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Background : Non-routine events (NRE) are defined as any suboptimal occurrences in a process being measured in the opinion of the reporter and comes from the field of human factors engineering. These typically occur well up-stream of an adverse event and NRE measurement has not been applied to the complex context of neonatal surgery. We sought to apply this novel safety event measurement methodology to neonates in the NICU undergoing gastrostomy tube placement. Methods : A prospective pilot study was conducted between November 2016 and August 2020 in the Level IV NICU and the pediatric operating rooms of an urban academic children's hospital to determine the incidence, severity, impact, and contributory factors of clinician-reported non-routine events (NREs, i.e., deviations from optimal care) and 30-day NSQIP occurrences in neonates receiving a G-tube. Results : Clinicians reported at least one NRE in 32 of 36 (89%) G-tube cases, averaging 3.0 (Standard deviation: 2.5) NRE reports per case. NSQIP-P review identified 7 cases (19%) with NSQIP-P occurrences and each of these cases had multiple reported NREs. One case in which NREs were not reported was without NSQIP-P occurrences. The odds ratio of having a NSQIP-P occurrence with the presence of an NRE was 0.695 (95% CI 0.06 – 17.04). Conclusion : Despite being considered a "simple" operation, >80% of neonatal G-tube placement operations had at least one reported NRE by an operative team member. In this pilot study, NRE occurrence was not significantly associated with the subsequent reporting of an NSQIP-P occurrence. Understanding contributory factors of NREs that occur in neonatal surgery may promote surgical safety efforts and should be evaluated in larger and more diverse populations. Level of evidence : IV

Background Quality improvement (QI) methods have been widely adopted in health care. Although theoretical frameworks and models for organizing successful QI programs have been described, few reports have provided practical examples to link existing QI theory to building a unit-based QI program. The purpose of this report is to describe the authors’ experience in building QI infrastructure in a large neonatal ICU (NICU). Methods A unit-based QI program was developed with the goal of fostering the growth of high-functioning QI teams. This program was based on six pillars: shared vision for QI, QI team capacity, QI team capability, actionable data for improvement, culture of improvement, and QI team integration with external collaboratives. Multiple interventions were developed, including a QI dashboard to align NICU metrics with unit and hospital quality goals, formal training for QI leaders, QI coaches imbedded in project teams, a day-long QI educational workshop to introduce QI methodology to unit staff, and a secure, Web-based QI data infrastructure. Results Over a five-year period, this QI infrastructure brought organization and support for individual QI project teams and improved patient outcomes in the unit. Two case studies are presented, describing teams that used support from the QI infrastructure. The Infection Prevention team reduced central line–associated bloodstream infections from 0.89 to 0.36 infections per 1,000 central line–days. The Nutrition team decreased the percentage of very low birth weight infants discharged with weights less than the 10th percentile from 51% to 40%. Conclusion The clinicians provide a pragmatic example of incorporating QI organizational and contextual theory into practice to support the development of high-functioning QI teams and build a unit-based QI program.

Despite significant improvements in recent years, maternal and neonatal health outcomes remain poor in many regions of the world. One such area is in the remote mountainous regions of Nepal. The purpose of this study is to describe the current antenatal care practices and delivery support in a mountainous district of Nepal.This study took place in Solukhumbu District between December 2015 and February 2018. A household survey was created using evidence-based maternal and neonatal care indicators. Women who had delivered within the previous two years were surveyed regarding antenatal and delivery care they received. A standardized health facility survey was used to evaluate the operational status of health facilities. The study was approved by the Nepal Ministry of Health and the University of Utah IRB.A total of 487 households and 19 facilities were surveyed. 35.7% (174/487) of deliveries occurred in a health facility (hospital, primary health care center or birthing center). 35.2% (171/486) of deliveries were attended by a skilled birth attendant. 52.8% (47/89) of women who did not deliver in a facility noted that transportation issues and not having sufficient time to travel during labor prevented them from delivering in a facility. No health posts had staff trained in obstetric and neonatal emergencies.The majority of women in Solukhumbu District do not receive high quality antenatal and delivery care. An intervention that would make antenatal care and delivery support more accessible could improve maternal and infant outcomes in this district and other similar regions.

