Management of Pulmonary Hypertension in Children Aneesa Vanker Department of Paediatrics & Child Health Red Cross War Memorial Children’s Children s Hospital University of Cape Town Overview • • • • • • • Conventional classifications and definitions Revised paediatric classification Diagnostic strategy Diagnostic strategy Aids to diagnosis Treatment options Controversies Way forward Pulmonaryy Arterial Hypertension yp (PAH) • “Critical determinant of morbidity and mortality in diverse paediatric cardiac, lung, haematologic and other diseases.”1 • Disease of entire pulmonary circulation. p y • Small pulmonary arteries Æ vascular narrowing, remodelling of vessel wall, intraluminal obstruction & remodelling of vessel wall, intraluminal obstruction & decreased vascular growth. • Larger arteriesÆ Larger arteriesÆ vascular stiffness ÎRV afterload vascular stiffness ÎRV afterload 1. Abman SH, Ivy DD. “Recent progress in understanding paediatric pulmonary hypertension”; Curr Opin Pediatr 23:298‐304 Conventional knowledge • Definitions and classifications • Based on adult data Based on adult data • No large paediatric based studies or registries. Definition – Pulmonary Arterial Hypertension (PAH) • Mean pulmonary arterial pressure (PAP): ( ) >/= 25mmHg at rest >/= 30mmHg with exercise • Generalisable across all ages (except very young infants) Classification • PAH generally categorised as “Primary” (now idiopathic) or “Secondary” idiopathic) or Secondary (associated with other (associated with other diseases) • The WHO classification differentiated various types of hypertension. (1998) fh ( ) • Classification updated at 4th World Symposium on Pulmonary Hypertension, Dana Point California, USA y yp , , (2008) So what is new? • Recognition that application of Dana Point g pp Classification to paediatric PAH sometimes difficult. Foetal origins and developmental mechanisms are • Foetal origins and developmental mechanisms are potentially important both in paediatric disease and as a risk factor for adult pulmonary HPT. as a risk factor for adult pulmonary HPT. • Aetiology of pulmonary HPT in children often multifactorial and factors such as perinatal multifactorial and factors such as perinatal maladaptation, maldevelopment and lung hypoplasia may be significant may be significant. Pulmonary Vascular Research Institute (PVRI) Panama P Classification Cl ifi i (2011) • Aim: to improve p diagnostic strategies, promote appropriate p pp p clinical investigations and improve p understanding of disease pathogenesis, p g , physiology and epidemiology. p gy • Figure Figure 1: Venn diagram 1: Venn diagram illustrating the heterogeneity and g y multifactorial elements pediatric pulmonary hypertensive vascular disease. Figure 1: Venn diagram illustrating the • heterogeneity and multifactorial elements in pediatric pulmonary hypertensive vascular disease. PVRI Panama Classification • “Paediatric Paediatric Pulmonary Vascular Hypertensive Disease Pulmonary Vascular Hypertensive Disease” – term used & not pulmonary HPT. • Excludes patients with pulmonary hypertension but without elevated pulmonary vascular resistance – ie patients with large systemic to pulmonary connections. • Such patients do not require drug Rx for PHT but rather p q g closure of defect. PVRI Panama Classification • Definition of paediatric pulmonary hypertensive vascular disease: l di mean pulmonary artery pressure > 25mmHG pulmonary vascular resistance index pulmonary vascular resistance index >3.0 Wood units m2 The Broad Schema of 10 Basic Categories of Paediatric Pulmonary Hypertensive Vascular Disease PVRI Panama Classification Purpose • Detailed Detailed classification is extensive classification is extensive • Allows for the categorisation of patients with multifactorial causes of pulmonary hypertension . l f l f l h • Also accommodates the fact that a single disease or condition may cause different types of pulmonary vascular disease eg Sickle cell disease or anti‐ phospholipid syndrome. Diagnostic Strategy Strategy…(briefly) (briefly) “Clinical Suspicion” • Suspect PHT in a child with shortness of breath, tires easily or is syncopal with no evidence of heart or lung disease. Or In children with these diseases when increasing • In children with these diseases when increasing shortness of breath cannot be explained by the underlying disease process underlying disease process. Diagnostic Strategy “Confirming Clinical Suspicion” g p Haworth SG, The Management of Pulmonary Hypertension in Children. Arch Dis Child 2008;93:620–625. doi:10 1136/adc 2007 12049 doi:10.1136/adc.2007.12049 Aids to diagnostic evaluation • Echocardiogram – non‐invasive diagnostic tool. S Screens for disease, determines L & R heart structure f di d i L&Rh and function and estimates pulmonary arterial pressure. • 6 minute walk test – useful in functional assessment of children with PHT. what’s normal? 