Pulmonary Vascular Disease in BPD. BrochBorc. Late Pulmonary Hypertension is Associated with Poor Survival in BPD
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1 Pulmonary Vascular Disease in PD Steven H. bman, MD Professor of Pediatrics Director, Pediatric Heart Lung enter University of olorado School of Medicine and hildren s Hospital olorado urora O Dr. Steve bman has documented that he has no financial relationships to disclose or conflicts of interests to resolve. ronchopulmonary Dysplasia (PD) Developmental Lung Diseases ssociated with Pulmonary Hypertension Down Syndrome lveolar apillary Dysplasia ronchopulmonary Dysplasia rochorc Late Pulmonary Hypertension is ssociated with Poor Survival in PD Reduced Lung Surface rea in Infants with hronic Lung Disease (from Khemani et al, 2007) (alinotti et al, JRM, 2010) 1
2 Lung Development and Preterm irth Endothelial Epithelial ell Interactions Disruption of ngiogenesis Impairs lveolarization in the Developing Lung (Jakkula M et al m J Physiol, 2000) VEGF Receptor Inhibition Impairs Lung Vascular Growth in Neonatal Rats Decreased ngiogenesis and Vascular Endothelial Growth Factor in Human PD Non PD PD ontrol SU5416 PEM VEGF (Jakkula M et al, m J Physiol. 2000) (hat et al, JRM, 2001) 2
3 Epigenetic and Genetic Factors Pathogenesis of PD Hyperoxia O 2 Inflammation O 2 Intra mniotic Endotoxin Impairs Lung Structure and VEGF Signaling in Infant Rats ontrol Endotoxin Premature irth Disruption of growth factor signaling pathways O 2 O 2 PD lveolarization Vascular Growth Lung Function VEGF VEGFR2 Prenatal factors Infection horioamnionitis Fetal infection Preeclampsia, IUGR Smoking drug use Ventilator Induced Injury (JR Tang et al, 2010) ntenatal Vitamin D Improves Survival in ETX Exposed Rat Pups Vitamin D Treatment Improves Late Lung Structure after ntenatal ETX Exposure Saline ETX ETX+ Post VD Magnification 40x Radial lveolar ounts # (Erica Mandell) p< ETX v ETX +VD (Erica Mandell) p< 0.05 # p<0.01 Vitamin D Decreases RVH and Preserves Pulmonary Vessel Density after ETX Exposure at Day 14 RVH Pulmonary Vessel Density # # Vitamin D Increases Tube Formation in Fetal PE Exposed to ETX # # # p< 0.01 #p < 0.05 (Erica Mandell) (Erica Mandell) p< 0.05 # p<
4 ord lood EF are Decreased at irth in Preterm Infants who Develop PD Lack of Decline in RIMP in Preterm Infants Who Later Develop PD (aker D et al. EurRespirJ, 2012) (RIMP = RV index of myocardial performance) (zernik et al, PLoS One, 2012) Diagnosis of Pulmonary Hypertension Increases Risk of Late Respiratory Morbidities Independent of PD Severity ds Ratio Odd ( p< 0.05 PH vs Other Groups) Pulmonary Vascular Disease in PD bnormal Growth Impaired ngiogenesis Intrapulmonary Shunt Vessels Decreased lveolarization bnormal Function Decreased Lung Surface High tone rea and Gas Exchange bnormal Reactivity bnormal Structure SM hyperplasia dventitial thickening Intimal occlusion (rare) Prolonged oxygen therapy ltered distribution of blood flow with infection, stress Exercise intolerance Pulmonary Hypertension Hospital Visits Respiratory Related Hospital Visits sthma/pd Exacerbation ronchiolitis/ Pneumonia Dx (Peter Mourani) (Mourani PM, bman SH. urr Op Peds, 2012) Histologic Evidence of Intrapulmonary Vascular Shunt Vessels in PD NORML D/MPV PD V V V L Patterns of bnormal Vasculature in the Distal Lung of Infants Dying with Severe PD L D E F L (Galambos, Sims Lucas S, bman SH. nn m Thorac Soc. 2013) L 4