Background Patient safety events result from failures in complex health care delivery processes. To ensure safety, teams must implement ways to identify events that occur in a nonrandom fashion and respond in a timely manner. To illustrate this, one children's hospital's experience with an outbreak of unplanned extubations (UEs) in the neonatal ICU (NICU) is described. Methods The quality improvement team measured UEs using three complementary data streams. Interventions to decrease the rate of UE were tested with success. Three statistical process control (SPC) charts (u-chart, g-chart, and an exponentially weighted moving average [EWMA] chart) were used for real-time monitoring. Results From July 2015 to May 2016, the UE rate was stable at 1.1 UE/100 ventilator days. In early June 2016, a cluster of UEs, including four events within one week, was observed. Two of three SPC charts showed special cause variation, although at different time points. The EWMA chart alerted the team more than two weeks earlier than the u-chart. Within days of discovering the outbreak, the team identified that the hospital had replaced the tape used to secure endotracheal tubes with a nearly identical product. After multiple tape products were tested over the next month, the team selected one that returned the system to a state of stability. Conclusion Ongoing monitoring using SPC charts allowed early detection and rapid mitigation of an outbreak of UEs in the NICU. This highlights the importance of continuous monitoring using tools such as SPC charts that can alert teams to both improvement and worsening of processes.

BACKGROUND: In preterm infants who require mechanical ventilation (MV), volume-targeted ventilation (VTV) modes are associated with lower rates of bronchopulmonary dysplasia compared with pressure-limited ventilation. Bronchopulmonary dysplasia rates in our NICU were higher than desired, prompting quality improvement initiatives to improve MV by increasing the use of VTV. METHODS: We implemented and tested interventions over a 3-year period. Primary outcomes were the percentage of conventional MV hours when any-VTV mode was used and the percentage of conventional MV hours when an exclusively VTV mode was used. Exclusively VTV modes were modes in which all breaths were volume targeted. We evaluated outcomes during 3 project periods: baseline (May 2016–December 2016); epoch 1 (December 2016–October 2018), increasing the use of any-VTV mode; and epoch 2 (October 2018–November 2019), increasing the use of exclusively VTV modes. RESULTS: Use of any-VTV mode increased from 18 694 of 22 387 (83%) MV hours during baseline to 72 846 of 77 264 (94%) and 58 174 of 60 605 (96%) MV hours during epochs 1 and 2, respectively (P < .001). Use of exclusively VTV increased from 5967 of 22 387 (27%) during baseline to 47 364 of 77 264 (61%) and 46 091 of 60 605 (76%) of all conventional MV hours during epochs 1 and 2, respectively (P < .001). In statistical process control analyses, multiple interventions were associated with improvements in primary outcomes. Measured clinical outcomes were unchanged. CONCLUSIONS: Quality improvement interventions were associated with improved use of VTV but no change in measured clinical outcomes.

Introduction. Respiratory distress (RD) contributes to common causes of neonatal mortality. Bubble continuous positive airway pressure (bCPAP) is a safe, low-cost therapy for RD; however, adoption of bCPAP programs remains challenging. Aim. To increase the percentage of neonates with RD treated with bCPAP from 2% to 25% by January 2019. Methods. In the newborn unit (NBU) at the Nakuru County and Referral Hospital in Kenya, a pre-initiative (pre) period (March 2016 to December 2017) and a post-initiative (post) period (January 2018 to December 2018) were defined. Tests of change included organization of infrastructure, staff trainings, development of a nurse educator role, and treatment protocols. Clinical and outcome data were abstracted from all available medical records. Results. A total of 405 infants were included in the pre group, with 2% bCPAP use. A total of 1157 infants were included in the post group, with 100 (17.6%) treated with bCPAP. bCPAP use increased during the post period. Rates of RD (49.9% pre, 49.0% post, P = .64) and mortality (30.9% pre, 29.1% post, P = .35) were similar. Neonates treated with bCPAP had lower mean birth weight and a higher risk of death (relative risk = 1.41, 95% confidence interval = 1.21-1.65) compared with those not treated with bCPAP. Conclusion. It was possible to build capacity for the use of bCPAP to treat neonates in this low-resource setting. Gaps in the delivery bCPAP remain, and the current capacity in the PGH NBU allows for application of bCPAP to smaller, likely, sicker neonates.

