Author: Krupa Desai, MD – Children’s Hospital of Philadelphia; Chinwe Unegbu, MD – Children’s National Hospital
A 14 year old male with Pulmonary Arterial Hypertension secondary to pulmonary venoocclusive disease managed with treprostinil, ambrisentan, and milrinone presents with increasing dyspnea. A transthoracic echocardiogram (TTE) demonstrates suprasystemic right ventricular (RV) systolic pressures, moderately decreased RV function, severe RV dilation, and moderate tricuspid regurgitation. What is the MOST APPROPRIATE treatment?
Correct!
Wrong!
Question of the Week 325
Pulmonary arterial hypertension (PAH) is a rare and progressive disease. Despite advances in medical therapy, there is significant morbidity and mortality associated with this disease. Patients with PAH often have elevations in pulmonary vascular resistance (PVR) because of pulmonary vascular bed remodeling. As this disease naturally progresses, the physiologic sequelae are increased PVR followed by right ventricular (RV) hypertrophy, RV dysfunction, and ultimately death.
Pulmonary veno-occlusive disease (PVOD) falls into a rare category of PAH and is caused by remodeling of the pulmonary venules with hallmark obliteration of the small pulmonary veins. The diagnosis of PAH secondary to PVOD carries a poor prognosis. In patients with PVOD, severe/life-threatening pulmonary edema can occur with the initiation of any class of pulmonary vasodilators. To date, strong evidence of the beneficial effect of pulmonary vasodilator therapy in patients with PVOD is lacking.
The goal of medical therapy in patients with PAH is to dilate the pulmonary vascular bed, reverse vascular remodeling, and restore endothelial function. The common treatment modalities target specific pathways involved in PAH pathogenesis: the prostacyclin, endothelin-1, and nitric oxide pathways to achieve these goals. This patient is on treprostinil, ambrisentan, and milrinone. Treprostinil is a prostacyclin analogue commonly administered to patients with PAH via continuous intravenous infusion. Prostacyclin analogues are important pulmonary and systemic vasodilators and patients with PAH often have decreased production of prostacyclins. Epoprostenol and treprostinil are the two most commonly administered prostacyclin analogues. Treprostinil has a longer half-life and greater stability than epoprostenol.
Endothelin (ET) is a peptide produced in the kidney with three isoforms - ET-1, ET-2, and ET-3. ET-1 is the predominant isoform and binds to two G-protein-coupled receptors ETA and ETB. ETA is the predominate form on vasculature and mediates vasoconstriction. Ambrisentan is a selective ETA receptor antagonist. Patients with PAH have increased levels of circulating ET-1 that bind to ETA to mediate pulmonary arterial vasoconstriction and promote proliferation of pulmonary vascular smooth muscle. Bosentan is a commonly utilized nonselective ETA and ETB receptor antagonist. The renal vascular endothelium expresses the ETB receptor and here ET-1acts in a manner to increase vasodilator secretion.
Milrinone is an additional outpatient medical therapy for this patient. Milrinone is a phosphodiesterase type-3 inhibitor that decreases pulmonary vascular resistance via agonism of the nitric oxide–cyclic guanosine monophosphate (NO–cGMP) pathway. In addition to causing pulmonary and systemic vasodilation, milrinone can potentially augment myocardial contractility and lusitropy.
Unfortunately despite maximal medical therapy, some patients progress to end-stage PAH and are quite symptomatic. Bilateral lung transplantation is the only definitive therapy that offers the possibility of long term survival, but survival to lung transplantation is low. The Potts shunt and balloon atrial septostomy (BAS) are two palliative procedures that can be used to manage medically refractory PAH. The patient in this scenario is failing medical therapy and is in need of a palliative procedure to reduce afterload on the right ventricle (RV). RV function is an important prognostic indicator in patients with PAH. Many medical therapies aim to reduce right ventricular afterload as a means to improve right ventricular function.
Of the options listed, the most appropriate treatment is placement of a Potts shunt, which is a connection from the left pulmonary artery to the descending thoracic aorta. This surgical technique was first described in 1946 by Dr. Willis Potts. It was originally intended to be used in children with Tetralogy of Fallot to provide pulmonary blood flow. In 2004, it was utilized to manage two children with refractory suprasystemic PAH.
A Potts shunt should be considered in patients with end stage, medically refractory, suprasystemic pulmonary hypertension. A Potts shunt would serve as a pop off for the right ventricle to reduce RV afterload thereby improving RV systolic function and possibly serving as a bridge to lung transplantation. Current literature demonstrates that the Potts shunt improves hemodynamics, functional status, and transplant-free survival in children with severe PAH. The Potts shunt is also more durable in teenagers and decompresses the right ventricle without causing upper body cyanosis. This shunt sends deoxygenated blood to the lower half of the body while preserving the highest oxygenated blood for the upper half of the body and the brain.
