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  2. 2. Persistent pulmonary hypertension of the newborn (PPHN)-Is a major clinical problem in the neonatal intensive care unit.-Can contribute significantly to morbidity and mortality in bothterm and preterm infants.-Hypoxemic respiratory failure or PPHN can place newborns atrisk for death, neurologic injury, and other morbidities.-Incidence is estimated at 0.2% of liveborn term infants.
  3. 3. PPHN is categorized into:• Parenchymal lung disease (meconium aspiration syndrome, respiratory distress syndrome, sepsis)• Idiopathic (or "black-lung")• Pulmonary hypoplasia (as seen in congenital diaphragmatic hernia).
  4. 4. The Fetal Pulmonary Vasculature-The fetal pulmonary circulation undergoes striking developmentalchanges in vascular growth, structure, and function.-Because the placenta, not the lung, serves as the organ of gasexchange, less than 10% of the combined ventricular output iscirculated through the pulmonary vascular bed, and most of theright ventricular output crosses the ductus arteriosus to the aorta .
  5. 5. Despite increases in pulmonary vascular surface area, PVR (pulmonary vascularresistance ) increases with gestationalage when corrected for lung or body weight,suggesting that vascular tone actuallyincreases during late gestation and is highprior to birth.
  6. 6. Pathways involved in maintaining high pulmonary vascular tone in utero:• low oxygen tension2) mediators such as endothelin-1 (ET-1) and leukotrienes.3) basal production of vasodilator products : prostacyclin (PGI2) and nitric oxide (NO) is relatively low4) the fetal vasculature also has the interesting ability to oppose vasodilation.
  7. 7. Normal Pulmonary Vascular Transition The pulmonary vascular transition at birth is characterized by :3) rapid increase in pulmonary blood flow5) reduction in PVR7) clearance of lung liquid.
  8. 8. Central role in the pulmonary vascular transition :1. Pulmonary endothelial cells2. NO3. Arachidonic acid metabolites
  9. 9. 2. NO-NO production increases dramatically at the time of birth.-Pulmonary expression of both endothelial nitric oxide synthase(eNOS) and its downstream target, soluble guanylate cyclase (sGC),increases during late gestation.
  10. 10. 1. NO-Ultimately, increased NO production and sGC activity lead toincreased cyclic guanosine monophosphate (cGMP) concentrationsin vascular smooth muscle cells, which produce vasorelaxation viadecreasing intracellular calcium concentrations.
  11. 11. Nitric oxide (NO) and prostacyclin (PG) signaling pathways in regulation ofvascular tone
  12. 12. 2.THE PROSTACYCLIN PATHWAY-Cyclooxygenase (COX) is the rate-limiting enzyme that generatesprostacyclin from arachidonic acid.-COX-1 in particular is upregulated during late gestation.
  13. 13. 2.THE PROSTACYCLIN PATHWAY-There is evidence that the increase in estrogen concentrations inlate gestation play a role in upregulating PGI synthesis. This leadsto an increase in prostacyclin production in late gestation and earlypostnatal life.-Prostacyclin interacts with adenylate cyclase to increaseintracellular cyclic adenosine monophosphate levels, which leads toVASORELAXATION.
  14. 14. At the time of birth, multiple factors regulate these pathways:• mechanical distention of the lung• a decrease in carbon dioxide tension3. an increase in oxygen tension in the lungs.
  15. 15. -Oxygen stimulates the activity of both eNOS andCOX-1 immediately after birth, leading to increasedlevels of NO and prostacyclin.- Oxygen also stimulates the release of adenosinetriphosphate from oxygenated red blood cells, whichincreases the activity of both eNOS and COX-1.
