Use of Phenobarbital to Treat Neonatal Abstinence Syndrome From Exposure to Single vs. Multiple Substances.

Drug use in pregnancy is a major public health issue. Intrauterine exposure to opioids alone or in addition to other substances may lead to neonatal abstinence syndrome (NAS). Little consensus exists on optimal therapy, especially for those exposed to multiple drugs. We aim to determine whether the use of opioids alone vs. in combination with phenobarbital will affect short-term neonatal outcomes. This retrospective review of infants admitted to the neonatal intensive care unit (NICU) included newborns ≥35 weeks of gestation exposed to opioids, or multiple substances including opioids, in utero. Treatment with opioids alone, and addition of phenobarbital as initial therapy vs. rescue, was evaluated. Out of 182 newborns, 54 (30%) were exposed to methadone alone vs. 128 (70%) to multiple drugs. Length of stay (LOS) in the hospital was not significantly affected (p = 0.684) by single vs. multiple drug exposure in utero. Treatment of NAS with opioid alone resulted in significantly shorter LOS (27 days), as compared to those treated with opioid and phenobarbital (45 days, p < 0.001). LOS was further prolonged in those treated with phenobarbital as a "rescue" medication in addition to an opioid (49 days, p < 0.0001). There was a significant increase in LOS and duration of opioid treatment for all infants treated with phenobarbital, both in those exposed to opioids alone, and to multiple substances in utero.

Nurses' Finnegan Scoring of Newborns with Neonatal Abstinence Syndrome Not Affected by Time or Day of the Week.

OBJECTIVE: Newborns exposed to drugs in utero are at risk of developing neonatal abstinence syndrome (NAS), characterized by behavioral changes and physiologic instability. Finnegan scoring tool quantifies severity of symptoms and guides treatment. This article evaluates whether time of day and the number of shift hours affects modified Finnegan scores, and the subjective component of these scores. STUDY DESIGN: Institutional review board-approved, retrospective chart review of newborns admitted to neonatal intensive care or transitional nursery from 2011 to 2014. INCLUSION CRITERIA: > 35 weeks' gestation, known maternal substance use, positive maternal or newborn urine, or meconium drug screen, NAS treatment. RESULTS: A total of 101 charts were evaluated. Mean treatment duration was 31.8 days (standard deviation ±18.3). There was no significant relationship between observer shift hour and high scores (> 8) (p = 0.83). Highest scores occurred in the afternoon, decreased at night (p = 0.03), and throughout admission (p < 0.0001). Weekend and weekday scores were similar (p = 0.4). The objective component of the scores remained similar throughout the day (p = 0.91) and week (p = 0.52). CONCLUSION: Finnegan scores given by nurses were not influenced by shift hour. Time of day did not influence overall high scores or the proportion of objective to total Finnegan score. Inter-rater reliability was maintained regardless of time of day or day of the week.

Unbound free fatty acids from preterm infants treated with intralipid decouples unbound from total bilirubin potentially making phototherapy ineffective.

Extremely low birth weight (ELBW; <1,000 g) infants have poor outcomes, often compromised by bilirubin neurotoxicity. We measured unbound bilirubin (Bf) and unbound free fatty acid (FFAu) levels in 5 ELBW infants in a trial examining the effects of pharmacologic ductal closure on infants treated with Intralipid infusion (3 g/kg/day). The levels for all infants (mean ± SD) were: total serum bilirubin (TSB) 4.6 ± 1.7 mg/dl, FFAu 376 ± 496 nM, and Bf 42 ± 30 nM. Of the 3 infants who died, 2 had TSB <5.9 mg/dl but FFAu >580 nM and Bf >75 nM. Multiple regression revealed a major effect on Bf levels due to FFAu, indicating that Intralipid elevated levels of FFAu and Bf. Indomethacin or ibuprofen reduced Bf levels, most likely by reducing FFAu levels through lipase inhibition. Because displacement of Bf by FFAu decouples Bf from TSB, phototherapy may not reduce the risk of bilirubin or FFAu toxicity in Intralipid-treated ELBW infants.

