6/22/2013 Disclosures Use of PH Directed Therapies in Patients with Single Ventricles • Any insight that I have into the single ventricle pulmonary bed comes from the effort of the Brian D Hanna, MDCM, PhD surgeons and cardiologists who look after our Director, Section of Pulmonary Hypertension Division of Cardiology single ventricle patients. The Children’s Hospital of Philadelphia • My institution receives grant support from Clinical Professor of Pediatrics Actelion, United Therapeutics, GSK, and Lily Perelman School of Medicine University of Pennsylvania who market PH specific therapies. • In this presentation I discuss off-label, non- approved use of pharmaceuticals in children. Pulmonary vascular biology with the Objectives physiology of single ventricle palliation • Pulmonary vascular biology with the physiology • In the 2 ventricle patient, morbidity and mortality of single ventricle palliation caused by PH is from right ventricular failure: • Monitoring pulmonary vascular adequacy in high RV afterload, low LV pre-load, reduced single ventricle physiology inotropy from ventriculo-ventricular interaction • Results of therapeutic trials of pulmonary and inadequate coronary flow. vasodilators for PH in single ventricle • In the SV patient, morbidity and mortality caused by PH is from high systemic venous pressures, low pulmonary blood flow and reduced inotropy from inadequate coronary flow. 1
6/22/2013 Pulmonary vascular biology with the What limits the pulmonary physiology of single ventricle palliation vascular bed in SV palliation? • Developmental challenges: non-pulsatile flow • Defining PH as mPAP > 25 mm Hg with PCW < 13, and PVRi > 3 WU is inadequate for SV. • Inflammation and lung destruction/vascular loss – mPAP >25 are just not tolerated! – Oxygen toxicity – QP estimation in SV is poor (VO 2 ; collateral flow) – Ventilator shear forces • Defining PH as a trans-pulmonary pressure – Infection gradient > 12 (?) mmHg might eliminate QP – Micro aspiration of pepsin errors but not ventricular diastolic dysfunction. • Mechanical obstruction and vasoconstriction • The effect of PH on mPAP, PVR or TPG is not • Vascular occlusion from uncontrolled invasion of linear nor is it currently predictable. transformed myofibroblasts Vascular development is a Monitoring pulmonary vascular postnatal event adequacy in SV • Clinical Status: O 2 Saturation; systemic venous congestion; systemic blood pressure; perfusion 14 • Echo: shunt adequacy; “Glen” anastomosis stenosis; LPA stenosis; IVC dynamics (?); ventricular diastolic dysfunction (?) 17 divisions = 40% 60% • Catheterization: QP (?); mean PAP; TPG; PA stenoses; veno-veno shunt; vasoreactivity (?) An infant is born with 4% of the pre-capillary arterials of • MRI: QP and aorto-pulmonary shunt flow; an adult. How much development is dependent on pulsatile vasoreactivity (?) flow? 2
6/22/2013 Monitoring pulmonary vascular Monitoring pulmonary vascular adequacy in SV adequacy in SV • Pulmonary Function tests: % predicted flows and • Chest CT angiogram: regional blood flow; air volumes assess adequate growth, large and small space disease; stenoses and veno-veno shunts; airway obstruction and reversibility; DLCO; controlled inspiration used for volumes MIF; MEF • 2 or 6 min walk test: sub-maximal exercise; O2 • Blood testing: BNP, pro-BNP and uric acid not desaturation; heart rate and pressure response; markers of pulmonary vascular biology • Metabolic stress test: maximal exercise; O2 • Liver enzyme and function testing: marker of desaturation; heart rate and blood pressure systemic vascular congestion from pulmonary response; estimate QS; maximal O2 vascular disease (either larger or small vessel) consumption; anaerobic threshold; O2 pulse MRI estimate of QP in SV Is there anything better to demonstrate an adequate pulmonary vascular bed in SV? Glatz, etal. Circ Cardiovasc Imaging. 2012; 5(2): 218–225. 3
6/22/2013 MRI estimate of energy loss in Pre-Fontan “vascular compliance” the Fontan Circuit predicts early outcome By multiple linear regression, PVC (P=0.002) and CPB (P=0.003) independently Predicted time of pleural effusion, explaining 22% of the variation. Int J Cardiol. 2009 Mar 20;133(1):55-61 Worse vascular compliance, Predicted Cross Sectional Area: A worse chest tube drainage multibranched model of the pulmonary vascular bed Variables: -BSA -Lung size -MV (% TLC) -Compliance -Pal, Ppl -Qp, LaP, PAP Bshouty Z, M Younes J Appl Physiol 68: 1514-27, 1990 International Journal of Cardiology 133 (2009) 55–61 4
