Congenital Cardiac Anesthesia Society
A Section of the the Society for Pediatric Anesthesia

{“questions”:{“akel6”:{“id”:”akel6″,”mediaType”:”image”,”answerType”:”text”,”imageCredit”:””,”image”:””,”imageId”:””,”video”:””,”imagePlaceholder”:””,”imagePlaceholderId”:””,”title”:”Author: Melissa Colizza, MD – Stollery Children\u2019s Hospital -Edmonton AB Canada \r\n\r\nA 1-week-old girl with severe pulmonary stenosis, intact ventricular septum, and moderate tricuspid valve regurgitation is status post balloon pulmonary valvuloplasty. Two hours later, the heart rate was 188, with an arterial blood pressure of 46\/19 and oxygen saturation of 88%. A transthoracic echocardiogram demonstrates a large patent ductus arteriosus with left-to-right shunting, along with severe pulmonary and tricuspid regurgitation. Which of the following management options is MOST likely to improve the patient\u2019s hemodynamics?\r\n”,”desc”:”EXPLANATION \r\nThe most likely explanation for this patient\u2019s hemodynamic instability is the development of a circular shunt. This is an uncommon physiological phenomenon in which blood from the systemic circulation enters the pulmonary circulation through the patent ductus arteriosus (PDA). The blood then flows into the right ventricle (RV) and the right atrium (RA) in a retrograde fashion through regurgitant pulmonary and tricuspid valves. From the RA, blood flows across an atrial septal defect (ASD) or a patent foramen ovale (PFO). Thus, a circular shunt occurs in the presence of a PDA, a right to left atrial shunt, and significant pulmonary and tricuspid valve insufficiency, following the pathway of least resistance. This is illustrated in Figure 1 below. Circular shunts usually lead to significant hemodynamic instability as both the pulmonary and tricuspid regurgitation effectively steal blood from both the systemic and pulmonary circulations, leading to low cardiac output and desaturation.\r\n\r\n\r\n \r\n\r\n\r\n\r\nFigure 1. Pathway of blood flow in a circular shunt.\r\n\r\n\r\nCircular shunts are typically described in the setting of severe Ebstein\u2019s anomaly (EA), though they can also be seen after relief of right ventricular outflow tract obstruction (RVOTO) in patients with right-sided obstructive lesions. Bautista-Rodriguez et al. described two patients with severe pulmonary stenosis who developed circular shunt physiology following balloon dilation of the pulmonary valve. In both cases, the PDA failed to close, resulting in a low cardiac output state refractory to medical treatment after the procedure. PDA ligation was attempted to interrupt the circular shunt. However, upon complete occlusion of the PDA, the oxygen saturation decreased to 50%. At this point, the PDA was partially banded, targeting a systemic saturation of 70% and a mean systemic arterial pressure increase of greater than 20 mmHg. Both patients had good outcomes. The authors concluded that pulmonary insufficiency caused by balloon pulmonary valvuloplasty in the setting of tricuspid regurgitation and a small dysfunctional RV likely worsened RV function and favored retrograde flow in the presence of a PDA. Patients with severe EA who have a small, dysfunctional RV, significant TR, and a PDA may present similarly before intervention. Other susceptible patients include those with severe pulmonary stenosis (PS) and pulmonary atresia with intact ventricular septum (PA\/IVS). \r\n\r\n\r\nMedical management of a hemodynamically unstable circular shunt remains difficult and consists mainly of supportive treatment until an interventional or surgical procedure can take place. The goal is to optimize forward flow into the systemic and pulmonary circulation, mainly with inotropic support, reduction of systemic vascular resistance, and discontinuation of prostaglandin E1. Increasing pulmonary vascular resistance has also been described to decrease \u201csteal\u201d from the systemic circulation, although this might increase RV afterload and worsen pulmonary insufficiency. Definitive management depends on the underlying pathology. Options include PDA banding or ligation. In the case of EA, some options include pulmonary artery ligation or the Starne\u2019s procedure.