Detection of pepsin in mouth swab: correlation with clinical gastroesophageal reflux in preterm infants.

OBJECTIVE: To study the relationship between pepsinogen/pepsin in a mouth swab and clinical gastroesophageal reflux (GER) in preterm infants. METHODS: Preterm infants (birth weight ≤ 2000 g) on full enteral feeds were enrolled. Mouth swabs from cheek and below the tongue were collected one, two and three hours after feeding. An enzymatic assay with substrate fluorescein isothiocyanate-casein was used to detect pepsin A and C activities with further confirmation by western blot. Blinded investigators reviewed the infant's medical record to clinically diagnose GER. RESULTS: A total of 101 premature infants were enrolled. Pepsinogen/pepsin was detected in 45/101 (44.5%) infants in at least one sample. A clinical diagnosis of GER was made in 36/101 (35.6%) infants. Mouth swabs were positive in 26/36 (72%) infants with clinical GER and only 19/65 (29%) infants without GER (p < 0.001). Similarly, the levels of pepsinogen/pepsin A and C were higher in the mouth swabs of infants with clinical GER. CONCLUSION: The detection of pepsinogen/pepsin in a mouth swab correlates with clinical GER in premature infants.

IFN-γ and IP-10 in tracheal aspirates from premature infants: relationship with bronchopulmonary dysplasia.

BACKGROUND: Interferon-gamma (IFN-γ) and interferon-inducible protein of 10 kDa (IP-10) are potent inflammatory mediators and contribute to acute lung injury in adults. Recently, a potential role for IFN-γ and IP-10 in the pathogenesis of bronchopulmonary dysplasia (BPD) has been reported in animal models. OBJECTIVE: To study the association between IFN-γ and IP-10 in tracheal aspirate (TA) and the development of BPD in premature infants. DESIGN/METHODS: TA samples collected within 48 hr after birth from 79 mechanically ventilated premature neonates [gestational age (GA) <30 weeks (w), birth weight (BW) <1,250 g (g)] were analyzed. IFN-γ was measured in a subgroup of 38 infants by using a biochip multi-analyte immunoassay. The level of IP-10 was determined using a commercially available ELISA kit. Total protein in TA was measured by Bradford assay to correct for sampling related dilution. BPD was defined as the need of supplemental oxygen at 36 weeks postmenstrual age (PMA). RESULTS: Twenty infants (GA 26.4 ± 1.9w, BW 860 ± 201 g) survived without BPD at 36 weeks PMA and 59 infants (GA 25.5 ± 1.5w, BW 751 ± 163 g) died before 36 weeks PMA or developed BPD. The mean IFN-γ level was higher in infants who died or developed BPD (9.7 ± 2.8 vs. 3.1 ± 1.1 pg/ml, P = 0.03). Similarly, the mean IP-10 level was higher in infants who died or developed BPD (63.4 ± 17.5 pg/ml) compared to those who survived without BPD (18.5 ± 7.5 pg/ml, P = 0.02). CONCLUSIONS: Higher IFN-γ and IP-10 levels in TA samples are associated with the development of BPD or death in premature infants.

Impact of histological chorioamnionitis on tracheal aspirate cytokines in premature infants.

