Shaun M. Kunisaki

Intravenous Fat Emulsions Reduction for Patients with Parenteral Nutrition–Associated Liver Disease

OBJECTIVE To test the hypothesis that implementation of a marked reduction in intravenous fat will result in reversal of parenteral nutrition-associated liver disease (PNALD) in infants. STUDY DESIGN Prospective study of intravenous fat emulsion reduction in parenteral nutrition to 1 g/kg/d 2 times per week in neonates diagnosed with PNALD. Primary outcome measure was total bilirubin levels compared with gestational age, birth weight, and diagnosis-matched historical controls receiving 3 g/kg/d of intravenous lipids. RESULTS Intravenous fat emulsion reduction resulted in a significant decline in total bilirubin levels compared with controls. Comparison of growth in the 2 groups was similar. Mild essential fatty acid deficiency was detected in 8 of 31 infants and was reversed with additional days of lipid infusion. No significant adverse events were noted. CONCLUSIONS An association between intravenous lipid emulsion administration and the development of PNALD seems probable. Use of intravenous fat emulsion reduction is a potential approach to reverse PNALD in young infants. Frequent monitoring of essential fatty acid deficiency is needed with the use of this regimen.

Thoracoscopic vs Open Lobectomy in Infants and Young Children with Congenital Lung Malformations

BACKGROUND Although thoracoscopic lobectomy is a widely accepted surgical procedure in adult thoracic surgery, its role in small children remains controversial. The purpose of this study was to evaluate perioperative outcomes after thoracoscopic and open lobectomy in infants and young children with congenital lung malformations at a single academic referral center. STUDY DESIGN A cohort study of 62 consecutive children who underwent elective pulmonary lobectomy for a congenital lung lesion between 2001 and 2013 was performed. Patient demographics and perioperative outcomes were evaluated in univariate and logistic regression analyses. RESULTS Forty-nine patients underwent thoracoscopy and 13 had a thoracotomy. Six children undergoing thoracoscopy required conversion to thoracotomy (conversion 12.2%). Perioperative outcomes, including median blood loss (2.0 vs 1.1 mL/kg; p = 0.34), chest tube duration (3 vs 3 days; p = 0.33), hospital length of stay (3 vs 3 days; p = 0.42), and morbidity as defined by the Accordion Grading Scale (30.6% vs 30.8%; p = 0.73), were similar between thoracoscopy and thoracotomy, respectively. Although thoracoscopy was associated with increased operative duration compared with thoracotomy (239.9 vs 181.2 minutes, respectively; p = 0.03), thoracoscopy operative times decreased with increasing institutional experience (p = 0.048). Thoracoscopic lobectomy infants younger than 5 months of age had a 2.5-fold higher rate of perioperative adverse outcomes compared with older children (p = 0.048). CONCLUSIONS In small children undergoing pulmonary lobectomy, both thoracoscopy and thoracotomy are associated with similar perioperative outcomes. The cosmetic and musculoskeletal benefits of the thoracoscopic approach must be balanced against institutional expertise and a potentially higher risk for complications in younger patients.

Fetal lung lesions: can we start to breathe easier?

OBJECTIVE The purpose of this study was to develop a simple and accurate approach for risk stratification of fetal lung lesions that are associated with respiratory compromise at birth. STUDY DESIGN We conducted a retrospective review of 64 prenatal lung lesions that were managed at a single fetal care referral center (2001-2011). Sonographic data were analyzed and correlated with perinatal outcomes. RESULTS Hydrops occurred in only 4 cases (6.3%). Among fetuses without hydrops, the congenital pulmonary airway malformation volume ratio (CVR) was the only variable that was associated significantly with respiratory compromise and the need for lung resection at birth (P < .01). Based on a maximum CVR >1.0, the sensitivity, specificity, positive predictive value, and negative predictive value for respiratory morbidity were 90%, 93%, 75%, and 98%, respectively. CONCLUSION Nonhydropic fetuses with a maximum CVR >1.0 are a subgroup of patients who are at increased risk for respiratory morbidity and the need for surgical intervention. These patients should be delivered at a tertiary care center with pediatric surgery expertise to ensure optimal clinical outcomes.

Congenital esophageal stenosis: the differential diagnosis and management.

