Persistierende pulmonale Hypertonie des Neugeborenen und chronisch progressive pulmonale Hypertonie im ersten Lebensjahr

Zusammenfassung

Die persistierende pulmonale Hypertonie des Neugeborenen (PPHN) ist eine seltene, heterogene Erkrankung mit hoher Mortalität. Die PPHN ist gekennzeichnet durch einen hohen pulmonalen Gefäßwiderstand (PVR, Rp) und einen erhöhten pulmonalarteriellen Druck (PAP) sowie extra- und intrapulmonale Rechts-Links-Shunts. Entstehen kann sie auf dem Boden von Lungenentwicklungsstörungen, intrauterinen Ereignissen oder bei der Anpassung an das extrauterine Leben. Die PPHN tritt häufig in Assoziation mit einer primären oder sekundären Lungen -erkrankung auf, die entweder das Broncho-Alveolar system, die Lungengefäße oder die pulmonalen Lymphgefäße betrifft. Betroffen sind meist reife oder fast reife Neugeborene (NG) innerhalb der ersten 30 Lebenstage. Auslöser können Erkrankungen sein, die zu einem respiratorischen Versagen mit alveolärer Hypoxie führen (Mekonium -aspirationssyndrom (MAS), angeborene Pneumonie, Sepsis, Geburtsasphyxie, Atemnotsyndrom (RDS), Lungenhypoplasie, Zwerchfellhernie (CDH), alveoläre kapilläre Dysplasie (ACD), pulmonale Lymphangiektasie). Ferner kommen als Ursachen Noxen wie die Einnahme von Medikamenten und Drogen während der Schwangerschaft infrage. Die PPHN kann ebenfalls idiopathisch auftreten. Postnatal kommt es durch die zunehmende Belüftung der Lunge zu einem physiologischen Abfall des Widerstandes in den Lungenarteriolen. Bleibt diese extrauterine Adaptation aus oder besteht eine vorbestehende anatomische oder funktionelle Beeinträchtigung der pulmonalen Arteriolen, kann sich eine PPHN entwickeln. Über den Ductus arteriosus, das Foramen ovale und intrapulmonale Kurzschlüsse wird nicht oxygeniertes Blut im Sinne eines Recht-Links-Shunts an den ventilierten Arealen der Lunge vorbeigeleitet. Klinisch resultiert eine Zyanose. Der erhöhte pulmonale Gefäßwiderstand führt des Weiteren zu einer Nachlasterhöhung und einer Druckbelastung des rechten Ventrikels (RV), die über Tage bis Wochen in ein Rechtsherz versagen münden kann.

Eine Sonderform der pulmonalen Hypertonie im ersten Lebensjahr stellt die chronisch progressive pulmonale Hypertonie (PH) dar, die sich im Laufe der ersten Lebenswochen bis -monate entwickeln kann. Im Vergleich zur neonatalen PPHN liegen hier wahrscheinlich andere Ursa-chen und Pathomechanismen zugrunde. Eine PPHN ist per se akut, kann aber auch in eine chronisch progressive PH übergehen.

Summary

Persistent pulmonary hypertension of the newborn (PPHN) is a rare disease. PPHN occurs as an heterogenic disorder that can have a high mortality rate: in strong association with abnormalities of lung development, preceding intrauterine events and/or postnatal maladaptation, or as a complex syndrome. PPHN often occurs in primary or secondary lung disease of the bronchiolalveolar system, pulmonary arteries/veins, and/ or lymphatic vessels. PPHN is a result of remainingly high pulmonary vascular resistance and suprasystemic pulmonary artery pressure. The postnatal maladaptation results in hypoxemia and cyanosis due to right-to-left shunting across the ductus arteriosus, the foramen ovale and intrapulmonary shunts. The right ventricular pressure overload leads to decreased right-ventricular stroke volume and ultimately right heart failure.

Often no cause is found for PPHN (idiopathic). Known triggering events are respiratory failure/alveolar hypoxia, lung hypoplasia, maternal medication or drug abuse. PPHN presents as an acute syndrome in the first 30 days of life. Chronic progressive pulmonary hypertension represents a special form of pulmonary hypertension (PH) that develops during the first weeks and months of life. Compared to PPHN, chronic progressive PH is caused by different disease mechanisms and has a higher rate of mortality.