6 minute walk test – “Healthy Children” * • The distance walked increased significantly from 4 to 7 years of age • 4 years 383+/−41 m; y / , • 5 years 420+/−39 m, • 6 years 463+/−40 m; – 7 years 488+/−35 m; 7 years 488+/ 35 m; • with further modest increases beyond 7 years of age **Lammers AE, Hislop l AA, Flynn Y, Haworth SG. The 6‐minute walk test: normal l h h lk l values for children of 4–11 years of age. Arch Dis Child 2008;93(6):455–6. Functional Classification of PH in children h ld • Also Also recently reviewed by PVRI task force. recently reviewed by PVRI task force • Based on adult “Evian pulmonary hypertension specific classification” specific classification” • Different classification for various paediatric age groups – 0‐0.5 years; 0.5‐1yr; 1‐2yrs; 2‐5yrs; 6‐15yrs. • 4 classes: Functional Class 1, 2, 3a and 3b and 4 (most severe) 0‐0.5 years 5‐ 16years What to expect in children in functional class 1 MRI • Potentially valuable tool in evaluating PH. • Limited data on it’s use in paediatrics. • Allows for measurement of right ventricular dimensions, blood flow velocities & metabolic , properties of the myocardium. Performed under anaesthesia in children (Limiting • Performed under anaesthesia in children. (Limiting factor) Cardiac Catherisation • Remains Remains absolute requirement for confirming the absolute requirement for confirming the diagnosis and guiding management. • Baseline measures include : right atrial pressure, Baseline measures include : right atrial pressure pulmonary arterial pressure, systemic arterial pressure mixed venous and systemic arterial pressure, mixed venous and systemic arterial saturation, cardiac index, pulmonary capillary wedge pressure pulmonary vascular resistance (PVR) & pressure, pulmonary vascular resistance (PVR) & systemic vascular resistance (SVR). • Acute vasodilator testing. Ac te asodilator testing Therapeutic p Options p • Aim to dilate and reverse abnormal remodelling of pulmonary vascular bed pulmonary vascular bed. • Medical therapy targets 3 key signalling pathways: prostacyclin, endothelin p y , & nitric oxide. • • Tissot C, Ivy DD, Beghetti Ti C I DD B h i M. Medical therapy for pediatric M M di l h f di i pulmonary l arterial hypertension. J Pediatr yp 2010; 157:528–532. Tissot C, Ivy DD, Beghetti M. Medical therapy for pediatric pulmonary arterial hypertension. J Pediatr 2010; 157:528–532. “The The Algorithm Algorithm” • Calcium Channel Blockers ‐ consider in those with acute vasodilator response. (Repaired congenital heart disease & “IPAH”) 7‐40% with chronic PH – respondersÆ Rx with oral calcium channel blockers • Non‐responders with RHF Æ iv prostacyclin. Prostacyclin analogues • Prostacyclin – metabolite of arachodonic acid – produced endogenously. • Potent systemic and pulmonary vasodilator with anti‐ y p y platelet activity. • Children with severe PAH show decreased prostacyclin in lung vasculature prostacyclin in lung vasculature. Prostacyclin analogues • Epoprostenol p p – synthetic prostacyclin, administered IV y p y infusion. Shown to improve haemodynamics and quality of life in IPAH and APAH. Short half‐life – 1‐2mins Æ continuous infusion and risk of complications assoc with central line. risk of complications assoc with central line. • IlIloprost‐ t inhaled agent. Half‐life 20‐30mins. Review of i h l d t H lf lif 20 30 i R i f its use show 35% had improvement in functional class, 50% 50% unchanged. Frequent administration makes h d F t d i i t ti k compliance problematic. Endothelin-1(ET-1) ( ) receptor p antagonists • ET‐1 – potent vasoconstrictor peptide. Produced primarily in endothelial cells . Acts by stimulating ET‐A and ET‐B receptors Æ Æ vasoconstriction and release of NO and prostacyclin. • Bosentan – oral dual ET‐1 receptor antagonist Æ p g lower PAP & PVR, may improve functional status and survival. However, if systemic‐to‐pulmonary shunt is , y p y present – only short‐term improvement. Endothelin-1(ET-1) receptor antagonists (ETRA) • Ambrisentan‐ oral, daily ETRA. Selectively inhibits