\r\n\r\n\r\nThe correct answer is A, patent ductus arteriosus ligation. This functions to eliminate retrograde flow into the pulmonary artery to the RV. Supportive measures with vasoactive agents or pulmonary vasodilators, such as milrinone and nitric oxide, are likely to be of short-term benefit without addressing the underlying mechanism of the circular shunt.\r\n\r\n\r\n\r\n\r\n \r\nREFERENCES \r\n\r\nKonstantinov IE, Chai P, Bacha E, et al. The American Association for Thoracic Surgery (AATS) 2024 expert consensus document: Management of neonates and infants with Ebstein anomaly. J Thorac Cardiovasc Surg<\/em>. 2024;168(2):311-324. doi:10.1016\/j.jtcvs.2024.04.018\r\n\r\n\r\nBautista-Rodriguez C, Rodriguez-Fanjul J, Moreno Hernando J, Mayol J, Caffarena-Calvar JM. Patent Ductus Arteriosus Banding for Circular Shunting After Pulmonary Valvuloplasty. World J Pediatr Congenit Heart Surg<\/em>. 2017;8(5):643-645. doi:10.1177\/2150135116655122\r\n\r\n\r\nAndropoulos DB. Anesthesia for Congenital Heart Disease<\/em>. 2nd ed. Wiley-Blackwell; 2010. Chapter 28: Anesthesia for Right-Sided Obstructive Lesions. Accessed August 12, 2024.\r\n”,”hint”:””,”answers”:{“77kxm”:{“id”:”77kxm”,”image”:””,”imageId”:””,”title”:”A.\tPatent ductus arteriosus ligation”,”isCorrect”:”1″},”58mif”:{“id”:”58mif”,”image”:””,”imageId”:””,”title”:”B.\tInhaled nitric oxide”},”4yyqf”:{“id”:”4yyqf”,”image”:””,”imageId”:””,”title”:”C.\tMilrinone infusion\r\n”}}}}}

{“questions”:{“cw7s2”:{“id”:”cw7s2″,”mediaType”:”image”,”answerType”:”text”,”imageCredit”:””,”image”:””,”imageId”:””,”video”:””,”imagePlaceholder”:””,”imagePlaceholderId”:””,”title”:”Author: Melissa Colizza, MD – Stollery Children\u2019s Hospital, Edmonton Canada \r\nA 15-month-old boy is started on a bivalirudin infusion after placement of a Berlin Heart ventricular assist device. Which of the following tests is MOST frequently used to monitor anticoagulation with bivalirudin? \r\n\r\n”,”desc”:”EXPLANATION \r\nBivalirudin is a direct thrombin inhibitor (DTI) that exerts its anticoagulant effect by binding both circulating and clot-bound thrombin, thus preventing cleavage of fibrinogen to fibrin. It is metabolized via proteolytic cleavage (80%) and renal excretion (20%), and its half-life is age-dependent, ranging from 15-18 minutes in children to 25 minutes in healthy adults. There are no reversal agents. While bivalirudin has been recently FDA-approved in adults in the setting of percutaneous coronary angioplasty, there are no approved indications in the pediatric population. It is, however, increasingly used in patients on mechanical circulatory support (MCS), including extracorporeal membrane oxygenation (ECMO). In most ICUs, bivalirudin is usually started at 0.3 mg\/kg\/h and titrated for an aPTT value of 1.5-2.5x normal. In contrast to unfractionated heparin (UFH), it does not depend on the action of antithrombin III (ATIII), thereby providing more stable levels of anticoagulation, which is particularly relevant in a population with highly variable ATIII levels. A study by Freniere et al. compared bivalirudin to UFH in children with Berlin Heart ventricular assist devices (VAD). Similar to other studies, they found there were no differences in thrombotic or hemorrhagic complications between both groups, but chest tube output was reduced in the bivalirudin group. Patients in the aPTT-monitored bivalirudin group had a shorter time to reach the therapeutic range (5.7 vs. 69.5 hours) and a greater percentage of test results and time in the therapeutic range compared to the anti-Xa-monitored UFH group. Interestingly, when anticoagulation was measured with aPTT for both drugs, the time to reach therapeutic levels was no longer statistically different, thus highlighting the importance of how anticoagulation is measured.