Effectiveness of Dual Medication Therapy (Oral Acetaminophen and Oral Ibuprofen) for the Management of Patent Ductus Arteriosus in Extremely Premature Infants: A Feasibility Trial.

OBJECTIVE: The study aimed to evaluate the efficacy of dual medication therapy (DMT) with oral acetaminophen and oral ibuprofen for the closure of a hemodynamically significant patent ductus arteriosus (hsPDA). STUDY DESIGN: In a prospective case-control cohort study (July 2017-May 2019), infants <29 weeks' gestational age and birth weight <1,000 g at ≤14 postnatal days with hsPDA and ratio of the smallest ductal diameter to the ostium of the left pulmonary artery diameter >0.5 were eligible. Infants received 10 mg/kg oral ibuprofen followed by two additional doses of 5 mg/kg at 24 and 48 hours after the initial ibuprofen dose and concomitant treatment with 15 mg/kg oral acetaminophen every 6 hours for 3 days (12 doses). Success of PDA treatment was defined as a small or absent PDA as ascertained by echocardiographic measurements. The p-values of comparisons were adjusted for multiple comparisons to preserve an error rate of 5%. RESULTS: Overall, 20 infants received oral DMT and 11 infants received intravenous single medication therapy (SMT) with ibuprofen. The rates of successful PDA treatment following the first treatment in DMT and SMT groups were not statistically different (11/20 [55%] vs. 4/11 [36%], p = 0.46). However, DMT significantly decreased PDA size (mean difference = 0.54 mm, 95% confidence interval [CI]: 0.21-0.96, adjusted p-value = 0.0002) and PDA/LPA ratio (mean difference = 0.27, 95% CI: 0.10-0.47, adjusted p-value = 0.0004). We observed no evidence of hematologic, hepatic, or renal impairment. CONCLUSION: DMT achieved a greater degree of PDA closure than SMT and did not result in abnormalities in hepatic and renal profile. KEY POINTS: · No consensus on optimal medication for PDA treatment is available.. · Dual oral medication therapy (ibuprofen and acetaminophen) could be an effective alternative treatment for PDA.. · Dual oral medication therapy (ibuprofen and acetaminophen) may have a better safety profile than currently approved medications such as intravenous indomethacin and intravenous ibuprofen..

Early versus Delayed Human Milk Fortification in Very Low Birth Weight Infants-A Randomized Controlled Trial.

OBJECTIVE: To compare the effect of initiating human milk fortification at 2 different feeding volumes on feeding intolerance and the time to reach full feeding volume. STUDY DESIGN: Very low birth weight infants (n = 100) were prospectively randomized to early fortification (EF) (beginning at a feeding volume of 20 mL/kg/d) or delayed fortification (at a feeding volume of 100 mL/kg/d). We employed a standardized feeding protocol and parenteral nutrition guidelines for the nutritional management of all study infants. RESULTS: The median days to reach full feeding volumes were equivalent in the 2 groups (20 vs 20, P = .45). No significant difference was observed in the total number of episodes of feeding intolerance (58 vs 57). Two cases of necrotizing enterocolitis (Bell stage ≥2) and deaths occurred in each group. Median daily protein intake (g/kg/d) was higher in EF group in week 1 (3.3 [3.2, 3.5] vs 3.1 [2.9, 3.3], P < .001), week 2 (3.6 [3.5, 3.8] vs 3.2 [2.9, 3.4], P < .001), and week 3 (3.7 [3.4, 3.9] vs 3.5 [2.8, 3.8], P = .006). Cumulative protein intake (g/kg) in the first 4 weeks of life was higher in EF group (98.6 [93.8, 104] vs 89.6 [84.2, 96.4], P < .001). CONCLUSIONS: Very early human milk fortification may improve early protein intake in very low birth weight infants without increasing frequencies of adverse events. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01988792.

Preterm Infants Can Mount Appropriate C-Reactive Protein Responses to Early Onset Sepsis.

OBJECTIVE: This study aims to evaluate whether infants born at ≤ 32 weeks' gestational age (GA) can mount C-reactive protein (CRP) responses during early onset bacterial sepsis that are comparable to infants born at > 32 weeks' GA. METHODS: Retrospectively (2003-2012) infants with a positive bacterial culture during the first 72 hours of life were identified and grouped into two categories based on their GA: ≤ 32 weeks (group A) and > 32 weeks (group B). RESULTS: Group A included 25 and group B included 122 infants. Both groups responded similarly to sepsis with an increase in CRP (p = 0.59). Each group had a significant change in intragroup CRP levels over time (p < 0.0001). However, in both groups, the degree of this change was at the same rate over time (p = 0.74). CONCLUSION: CRP responses to bacterial sepsis during the first 72 hours of life in infants born at ≤ 32 weeks' GA are comparable to infants born at > 32 weeks' GA.