Congenital esophageal stenosis (CES) is a rare congenital abnormality that is difficult to diagnose and often masquerades as other types of structural esophageal disease. We report three cases of CES with different presenting symptoms. We advocate for balloon dilation as the preferred first approach to therapeutic intervention. CES is an important clinical entity in the evaluation of pediatric esophageal disorders and should be suspected in young infants with dysphagia.

Vanishing fetal lung malformations: Prenatal sonographic characteristics and postnatal outcomes

BACKGROUND/PURPOSE The purpose of this study was to examine the natural history and outcomes of prenatally diagnosed lung masses that appear to undergo complete regression before birth. METHODS An IRB-approved retrospective review was performed on 100 consecutive fetuses with a congenital lung malformation at a single fetal center. Prenatal and postnatal imaging as well as outcomes of vanishing fetal masses was analyzed and compared to those with persistent fetal masses. RESULTS Seventeen lesions (17%) became sonographically undetectable at 35.3 ± 2.3 weeks gestation. Vanishing fetal masses were associated with microcystic disease (100% vs. 69%, p=0.005) and a low initial congenital pulmonary airway malformation volume ratio (CVR; 0.31 ± 0.35 vs. 0.70 ± 0.66, p=0.002) when compared to those with persistent fetal lesions. Based on postnatal CT imaging and pathology data, 10.3% of all fetal masses completely regressed. The positive predictive value and negative predictive value of prenatal ultrasound for detecting lung malformations in late gestation were 96% and 43%, respectively. All infants with vanishing fetal lesions were asymptomatic at birth and were more likely to be managed nonoperatively (75% vs. 22%, p<0.0001) when compared to infants with persistent fetal masses. CONCLUSIONS Vanishing lung lesions late in gestation are relatively common and are associated with a low CVR and microcystic disease.

Surgical Advances in the Fetus and Neonate: Esophageal Atresia

This article focuses on selected topics in the diagnosis and management of patients with esophageal atresia (EA) with or without tracheoesophageal fistula. The current status of prenatal diagnosis and recent advances in surgical techniques, including thoracoscopic repair for short-gap EA and tension-induced esophageal growth for long-gap EA, are reviewed. Although no consensus exists among pediatric surgeons regarding the role of these procedures in the treatment of EA, one can reasonably expect that, as they evolve, their application will become more widespread in this challenging patient population.

Paracrine regulation of fetal lung morphogenesis using human placenta-derived mesenchymal stromal cells.

BACKGROUND Recent experimental work suggests the therapeutic role of mesenchymal stromal cells (MSC) during perinatal lung morphogenesis. The purpose of this study was to investigate the potential paracrine effects of human placenta-derived mesenchymal stromal cells (PL-MSCs) on pulmonary development. METHODS Human MSCs were isolated from preterm placental chorion. Normal E14.5-15.5 fetal rat lungs were subsequently harvested and cultured ex vivo in the presence of conditioned media from PL-MSCs for 72 h. The lungs were analyzed morphometrically and by quantitative DNA, protein, and gene expression. Postnatal human bone marrow-derived mesenchymal stromal cells and neonatal foreskin fibroblasts (FF) were used as controls. RESULTS The MSC phenotype of the isolated placental cells was confirmed. Compared with lungs cultured in the absence of PL-MSCs, fetal lung growth was markedly accelerated on exposure to PL-MSC conditioned media as demonstrated by increases in Δlung surface area, terminal bud formation, and Δterminal bud formation. Pulmonary growth was predominantly impacted by enhanced branching morphogenesis, as shown by 73.5±6.1 terminal buds after stimulation with PL-MSCs compared with 46.7±5.7 terminal buds in control unconditioned media (P<0.05). Significant differences were noted favoring PL-MSCs over FFs based on terminal bud formation and Δterminal bud formation (P<0.05). There was significant upregulation of club cell secretory protein in lungs exposed to PL-MSCs compared with all other groups. CONCLUSIONS These data suggest that human PL-MSCs are potent paracrine stimulators of pulmonary morphogenesis in a fetal organ culture model. Cell therapies based on autologous or donor-derived PL-MSCs may represent a novel strategy for enhancing perinatal lung growth.