Objective To compare the incidence, severity, preventability, and contributing factors of non-routine events - deviations from optimal care based on the clinical situation - associated with team-based, nurse-to-nurse, and mixed handovers in a large cohort of surgical neonates. Study Design A prospective observational study and one-time cross-sectional provider survey were conducted at one urban academic children’s hospital. 130 non-cardiac surgical cases in 109 neonates who received pre- and post-operative NICU care. Results The incidence of clinician-reported NREs was high (101/130 cases, 78%) but did not differ significantly across acuity-tailored neonatal handover practices. National Surgical Quality Improvement – Pediatric occurrences of major morbidity were significantly higher (p

Background The key driver diagram (KDD) is an important tool used by improvement teams to guide and frame their work. Methods to build a KDD when little relevant literature or reliable local data exist are poorly described. This article describes the process used in our neonatal ICU (NICU) to build a KDD to decrease unplanned extubations (UE) in chronically ventilated infants. Methods Twenty-seven factors hypothesized to be associated with UE in our NICU were identified. An expert panel of 33 staff members completed three rounds of a modified Delphi process administered through an online interface. After the third round, panel members provided suggestions for interventions to target all factors meeting criteria for consensus. These qualitative data were analyzed by inductive thematic analysis. A follow-up survey to all panel members was used to assess the feasibility of this process for future use. Results After three Delphi rounds, 14 factors met consensus and eight main interventions were identified through thematic analysis. These data were used to build a KDD for testing. All participants who completed the follow-up survey (20/20) stated willingness to participate in this process in the future and 18/20 (90%) stated they would be "more willing" or "much more willing" to support interventions developed using this process. Conclusion A novel mixed-methods approach was used to generate a KDD combining a Delphi process with thematic analysis. This approach provides improvement teams a rigorous and reproducible method to understand local context, generate consensus KDDs, and improve local buy-in for improvement interventions.

Objective We aimed to clarify the impact of Extracorporeal Membrane Oxygenation (ECMO) as a platform to drive hemodialysis (HD) for ammonia clearance on outcomes of neonates with severe hyperammonemia. Study Design All neonates treated for hyperammonemia at a single children’s hospital between 1992 and 2016 were identified. Patient characteristics and outcomes were compared between those receiving medical management or ECMO/HD. Result Twenty-five neonates were treated for hyperammonemia, of which 13 (52%) received ECMO/HD. Peak ammonia levels among neonates treated with ECMO/HD were significantly higher than those medically-managed (1041 [IQR 902–1581] μmol/L versus 212 [IQR 110–410] μmol/L; p=0.009). Serum ammonia levels in the ECMO/HD cohort declined to the median of medically managed within 4.5 (IQR 2.9–7.0) hours and normalized within 7.3 (IQR 3.6–13.5) hours. All neonates survived ECMO/HD, and 9 (69.2%) survived to discharge. Conclusion ECMO/HD is an effective adjunct to rapidly clear severe hyperammonemia in newborns, reducing potential neurodevelopmental morbidity.