Pharmacokinetic and Pharmacodynamic Analysis of Acetaminophen and Ibuprofen Dual Therapy for Patent Ductus Arteriosus Closure in Preterm Neonates at Less Than 29 Weeks of Gestation.

Patent ductus arteriosus (PDA) is a blood vessel that critically supports fetal circulation. The ductus naturally closes within a few days after birth. However, it can stay open in premature neonates for an extended period of time, which is associated with increased mortality and various co-morbidities. Ibuprofen and indomethacin are currently the only 2 drugs approved for inducing PDA closure, but both have been associated with adverse renal and bleeding events. Clinical evidence suggests that combining acetaminophen (APAP) and ibuprofen treatments can decrease the need for surgical ligation. The objective of this study was to establish a disease-drug-trial model to characterize and predict PDA closure following single and combination drug therapy with ibuprofen and/or APAP in children at less than 29 weeks of gestation. The model was informed by a comprehensive literature review. The results of our analysis suggest that ibuprofen and APAP achieve therapeutic synergy. They further suggest that the younger the preterm neonates, the higher the treatment benefit. A 5-day oral dosing regimen consisting of ibuprofen (20 mg/kg Q24h on day 1, followed by 10 mg/kg Q24h on days 2-5) plus APAP (15 mg/kg Q6h) was deemed appropriate to achieve at least 90% PDA in all preterm neonates evaluated within 1 month of life. The model can now be used to design prospective pediatric trials to evaluate optimal drug combinations for PDA closure in preterm neonates and to refine optimal dosing regimens in cohorts of differing gestational age.

Prophylactic early low-dose hydrocortisone and survival without bronchopulmonary dysplasia among extremely preterm infants born at 22-27 weeks' gestation.

OBJECTIVE: To compare survival without BPD among extremely preterm infants (EPI) who received prophylactic early low-dose hydrocortisone (PEH) with those who did not (non-PEH). STUDY DESIGN: This single-center retrospective study compared risk-adjusted rates of survival without BPD, BPD, bowel perforation, and late-onset sepsis among infants (22-27 weeks' gestation at birth) who received PEH (n = 82) and who did not (n = 205). RESULTS: Infants in the PEH group were of lower gestational age, lower birthweight, and higher day-1 risk of death/BPD. After adjusting for risk of death/BPD, PEH-treated infants demonstrated increased survival without BPD (aOR 2.04, 95%CI 1.1-3.7), and lower BPD rates (aOR 0.46, 95%CI 0.25-0.87). Importantly, bowel perforation or sepsis rate were similar among both groups. CONCLUSION: After risk adjustment, PEH-treated infants demonstrated improved survival without BPD and did not increase rates of bowel perforation or sepsis. In our cohort of infants, PEH was safe and effective among the sickest preterm neonates.

A quality improvement initiative to reduce the time to initial maternal visit in the neonatal intensive care unit.

OBJECTIVE: We aimed to reduce the time interval between an infant's admission to the Neonatal Intensive Care Unit (NICU) and first maternal interaction. METHODS: We identified three key drivers: 1. Collaboration with Labor and Delivery, 2. Education of staff and parents, and 3. Improved documentation of maternal presence. We measured the time interval from NICU admission to the initial maternal presence. We followed length of stay as a balancing measure to assay whether use of remote televisitation impeded efficient parental teaching and delayed discharge. RESULTS: We reduced the time interval from an average of 19.7 h in February 2020 to 12.3 h in June 2021. We expanded an already existing televisitation program as a surrogate to in-person interaction during COVID-19 pandemic. Televisitation did not affect in-person parental presence or LOS. CONCLUSION: Our multidisciplinary efforts resulted in a significantly accelerated time to initial maternal presence and did not prolong LOS.

Dual medication therapy (acetaminophen and ibuprofen) for the management of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis.

OBJECTIVE: To examine the efficacy of dual medication therapy (intervention) (DMT: acetaminophen and ibuprofen) vs. single medication therapy (control) (SMT: ibuprofen) for medical management of PDA (outcomes) in preterm infants (population). STUDY DESIGN: We systematically searched multiple sources to identify randomized controlled trials (RCT) and non-randomized studies (NRS) that compared DMT to SMT for management of hemodynamically significant PDA. RESULTS: We identified two RCTs and four NRS. There were no differences in the rates of successful PDA closure following the first treatment course between DMT and SMT (RR = 1.23 [95% CI 0.89-1.70] for NRS and RR = 1.18 [95% CI 0.66-2.10] for RCTs), nor were there significant differences in secondary outcomes and adverse events including PDA ligation, bronchopulmonary dysplasia, and necrotizing enterocolitis etc. Markers of hepatic/renal function did not change significantly during treatment. CONCLUSION: We found no evidence for superiority of DMT over SMT in PDA management.