BACKGROUND: Histological chorioamnionitis (CHORIO) may increase inflammatory mediators in the lungs of preterm infants. OBJECTIVE: To study the impact of CHORIO on tracheal aspirate (TA) cytokines in ventilated infants. DESIGN/METHODS: TA samples collected within 48 hours after birth from 40 ventilated neonates (gestational age [GA] <30 weeks, body weight [BW] <1250 g) were analyzed. Levels of 12 cytokines (interleukin [IL]-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, epidermal growth factor [EGF], interferon-γ [IFN-γ], monocyte chemotactic protein-1 [MCP-1], tumor necrosis factor-α [TNF-α], vascular endothelial growth factor [VEGF]) were measured using a biochip multianalyte immunoassay (Randox Laboratories, Antrim, UK). Total protein was measured by the Bradford assay. CHORIO assessment was done by a blinded pathologist. RESULTS: Twenty-six infants (GA 26.6 ± 1.4 weeks, BW 852 ± 162 g) had no CHORIO and 14 (GA 25.1 ± 1.0 weeks, BW 776 ± 164 g) had CHORIO. IL-1α, IL-1ß, IL-8, and VEGF were significantly higher in TA of infants with CHORIO. After correction for dilution, IL-1α, IL-1ß, and IL-8 were significantly elevated. Increased TA total cell count correlated with CHORIO, VEGF, EGF, MCP-1, IL-8, and IL-6 TA levels (all p ≤ 0.02). Ventilator, oxygen supplementation, and hospital days correlated with TA IFN-γ levels (all p ≤ 0.01). CONCLUSION: CHORIO is associated with increased specific proinflammatory mediators in TA samples of preterm infants.

Sirtuin1 in tracheal aspirate leukocytes: possible role in the development of bronchopulmonary dysplasia in premature infants.

OBJECTIVE: To study the association between Sirtuin1 (Sirt1), a class III histone deacetylator, in tracheal aspirate (TA) leukocytes and the development of bronchopulmonary dysplasia (BPD) in premature infants and modulation of Sirt1 with dexamethasone (Dex) use. DESIGN/METHODS: Serial TA samples were collected on days 1, 3, 5 and 7 from ventilated premature neonates. Sirt1 was localized by immunocytochemistry and quantified on a scale of 0-4 by blinded observers. BPD was defined as the need of supplemental oxygen at 36 weeks postmenstrual age (PMA). RESULTS: A total of 130 TA samples were collected from 51 infants (mean ± SD: GA 25.5 ± 1.4 w, BW 762 ± 174 g). Eleven infants survived without BPD and 40 infants died before 36 weeks PMA or developed BPD. Sirt1 was localized in the cytoplasm and nuclei of mononuclear (MONO) as well as polymorphonuclear cells. Sirt1 was significantly more localized in the nuclei of MONO cells in infants without BPD compared to infants who developed BPD or died before 36 weeks PMA. Twenty six infants received Dex. There was no significant change in Sirt1 localization with steroid therapy. CONCLUSIONS: Lower Sirt1 in TA leukocytes is associated with the development of BPD or death in premature infants. Dex use had no effect on Sirt1.

Effects of prenatal exposure to cigarette smoke on use of xanthine and pneumogram evaluation at discharge in premature infants.

OBJECTIVE: Prenatal exposure to cigarette smoke is associated with an increased risk of sudden infant death syndrome and possible rate increase of obstructive apnea in full-term infants but unknown in premature infants. Therefore, the objective was to study the effect of prenatal exposure to cigarette smoke on the use of methylxanthines and discharge pneumograms in premature infants. METHODS: Preterm infants [gestational age (GA) ≤34 weeks] born between January 1997 and September 2007 were studied. A four-channel pneumogram was performed at discharge. Relevant clinical data were collected from the infant's records. Infants with prenatal exposure to cigarette smoke were compared with infants not exposed (controls). RESULTS: A total of 1656 infants were studied: 263 infants {birth weight (BW) (mean ± SD) 1682 ± 566 g, GA 31.0 ± 2.8 weeks} exposed to prenatal cigarette smoke and 1393 infants (BW 1638 ± 575 g, GA 31.1 ± 2.7 weeks) not exposed. Baseline patient characteristics were similar between the two groups. When comparing the smoking versus control groups, there was no significant difference in the infants for the following: xanthine therapy and abnormal pneumograms; presence of central, obstructed or mixed apnea and home discharge on monitors, oxygen and xanthines. CONCLUSIONS: Prenatal exposure to cigarette smoke was not associated with increased use of xanthines or abnormal pneumogram in premature infants.

Utility of performing routine head ultrasounds in preterm infants with gestational age 30-34 weeks.