ETA receptor. Can have benefit on exercise capacity and functional class in adults. f l l l Little data available for children. Phosphodiesterase type 5 inhibitors • Prevent the breakdown of cyclic guanosine monophosphate Æpulmonary vasodilation. • As efficient as inhaled NO (acute pulmonary vasodilator) • Potentiates NO pulmonary vasodilator effects. Phosphodiesterase p type yp 5 inhibitors • Sildenafil ‐ oral and IV preparations. • Number of studies showing the benefits of sildenafil use in children with various causes of PHT. • Small clinical trial of 14 children with PAH on oral sildenafil Æ deceased PAP & PVR + improved 6min sildenafil Æ deceased PAP & PVR + improved 6min walk test. However, effect plateaued after 6‐12 month * month. * Sildenafil – does it work? • Karatza et al showed an improvement in oxyhaemaglobin capacity and exercise tolerance in children with IPAH and PH assoc hl h with congenital heart h lh dx Rxed with Sildenafil.# • Children with chronic lung disease , treated with Sildenafil were also shown to have improved haemodynamics in 88% with few adverse effects* # * What’ss new? What • Intravenous sildenafil has been shown to have a beneficial role in newborns with PPHN (improved OI) and in postoperative cardiac disease. • Tadalafil – Long Long‐acting acting Phosphodiestrase Phosphodiestrase 5 inhibitor. 5 inhibitor. Approved for use in adults with chronic PAH. Experience with use in children limited. Experience with use in children limited. New approaches • Combined Combined therapy targeting each of the major therapy targeting each of the major signalling pathways may be better than monotherapy. Limited experience on what combinations to use and Limited experience on what combinations to use and when it should be initiated. Surgical options • Children not responding to conventional therapy may p g py y be candidates for atrioseptostomy or transplantation. • Atrioseptostomy – right‐to‐left shunt through interatrial defect. Decreases signs of RHF by defect Decreases signs of RHF by decompressing right heart. Maintains cardiac output but with increased hypoxaemia but with increased hypoxaemia. May be beneficial in severe PAH with recurrent syncope & i t t bl RHF (U & intractable RHF. (Unresponsive to medical Rx) i t di l R ) Surgical options • Transplantation – PAH that has progressed despite optimal medical Rx. Consider for transplantation when 2 year survival <50%. h l • Not always an option in our setting. Controversies • Focus on whether vasodilator therapy is actually beneficial in this form of PAH beneficial in this form of PAH. • Tendency to add medications without sound reasoning. i • Risk‐benefit ratio needs to be weighed. Controversies • Suggest Suggest – infants with CLD, long infants with CLD, long‐term term drug Rx drug Rx reserved for those with “sound and reproducible” evidence of PAP at or near systemic level & evidence evidence of PAP at or near systemic level & evidence of RV dysfunction. • Monitor closely and devise clear end‐point. Monitor closely and devise clear end‐point • Consider discontinuing Rx if end‐points not met. (E (Even if condition improves – if diti i PAH PAH may resolve l spontaneously). • RCT and paediatric networks focusing on PHT. Conclusion • Limited paediatric data especially in term of medical p p y therapy. Panama meeting made important inroads in to • Panama meeting made important inroads in to reclassifying Paediatric Pulmonary Hypertension. • Medical therapy requires close monitoring and a Medical therapy requires close monitoring and a willingness of the practioners to discontinue therpy if no improvement if no improvement. Way forward • On On – going battle for access to vasodilator Rx going battle for access to vasodilator Rx (Sildenafil). • National registry of children with PHT (cause, National registry of children with PHT (cause management). • National guideline management of paediatric N ti l id li t f di t i pulmonary hypertension. • Clinical trial – medical management option. References and useful reading Functional classification of pulmonary hypertension in children: Report from the PVRI pediatric taskforce, Panama 2011 Astrid E. Lammers,1 Ian Adatia,2 Maria Jesus del Cerro,3 Gabriel Diaz,4 Alexandra Heath Freudenthal,5 Franz Freudenthal,5 S. Harikrishnan,6 Dunbar Ivy,7 Antonio A. Lopes,8 J. Usha Raj,9 Julio Sandoval,9 Kurt S Stenmark, k 10 and Sheila G. Haworth d Sh il G H h11 Pulm Circ. 2011 Apr‐Jun; 1(2): 280–285.