5 Persistent Fetal Intrapulmonary Shunt Pathways in Severe PD Intrapulmonary Shunt Vessels in PD rtery: red Veins: blue irway: green Lymphatic: pink rt. media: aqua Vascular hannels: yellow (Galambos et al. nn m Thorac Soc. 2013) (Galambos et al. nn m Thorac Soc. 2013) Issues in the Diagnosis and Management of Pulmonary Hypertension in PD Whom to screen? How to screen? When to screen? What is the diagnostic evaluation? What is the role of cardiac catheterization? Which therapies are effective in PD? Whom to Screen? Extreme prematurity (< 26 weeks) IUGR or pre eclampsia Prolonged ventilator course Inability to wean FiO 2, lack of overall improvement with time, poor growth, recurrent spells Severity of PD Or, ll infants with PD near term corrected age, even if clinically stable? Low irth Weight and Risk for Pulmonary Hypertension in PD Pulmonary Hypertension and PD: ssociation with Disease Severity (52 %) (17 %) (heck J et al, J Perinatol, 2013) (Mourani PM, bman SH. urr Op Pediatr, 2013) Seoul: n et al. Korean irc J, 2010 labama: hat et al. Pediatrics,
6 Relationship of Pulmonary Hypertension and Severity of PD at 36 Weeks P (13% of study population with PH) Elements of Pulmonary Hypertension in PD Lung Disease Hyperinflation telectasis Hypoxemia Hypercarbia High Pulmonary rtery Pressure Heart Disease RV Dysfunction Impaired LV ontractility LV Diastolic Dysfunction Shunt (SD, PD, VSD) (PM Mourani et al, unpublished data) Pulmonary Vascular Disease High tone and reactivity Hypertensive arterial remodeling Decreased vascular growth Pulmonary Vascular Development in PD (del erro et al. Pediatric Pulmonol, 2013) Pulmonary Vein Stenosis in PD Severe Pulmonary Hypertension in a Preterm Infant with PD and PVS Pulmonary rtery Remodeling Pulmonary Vein Remodeling (del erro et al. Pediatric Pulmonol, 2013) 6
7 Increased Systemic to Pulmonary ollaterals in PD ssociated ardiovascular Lesions in PD Infants with Pulmonary Hypertension Retrospective study of 29 patients 21 patients had T scans, 14 had cath 66% with one associated findings (del erro et al. Pediatric Pulmonol, 2013) ourse and Outcomes of PD Infants with Pulmonary Hypertension linical Feature ge at diagnosis Diagnosed after NIU discharge Supplemental O2 therapy at diagnosis Mechanical Ventilation at diagnosis Echo at diagnosis (ratio of RVSP/Syst P) Death PH specific Drug Therapy Resolution of PH without Drug Therapy Required closure of shunt Median duration of follow up = 35 months Values or Proportion 4.5 months (median) 48% 59% 28% 70% (median) 8/29 (28%) 22/29 (76%) 3/29 (10%) 6/29 (21%) (del erro et al. Pediatric Pulmonol, 2013) Summary and Recommendations ll of these patients had moderate (24 %) or severe (76 %) PD; Most patients had perinatal risk factors for PD, including IUGR, preeclampsia, PPROM, chorioamnionitis, older maternal age; PH often late diagnosis, variable oxygen use; Screen all patients with mod/severe PD with serial echocardiograms at 2 3, 4 6 and months of age, especially with risk factors or prolonged oxygen course. (del erro M et al, Pediatri Pulmonol, 2013) hronic Sildenafil Therapy for Late Pulmonary Hypertension in LD linical Response to Prolonged Sildenafil Therapy in PD Percent of Patients Showing Hemodynamic Improvement by Echo ensored Observations (Mourani PM et al, J Peds, 2009 ) Days on Sildenafil Therapy (Mourani, J Pediatr, 2009) 7
8 onclusions Pulmonary vascular disease (PVD) can be identified early in preterm newborns and is associated with: an increased risk for developing PD higher mortality and late respiratory morbidities. Early endothelial cell injury disrupts angiogenesis and impairs alveolarization. ntenatal stress is sufficient to cause sustained abnormalities of postnatal lung growth. Prominent fetal intrapulmonary channels persist in severe PD. Pulmonary hypertension and associated cardiovascular abnormalities modulate the clinical course and outcomes of PD Pediatric Heart Lung enter linical Team Lab Group 8
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