A single center retrospective review performed from 2016 to 2019 at Columbia University Medical Center-New York Presbyterian demonstrated 100% survival at 33 months after Potts shunt in 5 pediatric patients with supra-systemic pulmonary arterial hypertension. Further studies are needed to assess long-term survival in patients with a Potts shunt. It is critical to remember that a Potts shunt, in theory, is an unrestrictive communication between the pulmonary and systemic circulations; therefore, its effectiveness lies in reducing right ventricular pressures from suprasystemic to systemic levels. Thus, a shunt placed in a child whose right ventricle cannot generate systemic pressure will prove ineffective. A valved Potts shunt is a modification that allows for unidirectional flow from pulmonary artery to the descending thoracic aorta. This prevents any reversal of flow from the aorta to the pulmonary circulation during diastole. The valved Potts shunt may serve to benefit the child who has systemic right ventricular pressures at rest but suprasystemic pressures with exertion.
Balloon atrial septostomy (BAS) is an interventional procedure in which an interatrial orifice is created by needle puncture and dilated with a balloon catheter. Possible contraindications for BAS include: severe RV failure, mean right atrial pressure greater than 20 mmHg, pulmonary vascular resistance index greater than 55U/m2, baseline oxygen saturation less than 90%, and LVEDP greater than 18mmHg. However, these criteria vary based on the center surveyed. Unlike the Potts shunt, which leads to lower extremity deoxygenation, the atrial septostomy leads to global deoxygenation. BAS is not the most appropriate intervention for this patient as studies have shown that BAS does not provide a lasting reduction of pulmonary artery pressure to preserve right ventricular function as does the Potts shunt. A patient with PAH who improves with BAS is often one in whom right ventricular failure is relatively advanced such that the right ventricular end diastolic pressure must be abnormally elevated to generate right-to-left atrial flow. Literature does support an improvement in symptoms after BAS in pediatric patients with subsystemic right ventricular pressure who had experienced syncope. The overall procedure-related mortality is high (16%) for BAS with refractory hypoxemia being the most common cause of death. The procedure may also need to be repeated due to spontaneous closure of the atrial septal defect.
Initiation of epoprostenol, a prostacyclin analogue, will unlikely provide additional benefit since the patient is already on treprostinil, which is in the same category of medications. Initiation of inhaled nitric oxide will likely not provide additional benefit in a patient with pulmonary veno-occlusive disease, which is a fixed obstruction. Placement of a Potts shunt is the most appropriate treatment in a patient with medically refractory, suprasystemic pulmonary arterial hypertension in order to decrease the RV afterload.
References
1. van Loon RL, Roofthooft MT, Hillege HL, et al. Pediatric pulmonary hypertension in the Netherlands: epidemiology and characterization during the period 1991 to 2005. Circulation. 2011; 124(16): 1755-1764.
2. Montani D, Lau EM, Dorfmüller P, et al. Pulmonary veno-occlusive disease. Eur Respir J. 2016; 47(5): 1518-1534. doi:10.1183/13993003.00026-2016
3. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999; 159(6): 1925-1932.
4. Cacoub P, Dorent R, Nataf P, Carayon A. Endothelin-1 in pulmonary hypertension. N Engl J Med. 1993; 329(26): 1967-1968.
5. Maguire JJ, Davenport AP. Endothelin receptors and their antagonists. Semin Nephrol. 2015; 35(2): 125-136.
6. Aggarwal M, Grady RM, Choudhry S, Anwar S, Eghtesady P, Singh GK. Potts Shunt Improves Right Ventricular Function and Coupling With Pulmonary Circulation in Children With Suprasystemic Pulmonary Arterial Hypertension. Circ Cardiovasc Imaging. 2018; 11(12): e007964. doi:10.1161/CIRCIMAGING.118.007964
7. Garekar S, Meeran T, Dhake S, Malankar D. Valved reverse Potts shunt in a case of pulmonary hypertension due to pulmonary veno-occlusive disease. Indian J Thorac Cardiovasc Surg. 2021; 37(1): 89-92. doi:10.1007/s12055-020-00993-2
8. Grady RM. Beyond transplant: Roles of atrial septostomy and Potts shunt in pediatric pulmonary hypertension. Pediatr Pulmonol. 2021; 56(3): 656-660. doi:10.1002/ppul.25049
9. Keogh AM, Mayer E, Benza RL, et al. Interventional and surgical modalities of treatment in pulmonary hypertension. J Am Coll Cardiol. 2009; 54(1 Suppl): S67-S77. doi:10.1016/j.jacc.2009.04.016
10. Kim SH, Jang WS, Lim HG, Kim YJ. Potts shunt in patients with primary pulmonary hypertension. Korean J Thorac Cardiovasc Surg. 2015; 48(1): 52-54. doi:10.5090/kjtcs.2015.48.1.52
11. Rosenzweig EB, Ankola A, Krishnan U, Middlesworth W, Bacha E, Bacchetta M. A novel unidirectional-valved shunt approach for end-stage pulmonary arterial hypertension: Early experience in adolescents and adults. J Thorac Cardiovasc Surg. 2021; 161(4): 1438-1446.e2. doi: 10.1016/j.jtcvs.2019.10.149. Epub 2019 Nov 14. PMID: 31839227.