Schlüsselwörter

PPHN - chronische progressive pulmonale Hypertonie - Neugeborene - Säuglinge

Keywords

PPHN - chronic progressive pulmonary hypertension - newborn - infant

• Literatur

• 1 Perez M, Wedgwood S, Lakshminrusimha S, Farrow KN, Steinhorn RH. Hydrocortisone normalizes phosphodiesterase-5 activity in pulmonary artery smooth muscle cells from lambs with persistent pulmonary hypertension of the newborn. Pulmonary circulation 2014; 4: 71-81.
• 2 Nair J, Lakshminrusimha S. Update on PPHN: mechanisms and treatment. Seminars in perinatology 2014; 38: 78-91.
• 3 Ivy DD, Abman SH, Barst RJ, Berger RM, Bonnet D, Fleming TR. et al. Pediatric pulmonary hypertension. Journal of the American College of Cardiology 2013; 62: D117-126.
• 4 Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A. et al. Updated clinical classification of pulmonary hypertension. Journal of the American College of Cardiology 2013; 62: D34-41.
• 5 Cerro MJ, Abman S, Diaz G, Freudenthal AH, Freudenthal F, Harikrishnan S. et al. A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: Report from the PVRI Pediatric Taskforce, Panama 2011. Pulmonary circulation 2011; 1: 286-298.
• 6 Fike CD, Summar M, Aschner JL. L-citrulline provides a novel strategy for treating chronic pulmonary hypertension in newborn infants. Acta paediatrica 2014; 103: 1019-1026.
• 7 Fike CD, Aschner JL. Looking beyond PPHN: the unmet challenge of chronic progressive pulmonary hypertension in the newborn. Pulmonary circulation 2013; 3: 454-466.
• 8 Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL. et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. The New England journal of medicine 2006; 354: 579-587.
• 9 Steinhorn RH. Diagnosis and treatment of pulmonary hypertension in infancy. Early human development 2013; 89: 865-874.
• 10 van Loon RL, Roofthooft MT, Hillege HL, ten Harkel AD, van Osch-Gevers M, Delhaas T. et al. Pediatric pulmonary hypertension in the Netherlands: epidemiology and characterization during the period 1991 to 2005. Circulation 2011; 124: 1755-1764.
• 11 Delaney C, Cornfield DN. Risk factors for persistent pulmonary hypertension of the newborn. Pulmonary circulation 2012; 2: 15-20.
• 12 Park MK. Pediatric cardiology for practitioners. 5th ed. St. Louis: Mosby; 2008: 704
• 13 Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2006; CD000399
• 14 Rosenberg AA. Outcome in term infants treated with inhaled nitric oxide. Journal of Pediatrics 2002; 140: 284-287.
• 15 Hoehn T. Therapy of pulmonary hypertension in neonates and infants. Pharmacology and Therapeutics 2007; 114: 318-326.
• 16 Clark RH, Kueser TJ, Walker MW, Southgate WM, Huckaby JL, Perez JA. et al. Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. Clinical Inhaled Nitric Oxide Research Group. The New England journal of medicine 2000; 342: 469-474.
• 17 Kahveci H, Yilmaz O, Avsar UZ, Ciftel M, Kilic O, Laloglu F. et al. Oral sildenafil and inhaled iloprost in the treatment of pulmonary hypertension of the newborn. Pediatric pulmonology 2014; 49: 1205-1213.
• 18 Yucel IK, Cevik A, Bulut MO, Dedeoglu R, Demir IH, Erdem A. et al. Efficacy of very low-dose prostaglandin E1 in duct-dependent congenital heart disease. Cardiology in the young 2015; 25: 56-62.
• 19 Tworetzky W, Bristow J, Moore P, Brook MM, Segal MR, Brasch RC. et al. Inhaled nitric oxide in neonates with persistent pulmonary hypertension. Lancet 2001; 357: 118-120.
• 20 Kinsella JP, Cutter GR, Steinhorn RH, Nelin LD, Walsh WF, Finer NN. et al. Noninvasive Inhaled Nitric Oxide Does Not Prevent Bronchopulmonary Dysplasia in Premature Newborns. The Journal of pediatrics 2014; 165: 1104-1108.
