Respiratory Management of the Newborn with an Omphalocele

Despite advances in neonatal care, infants with omphalocele have a mortality rate ranging between 5% and 25%. Respiratory insufficiency is a common clinical challenge and an independent predictor of mortality in these infants. The causes of respiratory failure are diverse and are not well understood. This chapter discusses the unique aspects of respiratory management in omphalocele infants. The authors have chosen references in this chapter with appropriate sample size, variable comparisons, regression analyses, and documented median follow-up times. Omphalocele is rare; therefore, the case reports of chapter references have important information

Congenital Diaphragmatic Hernia

Despite advances in neonatal and surgical care, the management of congenital diaphragmatic hernia (CDH) remains challenging with no definitive standard treatment guidelines. Several centers report mortality rates as low as 20%, but if extracorporeal membrane oxygenation (ECMO) support is required, the mortality rate rises to 50%. The disease severity is related to the degree of pulmonary hypoplasia and pulmonary hypertension that occurs with CDH. Both conditions decrease the infant’s ability to ventilate and oxygenate adequately at delivery. These physiologic conditions that impair gas exchange are the important determinants of morbidity and mortality in CDH infants. Presently, delivery of infants with CDH is recommended close to term gestation. The focus of care includes gentle ventilation, hemodynamic monitoring, and treatment of pulmonary hypertension followed by surgery for the defect. Extracorporeal membrane oxygenation (ECMO) is considered after failure of conventional medical management for infants ≥  34 weeks’ gestation or with weight >2 kg and no associated major lethal anomalies. This chapter discusses long‐term follow‐up recommendations for survivors, which should involve a multidisciplinary approach, as there are many surgical and nonsurgical consequences to the disease process. Clinical strategies that address these multifaceted aspects of care, from prenatal to long‐term follow‐up, may further reduce the high mortality rate for these infants

Aberrant Lymphatic Endothelial Progenitors in Lymphatic Malformation Development

Lymphatic malformations (LMs) are vascular anomalies thought to arise from dysregulated lymphangiogenesis. These lesions impose a significant burden of disease on affected individuals. LM pathobiology is poorly understood, hindering the development of effective treatments. In the present studies, immunostaining of LM tissues revealed that endothelial cells lining aberrant lymphatic vessels and cells in the surrounding stroma expressed the stem cell marker, CD133, and the lymphatic endothelial protein, podoplanin. Isolated patient-derived CD133+ LM cells expressed stem cell genes (NANOG, Oct4), circulating endothelial cell precursor proteins (CD90, CD146, c-Kit, VEGFR-2), and lymphatic endothelial proteins (podoplanin, VEGFR-3). Consistent with a progenitor cell identity, CD133+ LM cells were multipotent and could be differentiated into fat, bone, smooth muscle, and lymphatic endothelial cells in vitro. CD133+ cells were compared to CD133− cells isolated from LM fluids. CD133− LM cells had lower expression of stem cell genes, but expressed circulating endothelial precursor proteins and high levels of lymphatic endothelial proteins, VE-cadherin, CD31, podoplanin, VEGFR-3 and Prox1. CD133− LM cells were not multipotent, consistent with a differentiated lymphatic endothelial cell phenotype. In a mouse xenograft model, CD133+ LM cells differentiated into lymphatic endothelial cells that formed irregularly dilated lymphatic channels, phenocopying human LMs. In vivo, CD133+ LM cells acquired expression of differentiated lymphatic endothelial cell proteins, podoplanin, LYVE1, Prox1, and VEGFR-3, comparable to expression found in LM patient tissues. Taken together, these data identify a novel LM progenitor cell population that differentiates to form the abnormal lymphatic structures characteristic of these lesions, recapitulating the human LM phenotype. This LM progenitor cell population may contribute to the clinically refractory behavior of LMs

