围生期过渡医学课件

1、Perinatal Transition围生期过渡From intrauterine to extra-uterine environment从宫内到子宫外环境Lung and Cardiovascular Transition肺血管转换Common Cardiorespiratory Disorders of Perinatal Transition围产期过渡期常见的心肺障碍:Transient tachypnea of the newborn新生儿湿肺Respiratory distress syndrome呼吸窘迫综合征Persistent pulmonary hypertension

2、of the newborn新生儿持续性肺动脉高压Physiologic Transition 生理过渡Basic NRP question: How many babies require resuscitation after birth?关于新生儿复苏的问题，有多少宝宝出生需要新生儿复苏。Physiologic Transition10% of all infant require intervention and 1% will require extensive resuscitation at birthPrior to delivery, the fetus depends up

3、on the placenta for gas and nutrient exchange with the maternal circulationThe placenta has low vascular resistance and the fluid-filled fetal lungs have high vascular resistanceThe fetus grows and develops in a low O2 tension environmentHow much fetal cardiac output do the fetal lungs receive?Fetal

4、 Circulation胎儿循环13 to 21 % of CCOPA PaO2: 17-19 mmHg40 % of CCO32-37 mmHg PaO215-25 mmHg PaO2The Fetal LungThe lung develops as a liquid fluid organFetal lung fluid is produced by active Cl- secretion by lung epithelium This process provides a distending pressure sufficient to expand the lung to a v

5、olume of 30 ml/K in the third trimester, which approximates to the functional residual capacity of the neonatal lungWhen does alveolar fluid clearance happens?Perinatal Events:Alveolar fluid clearance: 33% occurs in the weeks before labor: in late gestation, the increase in catecholamine production

6、promotes active resorption of Na and water, through increased expression of amiloride-sensitive epithelial sodium channels (eNaC)33% during labor, with increased catecholamine release, there is increased blood flow to the fetal lung with concomitant increased PaO2 which increases gene expression of

7、eNaC33% at birth and short thereafter, initial effective breaths generate high transpulmonary pressures: up to -50 cmH2O during inspiration. The negative hydrostatic pressure drives alveolar fluid from the air spaces into the interstitium Perinatal Events:Drop in pulmonary vascular resistance:In ute

8、ro, pulmonary pressures are equivalent to systemic pressures due to elevated PVRPulmonary vasoconstrictors in the normal fetus: low PaO2, endothelin-1, thromboxane, leukotrienes, rho-kinase. Also promoted by low production of vasodilators: prostacyclin and nitric oxide9、 人的价值，在招收诱惑的一瞬间被决定。2022-4-282

9、022-4-28Thursday, April 28, 202210、低头要有勇气，抬头要有低气。2022-4-282022-4-282022-4-284/28/2022 2:32:02 AM11、人总是珍惜为得到。2022-4-282022-4-282022-4-28Apr-2228-Apr-2212、人乱于心，不宽余请。2022-4-282022-4-282022-4-28Thursday, April 28, 202213、生气是拿别人做错的事来惩罚自己。2022-4-282022-4-282022-4-282022-4-284/28/202214、抱最大的希望，作最大的努力。2022年

10、4月28日星期四2022-4-282022-4-282022-4-2815、一个人炫耀什么，说明他内心缺少什么。2022年4月2022-4-282022-4-282022-4-284/28/202216、业余生活要有意义，不要越轨。2022-4-282022-4-28April 28, 202217、一个人即使已登上顶峰，也仍要自强不息。2022-4-282022-4-282022-4-282022-4-28Variation in PVR and SVRRelationship between PAP and SAPFox WW, Gewitz MH, Dinwiddie R, Drummo

11、nd WH, Peckham GJ. Pulmonary hypertension in the perinatal aspiration syndromes. Pediatrics 1977;59:205211Critical signals for drop in PVR:Mechanical distension of the lung, decreased PaCO2 and increased PaO2The fetus in late gestation increases pulmonary expression of nitric oxide synthase (NOS) an

12、d soluble guanylate cyclaseThe prostacyclin pathway is also potentially important: COX-1 is upregulated during late gestation, leading to increase production of prostacyclin Beginning of transitionSuccessful transitionPathophysiology of PPHNIncidence: 2 per 1000 live term infants, some degree of PH