Pulmonary veno-occlusive disease (PVOD) falls into a rare category of PAH and is caused by remodeling of the pulmonary venules with hallmark obliteration of the small pulmonary veins. The diagnosis of PAH secondary to PVOD carries a poor prognosis. In patients with PVOD, severe/life-threatening pulmonary edema can occur with the initiation of any class of pulmonary vasodilators. To date, strong evidence of the beneficial effect of pulmonary vasodilator therapy in patients with PVOD is lacking.
The goal of medical therapy in patients with PAH is to dilate the pulmonary vascular bed, reverse vascular remodeling, and restore endothelial function. The common treatment modalities target specific pathways involved in PAH pathogenesis: the prostacyclin, endothelin-1, and nitric oxide pathways to achieve these goals. This patient is on treprostinil, ambrisentan, and milrinone. Treprostinil is a prostacyclin analogue commonly administered to patients with PAH via continuous intravenous infusion. Prostacyclin analogues are important pulmonary and systemic vasodilators and patients with PAH often have decreased production of prostacyclins. Epoprostenol and treprostinil are the two most commonly administered prostacyclin analogues. Treprostinil has a longer half-life and greater stability than epoprostenol.
Endothelin (ET) is a peptide produced in the kidney with three isoforms - ET-1, ET-2, and ET-3. ET-1 is the predominant isoform and binds to two G-protein-coupled receptors ETA and ETB. ETA is the predominate form on vasculature and mediates vasoconstriction. Ambrisentan is a selective ETA receptor antagonist. Patients with PAH have increased levels of circulating ET-1 that bind to ETA to mediate pulmonary arterial vasoconstriction and promote proliferation of pulmonary vascular smooth muscle. Bosentan is a commonly utilized nonselective ETA and ETB receptor antagonist. The renal vascular endothelium expresses the ETB receptor and here ET-1acts in a manner to increase vasodilator secretion.
Milrinone is an additional outpatient medical therapy for this patient. Milrinone is a phosphodiesterase type-3 inhibitor that decreases pulmonary vascular resistance via agonism of the nitric oxide–cyclic guanosine monophosphate (NO–cGMP) pathway. In addition to causing pulmonary and systemic vasodilation, milrinone can potentially augment myocardial contractility and lusitropy.
Unfortunately despite maximal medical therapy, some patients progress to end-stage PAH and are quite symptomatic. Bilateral lung transplantation is the only definitive therapy that offers the possibility of long term survival, but survival to lung transplantation is low. The Potts shunt and balloon atrial septostomy (BAS) are two palliative procedures that can be used to manage medically refractory PAH. The patient in this scenario is failing medical therapy and is in need of a palliative procedure to reduce afterload on the right ventricle (RV). RV function is an important prognostic indicator in patients with PAH. Many medical therapies aim to reduce right ventricular afterload as a means to improve right ventricular function.
Of the options listed, the most appropriate treatment is placement of a Potts shunt, which is a connection from the left pulmonary artery to the descending thoracic aorta. This surgical technique was first described in 1946 by Dr. Willis Potts. It was originally intended to be used in children with Tetralogy of Fallot to provide pulmonary blood flow. In 2004, it was utilized to manage two children with refractory suprasystemic PAH.
A Potts shunt should be considered in patients with end stage, medically refractory, suprasystemic pulmonary hypertension. A Potts shunt would serve as a pop off for the right ventricle to reduce RV afterload thereby improving RV systolic function and possibly serving as a bridge to lung transplantation. Current literature demonstrates that the Potts shunt improves hemodynamics, functional status, and transplant-free survival in children with severe PAH. The Potts shunt is also more durable in teenagers and decompresses the right ventricle without causing upper body cyanosis. This shunt sends deoxygenated blood to the lower half of the body while preserving the highest oxygenated blood for the upper half of the body and the brain.
A single center retrospective review performed from 2016 to 2019 at Columbia University Medical Center-New York Presbyterian demonstrated 100% survival at 33 months after Potts shunt in 5 pediatric patients with supra-systemic pulmonary arterial hypertension. Further studies are needed to assess long-term survival in patients with a Potts shunt. It is critical to remember that a Potts shunt, in theory, is an unrestrictive communication between the pulmonary and systemic circulations; therefore, its effectiveness lies in reducing right ventricular pressures from suprasystemic to systemic levels. Thus, a shunt placed in a child whose right ventricle cannot generate systemic pressure will prove ineffective. A valved Potts shunt is a modification that allows for unidirectional flow from pulmonary artery to the descending thoracic aorta. This prevents any reversal of flow from the aorta to the pulmonary circulation during diastole. The valved Potts shunt may serve to benefit the child who has systemic right ventricular pressures at rest but suprasystemic pressures with exertion.