\r\n\r\nAPTT is an assay that classically measures the activity of the tissue factor\/ extrinsic pathway. However, it is sensitive to a plethora of factors, including contact activation from artificial surfaces, inflammation, and variations in factor VIII levels. Moreover, anticoagulation with DTIs does not exhibit a linear correlation with commonly used tests, including aPTT, ACT, and kaolin-activated TEG, particularly at higher plasma concentrations. This may lead to erroneous dosing of bivalirudin, especially during MCS with ECMO or cardiopulmonary bypass (CPB). More recently, dilute thrombin time (dTT) has emerged as a more precise assay, as it provides a better correlation with bivalirudin plasma levels. A study by Engel et al. looked at several aPTT, dTT, and experimental bivalirudin-specific dTT assays in children on ECMO and with VADs who were anticoagulated with bivalirudin. They found the experimental and conventional dTT assays all correlated with the bivalirudin dosing but poorly correlated with aPTT. This supports the idea that while aPTT is widely used to measure bivalirudin anticoagulation due to its history and availability, it remains a suboptimal assay. \r\nUFH may also be monitored with a PTT, with a similar level of imprecision. The anti-Xa assay is used to measure UFH and low-molecular-weight heparin (LMWH) and is more sensitive than aPTT, leading to faster achievement of target anticoagulation and lower dose requirement. However, it cannot be used for bivalirudin monitoring as the latter does not exert its effect on factor X. The activated clotting time (ACT) is widely used to measure heparin anticoagulation during vascular or cardiac surgical procedures. It remains non-specific to any type of anticoagulant drug or physiologic disturbance and is unreliable to measure bivalirudin anticoagulation, even when used for CPB. \r\nThe correct answer is B. aPTT is the most commonly used test to monitor patients on bivalirudin. ACT and anti-Xa are used to monitor anticoagulation with UFH and LMWH. \r\n\r\n\r\n \r\nREFERENCES \r\nFaraoni D, DiNardo JA. Bivalirudin: The misunderstood alternative to heparin. Paediatr Anaesth<\/em>. 2024;34(5):394-395. doi:10.1111\/pan.14868 \r\nFreniere V, Salerno DM, Corbo H, et al. Bivalirudin Compared to Heparin as the Primary Anticoagulant in Pediatric Berlin Heart Recipients. ASAIO J<\/em>. 2023;69(5):e205-e211. doi:10.1097\/MAT.0000000000001921\r\n\r\nEngel ER, Perry T, Block M, Palumbo JS, Lorts A, Luchtman-Jones L. Bivalirudin Monitoring in Pediatric Ventricular Assist Device and Extracorporeal Membrane Oxygenation: Analysis of Single-Center Retrospective Cohort Data 2018-2022. Pediatr Crit Care Med<\/em>. 2024;25(7):e328-e337. doi:10.1097\/PCC.0000000000003527\r\n\r\nZaleski KL, DiNardo JA, Eaton MP. Bivalirudin: Are kids just adults to the \u00be power? Paediatr Anaesth<\/em>. 2021;31(6):628-630. doi:10.1111\/pan.14168\r\n\r\n”,”hint”:””,”answers”:{“7006r”:{“id”:”7006r”,”image”:””,”imageId”:””,”title”:”A.\tACT”},”drl3c”:{“id”:”drl3c”,”image”:””,”imageId”:””,”title”:”B.\taPTT”,”isCorrect”:”1″},”st0aa”:{“id”:”st0aa”,”image”:””,”imageId”:””,”title”:”C.\tAnti-Xa”}}}}}