  16. 16. Table 1. Mechanisms of Persistent PulmonaryHypertension of the Newborn1.Abnormally Constricted Pulmonary Vasculature-Meconium Aspiration Syndrome-Pneumonia-Respiratory Distress Syndrome2.Structurally Abnormal Pulmonary Vasculature-Idiopathic Persistent Pulmonary Hypertension ("black lungPPHN")3.Hypoplastic Pulmonary Vasculature-Congenital Diaphragmatic Hernia-Pulmonary Hypoplasia
  17. 17. 1. Parenchymal Lung Disease: MAS-the most common cause of PPHN-affects 25,000 to 30,000 infants-1,000 deaths annually in the United States-approximately 13% of all live births are complicated bymeconium-stained fluid, only 5% of affected infants subsequentlydevelop MAS
  18. 18. 1. Parenchymal Lung Disease: MASThe traditional belief is that aspiration occurswith the first breath after birth, but morerecent data suggest that for the more severelyaffected infants, aspiration more likely occursin utero.
  19. 19. 1.Parenchymal Lung Disease: MASMeconium aspiration injures the lung through multiple mechanisms:• mechanical obstruction of the airways .• chemical pneumonitis due to inflammation, activation of complement .• inactivation of surfactant .• vasoconstriction of pulmonary vessels.• acts as an airway obstruction with a "ball-valve" effect, preventing adequate ventilation in the immediate postnatal period.
  20. 20. 1.Parenchymal Lung Disease: MAS-Meconium has toxic effects in the lungs that are mediated byinflammation.-Within hours of the meconium aspiration event, neutrophils andmacrophages are found in the alveoli and lung parenchyma.-The release of cytokines such as tumor necrosis factor-alpha,interleukin 1-beta (IL-1-beta), and IL-8 may injure the lungparenchyma directly and lead to vascular leakage that causespneumonitis with pulmonary edema.
  21. 21. 1.Parenchymal Lung Disease: MAS-Meconium injury may trigger directly the postnatalrelease of vasoconstrictors such as ET-1, TXA2, andPGE2.-Meconium also inactivates surfactant, due to thepresence of surfactant inhibitors such as albumin,phosphatidylserine, and phospholipase A2.
  22. 22. 1.Parenchymal Lung Disease: MAS-The pneumonitis and surfactant inactivation impairadequate ventilation immediately after birth, which is akey mediator of normal pulmonary transition.-Such impairment of normal transition in combinationwith the postnatal release of vasoconstrictors ultimatelyleads to the pulmonary hypertension seen in conjunctionwith MAS.
  23. 23. 2.Idiopathic PPHN-Idiopathic (or "black lung") PPHN is most commonin term and near-term (>34 weeks’ gestation)newborns.-Means significant remodeling of the pulmonaryvasculature, with vessel wall thickening and smoothmuscle hyperplasia.-The smooth muscle extends to the level of the intra-acinar arteries
  24. 24. 2.Idiopathic PPHN-affected infants do not vasodilate their pulmonaryvasculature appropriately in response to birth-relatedstimuli, and they present with profound hypoxemia andclear, hyperlucent lung fields on radiography, thus theterm "black lung" PPHN.
  25. 25. 2.Idiopathic PPHNThe pathophysiology:1) constriction of the fetal ductus arteriosus in utero fromexposure to nonsteroidal anti-inflammatory drugs(NSAIDs) during the third trimester.2) biologic or genetic susceptibility .3) reactive oxygen species (ROS) such as superoxide andhydrogen peroxide may play a role in the vasoconstrictionand vascular remodeling associated with PPHN.
  26. 26. 3.Hypoplastic pulmonary vasculature- CDH-CDH occurs in 1 of every 2,000 to 4,000 live births-accounts for 8% of all major congenital anomalies.-CDH is a developmental abnormality ofdiaphragmatic development that results in a defectthat allows abdominal viscera to enter the chest andcompress the lung.
  27. 27. 3. Hypoplastic pulmonary vasculature- CDH-Herniation - most often in the posterolateral segmentsof the diaphragm, and 80% of the defects- on the leftside.-CDH is characterized by a variable degree ofpulmonary hypoplasia associated with a decrease incross-sectional area of the pulmonary vasculature.