• 21 Murray F, Patel HH, Suda RY, Zhang S, Thistlethwaite PA, Yuan JX. et al. Expression and activity of cAMP phosphodiesterase isoforms in pulmonary artery smooth muscle cells from patients with pulmonary hypertension: role for PDE1. Am J Physiol Lung Cell Mol Physiol 2007; 292: L294-303.
• 22 Schermuly RT, Pullamsetti SS, Kwapiszewska G, Dumitrascu R, Tian X, Weissmann N. et al. Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: target for reverse-remodeling therapy. Circulation 2007; 115: 2331-2339.
• 23 Weinberger B, Weiss K, Heck DE, Laskin DL, Laskin JD. Pharmacologic therapy of persistent pulmonary hypertension of the newborn. Pharmacology and Therapeutics 2001; 89: 67-79.
• 24 Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006; 117: 1077-1083.
• 25 Barst RJ, Beghetti M, Pulido T, Layton G, Konourina I, Zhang M. et al. STARTS-2: long-term survival with oral Sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension. Circulation 2014; 129: 1914-1923.
• 26 Ichinose F, Erana-Garcia J, Hromi J, Raveh Y, Jones R, Krim L. et al. Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Critical Care Medicine 2001; 29: 1000-1005.
• 27 Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A. et al. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 2001; 104: 424-428.
• 28 Humpl T, Reyes JT, Holtby H, Stephens D, Adatia I. Beneficial effect of oral sildenafil therapy on childhood pulmonary arterial hypertension: twelve-month clinical trial of a single-drug, open-label, pilot study. Circulation 2005; 111: 3274-3480.
• 29 Shah P, Ohlsson A. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev 2007; CD005494
• 30 (FDA) FaDA. Update, FDA Warning On Sildenafil Use In Children With PH 2014. Available from. www.fda.gov/drugs/drugsafety/ucm390876.htm
• 31 McNamara PJ, Laique F, Muang-In S, Whyte HE. Milrinone improves oxygenation in neonates with severe persistent pulmonary hypertension of the newborn. Journal of Critical Care 2006; 21: 217-222.
• 32 Hoeper MM, Schwarze M, Ehlerding S, Adler-Schuermeyer A, Spiekerkoetter E, Niedermeyer J. et al. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. New England Journal of Medicine 2000; 342: 1866-1870.
• 33 Wedgwood S, McMullan DM, Bekker JM, Fineman JR, Black SM. Role for endothelin-1-induced superoxide and peroxynitrite production in rebound pulmonary hypertension associated with inhaled nitric oxide therapy. Circulation Research 2001; 89: 357-364.
• 34 Moya MP, Gow AJ, Califf RM, Goldberg RN, Stamler JS. Inhaled ethyl nitrite gas for persistent pulmonary hypertension of the newborn. Lancet 2002; 360: 141-143.
• 35 Teng RJ, Wu TJ. Persistent pulmonary hypertension of the newborn. J Formos Med Assoc 2013; 112: 177-184.
• 36 Stewart A, Brion LP, Ambrosio-Perez I. Diuretics acting on the distal renal tubule for preterm infants with (or developing) chronic lung disease. The Cochrane database of systematic reviews 2011; CD001817
• 37 UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. UK Collaborative ECMO Trail Group. Lancet 1996; 348: 75-82.
• 38 Mirza H, Ziegler J, Ford S, Padbury J, Tucker R, Laptook A. Pulmonary Hypertension in Preterm Infants: Prevalence and Association with Bronchopulmonary Dysplasia. The Journal of pediatrics 2014; 165: 909-914.
• 39 Hansmann G. Neugeborenen-Notfälle. Stuttgart: Schattauer-Verlag; 2015
• 40 Mettauer N, Agrawal S, Pierce C, Ashworth M, Petros A. Outcome of children with pulmonary lymphangiectasis. Pediatric pulmonology 2009; 44: 351-357.