{“questions”:{“6i5h4”:{“id”:”6i5h4″,”mediaType”:”image”,”answerType”:”text”,”imageCredit”:””,”image”:””,”imageId”:””,”video”:””,”imagePlaceholder”:””,”imagePlaceholderId”:””,”title”:”Author: Melissa Colizza, MD – Stollery Children’s Hospital, University of Alberta, Edmonton, Canada\r\n\r\nA 5-month-old girl with Noonan syndrome and confirmed RIT1 mutation presents with failure to thrive. A transthoracic echocardiogram demonstrates biventricular hypertrophy with a peak subaortic gradient of 88 mmHg. Which of the following medications is MOST likely to produce regression of the underlying pathology?\r\n”,”desc”:”EXPLANATION \r\nNoonan syndrome (NS) is a classic example of \u201cRASopathy,\u201d a family of genetic conditions characterized by the activation of rat sarcoma (RAS)virus protein\/mitogen-activated protein kinase (MAPK) cascade. RASopathies result in \u201cgain-of-function\u201d germline mutations and lead to congenital anomalies and a predisposition to malignancy. Typical clinical features involve a short stature, abnormal facies, congenital heart defects, developmental delay, lymphatic abnormalities, bleeding tendencies, and skeletal anomalies. Other RASopathies include Costello syndrome, cardiofaciocutaneous syndrome, and Legius syndrome. A plethora of responsible genes have been identified, including SOS1, RIT1, KRAS, RAF1and PTPN11. Approximately half of NS patients carry a mutation in the PNPT11 gene, which is more likely to be associated with the development of pulmonary valve stenosis. While overall, about 20% of NS patients have hypertrophic cardiomyopathy (HCM), 95% of individuals with RAF1 mutations, and 75% with RIT1 mutation have HCM. Animal models have shown a correlation between the strength of RAS\/MAPK signaling and the severity of manifestations. Mild to moderately increased activation from germline mutations will result in RASopathy, whereas moderate to severely increased activation stemming from somatic mutations will result in neoplastic disease. \r\n\r\nRoughly 80% of RASopathy patients will suffer from a cardiac anomaly, pulmonic valve stenosis being the most common. Approximately 22-29% will develop hypertrophic cardiomyopathy (HCM). As the pathology arises from a gain-of-function mutation, myocardial hypertrophy tends to be more severe and rapidly progressive than other forms of HCM and carries a poorer prognosis, with a 1-year survival of 34% in infants less than six months of age with severe obstruction and heart failure. Since mutations of the RAS\/MAPK pathway are the most common cause of human neoplasia, its inhibition has been the target of extensive research and resulted in the use of several mitogen-activated protein\/extracellular signal-regulated kinase (MEK) inhibitors such as trametinib, cobimetinib, and selumetinib. Animal models have subsequently shown that some RASopathy clinical features, including cardiac hypertrophy, may be altered by MEK inhibitors (MEKi). A case report by Andelfinger et al. described the compassionate use of trametinib in two NS infants with RIT1 mutations and severe, rapidly progressive HCM despite aggressive medical management. The authors noted a regression of the hypertrophy, as well as an improvement in clinical status and biological markers within four months following the initiation of therapy. Patients remained on trametinib for three and a half years before successful weaning. Other publications also report the effectiveness of MEKi in RASopathy-related HCM or lymphatic disease. In a review by Chaput and Andelfinger, the authors suggest the MEKi drugs should only be used in the context of a confirmed gain-of-function mutation of the RAS\/MAPK pathway in consultation with RASopathy specialists. The authors also highlight the fact that no single molecule would apply to all RASopathy patients, nor would one address all clinical manifestations in a single