6/22/2013 Predicted Cross sectional area is now quantifiable 140 CI 0 to 2.5 120 CI 2.5 to 5 PH-specific treatment for SV CI 5 to 7.5 mPAP (mm Hg) 100 Power (CI 0 to 2.5) vascular insufficiency Power (CI 2.5 to 5) 80 Power (CI 5 to 7.5) 60 40 20 0 0 10 20 30 40 50 60 70 80 90 100 PVC (%) Frank, etal. ATS Annual Conference, 2011 PH early after Stage 1 palliation • PH associated with vasoconstriction, developmental inadequacy and pulmonary vein obstruction • No data on therapeutic options: – NO works – sildenafil sometimes works – “iv” prostacyclin can increase QP unless it drops SVR N Engl J Med 2004;351:1425-36. 5
6/22/2013 PH early after Stage 2 palliation PH early after the Fontan • PH associated with pre-Stage 2 lung injury • PH associated with pre-Fontan lung pathology (including (inflammatory : read aspiraton), CBP time, unrecognized hypoplasia), CPB time, ventilator effects and anatomic issues (pulmonary vein stenosis). unrecognized anatomic issues (pulmonary vein stenosis, Gamillscheg A, et al. Inhaled nitric oxide in patients AV regurgitation, ventricular dysfunction) • with critical pulmonary perfusion after Fontan-type • Takahashi K, et al. Effect of beraprost sodium on pulmonary procedures and bidirectional Glenn anastomosis. J vascular resistance in candidates for a Fontan procedure: a preliminary study. Pediatr Int. 2003;45:671-5. Thorac Cardiovasc Surg. 1997;113:435-42. • Miyaji K, et al . Combined therapy with inhaled nitric oxide and intravenous epoprostenol (prostacyclin) for critical pulmonary perfusion after the Fontan procedure. J Thorac Cardiovasc Surg. 2003;125:437-9. PH late after the Fontan • In addition to pre-Fontan lung pathology, AV regurgitation, ventricular dysfunction and aorto-pulmonary collateral flow. • Khambadkone S, etal. Basal pulmonary vascular resistance and nitric oxide responsiveness late after Fontan-type operation. Circ. 2003;107:3204-8. • Giardini A, etal. Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. Eur Heart J. 2008;29:1681-7. 9.5 year • Haseyama K, etal. Pulmonary vasodilation therapy with sildenafil citrate in a patient with plastic bronchitis after the Fontan procedure for hypoplastic left with heart syndrome. J Thorac Cardiovasc Surg. 2006;132:1232-3. • Uzun O, etal. Resolution of protein-losing enteropathy and normalization of HLHS and mesenteric Doppler flow with sildenafil after Fontan. Ann Thorac Surg. 2006;82:e39-40. PLE • Ovaert C, etal. The effect of bosentan in patients with a failing Fontan • circulation. Cardiol Young. 2009;19:331-9. 6
6/22/2013 Post-exercise VO2max following Randomized crossover 6 week trial single dose sildenafil in Fontan of sildenafil in Fontan: 8-18 y/o • Sildenafil improved ventilatory efficiency and exercise performance at the anaerobic threshold but did not alter VO2max. • The suggestion of improvement in VO2 at the anaerobic threshold for full population and significant improvement in 2 subgroups: – single LV or mixed morphology – BNP >100 pg/mL Goldberg, etal Circulation 2011, 123:1185-1193 Eur Heart J 2008;29:1681-7 Randomized crossover 6 week trial Bosentan: no impact on of sildenafil in Fontan: 8-18 y/o exercise testing in adult Fontan Decrease in PVR or increase in inotropic state? European J Heart Failure (2013) 15, 690–698 Goldberg, etal. Pediatr Cardiol. 2012 Feb 14. [Epub] 7
6/22/2013 Bosentan: no impact on Bosentan: no impact on exercise testing in adult Fontan exercise testing in adult Fontan European J Heart Failure (2013) 15, 690–698 European J Heart Failure (2013) 15, 690–698 Summary • The lung after single ventricle palliation is small and, when injured, has a restrictive vascular bed. • Combined with post surgical complications, a restrictive vascular bed increases morbidity and mortality. • Speculative conclusion: If you start looking for and treating PH late after Fontan, you are too darn late. 8
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