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

{“questions”:{“g8nc4”:{“id”:”g8nc4″,”mediaType”:”image”,”answerType”:”text”,”imageCredit”:””,”image”:””,”imageId”:””,”video”:””,”imagePlaceholder”:””,”imagePlaceholderId”:””,”title”:”Authors: Meera Gangadharan, MBBS, FAAP, FASA – Children\u2019s Memorial Hermann Hospital, University of Texas Health Science Center, Houston, TX
\r\nAND \r\nJehan Elliott, MD – Nemours Children\u2019s Hospital, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA \r\n\r\nA 2-year-old girl with developmental delay, hypertelorism, low-set ears, and a bulbous nose presents for a transthoracic echocardiogram due to a systolic murmur radiating to the upper left sternal border. A physical exam is normal, and a history of present illness is negative for failure to thrive. Genetic testing demonstrates a mutation in the RIT1<\/em> gene. Which of the following subtypes of cardiomyopathy is MOST likely in this patient?\r\n”,”desc”:”EXPLANATION \r\nNoonan syndrome (NS) is a RASopathy resulting from abnormalities in the RAS\/Mitogen-Activated-Protein-Kinase (MAPK) pathway. NS occurs in 1:1,000 to 2,500 live births. Most cases of NS are sporadic, but autosomal dominant forms also occur, leading to multiple cases in one family. Eighty percent of patients with NS will have a cardiac abnormality. Of these patients, 60% will have congenital heart disease and 20% will have hypertrophic cardiomyopathy. The most common congenital heart diseases associated with NS are pulmonary valve stenosis (40%), atrial septal defects (8%), and atrioventricular septal defects (15%). Left-sided lesions such as aortic stenosis, coarctation of the aorta, and mitral stenosis are less common. Combinations of pulmonary and aortic valve stenosis and hypertrophic cardiomyopathy have also been described in NS. \r\n\r\n\r\nMutations in several genes can result in NS, including the RAF1, MRAS, <\/em> and RIT1<\/em> genes, which are more commonly associated with a phenotype characterized by hypertrophic cardiomyopathy (HCM). According to one large registry, RASopathies, which include Noonan syndrome, Noonan syndrome with multiple lentigines, Cardiofaciocutaneous syndrome, Mazzanti syndrome, Costello syndrome, Type 1 Neurofibromatosis, and Legius syndrome, are associated with 18% of pediatric HCM. RASopathy-associated HCM differs from sarcomeric HCM in several ways. RASopathy-associated HCM presents earlier in life, at a mean age of six months versus adolescence in sarcomeric HCM. In addition, 24% will have congestive heart failure versus 9% of those with sarcomeric HCM. Finally, patients with RASopathy-associated HCM are more likely to require interventions, such as surgical myomectomy, pulmonary valvuloplasty, and hospitalization for heart failure treatment. Unlike patients with sarcomeric HCM, who experience progression of left ventricular hypertrophy with time, those with RASopathy-associated HCM often experience a reduction in left ventricular wall thickness and myocardial hypertrophy with reverse remodeling as they grow older. The role of the RAS\/MAPK pathway in the pathogenesis of HCM has been underscored by the resolution of myocardial hypertrophy in two patients with the RIT1<\/em> mutation who were treated with trametinib, an MEK inhibitor that targets the MAPK pathway. A marked reduction in myocardial hypertrophy was seen within four months of treatment with trametinib. \r\n\r\n\r\nThe correct answer is A. Hypertrophic cardiomyopathy is the most common type of cardiomyopathy associated with NS. Over 75% of these individuals have a RIT1<\/em> or RAF1<\/em> gene mutation. Dilated cardiomyopathy may occur with HCM when patients have progressed to heart failure. The patient in the stem is asymptomatic, making advanced heart failure and therefore dilated cardiomyopathy less likely. Restrictive cardiomyopathy has not been described in NS.