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OBJECTIVES. The objective was to investigate maternal and pregnancy characteristics associated with neonatal encephalopathy (NE). STUDY DESIGN. We queried an administrative birth cohort from California between 2011–2017 to determine the association between each factor and NE with and without hypothermia treatment. RESULTS. From 3 million infants born at 35 or more weeks of gestation, 6,857 cases of NE were identified (2.3 per 1,000 births), 888 (13%) which received therapeutic hypothermia. Risk factors for NE were stronger among cases receiving hypothermia therapy. Substance-related diagnosis, preexisting diabetes, preeclampsia, and any maternal infection were associated with a two-fold increase in risk. Maternal overweight/obesity, nulliparity, advanced maternal age, depression, gestational diabetes or hypertension, and short or long gestations also predicted NE. Young maternal age, Asian race and Hispanic ethnicity, and cannabis related diagnosis lowered risk of NE. CONCLUSIONS. By disseminating these results, we encourage further interrogation of these perinatal factors.

The diagnostic capabilities, palliative procedures, and critical care therapies for neonates with single ventricle heart disease have rapidly evolved. We aimed to review current trends for intensivists and cardiologists caring for this population. Enhanced diagnostics and 3-dimensional modeling can be instrumental in planning care pathways for these neonates. Additionally, the ability to palliate many of these patients with catheter-based therapies rather than traditional surgical approaches has allowed for reduced morbidity. There are significant improvements in the understanding of how critical care therapies affect survival and neurodevelopmental outcomes in this population. Despite advancements in the understanding of longer-term outcomes in this population, much remains to be discovered about how initial palliation, critical care strategies, surgical techniques, and extracorporeal support can be optimized for the most favorable neurodevelopmental outcomes, survival, and quality of life. This will be the major focus of future research through larger collaboratives.

OBJECTIVE To describe the outcome of young adults treated for hypoxemic respiratory failure with extracorporeal membrane oxygenation as neonates. DESIGN The study was designed as a multisite, cross sectional survey. SETTING The survey was completed electronically or on paper by subjects and stored in a secure data base. SUBJECTS Subjects were surviving neonatal extracorporeal membrane oxygenation patients from eight institutions who were18 years old or older. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS A questionnaire modified from the 2011 Behavioral Risk Factor Surveillance System and the 2011 National Health Interview Survey with additional unique questions was completed by subjects. Results were compared to age-matched national Behavioral Risk Factor Surveillance System and National Health Interview Survey data. One hundred and forty-six subjects participated (8.9% of eligible candidates). The age at questionnaire submission was 23.7 ± 2.89 years. Subjects differed statistically from national cohorts by being more satisfied with life (93% vs 84.2%); more educated (some college or degree; 80.1% vs 57.7%); more insured for healthcare (89.7% vs 72.3%); less frequent users of healthcare in the last 12 months (47.3% vs 58.2%); more limited because of physical, mental, and developmental problems (19.9% vs 10.9%); and having more medical complications. Furthermore, learning problems occurred in 29.5% of the study cohort. The congenital diaphragmatic hernia group was generally less healthy and less well educated, but equally satisfied with life. Perinatal variables contributed little to outcome prediction. CONCLUSIONS Most young adult survivors in this study cohort treated with extracorporeal membrane oxygenation as neonates are satisfied with their lives, working and/or in college, in good health and having families. These successes are occurring despite obstacles involving health issues such as asthma, attention deficit disorder, learning difficulties, and vision and hearing problems; this is especially evident in the congenital diaphragmatic hernia cohort. Selection bias inherent in such a long-term study may limit generalizability, and it is imperative to note that our sample may not be representative of the whole.

BACKGROUND: Congenital diaphragmatic hernia remains a complex disease with significant morbidity and mortality. Hypercarbia is a common derangement in this population, which often requires escalating ventilator support. By decreasing airway turbulence and enhancing CO2 removal, inhaled helium-oxygen mixture (heliox) has the potential to improve ventilation and thereby decrease ventilator support and its associated lung injury. METHODS: Retrospective cohort review of all neonates with congenital diaphragmatic hernia treated at Rady Children9s Hospital San Diego during 2011–2015. Clinical characteristics were compared between the infants who were treated with heliox and those who did not receive this intervention. To analyze the effect of heliox in the subgroup that received this treatment, ventilator settings and arterial blood gas values were compared before and after starting heliox by using paired t tests. RESULTS: During the study period, 45 neonates with congenital diaphragmatic hernia were admitted to our neonatal ICU, 28 received heliox, and 27 were analyzed. During heliox treatment, PaCO2 levels decreased from 68 to 49 mm Hg (P CONCLUSIONS: The addition of heliox to the standard practice of permissive hypercapnia facilitated improvement in gas exchange, which allowed a decrease in ventilator settings and oxygen exposure, both of which are known to contribute to lung injury in this population. A prospective trial is needed to more clearly define the acute and long-term impacts of this treatment.