13、complicates the course of approximately 10% of all neonates with respiratory failureIn the newborn, elevated PVR causes extrapulmonary shunting of blood with severe and potentially unresponsive hypoxemia Why?Mortality: 5-10%25% of infants with moderate or severe PPHN will exhibit neurodevelopmental

14、impairment at 12 and 24 monthsTypes:Abnormally constricted vasculature due to lung parenchymal disease: perinatal asphyxia, MAS, RDS, pneumoniaLung with normal parenchyma and remodeled pulmonary vasculature, known as idiopathic PPHNHypoplastic lung vasculature: CDH, lung hypoplasiaThere will be a qu

15、iz at the endUpdated Classification of Pulmonary Hypertension1. Pulmonary arterial hypertension: 1.1 Idiopathic PAH, 1.2 Heritable PAH, 1.2.1 BMPR2, 1.2.2 ALK-1, ENG, SMAD9, CAV1, KCNK3, 1.2.3 Unknown, 1.3 Drug and toxin induced, 1.4 Associated with: 1.4.1 Connective tissue disease, 1.4.2 HIV infect

16、ion, 1.4.3 Portal hypertension, 1.4.4 Congenital heart diseases, 1.4.5 Schistosomiasis, 1 Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis, Persistent pulmonary Persistent pulmonary hypertension of the newborn (PPHN)hypertension of the newborn (PPHN)2. Pulmonary hypertensi

17、on due to left heart disease: 2.1 Left ventricular systolic dysfunction, 2.2 Left ventricular diastolic dysfunction, 2.3 Valvular disease, 2.4 Congenital/acquired left heart inflow/outflow tract 2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathiesobstru

18、ction and congenital cardiomyopathies3. Pulmonary hypertension due to lung diseases and/or hypoxia: 3.1 Chronic obstructive pulmonary disease, 3.2 Interstitial lung disease,3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern,3.4 Sleep-disordered breathing, 3.5 Alveolar hypove

19、ntilation disorders, 3.6 Chronic exposure to high altitude, 3.7 Developmental lung diseases4. Chronic thromboembolic pulmonary hypertension (CTEPH)5. Pulmonary hypertension with unclear multifactorial mechanisms: 5.1 Hematologic disorders: chronic hemolytic chronic hemolytic anemiaanemia, myeloproli

20、ferative disorders, splenectomy, 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis, 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders, 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental P

21、Hsegmental PH BMPR = bone morphogenic protein receptor type II; CAV1 = caveolin-1; ENG = endoglinLung diseases associated with PPHN in 299 neonates enrolled in the early iNO study in FT and late Preterm newborns 2004 data.Konduri GG, Solimano A, Sokol GM, et al. A randomized trial of early versus st

22、andard inhaled nitric oxide therapy in term and near-term newborn infants with hypoxic respiratory failure. Pediatrics 2004;113(3 Pt 1):55964Etiology of PPHN (Steurer et al, Pediatrics 2017Idiopathic PPHN (?)Constriction of DA in utero (for example: after exposure of NSAID in the 3rd trimester by in

23、hibiting prostacyclin production)Exposure to SSRI during late gestation is associated with six-fold increase in the prevalence of PPHN (serotonin increases fetal PVR)Disruption in the NO-cGMP, prostacyclin-cAMP and endothelin signaling pathways Other causes of PHNeonatal pulmonary hypertension frequ

24、ently resolves and has not been associated with genetic factorsAlveolar capillary dysplasia: rare, lethal cause of pulmonary hypertension. 10% have familial associationBPD: developmental abnormalities of lung structure: impaired alveolarization and vascularization with altered pulmonary vascular gro

25、wth and significant pulmonary hypertensionSP-B deficiency, ABCA3 deficiency, variants of corticotropin-releasing hormone receptor 1ManagementGood intensive care:Normal temperatureNormal electrolytes, specially Ca, glucose and intravascular volume, avoid acidosisMaintain normal systemic blood pressur

26、e: judicious use of volume and cardiotonic therapy: dobutamine (?), dopamine (?), vasopressin and milrinone to enhance cardiac output and systemic O2 transportFail of medical management: ECMOVasopressin Potent vasoconstrictor and useful in vasodilatory shock: 0.01 to 0.04 units/Kg/hour (up to 0.1 ha