Objective To quantify the daily risk of unplanned extubation (UE) in newborns based on developmental and anatomical factors. Methods Prospective cohort of ventilated newborns over an 18-month period in a level IV neonatal intensive care unit (NICU). We captured UEs through four data streams. We generated multivariable logistic regression models to assess the association of UE with chronological age, birth weight, and postmenstrual age. Results During the study, 718 infants were ventilated for 5,611 patient days with 117 UEs in 81 infants. The daily risk of UE had a significant, nonlinear relationship (p 28 days, OR: 1.06, 95% CI: 1.0–1.14). Birth weight and postmenstrual age were not associated with UE. Adverse events occurred in 83/117 (71%) UE events. Iatrogenic causes of UE were more common in younger, smaller infants, whereas older, larger infants were more likely to self-extubate. Conclusion The daily risk and causes of UE change over the course of an infant's NICU hospitalization. These data can be used to identify infants at the highest risk of UE for whom targeted proactive interventions can be developed.

Background Concerted quality improvement (QI) efforts have been taken to discourage the practice of early elective deliveries (EEDs), but few studies have robustly examined the impact of directed QI interventions in reducing EED practices. Using quasi-experimental methods, we sought to evaluate the impact of a statewide QI intervention to reduce the practice of EEDs. Methods Retrospective cohort study of vital records data (2007 to 2013) for all singleton births occurring ≥36 weeks in 66 Tennessee hospitals grouped into three QI cohorts. We used interrupted-time series to estimate the effect of the QI intervention on the likelihood of an EED birth statewide, and by hospital cohort. We compared the distribution of hospital EED percentages pre- and post-intervention. Lastly, we used multivariable logistic regression to estimate the effect of QI interventions on maternal and infant outcomes. Results Implementation of the QI intervention was associated with significant declines in likelihood of EEDs immediately following the intervention (odds ratio, OR = 0.72; p

To utilize a probiotic protocol to achieve a 50% reduction in rates of necrotizing enterocolitis (NEC) ≥ Bell Stage 2 within 2 years of protocol implementation. Literature review guided probiotic selection and protocol design. A driver diagram identified key drivers to achieve our aim. A U chart followed monthly NEC ≥ Bell Stage 2 per 100 patient days and per monthly admissions. The process measure was protocol compliance and the balancing measure was probiotic sepsis. NEC ≥ Bell Stage 2 decreased from 0.14 to 0.04 per 100 patient days in infants

We report a statewide collaborative quality initiative to improve resuscitation and stabilization practices following introduction of the 6th edition of the Neonatal Resuscitation Program. Participants drafted a consensus toolkit of interventions and corresponding measures. Hospital teams collected baseline data, and implemented changes using PDSA-cycles and statistical process control charts. Nine Tennessee NICUs submitted data on 3771 resuscitations. “Special cause” improvements were achieved and sustained for pre-resuscitation checklists (77–90%) and team briefings (80–92%). Time to intravenous access (50–42 min), glucose infusion initiation (73–60 min), and antibiotic dosing (113–98 min) were also significantly reduced. Teams were unable to meet new NRP oxygen saturation targets. Improvements in post-resuscitation debriefing were not sustained, while communication with parents declined significantly (68–60%). Large-scale collaboration facilitated statewide implementation of new guidelines, while highlighting under-appreciated systems challenges among competing resource demands.

Tennessee has low breastfeeding rates and has identified opportunities for improvement to enhance maternity practices to support breastfeeding mothers. We sought a 10% relative increase in the aggregate Joint Commission measure of breastfeeding exclusivity at discharge (TJC PC-05) by focusing on high-reliability (≥90%) implementation of processes that promote breastfeeding in the delivery setting.A statewide, multidisciplinary development team reviewed evidence from the WHO-UNICEF "Ten Steps to Successful Breastfeeding" to create a consensus toolkit of process indicators aligned with the Ten Steps. Hospitals submitted monthly TJC PC-05 data for 6 months while studying local implementation of the Ten Steps to identify improvement opportunities, and for an additional 11 months while conducting tests of change to improve Ten Steps implementation using Plan-Do-Study-Act cycles, local process audits, and control charts. Data were aggregated at the state level and presented at 12 monthly webinars, 3 regional learning sessions, and 1 statewide meeting where teams shared their local data and implementation experiences.Thirteen hospitals accounting for 47% of live births in Tennessee submitted data on 31,183 mother-infant dyads from August 1, 2012, to December 31, 2013. Aggregate monthly mean PC-05 demonstrated "special cause" improvement increasing from 37.1% to 41.2%, an 11.1% relative increase. Five hospitals reported implementation of ≥5 of the Ten Steps and two hospitals reported ≥90% reliability on ≥5 of the Ten Steps using locally designed process audits.Using large-scale improvement methodology, a successful statewide collaborative led to10% relative increase in breastfeeding exclusivity at discharge in participating Tennessee hospitals. Further opportunities for improvement in implementing breastfeeding supportive practices were identified.