Respiratory support strategies in the management of severe, longstanding bronchopulmonary dysplasia.

Despite efforts to minimize ventilator-induced lung injury, some preterm infants require positive pressure support after 36 weeks' post-menstrual age. Infants with severe BPD typically experience progressive mismatch of ventilation and perfusion, which manifests as respiratory distress, hypoxemia in room air, hypercarbia, and growth failure. Lung compliance varies, but lung resistance generally increases with prolonged exposure to positive pressure ventilation and other sources of inflammation. Serial lung radiographs reveal a heterogeneous pattern, with areas of both hyperinflation and atelectasis; in extreme cases, macrocystic changes may be noted. Efforts to wean the respiratory support are often unsuccessful, and trials of high frequency ventilation, exogenous corticosteroids, and diuretics are common. The incidence of pulmonary hypertension increases with the severity of BPD, as does the mortality rate. Therefore, periodic screening and efforts to mitigate the risk of PH is fundamental to the management of longstanding BPD. Failure of conventional, lung-protective strategies (e.g., high rate/low tidal-volume and/or high frequency ventilation) warrants consideration of ventilatory strategies individualized to the disease physiology. Non-invasive modes of respiratory support may be successful in infants with mild to moderate BPD phenotypes. However, infants with moderate to severe BPD phenotypes often require invasive respiratory support, and pressure-limited or volume-targeted conventional ventilation may be better suited to the physiology than high-frequency ventilation. The consistent provision of adequate support is fundamental to the management of longstanding BPD and is best achieved with a stepwise increase in ventilator support until comfortable spontaneous respirations are achieved. Adequately supported infants typically experience improvements in both oxygenation and ventilation, which, if sustained, may arrest and generally reverses the course of a potentially lethal lung disease. Care should be individualized to address the most likely pulmonary mechanics, including variable lung compliance, elevated airway resistance, and variable airway obstruction.

Effects of standardized feeding protocol on growth velocity and necrotizing enterocolitis in extremely low birth weight infants.

OBJECTIVE: To assess the effect of a standardized feeding protocol (SFP) on growth velocity (GV) and necrotizing enterocolitis (NEC) in extremely low birth weight infants. METHODS: This single-study center retrospectively compared growth, nutritional, and gastrointestinal outcomes in two infant cohorts before (cohort 1; n = 145) and after (cohort 2; n = 69) SFP implementation. RESULTS: Although weekly GV in the first 4 weeks of life did not differ between the two cohorts, median GV at 36 weeks' post-menstrual age (PMA) was higher in cohort 2 compared with cohort 1 (26.8 g/day [24.7, 28.9] vs 24.9 g/day [22.9, 28.3], p = 0.02). The odds of NEC were lower in cohort 2 by 63% after adjusting for birth weight, small-for-gestational-age, and gender (OR = 0.38, 95% CI 0.142-0.993, p = 0.047). CONCLUSION: Our SFP was associated with improved GV at 36 weeks' PMA and a lower adjusted rate of NEC.

Steroid-responsive encephalopathy and autoimmune thyroiditis in a young boy.

Steroid-responsive encephalopathy with autoimmune thyroiditis is a relatively uncommon entity in the pediatric population. Although the pathogenesis of steroid-responsive encephalopathy with autoimmune thyroiditis is uncertain, an autoimmune mechanism is suspected to be the most likely cause. Seizures of unknown etiology are a common presenting sign in the pediatric intensive care unit, and steroid-responsive encephalopathy with autoimmune thyroiditis should be considered as a possible cause of recurrent seizures. The outcome of steroid-responsive encephalopathy with autoimmune thyroiditis is variable in children, and is partly dependent on early diagnosis and the administration of intravenous steroids. Only 31 pediatric cases of steroid-responsive encephalopathy with autoimmune thyroiditis were described in the English-language literature since 1966. Very few were reported in the United States or among males. We describe a 13-year-old boy presenting with a new onset of seizures as a manifestation of steroid-responsive encephalopathy with autoimmune thyroiditis. This report presents, to the best of our knowledge, the youngest male with steroid-responsive encephalopathy with autoimmune thyroiditis, and the only reported child with other autoimmune manifestations in addition to encephalopathy.