patient. \r\n\r\nWhile promising, the use of MEK inhibitors in RASopathies remains experimental, and most patients with HCM will be treated with conventional medical treatment, including beta-blockers, calcium channel blockers, and disopyramide. Beta-blockers reduce myocardial contractility and heart rate, thereby decreasing the dynamic subvalvular gradient and improving ventricular filling and ejection. Beta-blockers have been shown to decrease mortality in HCM. While some authors hypothesize that they might induce ventricular remodeling, beta blockers will not reverse the molecular process in the context of RASopathies. Calcium channel blockers may also be used as a treatment but have not been shown to decrease mortality or reverse underlying hypertrophy. \r\n\r\nThe correct answer is B. Trametinib is a mitogen-activated protein\/extracellular signal-regulated kinase (MEK) inhibitor that has been demonstrated to reverse the myocardial hypertrophy associated with NS. Propranolol and amlodipine provide symptomatic relief but do not alter the underlying pathological process.\r\n\r\n\r\n \r\nREFERENCES \r\nAndelfinger G, Marquis C, Raboisson MJ, et al. Hypertrophic cardiomyopathy in Noonan syndrome treated by MEK-inhibition. J Am Coll Cardiol<\/em>. 2019;73:2237-9. \r\n\r\nChaput D, Andelfinger G. MEK Inhibition for RASopathy-Associated Hypertrophic Cardiomyopathy: Clinical Application of a Basic Concept. Can J Cardiol<\/em>. 2024;40(5):789-799. doi:10.1016\/j.cjca.2024.02.020\r\n\r\nSaint-Laurent C, Mazeyrie L, Yart A, Edouard T. Novel therapeutic perspectives in Noonan syndrome and RASopathies. Eur J Pediatr<\/em>. 2024;183(3):1011-1019. doi:10.1007\/s00431-023-05263-y\r\n\r\n\r\n\u00d6stman-Smith I. Beta-Blockers in Pediatric Hypertrophic Cardiomyopathies. Rev Recent Clin Trials<\/em>. 2014;9(2):82-85. doi:10.2174\/1574887109666140908125158\r\n\r\n”,”hint”:””,”answers”:{“oht1p”:{“id”:”oht1p”,”image”:””,”imageId”:””,”title”:”A.\tPropranolol”},”jxr0x”:{“id”:”jxr0x”,”image”:””,”imageId”:””,”title”:”B.\tTrametinib”,”isCorrect”:”1″},”v4fqw”:{“id”:”v4fqw”,”image”:””,”imageId”:””,”title”:”C.\tAmlodipine\r\n”}}}}}

{“questions”:{“n9dwa”:{“id”:”n9dwa”,”mediaType”:”image”,”answerType”:”text”,”imageCredit”:””,”image”:””,”imageId”:””,”video”:””,”imagePlaceholder”:””,”imagePlaceholderId”:””,”title”:”Authors: M. Barbic, MD AND M. Gangadharan, MD, FAAP, FASA – Children\u2019s Memorial Hermann Hospital, University of Texas Health Science Center, Houston, TX \r\n\r\nAn echocardiogram obtained on a 26-hour-old, full-term girl due to differential cyanosis and suspected congenital heart disease demonstrates an interrupted aortic arch. Which of the following subtypes of interrupted aortic arch is MOST likely in this patient? \r\n\r\n\r\n”,”desc”:”EXPLANATION \r\nInterrupted aortic arch (IAA) is a rare, ductal-dependent, congenital cardiac anomaly with an incidence of about 0.03 to 0.19 per 10,000 live births and constitutes 1-5% of congenital heart diseases. It is characterized by a disruption in the lumen of the aortic arch at various sites between the ascending and descending aorta. \r\n \r\nClassification of IAA is based on the site of the interruption. Type A interruption occurs distal to the left subclavian artery and is the second most common type, representing 10-20 % of cases. Type B interruption occurs between the left carotid and left subclavian artery. It is the most common type of IAA, representing 70-80% of cases (Figure 1). Type C is the least common type, representing less than 5% of cases, and occurs between the innominate and left carotid artery. Over 70% of Type B interruptions are associated with deletion of chromosome 22q11. The most commonly associated cardiac abnormalities are a ventricular septal defect (VSD), a bicuspid aortic valve, and an aberrant right subclavian artery arising from the descending aorta. The VSD is typically posteriorly malaligned and can result in left ventricular outflow tract obstruction. Perfusion distal to the interruption is critically dependent on a patent ductus arteriosus (PDA). Ductal closure will lead to lower body hypoperfusion, severe metabolic acidosis, and multiorgan failure. Differential cyanosis, with lower pedal oxygen saturation, may or may not be present depending on the degree of mixing at the level of the VSD. The ratio of pulmonary vascular resistance to systemic vascular resistance will determine the direction of flow across the PDA. \r\n\r\n\r\n\r\n \r\n \r\n \r\n\r\n\r\n \r\n\r\n\r\n\r\n\r\n\r\n\r\n \r\n \r\n\r\n\r\n\r\n\r\nPrenatal diagnosis of IAA by ultrasound is possible in more than 50% of patients. The advantage of prenatal diagnosis is that treatment with prostaglandin E1 (PGE1) will begin immediately after birth. When the diagnosis is not made before birth, most patients will present with signs of cardiogenic shock after spontaneous closure of the PDA. Patients often present with end-organ dysfunction, such as necrotizing enterocolitis, liver and kidney dysfunction, and coagulopathy. Physical exam findings include lethargy, delayed capillary refill, cool skin, decreased peripheral pulses, and hypotension. Transthoracic echocardiography is usually adequate to delineate the anatomy of the aortic interruption, the patency of the PDA, the location of arch vessels, characteristics of the VSD, LV size and function, LVOT morphology, and size of aortic valve. A three-dimensional volume-rendered computed tomography angiogram may be obtained if further anatomic clarification is required. In extremely rare instances, in which the ductus arteriosus remains patent and collateral arterial vessels develop, patients may survive to adulthood before diagnosis.\r\n\r\nPrimary single-stage surgical repair is usually performed in the neonatal period after medical stabilization in the intensive care unit. The goals of medical management are maintenance of ductal patency with intravenous PGE1, avoiding decreases in pulmonary vascular resistance by minimizing fractional inspired oxygen concentration (FiO2), and maintaining cardiac output with inotropic agents, if needed, and balancing the ratio of pulmonary and systemic blood flow. The surgical repair consists of augmentation of the arch with graft material, if necessary, and anastomosis of the ascending and descending aorta to re-establish luminal continuity. Cardiopulmonary bypass may involve arterial cannulation through the ascending aorta or innominate artery for cerebral perfusion and the PDA for distal perfusion of the lower body. Selective cerebral perfusion or deep hypothermic circulatory arrest may be employed during arch repair. Early postoperative complications include bleeding, recurrent laryngeal nerve and phrenic nerve injury, and acute kidney injury. Late postoperative complications include aortic arch obstruction, LVOTO, and obstruction of the left main bronchus. Hybrid palliation with bilateral pulmonary artery bands and ductal stenting is an option when complete primary correction is not possible, such as prematurity or contraindications to cardiopulmonary bypass. Patients with IAA need lifelong follow-up by a cardiologist and for associated comorbidities. About 20-30% of patients will need repeat interventions in the cardiac catheterization suite or the cardiac operating room. \r\n\r\nThe correct answer is Type B, which is the most common type of IAA, representing 70 to 80% of cases of IAA. Type A is the second most common (10-20%), and Type C is the least common (<5%). \r\n\r\n\r\n \r\nREFERENCES \r\nBurbano-Vera N, Zaleski KL, Latham GJ, Nasr VG. Perioperative and Anesthetic Considerations in Interrupted Aortic Arch. Semin Cardiothorac Vasc Anesthesia<\/em>. 