PULMONARY HYPERTENSION IN THE NEONATES

1. PULMONARY HYPERTENSION IN THE NEONATES SIMONA NICHITA 01/30/2007

2. Persistent pulmonary hypertension of the newborn (PPHN) -Is a majorclinical problem in the neonatal intensive care unit. -Can contributesignificantly to morbidity and mortality in both term and preterminfants. -Hypoxemic respiratory failure or PPHN can place newbornsat risk for death,neurologic injury, and other morbidities. -Incidence is estimated at 0.2% of liveborn term infants.

3. PPHN is categorized into: • Parenchymal lung disease (meconiumaspiration syndrome, respiratory distress syndrome, sepsis) • Idiopathic (or "black-lung") • Pulmonary hypoplasia (as seenin congenital diaphragmatic hernia).

4. The Fetal Pulmonary Vasculature -The fetal pulmonary circulation undergoes striking developmental changes in vascular growth,structure, and function. -Becausethe placenta, not the lung, serves as the organ of gas exchange,less than 10% of the combined ventricular output is circulatedthrough the pulmonary vascular bed, and most of the right ventricularoutput crosses the ductus arteriosus to the aorta .

5. Despite increasesin pulmonary vascular surface area, PVR (pulmonary vascular resistance ) increases with gestational age when corrected for lung or body weight, suggesting thatvascular tone actually increases during late gestation and ishigh prior to birth.

6. Pathways involved in maintaining high pulmonaryvascular tone in utero: • low oxygen tension • 2) mediatorssuch as endothelin-1 (ET-1) and leukotrienes. • 3) basalproduction of vasodilator products : prostacyclin (PGI2)and nitric oxide (NO) is relatively low • 4) the fetal vasculature also has the interesting abilityto oppose vasodilation.

7. Normal Pulmonary Vascular Transition • The pulmonary vascular transition at birth is characterizedby : • rapid increase in pulmonary blood flow • reduction in PVR • clearance of lung liquid.

8. Central role in the pulmonary vascular transition : 1. Pulmonary endothelial cells 2. NO 3. Arachidonic acid metabolites

9. NO • -NO production increases dramatically at the time of birth. • -Pulmonaryexpression of both endothelial nitric oxide synthase • (eNOS)and its downstream target, soluble guanylate cyclase (sGC), • increases during late gestation.

10. 1. NO -Ultimately, increased NO productionand sGC activity lead to increased cyclic guanosine monophosphate(cGMP) concentrations in vascular smooth muscle cells, whichproduce vasorelaxation via decreasing intracellular calciumconcentrations.

11. Nitric oxide (NO) and prostacyclin (PG) signaling pathways in regulation of vascular tone

12. 2.THE PROSTACYCLIN PATHWAY • -Cyclooxygenase(COX) is the rate-limiting enzyme that generates • prostacyclinfrom arachidonic acid. • -COX-1 in particular is upregulated during late gestation.

13. 2.THE PROSTACYCLIN PATHWAY • There is evidence that the increase in estrogen concentrationsin late gestation play a role in upregulating PGI synthesis.This leads to an increase in prostacyclin productionin late gestation and early postnatal life. • Prostacyclin interactswith adenylate cyclase to increase intracellular cyclic adenosinemonophosphate levels, which leads to VASORELAXATION.

14. At the time of birth, multiple factors regulate these pathways: • mechanical distention of the lung • a decreasein carbon dioxide tension • 3. an increase in oxygen tensionin the lungs.

15. -Oxygen stimulates the activity of both eNOS and COX-1 immediatelyafter birth, leading to increased levels of NO and prostacyclin. -Oxygen also stimulates the release of adenosine triphosphatefrom oxygenated red blood cells, which increases the activityof both eNOS and COX-1.

