Disclosures Use of PH Directed Therapies in Patients with Single - - PowerPoint PPT Presentation

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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

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6/22/2013 1

Use of PH Directed Therapies in Patients with Single Ventricles

Brian D Hanna, MDCM, PhD

Director, Section of Pulmonary Hypertension Division of Cardiology The Children’s Hospital of Philadelphia Clinical Professor of Pediatrics Perelman School of Medicine University of Pennsylvania

Disclosures

  • Any insight that I have into the single ventricle

pulmonary bed comes from the effort of the surgeons and cardiologists who look after our single ventricle patients.

  • My institution receives grant support from

Actelion, United Therapeutics, GSK, and Lily who market PH specific therapies.

  • In this presentation I discuss off-label, non-

approved use of pharmaceuticals in children.

Objectives

  • Pulmonary vascular biology with the physiology
  • f single ventricle palliation
  • Monitoring pulmonary vascular adequacy in

single ventricle physiology

  • Results of therapeutic trials of pulmonary

vasodilators for PH in single ventricle

Pulmonary vascular biology with the physiology of single ventricle palliation

  • In the 2 ventricle patient, morbidity and mortality

caused by PH is from right ventricular failure: high RV afterload, low LV pre-load, reduced inotropy from ventriculo-ventricular interaction and inadequate coronary flow.

  • 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.

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Pulmonary vascular biology with the physiology of single ventricle palliation

  • Defining PH as mPAP > 25 mm Hg with PCW <

13, and PVRi > 3 WU is inadequate for SV.

– mPAP >25 are just not tolerated! – QP estimation in SV is poor (VO2; collateral flow)

  • Defining PH as a trans-pulmonary pressure

gradient > 12 (?) mmHg might eliminate QP errors but not ventricular diastolic dysfunction.

  • The effect of PH on mPAP, PVR or TPG is not

linear nor is it currently predictable.

What limits the pulmonary vascular bed in SV palliation?

  • Developmental challenges: non-pulsatile flow
  • Inflammation and lung destruction/vascular loss

– Oxygen toxicity – Ventilator shear forces – Infection – Micro aspiration of pepsin

  • Mechanical obstruction and vasoconstriction
  • Vascular occlusion from uncontrolled invasion of

transformed myofibroblasts

Vascular development is a postnatal event

17 divisions = 40% 60%

An infant is born with 4% of the pre-capillary arterials of an adult. How much development is dependent on pulsatile flow?

14

Monitoring pulmonary vascular adequacy in SV

  • Clinical Status: O2 Saturation; systemic venous

congestion; systemic blood pressure; perfusion

  • Echo: shunt adequacy; “Glen” anastomosis

stenosis; LPA stenosis; IVC dynamics (?); ventricular diastolic dysfunction (?)

  • Catheterization: QP (?); mean PAP; TPG; PA

stenoses; veno-veno shunt; vasoreactivity (?)

  • MRI: QP and aorto-pulmonary shunt flow;

vasoreactivity (?)

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Monitoring pulmonary vascular adequacy in SV

  • Chest CT angiogram: regional blood flow; air

space disease; stenoses and veno-veno shunts; controlled inspiration used for volumes

  • 2 or 6 min walk test: sub-maximal exercise; O2

desaturation; heart rate and pressure response;

  • Metabolic stress test: maximal exercise; O2

desaturation; heart rate and blood pressure response; estimate QS; maximal O2 consumption; anaerobic threshold; O2 pulse

Monitoring pulmonary vascular adequacy in SV

  • Pulmonary Function tests: % predicted flows and

volumes assess adequate growth, large and small airway obstruction and reversibility; DLCO; MIF; MEF

  • Blood testing: BNP, pro-BNP and uric acid not

markers of pulmonary vascular biology

  • Liver enzyme and function testing: marker of

systemic vascular congestion from pulmonary vascular disease (either larger or small vessel)

Is there anything better to demonstrate an adequate pulmonary vascular bed in SV? MRI estimate of QP in SV

Glatz, etal. Circ Cardiovasc Imaging. 2012; 5(2): 218–225.