  28. 28. Treatment of PPHN1.Initial Therapies-Treat metabolic derangements: correct acidosis, hypoglycemia,hypocalcemia-Optimize lung recruitment: mechanical ventilation, high-frequency oscillatory ventilation, surfactant-Optimize cardiac output and left ventricular function:vasopressors, inotropic agents2. Pulmonary Vasodilators-Inhaled nitric oxide3.Future Therapies-Phosphodiesterase Inhibitors (sildenafil)-Inhaled prostacyclin analogs (iloprost, prostacyclin)-Recombinant superoxide dismutase
  29. 29. 1.THE INITIAL THERAPY 1) correction of factors that may promote vasoconstriction( hypothermia, hypoglycemia, hypocalcemia, anemia, andhypovolemia)2) correction of metabolic acidosis. 3) Cardiac function should be optimized with volumeexpansion and inotropic agents (dobutamine, dopamine),to enhance cardiac output and systemic oxygen transport.
  30. 30. 4) The goal of mechanical ventilation is to achieve optimallung volume to allow for lung recruitment whileminimizing the risk for lung injury.5) Parenchymal lung disease of the term and near-terminfant often is associated with surfactant deficiency orinactivation.-Single-center trials have shown that surfactant improvesoxygenation in infants who have MAS.-A large multicenter trial demonstrated that surfactanttreatment decreased the need for ECMO.
  31. 31. 2. PULMONARY VASODILATORSInhaled Nitric Oxide-It has a rapid and potent vasodilator effect.-Because it is a small gas molecule, NO can be deliveredthrough a ventilator directly to airspaces approximatingthe pulmonary vascular bed.-Once in the bloodstream, NO binds avidly to hemoglobin,limiting its systemic vascular activity and increasing itsselectivity for the pulmonary circulation.
  32. 32. Inhaled Nitric Oxide-Large placebo-controlled trials demonstrated that iNOsignificantly decreased the need for ECMO in newbornswho had PPHN, although iNO did not reduce mortality orlength of hospitalization.-iNO did not reduce the need for ECMO in infants whohad unrepaired CDH.
  33. 33. In general, iNO should be begun when theoxygenation index (OI) exceeds 25, the entrycriteria for the multicenter studies notedpreviously. The OI is a commonly usedcalculation to describe the severity of pulmonaryhypertension and is calculated as:OI=((mean airway pressure xFiO2)/postductalPaO2)x100
  34. 34. Contraindications to iNO therapy-congenital heart disease that is dependent on right-to-leftshunting across the ductus arteriosus (eg, critical aorticstenosis, interrupted aortic arch, and hypoplastic left heartsyndrome).-iNO may worsen pulmonary edema in infants who haveobstructed total anomalous pulmonary venous return dueto the fixed venous obstruction.An initial echocardiographic evaluation is essential to ruleout structural heart lesions and establish the presence ofpulmonary hypertension
  35. 35. 3.FUTURE THERAPIES1)Sildenafil, a potent and highly specific PDE5 inhibitor, that increase cGMP concentrations and result in pulmonary vasodilation-Sildenafil may attenuate rebound pulmonary hypertension after withdrawal of iNO in newborn and pediatric patients.-Use of sildenafil in PPHN has been limited by its availability only as an enteric form-An intravenous preparation recently was investigated in newborns who had pulmonary hypertension, and data should be available soon.
  36. 36. 2) Milrinone- inhibit PDE3, the phosphodiesterasethat metabolizes cAMP, and result in an increase ofcMAP ,which also stimulates vasodilatation.
  37. 37. 3) PGI2 stimulates membrane-bound adenylatecyclase, increases cAMP, and inhibits pulmonaryartery smooth muscle cell proliferation in vitro-Although the use of systemic infusions of PGI2 maybe limited by systemic hypotension, inhaled PGI2 hasbeen shown to have vasodilator effects limited to thepulmonary circulation.
  38. 38. 4) New studies indicate that scavengers of ROS such assuperoxide dismutase (SOD) may augment responsivenessto iNO.-Because iNO usually is delivered with high concentrationsof oxygen, there is the potential for enhanced productionof free radicals such as superoxide and peroxynitrite.
  39. 39. -SOD scavenges and converts superoxide radical tohydrogen peroxide, which subsequently is converted towater by the enzyme catalase.-Scavenging superoxide may make both endogenous andinhaled NO more available to stimulate vasodilatation andmay reduce oxidative stress and limit lung injury.
  40. 40. THANK YOU