BACKGROUND Inhaled nitric oxide (iNO) is a well-established treatment for neonatal hypoxic respiratory failure (HRF). However, iNO therapy initiation criteria have not been standardized. This report describes a follow-up survey administered to neonatologists who had completed an Awareness, Trial, and Usage Survey. The objectives were to compare stated target oxygenation index (OI) versus actual OI at which iNO is initiated in respondents' patients and identify factors associated with iNO initiation at other levels. METHODS Neonatologists provided iNO-treated HRF patient data. Target and actual OI at initiation were determined. Patient groups were stratified by actual OI deviation from target [ 20; not measured]. Reasons for above-target OI were determined. RESULTS Of 83 invited neonatologists, 26 (31%) participated, providing data for 128 patients; 85/128 patients (66%) had OI measured at initiation with neonatologist-stated mean target OI 18.8±5.8. Actual mean OI was 26.2±10.3. iNO was initiated ≤ target in 30/85 patients (35%); most [55/85 (65%)] had iNO initiated when OI was above target. Patients aged ≤1 day and those receiving a fraction of inspired oxygen (FiO2) of 1.0 for more than 1 h had highest OIs at initiation. CONCLUSIONS Among surveyed neonatologists who treat infants with HRF with pulmonary hypertension (PH), there is a disparity between stated target versus actual OI for iNO initiation, particularly among infants

The bleeding time is a measurement of platelet and capillary interaction following a small standardized cutaneous incision. In adults, anemia causes a prolongation of the bleeding time, and we hypothesized that the same would be true in very low birth weight (VLBW) infants during their first week of life.Template bleeding times, using the Surgicutt Newborn device, were performed on 20 VLBW weight infantsor=7 days old, before, and again following a clinically ordered erythrocyte transfusion.Neonates who had pretransfusion hematocritsor=0.28 l/l had longer bleeding times, which fell 164+/-25 seconds (mean+/-SD; p0.0001) following transfusion. Patients with pretransfusion hematocrits0.28 l/l had no significant reduction in bleeding time following transfusion.In VLBW infants, during their first week of life (the time when their risk of intraventricular hemorrhage is greatest), a low hematocrit is associated with a significant prolongation in the bleeding time.

Objective: Over the last decade, several new therapies, including high-frequency oscillatory ventilation (HFOV), exogenous surfactant therapy, and inhaled nitric oxide (iNO), have become available for the treatment of neonatal hypoxemic respiratory failure. The purpose of this retrospective study was to ascertain to what extent these modalities have impacted the use of neonatal extracorporeal membrane oxygenation (ECMO) at our institution. Methods. Patients from 2 time periods were evaluated: May 1, 1993 to November 1, 1994 (group 1) and May 1, 1996 to November 1, 1997 (group 2). During the first time period (group 1), HFOV was not consistently used; beractant (Survanta) use for meconium aspiration syndrome (MAS), persistent pulmonary hypertension of the newborn (PPHN), and pneumonia was under investigation; and iNO was not yet available. During the second time period (group 2), HFOV and beractant treatment were considered to be standard therapies, and iNO was available to patients with oxygenation index (OI) ≥25 × 2 at least 30 minutes apart, or on compassionate use basis. Patients were included in the data collection if they met the following entry criteria: 1) OI >15 × 1 within the first 72 hours of admission; 2) EGA ≥35 weeks; 3) diagnosis of MAS, PPHN or sepsis/pneumonia; 4) Results. Of the 49 patient in group 1, 21 (42.8%) required ECMO therapy. Of these ECMO patients, 14 (66.6%) had received diagnoses of MAS or PPHN. Only 3 of the patients that went on to ECMO received beractant before the initiation of bypass (14.3%). All ECMO patients in group 1 would have met criteria for iNO had it been available. Of all patients in group 1, 18 (36.7%) were treated with HFOV, and 13 (26.5%) received beractant. Of the 47 patients in group 2, only 13 (27.7%) required ECMO therapy (compared with group 1). Of these ECMO patients, only 5 (38.5%) had diagnoses of MAS or PPHN, with the majority of patients (61.5%) requiring ECMO for sepsis/pneumonia, with significant cardiovascular compromise. Only 5 of these ECMO patients, all outborn, did not receive iNO before cannulation because of the severity of their clinical status on admission. Of all patients in group 2, 41 (87.2%) were treated with HFOV (compared with group 1), 42 (89.3%) received beractant (compared with group 1), and 18 (44.7%) received iNO. Conclusions. The results indicate that ECMO was used less frequently when HFOV, beractant and iNO was more commonly used. The differences in treatment modalities used and subsequent use of ECMO were statistically significant. We speculate that, in this patient population, the diagnostic composition of neonatal ECMO patients has changed over time.