Aberrant Lymphatic Endothelial Progenitors in Lymphatic Malformation Development

Lymphatic malformations (LMs) are vascular anomalies thought to arise from dysregulated lymphangiogenesis. These lesions impose a significant burden of disease on affected individuals. LM pathobiology is poorly understood, hindering the development of effective treatments. In the present studies, immunostaining of LM tissues revealed that endothelial cells lining aberrant lymphatic vessels and cells in the surrounding stroma expressed the stem cell marker, CD133, and the lymphatic endothelial protein, podoplanin. Isolated patient-derived CD133+ LM cells expressed stem cell genes (NANOG, Oct4), circulating endothelial cell precursor proteins (CD90, CD146, c-Kit, VEGFR-2), and lymphatic endothelial proteins (podoplanin, VEGFR-3). Consistent with a progenitor cell identity, CD133+ LM cells were multipotent and could be differentiated into fat, bone, smooth muscle, and lymphatic endothelial cells in vitro. CD133+ cells were compared to CD133− cells isolated from LM fluids. CD133− LM cells had lower expression of stem cell genes, but expressed circulating endothelial precursor proteins and high levels of lymphatic endothelial proteins, VE-cadherin, CD31, podoplanin, VEGFR-3 and Prox1. CD133− LM cells were not multipotent, consistent with a differentiated lymphatic endothelial cell phenotype. In a mouse xenograft model, CD133+ LM cells differentiated into lymphatic endothelial cells that formed irregularly dilated lymphatic channels, phenocopying human LMs. In vivo, CD133+ LM cells acquired expression of differentiated lymphatic endothelial cell proteins, podoplanin, LYVE1, Prox1, and VEGFR-3, comparable to expression found in LM patient tissues. Taken together, these data identify a novel LM progenitor cell population that differentiates to form the abnormal lymphatic structures characteristic of these lesions, recapitulating the human LM phenotype. This LM progenitor cell population may contribute to the clinically refractory behavior of LMs.</p

Endothelial precursor and lymphatic endothelial protein expression in isolated CD133⁺ and CD133⁻ LM cells.

<p>FACS of patient-matched CD133⁺ and CD133⁻ LM cells isolated from microcystic mesenteric (Micro Mes) LM, microcystic subcutaneous (Micro SC) LM and general lymphatic anomaly (GLA) specimens. (A) Endothelial precursor markers, CD34, CD90, CD146 and VEGFR-2. (B) Lymphatic endothelial cell markers, podoplanin and VEGFR-3. Blue line represents antibody data, and red line IgG control.</p

Identification of CD133⁺ cells in LMs of different subtypes and anatomical locations.

<p>(A) LYVE1 and podoplanin staining of cervicofacial mixed LM tissue and patient-matched uninvolved tissue. White arrowheads mark normal lymphatics. (B) Podoplanin and CD133 staining of neonatal foreskin (postnatal day 1), uninvolved tissue, mixed cervicofacial (Mixed CF) LM tissues (2x), and Gorham’s dermal tissue. White arrowheads mark CD133⁺/podoplanin⁺ lymphatic endothelium. Red arrowheads mark CD133^low/podoplanin⁺ lymphatic endothelium. Yellow arrowheads mark CD133⁺/podoplanin⁺ stromal cells. Blue asterisks mark blood vessels with autofluorescing red blood cells. Scale bars: 50μm. lymphatic channel (lc)</p

Patient-matched LMPC and LMEC implants expressed the lymphatic proteins, LYVE1 and VEGFR-3.

<p>CD133+ LMPCs and CD133- LMECs isolated from a microcystic subcutaneous LM were suspended in Matrigel and implanted in immunocompromised mice. Staining of implants was compared to microcystic subcutaneous LM patient tissue (Micro LM tissue). (A) Podoplanin and LYVE1 and (B) podoplanin and VEGFR-3 staining. Scale bars: 50μm.</p

Expression of markers for mature lymphatic endothelial cells in isolated CD133⁺ and CD133⁻ LM cells.

<p>(A) Podoplanin, VE-cadherin, VEGFR-2, VEGFR-3, Prox1, and LYVE1 qRT-PCR of RNA isolated from CD133⁺ and CD133⁻ cells from LMs of different subtypes and anatomical locations and GLA compared to control HdLECs. Data normalized to β-actin qRT-PCR and represented as mean ± s.e.m. (B) CD31 and VE-cadherin FACS of patient-matched CD133⁺ and CD133⁻ LM cells isolated from microcystic mesenteric (Micro Mes) LM, microcystic subcutaneous (Micro SC) LM and general lymphatic anomaly (GLA) specimens. Thick gray line represents antibody data, and black line IgG control. (C) VE-cadherin/CD31 and (D) podoplanin/LYVE1 staining of patient-matched CD133⁺ and CD133⁻ LM cells isolated from microcystic mesenteric (Micro Mes) LM, microcystic subcutaneous (Micro SC) LM, and GLA compared to control HdLEC. Scale bars: 50μm.</p