27、s been used in PPHN)Works in different receptors: arginine vasopressin receptor agonist: AVPR1a (V1)= increases SVR and MBP and decreases PVR; AVPR2 (V2) = increases cAMPIt has been used in catecholamine- resistant septic shock; because it acts through independent mechanisms, it may overcome alpha-r

28、eceptor down-regulation in this setting Steroids before considering vasopressin (?)Respiratory Management:High frequency ventilation: in NB with parenchymal lung disease (MAS, RDS, pneumonia) high frequency ventilation is often useful to optimize lung expansion and enhance the effect of iNOSurfactan

29、t administration: may promote lung expansion and reverse surfactant inactivation associated with parenchymal lung diseaseAlkalosis: no longer recommended, the response to alkalosis is transient, may worsen vascular tone, reactivity and edema. Reduces cerebral blood flow and O2 delivery to the brainO

30、xygen and VentilationIn the ovine ductal ligation model of PPHN, maintaining oxygen saturations in the 90-97% range results in low PVRMaintaining preductal oxygen saturations in low to mid-90s during management of infants with PPHN with PaO2 levels between 55 and 80 mmHg“Gentle” ventilation strategi

31、es with optimal PEEP, relatively low PIP and some permissive hypercapnia are now being recommended to ensure adequate lung expansion without causing barotraumaMedications: iNOPulmonary vasodilators: iNO is the only pulmonary hypertension therapy approved for childreniNO: initiate at 20 ppm when the

32、OI = (MAPxFiO2x100)/PaO2 exceeds 15-25. iNO is a small gas molecule, delivered as inhalation therapy and it has shown to decrease the need for ECMO in moderate/severe PPHN. However, does not reduce mortality, LOS or risk of neurodevelopmental impairment. As many as 40% of infant will not respond to

33、iNONO signaling pathwayO2, estrogen, shear stressEndotheliumSmooth MuscleReceptorLigand: ATP, VEGFeNOSL-ArginineL-CitrullineNOGTPGuanylate cyclasec-GMP: Ca2+5-GMPPDE-5StimulatesVasodilationSildenafilBlood vessel lumenSildenafilSildenafil: PDE5 inhibitor: augment nitric oxide-cGMP signaling by inhibi

34、ting the degradation of cGMP. Increased cGMP results in pulmonary vascular relaxationIV sildenafil is a selective pulmonary vasodilator in piglet modelHuman data: 72 hours of enteral sildenafil administration in neonates with PPHN to meconium aspiration or sepsis: no significant decrease in MBP or i

35、ncrease in vasopressor/inotrope requirement occurredLimjoco J et al: Changes in Mean Arterial Blood Pressure During Sildenafil Use in Neonates With Meconium Aspiration Syndrome or Sepsis. Am J Ther, Jan 23, 2013SildenafilIncreased mortality was reported in pediatric patients randomized to high dose

36、sildenafil mono-therapy at 3-years F/URisk factors for death included patients with IPAH. Children with PH associated with CHD and children weighing less than 20 Kg did not have increase mortalityBarst R J et al: A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil c

37、itrate in treatment-nave Children with pulmonary arterial hypertension. Circulation Jan 17; 2012Sildenafil in PPHN13 neonates (OI 25) received either placebo or enteral sildenafil. The OI decreased by 30 h in all 7 sildenafil patients, and 6 of those 7 neonates survived. There was no systemic hypote

38、nsion in either group. In the placebo group, only 1 of the 6 patients survivedOpen-label, dose-escalation trial that included 36 newborns with PPHN and an OI 15 (most on iNO), a continuous intravenous infusion of sildenafil for 27 days improved oxygenation index by 4 hours at higher dosesBaquero H,

39、at al. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006;117(4):1077-1083Steinhorn RH, et al. Intravenous sildenafil in the treatment of neonates with persistent pulmonary hypertension. J Pediatr 2009;155(6):841847. e8

40、41Prostanoids: EpoprosterolIntravenous PGI2, epoprostenol, remains the best-proven and most effective therapy for chronic PHEven without an initial vasodilating response to PGI2 patients often gain long-term benefit, suggesting effects beyond vasodilation, such as anti-platelet effects, cAMP-mediate