16. Table 1. Mechanisms of Persistent Pulmonary Hypertension ofthe Newborn 1.Abnormally Constricted Pulmonary Vasculature-MeconiumAspiration Syndrome-Pneumonia-Respiratory Distress Syndrome 2.StructurallyAbnormal Pulmonary Vasculature-Idiopathic Persistent PulmonaryHypertension ("black lung PPHN") 3.Hypoplastic Pulmonary Vasculature-CongenitalDiaphragmatic Hernia-Pulmonary Hypoplasia

17. 1. Parenchymal Lung Disease: MAS -the most common cause of PPHN -affects 25,000 to30,000 infants -1,000 deaths annually in the UnitedStates -approximately 13% of all live births are complicatedby meconium-stained fluid, only 5% of affected infantssubsequently develop MAS

18. 1. Parenchymal Lung Disease: MAS The traditional belief is that aspirationoccurs with the first breath after birth, but more recent datasuggest that for the more severely affected infants, aspirationmore likely occurs in utero.

19. 1.Parenchymal Lung Disease: MAS • Meconium aspirationinjures the lung through multiple mechanisms: • mechanicalobstruction of the airways . • chemical pneumonitis due to inflammation,activation of complement . • inactivation of surfactant . • vasoconstrictionof pulmonary vessels. • acts as an airway obstructionwith a "ball-valve" effect, preventing adequate ventilationin the immediate postnatal period.

20. 1.Parenchymal Lung Disease: MAS -Meconium has toxic effects in the lungs thatare mediated by inflammation. -Within hours of the meconium aspirationevent, neutrophils and macrophages are found in the alveoliand lung parenchyma. -The release of cytokines such as tumornecrosis factor-alpha, interleukin 1-beta (IL-1-beta), and IL-8may injure the lung parenchyma directly and lead to vascularleakage that causes pneumonitis with pulmonary edema.

21. 1.Parenchymal Lung Disease: MAS • Meconium injury may trigger directly thepostnatal release of vasoconstrictors such as ET-1, TXA2, andPGE2. • Meconium also inactivatessurfactant, due to the presence of surfactant inhibitorssuch as albumin, phosphatidylserine, and phospholipase A2.

22. 1.Parenchymal Lung Disease: MAS -Thepneumonitis and surfactant inactivation impair adequate ventilationimmediately after birth, which is a key mediator of normal pulmonarytransition. -Such impairment of normal transition in combinationwith the postnatal release of vasoconstrictors ultimately leadsto the pulmonary hypertension seen in conjunction with MAS.

23. 2.Idiopathic PPHN -Idiopathic (or "black lung") PPHN is most common in term andnear-term (>34 weeks’ gestation) newborns. -Means significant remodeling ofthe pulmonary vasculature, with vessel wall thickening and smoothmuscle hyperplasia. -The smooth muscle extends to thelevel of the intra-acinar arteries

24. 2.Idiopathic PPHN -affected infants do not vasodilate their pulmonary vasculatureappropriately in response to birth-related stimuli, and theypresent with profound hypoxemia and clear, hyperlucent lungfields on radiography, thus the term "black lung" PPHN.

25. 2.Idiopathic PPHN The pathophysiology: 1) constriction of the fetal ductus arteriosus in uterofrom exposure to nonsteroidal anti-inflammatory drugs (NSAIDs)during the third trimester. 2) biologic or genetic susceptibility . 3) reactive oxygen species (ROS) suchas superoxide and hydrogen peroxide may play a role in the vasoconstrictionand vascular remodeling associated with PPHN.

26. 3.Hypoplastic pulmonary vasculature- CDH -CDH occurs in 1 of every 2,000 to 4,000 live births -accountsfor 8% of all major congenital anomalies. -CDH is a developmentalabnormality of diaphragmatic development that results in a defectthat allows abdominal viscera to enter the chest and compressthe lung.

27. 3. Hypoplastic pulmonary vasculature- CDH -Herniation - most often in the posterolateralsegments of the diaphragm, and 80% of the defects- on theleft side. -CDH is characterized by a variable degree of pulmonary hypoplasiaassociated with a decrease in cross-sectional area of the pulmonaryvasculature.