2018;22(3):270-277. doi:10.1177\/1089253218775954\r\n\r\nLaPar DJ, Baird CW. Surgical Considerations in Interrupted Aortic Arch. Semin Cardiothorac Vasc Anesth<\/em>. 2018;22(3):278-284. doi: 10.1177\/1089253218776664. \r\n\r\nBoutaleb AM, Tabat M, Mekouar Y, Bennani G, Drighil A, Habbal R. Rare case series of adult interrupted aortic arch. J Cardiol Cases<\/em>. 2023;28(5):206-209. doi:10.1016\/j.jccase.2023.07.004″,”hint”:””,”answers”:{“f5vfd”:{“id”:”f5vfd”,”image”:””,”imageId”:””,”title”:”A.\tType A”},”ojz7q”:{“id”:”ojz7q”,”image”:””,”imageId”:””,”title”:”B.\tType B”,”isCorrect”:”1″},”6jy62″:{“id”:”6jy62″,”image”:””,”imageId”:””,”title”:”C.\tType C”}}}}}

{“questions”:{“wxgng”:{“id”:”wxgng”,”mediaType”:”image”,”answerType”:”text”,”imageCredit”:””,”image”:””,”imageId”:””,”video”:””,”imagePlaceholder”:””,”imagePlaceholderId”:””,”title”:”Authors: Katarzyna Dlugosz Sledz, MD and M. Gangadharan, MD, FAAP, FASA – Children\u2019s Memorial Hermann Hospital, University of Texas Health Science Center, Houston, TX AND Destiny F. Chau, MD – Arkansas Children\u2019s Hospital\/University of Arkansas for Medical Sciences, Little Rock, AR \r\n\r\nA 20-year-old woman with a history of pulmonary hypertension treated with riociguat presents for a pulmonary hypertension study. Which of the following mechanisms BEST describes the pharmacologic action of riociguat? “,”desc”:”EXPLANATION \r\nPulmonary hypertension is defined by mean pulmonary artery pressure (PAP) greater than 20 mmHg at rest in a biventricular heart and the transpulmonary gradient is > 6mmHg in a univentricular heart in pediatric patients greater than three months of age. Pulmonary arterial hypertension, also termed precapillary pulmonary hypertension, is additionally characterized by a pulmonary vascular resistance index (PVRI) greater than three wood units per m^{2<\/sup>. Referral to a pediatric pulmonary hypertension specialist is a necessity for the diagnosis and management of pediatric patients with pulmonary hypertension. Formal diagnosis is made by cardiac catheterization and acute vasoreactivity testing. Treatment consists of diuretics, anticoagulants, digoxin, supplemental oxygen, and calcium channel blockers in patients with positive acute pulmonary vasoreactivity. Patients with negative vasoreactivity testing are typically treated with the addition of one or more pulmonary vasodilators.\r\n \r\n\r\nThree mediators, endothelin, nitric oxide, and prostacyclin, regulate pulmonary arterial vascular tone. The molecular pathways for these mediators are illustrated in the figure 1 below, along with the therapeutic targets for each. The endothelin pathway mediates vasoconstriction, whereas the prostacyclin and nitric oxide pathways mediate vasodilatation. Targeted therapies are aimed at improving the balance between vasoconstriction and vasodilation which is abnormal in pulmonary hypertension.\r\n \r\n\r\n \r\n\r\nFigure 1. Molecular targets for pulmonary hypertension drug therapies. Newly approved therapies are listed in blue. cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanylate monophosphate; ERA, endothelin receptor antagonist; FDA, US Food and Drug Administration; INH, inhaled; IP2, prostacyclin receptor 2; IV, intravenous; NO, nitric oxide; PAH, pulmonary arterial hypertension; PDE-5, phosphodiesterase-5; PDE-5i, phosphodiesterase-5 inhibitor; PGI2, prostaglandin I2; sGC, soluble guanylate cyclase; SQ, subcutaneous. (Tsai H, Sung YK, and de Jesus Perez V. Recent advances in the management of pulmonary arterial hypertension. F1000Research<\/em>. 