\r\n\r\n\r\n\r\n \r\nREFERENCES \r\n\r\nLinglart L, Gelb BD. Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment. Am J Med Genet C Semin Med Genet<\/em>. 2020;184(1):73-80. doi:10.1002\/ajmg.c.31765\r\n\r\n\r\nLioncino M, Monda E, Verrillo F, et al. Hypertrophic Cardiomyopathy in RASopathies: Diagnosis, Clinical Characteristics, Prognostic Implications, and Management. Heart Fail Clin<\/em>. 2022;18(1):19-29. doi:10.1016\/j.hfc.2021.07.004\r\n\r\n\r\nMital S, Breckpot J., Genetic Aspects of Congenital Heart defects. In: Shaddy RE, Penny DJ, Cetta F, Feltes TF, Mital S, eds. Moss and Adams\u2019 Heart Disease in Infants, children and adolescents including the fetus and young adult<\/em>. 10th ed. Philadephia, PA: Wolters Kluwer; 2022: 98-100\r\n\r\n”,”hint”:””,”answers”:{“ec2ee”:{“id”:”ec2ee”,”image”:””,”imageId”:””,”title”:”A.\tHypertrophic”,”isCorrect”:”1″},”pjy6l”:{“id”:”pjy6l”,”image”:””,”imageId”:””,”title”:”B.\tDilated”},”1j6m6″:{“id”:”1j6m6″,”image”:””,”imageId”:””,”title”:”C.\tRestrictive”}}}}}

{“questions”:{“h00jw”:{“id”:”h00jw”,”mediaType”:”image”,”answerType”:”text”,”imageCredit”:””,”image”:””,”imageId”:””,”video”:””,”imagePlaceholder”:””,”imagePlaceholderId”:””,”title”:”Authors: Meera Gangadharan, MBBS, FAAP, FASA – Children\u2019s Memorial Hermann Hospital, University of Texas Health Science Center, Houston, TX AND \r\nDestiny F. Chau, MD – Arkansas Children\u2019s Hospital, UAMS, Little Rock, AR \r\n\r\nAn 18-year-old girl with a history of tricuspid atresia palliated with a Fontan presents for emergent craniotomy after a motor vehicle collision. The patient is treated with rivaroxaban for thromboprophylaxis. Which of the following medications is MOST appropriate to reverse the anticoagulant effects of rivaroxaban?”,”desc”:”EXPLANATION \r\nPatients with the Fontan physiology are at risk for thromboembolism secondary to \u201cpassive\u201d pulmonary blood flow, venous hypertension, and hemostatic abnormalities. The risk for thromboembolism appears to be highest in the first three to twelve months following the Fontan operation, although a lower risk persists for life. The optimal anticoagulation strategy in children is still under debate. It is quite challenging with traditional medications such as warfarin and low-molecular-weight heparins, which require frequent blood draws for monitoring therapeutic levels and\/or are administered subcutaneously. These patients are usually maintained on acetylsalicylic acid (ASA) despite the paucity of data on optimal dosing and aspirin resistance. A new class of anticoagulant drugs known as direct oral anticoagulants (DOACs) are now available, with significant advantages over current medications. These include dabigatran, rivaroxaban, apixaban, edoxaban and betrixaban. Only rivaroxaban and dabigatran are FDA-approved for use in children.\r\n\r\nRivaroxaban is an orally administered anticoagulant that binds directly and reversibly to free factor Xa (activated factor X) and prothrombinase-bound factor Xa (see Fig. 1). Rivaroxaban was approved by the Federal Drug Administration (FDA) in 2021 for two pediatric indications, including treatment of venous thromboembolism and risk reduction of recurrent venous thromboembolism and for thromboprophylaxis in pediatric patients with the Fontan palliation. Advantages of rivaroxaban include oral administration, no requirement for therapeutic monitoring, eliminating the need for repeated venipunctures, and fewer drug-drug and drug-food interactions. Rivaroxaban is excreted and eliminated by the kidneys and in the feces. P-glycoprotein and cytochrome P450 3A4 enzyme inducers and inhibitors will affect the pharmacology of rivaroxaban. Although the prothrombin time (PT) and the activated partial thromboplastin time (aPTT) are prolonged, there is no requirement to monitor these levels during therapy.