that were assessed during the first 3 months of postnatal age included in-hospital safety, unscheduled health care visits, and nonaccidental trauma or death. RESULTS: A total of 1305 infants were enrolled. In an intention-to-treat analysis that included 837 infants who met the trial definition for medical readiness for discharge, the number of days from birth until readiness for hospital discharge was 8.2 in the Eat, Sleep, Console group and 14.9 in the usual-care group (adjusted mean difference, 6.7 days; 95% confidence interval [CI], 4.7 to 8.8), for a rate ratio of 0.55 (95% CI, 0.46 to 0.65; P<0.001). The incidence of adverse outcomes was similar in the two groups. CONCLUSIONS: As compared with usual care, use of the Eat, Sleep, Console care approach significantly decreased the number of days until infants with neonatal opioid withdrawal syndrome were medically ready for discharge, without increasing specified adverse outcomes. (Funded by the Helping End Addiction Long-term (HEAL) Initiative of the National Institutes of Health; ESC-NOW ClinicalTrials.gov number, NCT04057820.).

Comparing Medical Record Abstraction (MRA) Error Rates in an Observational Study to Pooled Rates Identified in the Data Quality Literature.

Background: Medical record abstraction (MRA) is a commonly used method for data collection in clinical research, but is prone to error, and the influence of quality control (QC) measures is seldom and inconsistently assessed during the course of a study. We employed a novel, standardized MRA-QC framework as part of an ongoing observational study in an effort to control MRA error rates. In order to assess the effectiveness of our framework, we compared our error rates against traditional MRA studies that had not reported using formalized MRA-QC methods. Thus, the objective of this study was to compare the MRA error rates derived from the literature with the error rates found in a study using MRA as the sole method of data collection that employed an MRA-QC framework. Methods: Using a moderator meta-analysis employed with Q-test, the MRA error rates from the meta-analysis of the literature were compared with the error rate from a recent study that implemented formalized MRA training and continuous QC processes. Results: The MRA process for data acquisition in clinical research was associated with both high and highly variable error rates (70 - 2,784 errors per 10,000 fields). Error rates for the study using our MRA-QC framework were between 1.04% (optimistic, all-field rate) and 2.57% (conservative, populated-field rate) (or 104 - 257 errors per 10,000 fields), 4.00 - 5.53 percentage points less than the observed rate from the literature (p<0.0001). Conclusions: Review of the literature indicated that the accuracy associated with MRA varied widely across studies. However, our results demonstrate that, with appropriate training and continuous QC, MRA error rates can be significantly controlled during the course of a clinical research study.

The Influence of Mediators on the Relationship Between Antenatal Opioid Agonist Exposure and the Severity of Neonatal Opioid Withdrawal Syndrome.

OBJECTIVES: (1) To evaluate the direct (un-mediated) and indirect (mediated) relationship between antenatal exposure to opioid agonist medication as treatment for opioid use disorder (MOUD) and the severity of neonatal opioid withdrawal syndrome (NOWS), and (2) to understand the degree to which mediating factors influence the direct relationship between MOUD exposure and NOWS severity. METHODS: This cross-sectional study includes data abstracted from the medical records of 1294 opioid-exposed infants (859 MOUD exposed and 435 non-MOUD exposed) born at or admitted to one of 30 US hospitals from July 1, 2016, to June 30, 2017. Regression models and mediation analyses were used to evaluate the relationship between MOUD exposure and NOWS severity (i.e., infant pharmacologic treatment and length of newborn hospital stay (LOS)) to identify potential mediators of this relationship in analyses adjusted for confounding factors. RESULTS: A direct (un-mediated) association was found between antenatal exposure to MOUD and both pharmacologic treatment for NOWS (aOR 2.34; 95%CI 1.74, 3.14) and an increase in LOS (1.73 days; 95%CI 0.49, 2.98). Delivery of adequate prenatal care and a reduction in polysubstance exposure were mediators of the relationship between MOUD and NOWS severity and as thus, were indirectly associated with a decrease in both pharmacologic treatment for NOWS and LOS. CONCLUSIONS FOR PRACTICE: MOUD exposure is directly associated with NOWS severity. Prenatal care and polysubstance exposure are potential mediators in this relationship. These mediating factors may be targeted to reduce the severity of NOWS while maintaining the important benefits of MOUD during pregnancy.