BACKGROUND: The American Academy of Neurology and Child Neurology Society recommend performing routine screening head ultrasounds (HUS) on preterm infants of less than 30 weeks gestation. OBJECTIVE: To study the incidence of intraventricular hemorrhage (IVH) and evaluate the need for screening HUS in preterm infants with gestational age (GA) of 30-34 weeks. DESIGN/METHODS: Preterm infants (GA; 30-34 weeks) admitted to the neonatal intensive care unit (NICU) between January 1997 and September 2007 were included in this study. Grades of IVH were defined as per the Papile classification. RESULTS: Screening HUS were performed on 463 infants with GA of 30-34 weeks. Twenty-seven (5.8%) infants had abnormal cranial ultrasound (US) (IVH or periventricular leucomalacia [PVL]). The incidence of IVH ranged from 3.3% to 6.3% at various GA. Seven (1.5%) infants had severe abnormalities on HUS (grades III/IV or PVL). CONCLUSIONS: A significant number of infants born between 30 and 34 weeks of gestation have abnormalities on screening cranial US. Since not all infants born at 30-34 weeks of gestation received a HUS, the incidence of HUS abnormalities might have been overestimated due to a possible 'selection bias'. Additional studies are needed to examine the adverse neurodevelopmental outcomes in this group of preterm infants with mild abnormalities (IVH grades I or II) on cranial US before recommending routine screenings for IVH.

The effect of comprehensive infection control measures on the rate of late-onset bloodstream infections in very low-birth-weight infants.

Late-onset bloodstream infection (LOBI) is a significant problem in very low-birth-weight (VLBW) infants and can lead to increased mortality and morbidity. The incidence of LOBI in VLBW infants in our unit was >35% before 2004, much higher than 20% reported in other studies. A comprehensive infection control measure was introduced in our unit in 2005. Here we report the effects of comprehensive infection control measures on the rate of LOBI in VLBW infants. Infants in the preintervention group (born 2001 to 2004) were compared with the intervention group (born 2005 to 2008) for baseline demographics, risk factors for infection, and the rate of LOBI. LOBI was defined as a positive blood and/or cerebrospinal fluid culture after 3 days of life. Three hundred thirty-four VLBW infants were admitted to our unit during the preintervention period and 303 during the intervention period. There was no significant difference in baseline demographics and risk factors for LOBI between the two groups. The incidence of LOBI was significantly reduced from 38% before intervention to 23% after intervention ( P < 0.001). Comprehensive infection control measures significantly reduced the rate of LOBI in VLBW infants.

Twice-weekly fluconazole prophylaxis in premature infants: association with cholestasis.

BACKGROUND: Fluconazole prophylaxis is effective in preventing invasive candidiasis in extremely low-birthweight (ELBW) infants. The authors previously reported an increased incidence of cholestasis with fluconazole prophylaxis in ELBW infants, which led to fluconazole prophylaxis being changed to a less frequent dosing (LFD) schedule of twice a week at their institution. The purpose of the present study was therefore to evaluate the effectiveness and safety of LFD fluconazole prophylaxis in preventing invasive candidiasis in ELBW infants. METHODS: ELBW infants who received the LFD regimen of fluconazole (twice a week for up to 6 weeks) were compared with infants who received the frequent dosing (FD) schedule (every 72 h for first 2 weeks, every 48 h for next 2 weeks and every 24 h for the final 2 weeks). The two groups were compared for baseline demographics, risk factors for candidiasis, the rate of invasive fungal infection and the incidence and severity of cholestasis. RESULTS: There was no significant difference in the incidence of invasive candidiasis in infants who received the LFD (2/104, 2%) compared to FD (0/140, 0%; P= 0.4) fluconazole prophylaxis. The severity of cholestasis was lower and a trend towards decreased incidence of cholestasis was observed on the LFD schedule. CONCLUSION: The LFD regimen of fluconazole prophylaxis is effective in preventing invasive fungal infection in ELBW infants. The severity of cholestasis was decreased with the LFD schedule.

Intractable neonatal seizures: an unusual presentation of congenital hypothyroidism.