2016;5:2755. Creative Commons License)\r\n\r\n\r\nProstacyclin analogs, such as iloprost, epoprostenol, and treprostinil, increase cyclic adenosine monophosphate (cAMP) levels in pulmonary vascular smooth muscle cells resulting in vasodilation. Endothelin receptor blockers, such as bosentan, ambrisentan, and macitentan prevent vasoconstriction and smooth muscle proliferation via endothelin A and B receptor blockade. The nitric oxide pathway results in increased levels of cyclic guanylate monophosphate (cGMP), which mediates pulmonary vasodilation. Exogenous administration of nitric oxide increases the production of cGMP, while phosphodiesterase inhibitors, such as sildenafil and tadalafil, reduce the breakdown of cGMP.\r\n\r\n\r\nRiociguat is a direct soluble guanylate cyclase (sGC) stimulator that increases the sensitivity of guanylate cyclase to nitric oxide, resulting in increased intracellular cGMP levels, which in turn leads to a vasodilatory and antiproliferative effect on vascular smooth muscle. Riociguat (trade name Adempas\u00ae) has been approved by the European Medicines Agency to treat pulmonary hypertension in children older than six 6 years with systolic blood pressure greater than 90 mmHg and children older than 12 years with systolic blood pressure greater than 95mmHg. Riociguat has not received FDA approval for pediatric use in the United States. The side effects of riociguat include systemic hypotension, hemoptysis, pulmonary hemorrhage, headache, and nausea. Concomitant use of riociguat with a phosphodiesterase-5 inhibitor is contraindicated due to an exaggerated effect on blood pressure. There are case reports of the successful use of riociguat in children. Domingo and colleagues reported two cases of infants with refractory supra-systemic pulmonary hypertension who were weaned off nitric oxide after the administration of riociguat.\r\n\r\n\r\nThe correct answer is B. Riociguat is a direct soluble guanylate cyclase (sGC) stimulator that increases the sensitivity of guanylate cyclase to nitric oxide, resulting in increased levels of intracellular cGMP. Although sildenafil and tadalafil also act via the nitric oxide pathway, they produce their therapeutic effect via phosphodiesterase-5 inhibition. Bosentan and ambrisentan are endothelin receptor antagonists. \r\n\r\n\r\n \r\nREFERENCES \r\n\r\nBeghetti M, Gorenflo M, Ivy DD, Moledina S, Bonnet D. Treatment of pediatric pulmonary arterial hypertension: A focus on the NO-sGC-cGMP pathway. Pediatr Pulmonol<\/em>. 2019;54(10):1516-1526. doi:10.1002\/ppul.24442\r\n\r\n\r\nhttps:\/\/www.ema.europa.eu\/en\/documents\/product-information\/adempas-epar-product-information_en.pdf Accessed on 9.7.2024\r\n\r\n\r\nDomingo LT, Ivy DD, Abman SH, et al. Novel use of riociguat in infants with severe pulmonary arterial hypertension unable to wean from inhaled nitric oxide. Front Pediatr<\/em>. 2022; 10:1014922. doi:10.3389\/fped.2022.1014922\r\n\r\n\r\nHansmann G, Koestenberger M, Alastalo TP, et al. 2019 updated consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension: The European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR, and ISHLT. J Heart Lung Transplant<\/em>. 2019;38(9):879-901. doi:10.1016\/j.healun.2019.06.022\r\n\r\n\r\nJone PN, Ivy DD, Hauck A, et al. Pulmonary Hypertension in Congenital Heart Disease: A Scientific Statement From the American Heart Association. Circ Heart Fail<\/em>. 2023;16(7):e00080. doi:10.1161\/HHF.0000000000000080\r\n\r\n”,”hint”:””,”answers”:{“eig31”:{“id”:”eig31″,”image”:””,”imageId”:””,”title”:”A)\tEndothelin receptor blockade”},”0h8g8″:{“id”:”0h8g8″,”image”:””,”imageId”:””,”title”:”B)\tDirect stimulation of soluble guanylate cyclase”,”isCorrect”:”1″},”cxut0″:{“id”:”cxut0″,”image”:””,”imageId”:””,”title”:”C)\tInhibition of phosphodiesterase-5 \r\n\r\n”}}}}}}