Error Rates of Data Processing Methods in Clinical Research: A Systematic Review and Meta-Analysis of Manuscripts Identified Through PubMed.

Background: In clinical research, prevention of systematic and random errors of data collected is paramount to ensuring reproducibility of trial results and the safety and efficacy of the resulting interventions. Over the last 40 years, empirical assessments of data accuracy in clinical research have been reported in the literature. Although there have been reports of data error and discrepancy rates in clinical studies, there has been little systematic synthesis of these results. Further, although notable exceptions exist, little evidence exists regarding the relative accuracy of different data processing methods. We aim to address this gap by evaluating error rates for 4 data processing methods. Methods: A systematic review of the literature identified through PubMed was performed to identify studies that evaluated the quality of data obtained through data processing methods typically used in clinical trials: medical record abstraction (MRA), optical scanning, single-data entry, and double-data entry. Quantitative information on data accuracy was abstracted from the manuscripts and pooled. Meta-analysis of single proportions based on the Freeman-Tukey transformation method and the generalized linear mixed model approach were used to derive an overall estimate of error rates across data processing methods used in each study for comparison. Results: A total of 93 papers (published from 1978 to 2008) meeting our inclusion criteria were categorized according to their data processing methods. The accuracy associated with data processing methods varied widely, with error rates ranging from 2 errors per 10,000 fields to 2,784 errors per 10,000 fields. MRA was associated with both high and highly variable error rates, having a pooled error rate of 6.57% (95% CI: 5.51, 7.72). In comparison, the pooled error rates for optical scanning, single-data entry, and double-data entry methods were 0.74% (0.21, 1.60), 0.29% (0.24, 0.35) and 0.14% (0.08, 0.20), respectively. Conclusions: Data processing and cleaning methods may explain a significant amount of the variability in data accuracy. MRA error rates, for example, were high enough to impact decisions made using the data and could necessitate increases in sample sizes to preserve statistical power. Thus, the choice of data processing methods can likely impact process capability and, ultimately, the validity of trial results.

Measuring and controlling medical record abstraction (MRA) error rates in an observational study.

BACKGROUND: Studies have shown that data collection by medical record abstraction (MRA) is a significant source of error in clinical research studies relying on secondary use data. Yet, the quality of data collected using MRA is seldom assessed. We employed a novel, theory-based framework for data quality assurance and quality control of MRA. The objective of this work is to determine the potential impact of formalized MRA training and continuous quality control (QC) processes on data quality over time. METHODS: We conducted a retrospective analysis of QC data collected during a cross-sectional medical record review of mother-infant dyads with Neonatal Opioid Withdrawal Syndrome. A confidence interval approach was used to calculate crude (Wald's method) and adjusted (generalized estimating equation) error rates over time. We calculated error rates using the number of errors divided by total fields ("all-field" error rate) and populated fields ("populated-field" error rate) as the denominators, to provide both an optimistic and a conservative measurement, respectively. RESULTS: On average, the ACT NOW CE Study maintained an error rate between 1% (optimistic) and 3% (conservative). Additionally, we observed a decrease of 0.51 percentage points with each additional QC Event conducted. CONCLUSIONS: Formalized MRA training and continuous QC resulted in lower error rates than have been found in previous literature and a decrease in error rates over time. This study newly demonstrates the importance of continuous process controls for MRA within the context of a multi-site clinical research study.

Neonatal opioid withdrawal syndrome: a review of the science and a look toward the use of buprenorphine for affected infants.

Neonates born to mothers taking opioids during pregnancy are at risk for neonatal opioid withdrawal syndrome (NOWS), for which there is no recognized standard approach to care. Nonpharmacologic treatment is typically used as a first-line approach for management, and pharmacologic treatment is added when clinical signs are not responding to nonpharmacologic measures alone. Although morphine and methadone are the most commonly used pharmacotherapies for NOWS, buprenorphine has emerged as a treatment option based on its pharmacologic profile and results from initial single site clinical trials. The objective of this report is to provide an overview of NOWS including a summary of ongoing work in the field and to review the state of the science, knowledge gaps, and practical considerations specific to the use of buprenorphine for the treatment of NOWS as discussed by a panel of experts during a virtual workshop hosted by the National Institutes of Health.