It is often postulated that the cytoprotective nature of heme oxygenase (HO-1) explains the inducible nature of this enzyme. However, the mechanisms by which protection occurs are not verified by systematic evaluation of the physiological effects of HO. To explain how induction of HO-1 results in protection against oxygen toxicity, hamster fibroblasts (HA-1) were stably transfected with a tetracycline response plasmid containing the full-length rat HO-1 cDNA construct to allow for regulation of gene expression by varying concentrations of doxycycline (Dox). Transfected cells were exposed to hyperoxia (95% O(2)/5% CO2) for 24 h and several markers of oxidative injury were measured. With varying concentrations of Dox, HO activity was regulated between 3- and 17-fold. Despite cytoprotection with low (less than fivefold) HO activity, high levels of HO-1 expression (greater than 15-fold) were associated with significant oxygen cytotoxicity. Levels of non-heme reactive iron correlated with cellular injury in hyperoxia whereas lower levels of heme were associated with cytoprotection. Cellular levels of cyclic GMP and bilirubin were not significantly altered by modification of HO activity, precluding a substantial role for activation of guanylate cyclase by carbon monoxide or for accumulation of bile pigments in the physiological consequences of HO-1 overexpression. Inhibition of HO activity or chelation of cellular iron prior to hyperoxic exposure decreased reactive iron levels in the samples and significantly reduced oxygen toxicity. We conclude that there is a beneficial threshold of HO-1 overexpression related to the accumulation of reactive iron released in the degradation of heme. Therefore, despite the ready induction of HO-1 in oxidant stress, accumulation of reactive iron formed makes it unlikely that exaggerated expression of HO-1 is a cytoprotective response.

Rat fetal lung cells (RFL-6) were transiently transfected with a full-length rat heme oxygenase (HO)-1 cDNA construct and then exposed to hyperoxia (95% O2-5% CO2) for 48 h. Total HO activity and HO-1 protein were measured as well as cell viability, lactate dehydrogenase (LDH) release, protein oxidation, lipid peroxidation, and total glutathione to measure oxidative injury. HO-1 overexpression resulted in increased total HO activity (2-fold), increased HO-1 protein (1.5-fold), and increased cell proliferation. Immunohistochemistry revealed perinuclear HO-1 localization, followed by migration to the nucleus by day 3. Decreased cell death, protein oxidation, and lipid peroxidation but increased LDH release and glutathione depletion were seen with HO-1 overexpression. Reactive iron content could not explain the apparent loss of cell membrane integrity. With the addition of tin mesoporphyrin, total HO activity was decreased and all changes in injury parameters were normalized to control values. We conclude that moderate overexpression of HO-1 is protective against oxidative injury, but we speculate that there is a beneficial threshold of HO-1 expression.

Heme oxygenase (HO) is the rate limiting enzyme in bilirubin production. The HO-1 isoform is inducible by a variety of oxidant stresses including hyperoxia(1). In its reaction, heme, a prooxidant is degraded, bilirubin, an antioxidant is formed(2). Thus, the overall effect of HO may be to protect against oxidative stress. Previous results from rat fibroblasts transfected with an expression vector containing the rat HO-1 cDNA have led us to speculate that there may be a beneficial threshold of HO-1 overexpression. To further investigate this hypothesis, we have established a variable overexpression model of HO-1 using the Tet-Off™ Gene Expression System (Clontech) which is based on the tetracycline resistance system found in E. coli(3). In this system, gene expression is controlled by the interaction of a tet-responsive transcriptional activator protein and a tet-responsive element where gene expression is tightly regulated by varying concentrations of either tetracycline or doxycycline (Dox) in a dose dependent manner. After insertion of the full length rat HO-1 cDNA into the pBI-L response plasmid, two consecutive stable transfections were performed and >60 stable colonies were screened in order to find a cell line allowing for regulated variable HO-1 overexpression. This cell line was grown in 75cm flasks to >80% confluence. To verify HO-1 overexpression, total HO activity was measured by gas chromatography and HO-1 protein was assessed by Western analysis. By varying the concentration of Dox between 0 and 10ng/ml, we were able to regulate HO-1 expression between 1.5 and 20 fold. Once confluent, cell lines expressing a range of HO-1 protein were exposed to hyperoxia (95% O2/5% CO2) for 72 h and non-specific indicators of cell injury were measured by Trypan blue exclusion and LDH release. Lipid peroxidation, protein oxidation, and total glutathione were also evaluated as specific markers of oxygen toxicity. Lower HO-1 overexpression was associated with increased protection against oxygen damage; however, higher expression was associated with increased markers of cell injury. In this model, we conclude that there is a beneficial threshold of HO-1 overexpression beyond which detrimental effects become apparent. We suggest that measures to enhance protection against oxygen toxicity by HO-1 overexpression be undertaken with a thorough understanding of the potential dual nature of HO-1.

OVEREXPRESSION OF HEME OXYGENASE BY CALCIUM PHOSPHATE MEDIATED TRANSFECTION IN CULTURED FETAL LUNG CELLS † 1470