Balloon atrial septostomy (BAS) is an interventional procedure in which an interatrial orifice is created by needle puncture and dilated with a balloon catheter. Possible contraindications for BAS include: severe RV failure, mean right atrial pressure greater than 20 mmHg, pulmonary vascular resistance index greater than 55U/m2, baseline oxygen saturation less than 90%, and LVEDP greater than 18mmHg. However, these criteria vary based on the center surveyed. Unlike the Potts shunt, which leads to lower extremity deoxygenation, the atrial septostomy leads to global deoxygenation. BAS is not the most appropriate intervention for this patient as studies have shown that BAS does not provide a lasting reduction of pulmonary artery pressure to preserve right ventricular function as does the Potts shunt. A patient with PAH who improves with BAS is often one in whom right ventricular failure is relatively advanced such that the right ventricular end diastolic pressure must be abnormally elevated to generate right-to-left atrial flow. Literature does support an improvement in symptoms after BAS in pediatric patients with subsystemic right ventricular pressure who had experienced syncope. The overall procedure-related mortality is high (16%) for BAS with refractory hypoxemia being the most common cause of death. The procedure may also need to be repeated due to spontaneous closure of the atrial septal defect.
Initiation of epoprostenol, a prostacyclin analogue, will unlikely provide additional benefit since the patient is already on treprostinil, which is in the same category of medications. Initiation of inhaled nitric oxide will likely not provide additional benefit in a patient with pulmonary veno-occlusive disease, which is a fixed obstruction. Placement of a Potts shunt is the most appropriate treatment in a patient with medically refractory, suprasystemic pulmonary arterial hypertension in order to decrease the RV afterload.
References
1. van Loon RL, Roofthooft MT, Hillege HL, et al. Pediatric pulmonary hypertension in the Netherlands: epidemiology and characterization during the period 1991 to 2005. Circulation. 2011; 124(16): 1755-1764.
2. Montani D, Lau EM, Dorfmüller P, et al. Pulmonary veno-occlusive disease. Eur Respir J. 2016; 47(5): 1518-1534. doi:10.1183/13993003.00026-2016
3. Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999; 159(6): 1925-1932.
4. Cacoub P, Dorent R, Nataf P, Carayon A. Endothelin-1 in pulmonary hypertension. N Engl J Med. 1993; 329(26): 1967-1968.
5. Maguire JJ, Davenport AP. Endothelin receptors and their antagonists. Semin Nephrol. 2015; 35(2): 125-136.
6. Aggarwal M, Grady RM, Choudhry S, Anwar S, Eghtesady P, Singh GK. Potts Shunt Improves Right Ventricular Function and Coupling With Pulmonary Circulation in Children With Suprasystemic Pulmonary Arterial Hypertension. Circ Cardiovasc Imaging. 2018; 11(12): e007964. doi:10.1161/CIRCIMAGING.118.007964
7. Garekar S, Meeran T, Dhake S, Malankar D. Valved reverse Potts shunt in a case of pulmonary hypertension due to pulmonary veno-occlusive disease. Indian J Thorac Cardiovasc Surg. 2021; 37(1): 89-92. doi:10.1007/s12055-020-00993-2
8. Grady RM. Beyond transplant: Roles of atrial septostomy and Potts shunt in pediatric pulmonary hypertension. Pediatr Pulmonol. 2021; 56(3): 656-660. doi:10.1002/ppul.25049
9. Keogh AM, Mayer E, Benza RL, et al. Interventional and surgical modalities of treatment in pulmonary hypertension. J Am Coll Cardiol. 2009; 54(1 Suppl): S67-S77. doi:10.1016/j.jacc.2009.04.016
10. Kim SH, Jang WS, Lim HG, Kim YJ. Potts shunt in patients with primary pulmonary hypertension. Korean J Thorac Cardiovasc Surg. 2015; 48(1): 52-54. doi:10.5090/kjtcs.2015.48.1.52
11. Rosenzweig EB, Ankola A, Krishnan U, Middlesworth W, Bacha E, Bacchetta M. A novel unidirectional-valved shunt approach for end-stage pulmonary arterial hypertension: Early experience in adolescents and adults. J Thorac Cardiovasc Surg. 2021; 161(4): 1438-1446.e2. doi: 10.1016/j.jtcvs.2019.10.149. Epub 2019 Nov 14. PMID: 31839227.