Opioids and the developing brain: time to rethink perinatal care for infants of opioid-dependent mothers.

Illicit use of opioids is a global health crisis with major implications for women and children. Strategies for managing opioid use disorder (OUD) in pregnancy have been tested over the past 40 years, but studies have focused on maternal and pregnancy outcomes, with less attention given to long-term follow-up of exposed children. Here, we provide a narrative review of recent advances in the assessment and management of neonatal opioid withdrawal syndrome (NOWS), and we summarise evidence from multiple domains-neuroimaging, electrophysiology, visual development and function, neurodevelopment, behaviour, cognition and education-which suggests that prenatal opioid exposure modifies child development. Further studies are required to determine the optimal management of pregnant women with OUD and babies with NOWS. We identify knowledge gaps and suggest that future study designs should evaluate childhood outcomes, including infant brain development and long-term neurocognitive and visual function.

Phenobarbital and Clonidine as Secondary Medications for Neonatal Opioid Withdrawal Syndrome.

BACKGROUND AND OBJECTIVES: Despite the neonatal opioid withdrawal syndrome (NOWS) epidemic in the United States, evidence is limited for pharmacologic management when first-line opioid medications fail to control symptoms. The objective with this study was to evaluate outcomes of infants receiving secondary therapy with phenobarbital compared with clonidine, in combination with morphine, for the treatment of NOWS. METHODS: We performed a retrospective cohort study of infants with NOWS from 30 hospitals. The primary outcome measures were the length of hospital stay, duration of opioid treatment, and peak morphine dose. Outcomes were compared by group by using analysis of variance and multivariable linear regression controlling for relevant confounders. RESULTS: Of 563 infants with NOWS treated with morphine, 32% (n = 180) also received a secondary medication. Seventy-two received phenobarbital and 108 received clonidine. After adjustment for covariates, length of hospital stay was 10 days shorter, and, in some models, duration of morphine treatment was 7.5 days shorter in infants receiving phenobarbital compared with those receiving clonidine, with no difference in peak morphine dose. Infants were more likely to be discharged from the hospital on phenobarbital than clonidine (78% vs 29%, P < .0001). CONCLUSIONS: Among infants with NOWS receiving morphine and secondary therapy, those treated with phenobarbital had shorter length of hospital stay and shorter morphine treatment duration than clonidine-treated infants but were discharged from the hospital more often on secondary medication. Further investigation is warranted to determine if the benefits of shorter hospital stay and shorter duration of morphine therapy justify the possible neurodevelopmental consequences of phenobarbital use in infants with NOWS.

Site-Level Variation in the Characteristics and Care of Infants With Neonatal Opioid Withdrawal.

BACKGROUND AND OBJECTIVES: Variation in pediatric medical care is common and contributes to differences in patient outcomes. Site-to-site variation in the characteristics and care of infants with neonatal opioid withdrawal syndrome (NOWS) has yet to be quantified. Our objective was to describe site-to-site variation in maternal-infant characteristics, infant management, and outcomes for infants with NOWS. METHODS: Cross-sectional study of 1377 infants born between July 1, 2016, and June 30, 2017, who were ≥36 weeks' gestation, with NOWS (evidence of opioid exposure and NOWS scoring within the first 120 hours of life) born at or transferred to 1 of 30 participating hospitals nationwide. Site-to-site variation for each parameter within the 3 domains was measured as the range of individual site-level means, medians, or proportions. RESULTS: Sites varied widely in the proportion of infants whose mothers received adequate prenatal care (31.3%-100%), medication-assisted treatment (5.9%-100%), and prenatal counseling (1.9%-75.5%). Sites varied in the proportion of infants with toxicology screening (50%-100%) and proportion of infants receiving pharmacologic therapy (6.7%-100%), secondary medications (1.1%-69.2%), and nonpharmacologic interventions including fortified feeds (2.9%-90%) and maternal breast milk (22.2%-83.3%). The mean length of stay varied across sites (2-28.8 days), as did the proportion of infants discharged with their parents (33.3%-91.1%). CONCLUSIONS: Considerable site-to-site variation exists in all 3 domains. The magnitude of the observed variation makes it unlikely that all infants are receiving efficient and effective care for NOWS. This variation should be considered in future clinical trial development, practice implementation, and policy development.