OBJECTIVE: To improve patient safety in our NICU by decreasing the incidence of intubation-associated adverse events (AEs). METHODS: We sequentially implemented and tested 3 interventions: standardized checklist for intubation, premedication algorithm, and computerized provider order entry set for intubation. We compared baseline data collected over 10 months (period 1) with data collected over a 10-month intervention and sustainment period (period 2). Outcomes were the percentage of intubations containing any prospectively defined AE and intubations with bradycardia or hypoxemia. We followed process measures for each intervention. We used risk ratios (RRs) and statistical process control methods in a times series design to assess differences between the 2 periods. RESULTS: AEs occurred in 126/273 (46%) intubations during period 1 and 85/236 (36%) intubations during period 2 (RR = 0.78; 95% confidence interval [CI], 0.63–0.97). Significantly fewer intubations with bradycardia (24.2% vs 9.3%, RR = 0.39; 95% CI, 0.25–0.61) and hypoxemia (44.3% vs 33.1%, RR = 0.75, 95% CI 0.6–0.93) occurred during period 2. Using statistical process control methods, we identified 2 cases of special cause variation with a sustained decrease in AEs and bradycardia after implementation of our checklist. All process measures increased reflecting sustained improvement throughout data collection. CONCLUSIONS: Our interventions resulted in a 10% absolute reduction in AEs that was sustained. Implementation of a standardized checklist for intubation made the greatest impact, with reductions in both AEs and bradycardia.

The purpose of this project was to examine the American College of Surgeons National Surgical Quality Improvement Program Pediatric (ACSNSQIP-P) Participant Use File (PUF) to compare risk-adjusted outcomes of neonates versus other pediatric surgical patients.In the ACS-NSQIP-P 2012-2013 PUF, patients were classified as preterm neonate, term neonate, or nonneonate at the time of surgery. The primary outcomes were 30-day mortality and composite morbidity. Patient characteristics significantly associated with the primary outcomes were used to build a multivariate logistic regression model.The overall 30-day mortality rate for preterm neonates, term neonate, and nonneonates was 4.9%, 2.0%, 0.1%, respectively (p0.0001). The overall 30-day morbidity rate for preterm neonates, term neonates, and nonneonates was 27.0%, 17.4%, 6.4%, respectively (p0.0001). After adjustment for preoperative and operative risk factors, both preterm (adjusted odds ratio, 95% CI: 2.0, 1.4-3.0) and term neonates (aOR, 95% CI: 1.9, 1.2-3.1) had a significantly increased odds of 30-day mortality compared to nonneonates.Surgical neonates are a cohort who are particularity susceptible to postoperative morbidity and mortality after adjusting for preoperative and operative risk factors. Collaborative efforts focusing on surgical neonates are needed to understand the unique characteristics of this cohort and identify the areas where the morbidity and mortality can be improved.