28. Treatment of PPHN 1.Initial Therapies-Treat metabolic derangements:correct acidosis, hypoglycemia, hypocalcemia-Optimize lungrecruitment: mechanical ventilation, high-frequency oscillatoryventilation, surfactant-Optimize cardiac output and left ventricularfunction: vasopressors, inotropic agents2. Pulmonary Vasodilators-Inhalednitric oxide3.Future Therapies-Phosphodiesterase Inhibitors(sildenafil)-Inhaled prostacyclin analogs (iloprost, prostacyclin)-Recombinantsuperoxide dismutase

29. 1.THE INITIAL THERAPY 1) correctionof factors that may promote vasoconstriction ( hypothermia,hypoglycemia, hypocalcemia, anemia, and hypovolemia) 2) correctionof metabolic acidosis. 3) Cardiac function should beoptimized with volume expansion and inotropic agents(dobutamine, dopamine), to enhance cardiac outputand systemic oxygen transport.

30. 4) The goal of mechanical ventilation is to achieve optimal lungvolume to allow for lung recruitment while minimizing the riskfor lung injury. 5) Parenchymal lung disease of the term and near-term infant oftenis associated with surfactant deficiency or inactivation. -Single-centertrials have shown that surfactant improves oxygenation in infantswho have MAS. -A large multicenter trial demonstrated thatsurfactant treatment decreased the need for ECMO.

31. 2. PULMONARY VASODILATORS • Inhaled Nitric Oxide • -It has a rapid and potent vasodilator effect. • Because it isa small gas molecule, NO can be delivered through a ventilatordirectly to airspaces approximating the pulmonary vascular bed. • Once in the bloodstream, NO binds avidly to hemoglobin, limitingits systemic vascular activity and increasing its selectivityfor the pulmonary circulation.

32. Inhaled Nitric Oxide -Large placebo-controlled trials demonstrated that iNO significantlydecreased the need for ECMO in newborns who had PPHN, althoughiNO did not reduce mortality or length of hospitalization. -iNO did not reduce the need for ECMO in infants who had unrepaired CDH.

33. In general, iNO should be begun when the oxygenation index (OI)exceeds 25, the entry criteria for the multicenter studies notedpreviously. The OI is a commonly used calculation to describethe severity of pulmonary hypertension and is calculated as: OI=((mean airway pressure xFiO2)/postductal PaO2)x100

34. Contraindicationsto iNO therapy -congenital heart disease that is dependent on right-to-leftshunting across the ductus arteriosus (eg, critical aortic stenosis,interrupted aortic arch, and hypoplastic left heart syndrome). -iNO may worsen pulmonary edema in infants who haveobstructed total anomalous pulmonary venous return due to thefixed venous obstruction. An initial echocardiographic evaluation is essentialto rule out structural heart lesions and establish the presenceof pulmonary hypertension

35. 3.FUTURE THERAPIES • 1)Sildenafil, a potent and highly specific PDE5 inhibitor, that increase cGMPconcentrations and result in pulmonary vasodilation • -Sildenafil may attenuate rebound pulmonary hypertension afterwithdrawal of iNO in newborn and pediatric patients. • -Use ofsildenafil in PPHN has been limited by its availability onlyas an enteric form • -An intravenous preparation recently was investigated in newborns who had pulmonary hypertension,and data should be available soon.

36. 2) Milrinone-inhibit PDE3, the phosphodiesterase that metabolizes cAMP, and result in an increase of cMAP ,which also stimulates vasodilatation.

37. 3) PGI2stimulates membrane-bound adenylate cyclase, increasescAMP, and inhibits pulmonary artery smooth muscle cell proliferationin vitro -Although the use of systemic infusions of PGI2 may be limited by systemic hypotension, inhaled PGI2 has been shownto have vasodilator effects limited to the pulmonary circulation.

38. 4) New studies indicate that scavengers of ROS such as superoxidedismutase (SOD) may augment responsiveness to iNO. -Because iNOusually is delivered with high concentrations of oxygen, thereis the potential for enhanced production of free radicals suchas superoxide and peroxynitrite.

39. -SOD scavenges and converts superoxide radicalto hydrogen peroxide, which subsequently is converted to waterby the enzyme catalase. -Scavenging superoxidemay make both endogenous and inhaled NOmore available to stimulatevasodilatation and may reduce oxidative stress and limit lunginjury.

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