Association of a Simplified Finnegan Neonatal Abstinence Scoring Tool With the Need for Pharmacologic Treatment for Neonatal Abstinence Syndrome.

Importance: Observer-rated scales, such as the Finnegan Neonatal Abstinence Scoring Tool (FNAST), are used to quantify the severity of neonatal abstinence syndrome (NAS) and guide pharmacologic therapy. The FNAST, a comprehensive 21-item assessment tool, was developed for research and subsequently integrated into clinical practice; a simpler tool, designed to account for clinically meaningful outcomes, is urgently needed to standardize assessment. Objectives: To identify FNAST items independently associated with the decision to use pharmacologic therapy and to simplify the FNAST while minimizing loss of information for the treatment decision. Design, Setting, and Participants: This multisite cohort study included 424 neonates with opioid exposure who had a gestational age of at least 36 weeks with follow-up from birth to hospital discharge in the derivation cohort and 109 neonates with opioid exposure from the Maternal Opioid Treatment: Human Experimental Research Study in the validation cohort. Neonates in the derivation cohort were included in a medical record review at the Universities of Louisville and Kentucky or in a randomized clinical trial and observational study conducted at Tufts University (2014-2018); the Maternal Opioid Treatment: Human Experimental Research was conducted from 2005 to 2008. Data analysis was conducted from May 2017 to August 2019. Exposures: Prenatal opioid exposure. Main Outcomes and Measures: All FNAST items were dichotomized as present or not present, and logistic regression was used to identify binary items independently associated with pharmacologic treatment. The final model was validated with an independent cohort of neonates with opioid exposure. Results: Among 424 neonates (gestational age, ≥36 weeks; 217 [51%] female infants), convulsions were not observed, and high-pitched cry and hyperactive Moro reflex had extremely different frequencies across cohorts. Therefore, these 3 FNAST items were removed from further analysis. The 2 tremor items were combined, and 8 of the remaining 17 items were independently associated with pharmacologic treatment, with an area under the curve of 0.86 (95% CI, 0.82-0.89) compared with 0.90 (95% CI, 0.87-0.94) for the 21-item FNAST. External validation of the 8 items resulted in an area under the curve of 0.86 (95% CI, 0.79-0.93). Thresholds of 4 and 5 on the simplified scale yielded the closest agreement with FNAST thresholds of 8 and 12 (weighted κ = 0.55; 95% CI, 0.48-0.61). Conclusions and Relevance: The findings of this study suggest that 8 signs of NAS may be sufficient to assess whether a neonate meets criteria for pharmacologic therapy. A focus on these signs could simplify the FNAST tool and may enhance its clinical utility.

Diverse changes in myelin protein expression in rat brain after perinatal methadone exposure.

The national incidence of neonatal abstinence syndrome has dramatically increased over the last decade due to an increase in antenatal opioid exposure. Recent human and animal studies suggest that antenatal opioid exposure impacts the developing brain. The purpose of this study is to evaluate the effects of perinatal methadone exposure on myelination in multiple regions in the developing rat brain. Pregnant Sprague-Dawley rats were randomly assigned into three experimental groups and subsequently exposed to drinking water alone or drinking water containing methadone from 7 days post coitum through day 7 or through day 19 after delivery. Two male neonatal rats were randomly selected from each litter and terminated at day 19. The cerebral cortex, hippocampus, cerebellum, and brainstem were dissected and analyzed for three myelin specific proteins - CNP, PLP, and MBP - by Western blot analysis. All pups with exposure to methadone demonstrated decreased expression of CNP, PLP, and MBP in the cerebral cortex and hippocampus. In the cerebellum, PLP expression was down­regulated without apparent alteration of CNP and MBP expression. PLP and MBP expression, but not CNP expression, were significantly inhibited in the brainstem. Compared to the pups with postnatal methadone exposure via maternal milk through day 7, partial recovery of CNP and PLP expression only occurred in the cerebral cortices of the pups exposed through day 19. The findings show that antenatal opioid exposure in rat pups is associated with regionally­specific alterations in brain myelination that diversely affects myelin proteins.