Objective To determine the rate of adverse events associated with endotracheal intubation in newborns and modifiable factors contributing to these events. Study design We conducted a prospective, observational study in a 100-bed, academic, level IV neonatal intensive care unit from September 2013 through June 2014. We collected data on intubations using standardized data collection instruments with validation by medical record review. Intubations in the delivery or operating rooms were excluded. The primary outcome was an intubation with any adverse event. Adverse events were defined and tracked prospectively as nonsevere or severe. We measured clinical variables including number of attempts to successful intubation and intubation urgency (elective, urgent, or emergent). We used logistic regression models to estimate the association of these variables with adverse events. Results During the study period, 304 intubations occurred in 178 infants. Data were available for 273 intubations (90%) in 162 patients. Adverse events occurred in 107 (39%) intubations with nonsevere and severe events in 96 (35%) and 24 (8.8%) intubations, respectively. Increasing number of intubation attempts (OR 2.1, 95% CI, 1.6-2.6) and emergent intubations (OR 4.7, 95% CI, 1.7-13) were predictors of adverse events. The primary cause of emergent intubations was unplanned extubation (62%). Conclusions Adverse events are common in the neonatal intensive care unit, occurring in 4 of 10 intubations. The odds of an adverse event doubled with increasing number of attempts and quadrupled in the emergent setting. Quality improvement efforts to address these factors are needed to improve patient safety.

Bronchopulmonary dysplasia, or chronic lung disease (CLD), of premature infants involves injury from hyperoxia and mechanical ventilation to an immature lung. We examined surfactant and nitric oxide (NO), which are developmentally deficient in premature infants, in the baboon model of developing CLD. Fetuses were delivered at 125 d gestation and were managed for 14 d with ventilation and oxygen prn without (controls) or with inhaled NO at 5 ppm. Compared with term infants, premature control infants had reduced maximal lung volume, decreased tissue content of surfactant proteins SP-A, -B, and -C, abnormal lavage surfactant as assessed by pulsating bubble surfactometer, and a low concentration of SP-B/phospholipid. NO treatment significantly increased maximal lung volume and tissue SP-A and SP-C, reduced recovery of lavage surfactant by 33%, decreased the total protein:phospholipid ratio of surfactant by 50%, and had no effect on phospholipid composition or SP content except for SP-C (50%). In both treatment groups, levels of SP-B and SP-C in surfactant were negatively correlated with STmin, with a 5-fold greater SP efficiency for NO versus control animals. By contrast, lung volume and compliance were not correlated with surfactant function. We conclude that surfactant is often dysfunctional in developing CLD secondary to SP-B deficiency. NO treatment improves the apparent ability of hydrophobic SP to promote low surface tension, perhaps secondary to less protein inactivation of surfactant, and improves lung volume by a process unrelated to surfactant function.

The role of the patent ductus arteriosus in the development of chronic lung disease in surfactant-treated premature newborns remains unclear.To examine the effects of ductus ligation on cardiopulmonary function and lung histopathology in premature primates.Baboons were delivered at 125 d, (term = 185 d) treated with surfactant, and ventilated for 14 d. Serial echocardiograms and pulmonary function tests were performed. Animals were randomized to ligation (n = 12) or no ligation (controls, n = 13) on Day 6 of life. Necropsy was performed on Day 14.Compared with nonligated control animals, ligated animals had lower pulmonary-to-systemic flow ratios, higher systemic blood pressures, and improved indices of right and left ventricular performance. The ligated animals tended to have better compliance and ventilation indices for the last 3 d of the study. There were no differences between the groups in proinflammatory tracheal cytokines (interleukin [IL] 6 and IL-8), static lung compliance, or lung histology.Although a persistent patent ductus arteriosus results in diminished cardiac function and increased ventilatory requirements at the end of the second week of life, ligation on Day 6 had no measurable effect on the histologic evolution of chronic lung injury in this 14-d baboon model.