41、d inhibition of smooth-muscle cell growth, or other unknown mechanismsProstanoids:Complications associated with long-term epoprostenol include thrombosis and infection secondary to the required indwelling central venous catheter, the need for dose escalation, and life-threatening rebound PH on disco

42、ntinuation Push towards inhaled prostanoids: iloprost and trepostinil; SQ: trepostinil and PO: beraprost: mixed resultsProstacyclin signaling pathwayO2, lung distensionEndotheliumSmooth MuscleReceptorLigand: ATPCOX, PGI2 synthaseArachidonic acidProstaglandinsPGI2ATPAdenylate cyclasecAMP: Ca2+5-AMPPD

43、E-3StimulatesVasodilationMilrinoneBlood vessel lumenProstanoids: IloprostIloprost is a PGI2 analog that is FDA approved for administration via nebulization. A study of iloprost in 22 children with PH found that inhaled iloprost decreased PAP to a degree equivalent to iNO with oxygen. A minority of p

44、atients (35%) demonstrated improved functional class, but up to 10% experienced acute bronchoconstrictionIvy DD, et al. Short- and long-term effects of inhaled iloprost therapy in children with pulmonary arterial hypertension. J Am Coll Cardiol 2008;51(2):161169Endothelin-1Circulating plasma levels

45、of ET-1 are raised in patients with PHIncreased circulating levels of ET-1 correlate with increased right atrial pressure, increased pulmonary vascular resistance, decreased pulmonary artery oxygen saturation and increased mortalityGivertz MM, et al. Acute endothelin A receptor blockade causes selec

46、tive pulmonary vasodilation in patients with chronic heart failure. Circulation 2000;101:29227.Endothelin-1 Receptors: ETA and ETBETA antagonism causes vasodilation, ETB antagonism causes vasoconstrictionUnlike augmentation of the NO/cGMP and prostanoid cascades, inhibition of endothelin-1 (ET-1) si

47、gnaling does not reliably cause acute pulmonary vascular relaxation Givertz MM, et al. Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure. Circulation 2000;101:29227.(?), Hypoxia, shear stress, decreased blood flow,adrenaline, IL-1, TG

48、F-, thrombin, glucose.Endothelial CellSmooth Muscle Cell+ +ETANO, PGI2 productionVasoconstrictionPhospholipase C activationRelease of intracellular Ca2+1,4,5-inositol triphosphate = VasoconstrictionBlood vessel lumenModified from McLaughlin V ey al: Pulmonary arterial hypertension. Current Problems

49、in Cardiology vol 36, 12 (2011) 461-517 and from Shao D et al: the role of endothelin-1 in the pathogenesis of PAH. Pharmacological Research 63 (2011) 504-511 Endothelin-1 PathwayETBETB= VasodilationPreProETBigETET-1ET-1ECECirculating ET clearanceBosentanNon selective endothelin receptor antagonistB

50、osentan also has direct anti-fibrotic effect: reverses smooth muscle hypertrophy and hyperplasiaContraindicated in children with moderate to severe liver impairment; sulfonamide-based agent metabolized by cytochrome P450 enzymesApproved in Europe for children 2 years and olderAmbrisentanOral selecti

51、ve ETA-receptor antagonist that is metabolized by hepatic glucuronidation, with less involvement of the P450 enzyme pathwayData are not yet available on the efficacy of ambrisentan for children under 12 years of age with PHECMOAn OI 40 is often used as an indication for ECMO evaluationCostly, labor

52、intensive, associated with potential adverse effects: IVH, ligation of the right common carotid arteryCannulation should be considered for term and late preterm NB with pulmonary hypertension and/or hypoxemia that remains refractory to iNO after optimization of respiratory and cardiac function New I

53、nsightsOxidant stress plays an important role in the pathogenesis of PPHNIncrease ROS such as superoxide and hydrogen peroxide in SMC has been demonstrated in the PPHN lamb modelThe extreme hyperoxia that was routinely used in PPHN management is toxic to the developing lung by formation of ROS: isop

54、rostanes and peroxynitrite ROS Impairs normal transitionPPHN100% O2ROSeNOS expressionPDE5 ActivityBlunted cGMPO2 and PPHN 30 min of exposure to 100% oxygen increase reactivity of pulmonary vessels in the normal lambDiminishes the response of the pulmonary vasculature to endogenous and exogenous NOIncreases activity of c-GMP-specific phosphodiast