Congenital hypothyroidism is the most common treatable cause of mental retardation. We report an unusual case of congenital hypothyroidism presenting as intractable seizures in an infant delivered to a mother known to have autoimmune hypothyroidism and who was noncompliant with therapy. To our knowledge, this rare presentation of congenital hypothyroidism has not been reported previously.

Effect of antenatal corticosteroids on survival for neonates born at 23 weeks of gestation.

OBJECTIVE: To estimate if exposure to antenatal corticosteroids was associated with decreased rate of death in neonates born at 23 weeks of gestation. METHODS: This is a retrospective cohort study performed at three tertiary centers of neonates born at 23 weeks of gestation between 1998 and 2007. Stillbirths, voluntary terminations, or parental elected nonresuscitations were excluded. Clinical and demographic variables were examined to determine possible confounding variables. A multivariable logistic regression model was used to assess the effect of steroids on the odds of death after adjustment for these confounders. RESULTS: The sample included 181 neonates. Of the multiple variables examined (institution, race, diagnosis, illicit drug use, antibiotics, assisted reproduction, birth weight, gender, and route of delivery), only multiple gestations were significantly associated (P

Pepsin, a marker of gastric contents, is increased in tracheal aspirates from preterm infants who develop bronchopulmonary dysplasia.

OBJECTIVE: The objective of this study was to study the association between pepsin in tracheal aspirate samples and the development of bronchopulmonary dysplasia in preterm infants. METHODS: Serial tracheal aspirate samples were collected during the first 28 days from mechanically ventilated preterm neonates. Bronchopulmonary dysplasia was defined as the need for supplemental oxygen at 36 weeks' postmenstrual age. An enzymatic assay with a fluorescent substrate was used to detect pepsin. Total protein was measured by the Bradford assay to correct for the dilution during lavage. Immunohistochemistry using antibody against human pepsinogen was performed in 10 lung tissue samples from preterm infants. RESULTS: A total of 256 tracheal aspirate samples were collected from 59 preterm neonates. Pepsin was detected in 234 (91.4%) of 256 of the tracheal aspirate samples. Twelve infants had no bronchopulmonary dysplasia, 31 infants developed bronchopulmonary dysplasia, and 16 infants died before 36 weeks' postmenstrual age. The mean pepsin concentration was significantly lower in infants with no bronchopulmonary dysplasia compared with those who developed bronchopulmonary dysplasia or developed bronchopulmonary dysplasia/died before 36 weeks' postmenstrual age. Moreover, the mean pepsin level was significantly higher in infants with severe bronchopulmonary dysplasia compared with moderate bronchopulmonary dysplasia. The mean pepsin level in tracheal aspirate samples from the first 7 days was also lower in infants with no bronchopulmonary dysplasia compared with those who developed bronchopulmonary dysplasia or developed bronchopulmonary dysplasia/died before 36 weeks' postmenstrual age. Pepsinogen was not localized in the lung tissues by immunohistochemistry. CONCLUSION: The concentration of pepsin was increased in the tracheal aspirate of preterm infants who developed bronchopulmonary dysplasia or died before 36 weeks' postmenstrual age. Recovery of pepsin in tracheal aspirate samples is secondary to gastric aspiration, not by hematogenous spread or local synthesis in the lungs. Chronic aspiration of gastric contents may contribute in the pathogenesis of bronchopulmonary dysplasia.

Azithromycin suppresses activation of nuclear factor-kappa B and synthesis of pro-inflammatory cytokines in tracheal aspirate cells from premature infants.