We report on developmental changes of pulmonary and systemic nitric oxide (NO) metabolites in a baboon model of chronic lung disease with or without exposure to inhaled NO. The plasma levels of nitrite and nitrate, staining for S-nitrosothiols and 3-nitrotyrosine in the large airways, increased between 125 d and 140 d of gestation (term 185 d) in animals developing in utero. The developmental increase in NO-mediated protein modifications was not interrupted by delivery at 125 d of gestation and mechanical ventilation for 14 d, whereas plasma nitrite and nitrate levels increased in this model. Exposure to inhaled NO resulted in a further increase in plasma nitrite and nitrate and an increase in plasma S-nitrosothiol without altering lung NO synthase expression. These data demonstrate a developmental progression in levels of pulmonary NO metabolites that parallel known maturational increases in total NO synthase activity in the lung. Despite known suppression of total pulmonary NO synthase activity in the chronic lung disease model, pulmonary and systemic NO metabolite levels are higher than in the developmental control animals. Thus, a deficiency in NO production and biological function in the premature baboon was not apparent by the detection and quantification of these surrogate markers of NO production.

Nitric oxide (NO) serves multiple functions in the developing lung, and pulmonary NO production is decreased in a baboon model of chronic lung disease (CLD) after premature birth at 125 days (d) gestation (term = 185d). To determine whether postnatal NO administration alters the genesis of CLD, the effects of inhaled NO (iNO, 5 ppm) were assessed in the baboon model over 14d. iNO caused a decrease in pulmonary artery pressure in the first 2d and a greater rate of spontaneous closure of the ductus arteriosus, and lung compliance was greater and expiratory resistance was improved during the first week. With iNO, postmortem pressure-volume curves were shifted upward, lung DNA content and cell proliferation were increased, and lung growth was preserved to equal that which occurs during the same period in utero. In addition, the excessive elastin deposition characteristic of CLD was normalized by iNO, and there was evidence of stimulation of secondary crest development. Thus, in the baboon model of CLD, iNO improves early pulmonary function and alters lung growth and extracellular matrix deposition. As such, NO biosynthetic pathway dysfunction may contribute to the pathogenesis of CLD.

During a period of 7 years at our institution, four girls and one boy with Down's syndrome, ages 9 to 16 years, were examined and treated for hyperthyroidism. Two patients had Graves' disease and they responded to propylthiouracil (PTU) with a predictable clinical course resulting in remission within 4 years. The remaining three patients included in this report had hyperthyroid profiles similar to those of the two with Graves' disease except for their antibody panels. These patients, in addition to the elevated thyroid-stimulating immunoglobulin (TSI) level observed in Graves' disease, also had significantly elevated antimicrosomal antibody (AMA) and antithyroglobulin antibody (ATGA) at the time of diagnosis. Elevated TSI level was again present in two patients who had a recurrence of hyperthyroidism after PTU therapy was discontinued. Treatment of these three patients was best done with the continuation of PTU therapy at a lower dose and the addition of thyroxine as soon as mild hypothyroidism developed. Treatment with PTU and thyroxine was continued until the TSI level was no longer elevated. Levels of AMA and ATGA remained elevated long after the TSI level became normal. All three patients eventually had hypothyroidism and continue to require thyroxine replacement.

Rationale: Nitric oxide (NO) plays an important role in lung development and perinatal lung function, and pulmonary NO synthases (NOS) are decreased in bronchopulmonary dysplasia (BPD) following preterm birth. Fetal estradiol levels increase during late gestation and estradiol up-regulates NOS, suggesting that after preterm birth estradiol deprivation causes attenuated lung NOS resulting in impaired pulmonary function. Objective: To test the effects of postnatal estradiol administration in a primate model of BPD over 14 days after delivery at 125 days of gestation (term = 185 d). Methods: Cardiopulmonary function was assessed by echocardiography and whole body plethysmography. Lung morphometric and histopathologic analyses were performed, and NOS enzymatic activity and abundance were measured. Measurements and Main Results: Estradiol caused an increase in blood pressure and ductus arteriosus closure. Expiratory resistance and lung compliance were also improved, and this occurred before spontaneous ductal closure. Furthermore, both oxygenation and ventilation indices were improved with estradiol, and the changes in lung function and ventilatory support requirements persisted throughout the study period. Whereas estradiol had negligible effect on indicators of lung inflammation and on lung structure assessed after the initial 14 days of ventilatory support, it caused an increase in lung neuronal and endothelial NOS enzymatic activity. Conclusions: In a primate model of BPD, postnatal estradiol treatment had favorable cardiovascular impact, enhanced pulmonary function, and lowered requirements for ventilatory support in association with an up-regulation of lung NOS. Estradiol may be an efficacious postnatal therapy to improve lung function and outcome in preterm infants.