Contemporary Outcomes in Infants With Congenital Heart Disease and Bochdalek Diaphragmatic Hernia

BACKGROUND Fifteen percent of infants with congenital diaphragmatic hernia (CDH) are born with a coexisting cardiac anomaly. The purpose of this study was to evaluate contemporary outcomes in this patient population and to identify potential risk factors for in-hospital mortality. METHODS Data from all CDH neonates with congenital heart disease managed at a single pediatric tertiary care referral center between 1997 and 2011 were retrospectively analyzed. RESULTS Forty (18%) of 216 CDH patients had a cardiac anomaly. This group was associated with a significant decrease in overall survival when compared with patients without cardiac anomaly (55% versus 81%; p = 0.001). There was no association between type of cardiac anomaly and mortality based on risk stratification according to the Risk Adjustment for Congenital Heart Surgery and The Society of Thoracic Surgeons-European Association for Cardiothoracic Surgery scoring systems (p = 0.86 and p = 0.87, respectively). Birth weight was similarly no different between survivors and nonsurvivors (2.8 ± 0.6 kg versus 2.8 ± 0.9 kg, respectively; p = 0.98). There was a trend toward increased extracorporeal membrane oxygenation use among nonsurvivors (p = 0.13). Infants with hemodynamic stability enabling subsequent cardiac repair were associated with lower mortality (p = 0.04). Survivors had a wide spectrum of long-term morbidity, but most had some evidence of neurodevelopmental impairment. CONCLUSIONS This large single-institution series suggests that the overall prognosis of infants with concomitant CDH and congenital heart disease can be quite variable, regardless of the type of heart anomaly. Hemodynamic instability and need for extracorporeal membrane oxygenation correlate with higher mortality. Although some long-term survivors have excellent outcomes, most suffer from chronic, long-term morbidities.

Novel non-surgical prenatal approaches to treating congenital diaphragmatic hernia

This review focuses on the emerging field of non-surgical in-utero therapies in the management of fetal pulmonary hypoplasia and pulmonary hypertension associated with congenital diaphragmatic hernia (CDH). These experimental approaches include pharmacologic as well as stem-cell-based strategies. Current barriers of non-surgical therapies toward clinical translation are emphasized. As the severity of CDH will likely influence the efficacy of any in-utero therapy, the current status of prenatal imaging and the role of novel biomarkers, especially those related to fetal inflammation, are also reviewed.

Human Cardiomyocytes Prior to Birth by Integration-Free Reprogramming of Amniotic Fluid Cells

The establishment of an abundant source of autologous cardiac progenitor cells would represent a major advance toward eventual clinical translation of regenerative medicine strategies in children with prenatally diagnosed congenital heart disease. In support of this concept, we sought to examine whether functional, transgene‐free human cardiomyocytes (CMs) with potential for patient‐specific and autologous applications could be reliably generated following routine amniocentesis. Under institutional review board approval, amniotic fluid specimens (8–10 ml) at 20 weeks gestation were expanded and reprogrammed toward pluripotency using nonintegrating Sendai virus (SeV) expressing OCT4, SOX2, cMYC, and KLF4. Following exposure of these induced pluripotent stem cells to cardiogenic differentiation conditions, spontaneously beating amniotic fluid‐derived cardiomyocytes (AF‐CMs) were successfully generated with high efficiency. After 6 weeks, quantitative gene expression revealed a mixed population of differentiated atrial, ventricular, and nodal AF‐CMs, as demonstrated by upregulation of multiple cardiac markers, including MYH6, MYL7, TNNT2, TTN, and HCN4, which were comparable to levels expressed by neonatal dermal fibroblast‐derived CM controls. AF‐CMs had a normal karyotype and demonstrated loss of NANOG, OCT4, and the SeV transgene. Functional characterization of SIRPA+ AF‐CMs showed a higher spontaneous beat frequency in comparison with dermal fibroblast controls but revealed normal calcium transients and appropriate chronotropic responses after β‐adrenergic agonist stimulation. Taken together, these data suggest that somatic cells present within human amniotic fluid can be used to generate a highly scalable source of functional, transgene‐free, autologous CMs before a child is born. This approach may be ideally suited for patients with prenatally diagnosed cardiac anomalies.