Nuclear factor-kappaB (NF-kappaB) plays a central role in regulating key proinflammatory mediators. The activation of NF-kappaB is increased in tracheal aspirate (TA) cells from premature infants developing bronchopulmonary dysplasia (BPD). We studied the effect of azithromycin (AZM) on the suppression of NF-kappaB activation and the synthesis of pro-inflammatory cytokines IL-6 and IL-8 by TA cells obtained from premature infants. Tracheal aspirate cells were stimulated with tumor necrosis factor-alpha (TNF-alpha) and incubated with AZM. The nuclear NF-kappaB-DNA binding activity, the levels of inhibitory kappaB-alpha (IkappaB-alpha) in the cytoplasmic fraction and IL-6 and IL-8 release in the cell culture media were measured. Stimulation of TA cells by TNF-alpha increased the activation of NF-kappaB, which was suppressed by the addition of AZM. Increased activation of NF-kappaB was also associated with increased levels of pro-inflammatory cytokines (IL-6 and IL-8). AZM significantly reduced the IL-6 and IL-8 production to the levels similar to control. TNF-alpha stimulation also increased the degradation of IkappaB-alpha, which was restored with the addition of AZM. Our data suggest that AZM therapy may be an effective alternative to steroids in reducing lung inflammation and prevention of BPD in ventilated premature infants.

Synchronized nasal intermittent positive pressure ventilation (SNIPPV) decreases work of breathing (WOB) in premature infants with respiratory distress syndrome (RDS) compared to nasal continuous positive airway pressure (NCPAP).

Synchronized nasal intermittent positive pressure ventilation (SNIPPV) is non-invasive respiratory support that delivers ventilator breaths via the nasal prongs. We hypothesized that SNIPPV is more effective than nasal continuous positive airway pressure (NCPAP) in premature neonates due to decreased work of breathing (WOB). Fifteen infants (BW: 1,367 +/- 325 g, GA: 29.5 +/- 2.4 weeks) were studied on (a) NCPAP at 5 cmH(2)O (NCPAP5) and (b) three increasing SNIPPV settings achieved by NCPAP5 with additional delivered peak inspiratory pressures (PIP) of 10, 12, and 14 cmH(2)O. Tidal volumes and transpulmonary pressures were estimated via calibrated respiratory inductance plethysmography (RIP) and esophageal pressures, respectively. Inspiratory (WOB(insp)), resistive (RWOB), and elastic (WOB(E)) components of WOB were calculated using standard methods. Compared to NCPAP5, (a) WOB(insp) and RWOB were significantly lower with SNIPPV12, and were similarly lower with SNIPPV14 and (b) WOB(E) was significantly lower only with SNIPPV14. WOB components did not differ significantly for the three SNIPPV settings. Tidal volume, respiratory rate (RR), minute ventilation, compliance, and phase angle were similar for all four measurements. In conclusion, compared to NCPAP, the addition of ventilator-delivered PIP during SNIPPV decreases WOB in premature infants.

Dexamethasone suppresses expression of Nuclear Factor-kappaB in the cells of tracheobronchial lavage fluid in premature neonates with respiratory distress.

Nuclear Factor-kappaB (NF-kappaB) plays a central role in regulating the key mediators of inflammation involved in acute lung injury. The anti-inflammatory effect of steroids by suppressing pro-inflammatory cytokines may be mediated by inhibition of transcription factor NF-kappaB. The objective of this study was to determine the effect of glucocorticoid therapy on the expression of NF-kappaB in the cells of tracheobronchial lavage fluid (TBLF) in premature neonates with respiratory distress. Nineteen premature neonates requiring mechanical ventilation and receiving glucocorticoids were enrolled. Their gestational age (mean +/- SD) was 25.0 +/- 1.2 wk, birth weight 714 +/- 105 g and age of starting dexamethasone was 33 +/- 15 d. Tracheobronchial lavage fluid was collected before and 48-72 h after starting dexamethasone. NF-kappaB expression was measured by immunocytochemistry using mouse MAb against the p65 subunit of NF-kappaB on cytospin slides. The percent of cells stained and the intensity staining index were significantly higher before starting dexamethasone compared with after steroid therapy. Localization of NF-kappaB was significantly decreased in the cytoplasm and nuclei of mononuclear cells after initiation of dexamethasone therapy. The concentration of IL-8 was also significantly lower after starting dexamethasone. In conclusion, dexamethasone suppressed the expression of NF-kappaB in the cytoplasm and nuclei of mononuclear cells and decreased levels of IL-8 in TBLF from premature neonates with respiratory distress. The anti-inflammatory effects of corticosteroids may be mediated through NF-kappaB.