Nitric oxide (NO), produced by NO synthase (NOS), serves multiple functions in the perinatal lung. In fetal baboons, neuronal (nNOS), endothelial (eNOS), and inducible NOS (iNOS) are all primarily expressed in proximal respiratory epithelium. In the present study, NOS expression and activity in proximal lung and minute ventilation of NO standard temperature and pressure (V˙eNOSTP) were evaluated in a model of chronic lung disease (CLD) in baboons delivered at 125 days (d) of gestation (term = 185 d) and ventilated for 14 d, obtaining control lung samples from fetuses at 125 or 140 d of gestation. In contrast to the normal 73% increase in total NOS activity from 125 to 140 d of gestation, there was an 83% decline with CLD. This was related to marked diminutions in both nNOS and eNOS expression and enzymatic activity. nNOS accounted for the vast majority of enzymatic activity in all groups. The normal 3.3-fold maturational rise in iNOS protein expression was blunted in CLD, yet iNOS activity was elevated in CLD compared with at birth. The contribution of iNOS to total NOS activity was minimal in all groups.V˙eNOSTPremained stable in the range of 0.5–1.0 nl · kg−1· min−1from birth to day 7 of life, and it then rose by 2.5-fold. Thus the baboon model of CLD is characterized by deficiency of the principal pulmonary isoforms, nNOS and eNOS, and enhanced iNOS activity over the first 2 wk of postnatal life. It is postulated that these alterations in NOS expression and activity may contribute to the pathogenesis of CLD.

Nitric oxide (NO), produced by NO synthase (NOS), plays a critical role in multiple processes in the lung during the perinatal period. To better understand the regulation of pulmonary NO production in the developing primate, we determined the cell specificity and developmental changes in NOS isoform expression and action in the lungs of third-trimester fetal baboons. Immunohistochemistry in lungs obtained at 175 days (d) of gestation (term = 185 d) revealed that all three NOS isoforms, neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS), are primarily expressed in proximal airway epithelium. In proximal lung, there was a marked increase in total NOS enzymatic activity from 125 to 140 d gestation due to elevations in nNOS and eNOS, whereas iNOS expression and activity were minimal. Total NOS activity was constant from 140 to 175 d gestation, and during the latter stage (160–175 d gestation), a dramatic fall in nNOS and eNOS was replaced by a rise in iNOS. Studies done within 1 h of delivery at 125 or 140 d gestation revealed that the principal increase in NOS during the third trimester is associated with an elevation in exhaled NO levels, a decline in expiratory resistance, and greater pulmonary compliance. Thus, there are developmental increases in pulmonary NOS expression and NO production during the early third trimester in the primate that may enhance airway and parenchymal function in the immediate postnatal period.

Increased levels of nitric oxide (NO) have been measured in exhaled gas in a variety of pulmonary pathologies with a prominent inflammatory component. Inflammation with both the appearance of inflammatory cells and elevation of a variety of inflammatory mediators appears to be a consistent component in the pathology of hyaline membrane disease (HMD) and early neonatal chronic lung disease (CLD). We report pulmonary NO production in the baboon model of HMD and CLD. Ten premature baboons, Papio sp., at 140 days (77%) gestation were delivered by hysterotomy and placed on IMV at an FiO2=1.0 (5 animals-induced HMD/CLD), or at an FiO2 adjusted “prn” (5 animals- controls) to maintain normal arterial oxygen levels. Four additional baboons were delivered at 125 days (70%) gestation and were managed on IMV with FiO2 adjusted “prn.” Gas was sampled and measurements were paired from both the proximal limb of the ventilator(