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MRI estimate of energy loss in the Fontan Circuit

Pre-Fontan “vascular compliance” predicts early outcome

Int J Cardiol. 2009 Mar 20;133(1):55-61

By multiple linear regression, PVC (P=0.002) and CPB (P=0.003) independently Predicted time of pleural effusion, explaining 22% of the variation.

Worse vascular compliance, worse chest tube drainage

International Journal of Cardiology 133 (2009) 55–61

Predicted Cross Sectional Area: A multibranched model of the pulmonary vascular bed

Bshouty Z, M Younes J Appl Physiol 68: 1514-27, 1990

Variables:

  • BSA
  • Lung size
  • MV (% TLC)
  • Compliance
  • Pal, Ppl
  • Qp, LaP, PAP
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Predicted Cross sectional area is now quantifiable

Frank, etal. ATS Annual Conference, 2011

20 40 60 80 100 120 140 10 20 30 40 50 60 70 80 90 100

mPAP (mm Hg) PVC (%)

CI 0 to 2.5 CI 2.5 to 5 CI 5 to 7.5 Power (CI 0 to 2.5) Power (CI 2.5 to 5) Power (CI 5 to 7.5)

PH-specific treatment for SV vascular insufficiency

N Engl J Med 2004;351:1425-36.

PH early after Stage 1 palliation

  • PH associated with vasoconstriction,

developmental inadequacy and pulmonary vein

  • bstruction
  • No data on therapeutic options:

– NO works – sildenafil sometimes works – “iv” prostacyclin can increase QP unless it drops SVR

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PH early after Stage 2 palliation

  • PH associated with pre-Stage 2 lung injury

(inflammatory : read aspiraton), CBP time, unrecognized anatomic issues (pulmonary vein stenosis).

  • Gamillscheg A, et al. Inhaled nitric oxide in patients

with critical pulmonary perfusion after Fontan-type procedures and bidirectional Glenn anastomosis. J Thorac Cardiovasc Surg. 1997;113:435-42.

PH early after the Fontan

  • PH associated with pre-Fontan lung pathology (including

hypoplasia), CPB time, ventilator effects and unrecognized anatomic issues (pulmonary vein stenosis, AV regurgitation, ventricular dysfunction)

  • Takahashi K, et al. Effect of beraprost sodium on pulmonary

vascular resistance in candidates for a Fontan procedure: a preliminary study. Pediatr Int. 2003;45:671-5.

  • 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.

  • Haseyama K, etal. Pulmonary vasodilation therapy with sildenafil citrate in a

patient with plastic bronchitis after the Fontan procedure for hypoplastic left heart syndrome. J Thorac Cardiovasc Surg. 2006;132:1232-3.

  • Uzun O, etal. Resolution of protein-losing enteropathy and normalization of

mesenteric Doppler flow with sildenafil after Fontan. Ann Thorac Surg. 2006;82:e39-40.

  • Ovaert C, etal. The effect of bosentan in patients with a failing Fontan
  • circulation. Cardiol Young. 2009;19:331-9.

9.5 year with HLHS and PLE

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Post-exercise VO2max following single dose sildenafil in Fontan

Eur Heart J 2008;29:1681-7

Randomized crossover 6 week trial

  • f 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

Randomized crossover 6 week trial

  • f sildenafil in Fontan: 8-18 y/o

Goldberg, etal. Pediatr Cardiol. 2012 Feb 14. [Epub] Decrease in PVR or increase in inotropic state?

Bosentan: no impact on exercise testing in adult Fontan

European J Heart Failure (2013) 15, 690–698

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Bosentan: no impact on exercise testing in adult Fontan

European J Heart Failure (2013) 15, 690–698

Bosentan: no impact on exercise testing in adult Fontan

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.