The ACT NOW Clinical Practice Survey: Gaps in the Care of Infants With Neonatal Opioid Withdrawal Syndrome.

OBJECTIVES: The incidence of neonatal opioid withdrawal syndrome (NOWS) has increased fivefold over the last 10 years. Standardized NOWS care protocols have revealed many improved patient outcomes. Our objective for this study is to describe results of a clinical practice survey of NOWS management practices designed to inform future clinical studies in the diagnosis and management of NOWS. METHODS: A cross-sectional survey was administered to medical unit directors at 32 Institutional Development Award States Pediatric Clinical Trial Network and 22 Neonatal Research Network sites in the fall of 2017. Results are presented as both the number and percentage of positive responses. Ninety-five percent Wilson confidence intervals (CIs) were generated around estimates, and χ2 and Fisher's exact tests were used to compare the association between unit type and reporting of each protocol. RESULTS: Sixty-two responses representing 54 medical centers were received. Most participating NICU and non-ICU sites reported protocols for NOWS management, including NOWS scoring (98% NICU; 86% non-ICU), pharmacologic treatment (92% NICU; 64% non-ICU), and nonpharmacologic care (79% NICU; 79% non-ICU). Standardized protocols for pharmacologic care and weaning were reported more frequently in the NICU (92% [95% CI: 80%-97%] and 94% [95% CI: 83%-98%], respectively) compared with non-ICU settings (64% [95% CI: 39%-84%] for both) (P < .05 for both comparisons). Most medical centers reported morphine as first-line therapy (82%; 95% CI: 69%-90%) and level 3 and level 4 NICUs as the location of pharmacologic treatment (83%; 95% CI: 71%-91%). CONCLUSIONS: Observed variations in care between NICUs and non-ICUs revealed opportunities for targeted interventions in training and standardized care plans in non-ICU sites.

Training as an Intervention to Decrease Medical Record Abstraction Errors Multicenter Studies.

Studies often rely on medical record abstraction as a major source of data. However, data quality from medical record abstraction has long been questioned. Electronic Health Records (EHRs) potentially add variability to the abstraction process due to the complexity of navigating and locating study data within these systems. We report training for and initial quality assessment of medical record abstraction for a clinical study conducted by the IDeA States Pediatric Clinical Trials Network (ISPCTN) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) using medical record abstraction as the primary data source. As part of overall quality assurance, study-specific training for medical record abstractors was developed and deployed during study start-up. The training consisted of a didactic session with an example case abstraction and an independent abstraction of two standardized cases. Sixty-nine site abstractors from thirty sites were trained. The training was designed to achieve an error rate for each abstractor of no greater than 4.93% with a mean of 2.53%, at study initiation. Twenty-three percent of the trainees exceeded the acceptance limit on one or both of the training test cases, supporting the need for such training. We describe lessons learned in the design and operationalization of the study-specific, medical record abstraction training program.

A Practical Approach to Neonatal Opiate Withdrawal Syndrome.

Perinatal opioid misuse and neonatal opioid withdrawal syndrome (NOWS) are a significant public health problem that has grown exponentially over the past decade. In the United States, a woman seeks emergency room care for prescription opioid misuse every 3 minutes and approximately every 25 minutes, a child is born with signs of drug withdrawal. The economic impact of perinatal opioid misuse is significant with annual hospital charges for NOWS in 2012 as $1.5 billion dollars. Perinatal opioid misuse is a complex, multifaceted problem that demands a multidisciplinary cross specialty approach. This article will review the current state of NOWS and provide medical practitioners with a practical guide to enhance evidence based practice.

Decreasing Total Medication Exposure and Length of Stay While Completing Withdrawal for Neonatal Abstinence Syndrome during the Neonatal Hospital Stay.

INTRODUCTION: Neonatal abstinence syndrome (NAS) is a rapidly growing public health concern that has considerably increased health-care utilization and health-care costs. In an effort to curtail costs, attempts have been made to complete withdrawal as an outpatient. Outpatient therapy has been shown to prolong exposure to medications, which may negatively impact neurodevelopmental and behavioral outcomes. We hypothesized that the implementation of a modified NAS protocol would decrease total drug exposure and length of stay while allowing for complete acute drug withdrawal during the neonatal hospital stay. METHODS: Data were derived retrospectively from medical records of term (≥37 0/7) infants with NAS who were treated with pharmacologic therapy in the University of Louisville Hospital Neonatal Intensive Care Unit from 2005 to 2015. The pharmacologic protocol (SP1) for infants treated between 2005 and March 2014 (n = 146) dosed oral morphine every 4 h and utilized phenobarbital as adjuvant therapy. Protocol 2 (SP2) initiated after March 2014 (n = 44) dosed morphine every 3 h and used clonidine as adjuvant therapy. Charts were reviewed for demographic information and maternal drug history. Maternal and infant toxicology screens were recorded. The length of morphine therapy and need for adjuvant drug therapy were noted. Length of stay was derived from admission and discharge dates. RESULTS: The length of morphine therapy was decreased by 8.5 days from 35 to 26.5 days (95% CI 4.5-12 days) for infants treated with SP2 vs. SP1 (p < 0.001). The need for adjuvant pharmacologic therapy was decreased by 24% in patients treated with SP2 vs. SP1 (p = 0.004). The length of stay was decreased by 9 days from 42 to 33 days (95% CI 5.1-13 days) for infants treated with SP2 vs. SP1 (p < 0.001). The decreased length of stay resulted in an average reduction of hospital charges by $27,090 per patient in adjusted 2015 US Dollars. CONCLUSION: This study demonstrates that total drug exposure and length of stay can be reduced while successfully completing acute withdrawal during the neonatal hospital stay.

Effects of endotoxin administration and cerebral hypoxia-ischemia on complement activity and local transcriptional regulation in neonatal rats.

It is not known whether up-regulation of complement components, either circulating or locally synthesized, contributes to an increased susceptibility to neonatal hypoxic-ischemic (HI) cerebral injury. Therefore, we tested the hypothesis that in neonatal rats subjected to a unilateral HI cerebral insult, prior administration of E. coli lipopolysaccharide (LPS) augments (1) complement-mediated serum hemolytic activity, and (2) C3 mRNA and C9 mRNA levels in hepatic and cerebral tissue. Pregnant rats were injected subcutaneously with sterile normal saline (NS) or 500 microg/kg of LPS on gestational days 18 and 19. Following birth, the pups received intraperitoneal injections of NS or 250 microg/kg of LPS on postnatal days 3 and 5. On postnatal day 7, each animal was subjected to ligation of the right common carotid artery followed by 2.5h of hypoxia (8% O(2)). At 3, 6,18, 24 and 48 h after hypoxia, the complement-mediated hemolytic activity of pooled serum was measured. Hepatic and cerebral C3 mRNA and C9 mRNA were quantified by qRT-PCR at 3, 6, and 18 h after HI. Serum hemolytic activity, hepatic C3 mRNA, and hepatic C9 mRNA were up-regulated after cerebral HI. LPS administration potentiated the effect of HI on serum hemolytic activity and increased cerebral C3 mRNA levels. Cerebral C9 mRNA was not detected and was not affected by HI, with or without the prior LPS administration. These observations support the theory that previously reported C9-mediated neurotoxicity following cerebral HI is induced by circulating, rather than locally synthesized C9.

Immunoenhancement to prevent nosocomial coagulase-negative staphylococcal sepsis in very low-birth-weight infants.

Extremely low-birth-weight infants are susceptible to invasion by coagulase-negative staphylococci (CONS). This article reviews the epidemiology, immunology, and microbiology of CONS and describes recent clinical trials of immunoenhancing agents such as intravenous immunoglobulin, granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, and mouse humanized chimeric anti-lipoteichoic acid antibody. Potential avenues of research to reduce the incidence of nosocomial CONS sepsis in premature neonates are presented.