\r\n\r\n\r\n\r\nFig. 1. Mechanisms of action of DOACs. From: Al-Ghafry M, Sharathkumar A. Direct oral anticoagulants in pediatric venous thromboembolism: Review of approved products rivaroxaban and dabigatran. Front Pediatr<\/em>. 2022;10:1005098. Used under Creative Commons License.\r\n\r\nRivaroxaban was compared to ASA in the randomized, multi-center, 2-part, open-label UNIVERSE study to evaluate its dosing regimen, safety, and efficacy. Part A was a dose-finding and safety determination, while Part B enrolled 100 subjects with the Fontan palliation. A total of 66 patients received rivaroxaban, and 34 received ASA for thromboprophylaxis. One patient in the rivaroxaban group experienced a major bleeding episode consisting of epistaxis. No major bleeding was reported in the ASA group. Six percent of the rivaroxaban group and nine percent of the ASA group experienced a clinically relevant non-major bleeding event. With regards to efficacy, one patient (2%) in the rivaroxaban group experienced a pulmonary embolism. In contrast, three participants (9%) in the ASA group reported thrombotic events, two venous thromboses and one ischemic stroke. Notably, the study was not powered to determine efficacy. The authors concluded that rivaroxaban had similar safety<\/bold> as ASA for thromboprophylaxis in patients with Fontan physiology.\r\n\r\nPatients on rivaroxaban should have the medication stopped 24 to 48 hours before surgery, depending on the surgical procedure and renal function. If emergent reversal of anticoagulation by rivaroxaban is required, prothrombin complex concentrates (PCCs) or andexanet alfa may be administered. Andexanet alfa, an inactive recombinant factor Xa, has been approved for emergent reversal of rivaroxaban in adults. In a survey study, 44% of pediatric hematologists expressed that they prefer to administer andexanet alfa for emergent reversal of rivaroxaban in children versus PCCs. \r\n\r\nDabigatran is an orally administered direct thrombin inhibitor that has been FDA-approved for children older than three months of age. Dabigatran can be reversed with idarucizumab, an anti\u2010dabigatran monoclonal antibody fragment, which is approved for adults with major hemorrhage, and those requiring emergency surgery. Vitamin K antagonists (VKA) include warfarin, which works by inhibiting the vitamin K\u2010dependent coagulation factors, Prothrombin, Factor VII, Factor IX, and Factor X. Vitamin K should be given for reversal of VKA. However, it takes six hours for therapeutic effect after oral or intravenous administration of vitamin K. In emergent situations, four\u2010factor PCCs are recommended for rapid reversal of VKA if clinically indicated. \r\n\r\nThe correct answer is A. Andexanet alfa is recommended for reversal of rivaroxaban. Idarucizumab is recommended for reversal of dabigatran. Vitamin K is recommended for reversal of VKA,while four-factor PCCs are useful for emergent reversal.\r\n\r\n \r\nREFERENCES \r\nUS Food and Drug Administration. FDA approves drug to treat, help prevent types of blood clots in certain pediatric populations. Accessed on January 4 2025 at\r\nhttps:\/\/www.fda.gov\/drugs\/news-events-human-drugs\/fda-approves-drug-treat-help-prevent-types-blood-clots-certain-pediatric-populations#:~:text=FDA%20has%20approved%20Xarelto%20(rivaroxaban,populations%20and%20for%20other%20uses\r\n\r\nMcCrindle BW, Michelson AD, Van Bergen AH, et al. Thromboprophylaxis for children post-Fontan procedure: Insights from the UNIVERSE Study J Am Heart Assoc<\/em>.2021;10(22):e021765. doi:10.1161\/JAHA.120.021765.\r\n\r\nAl-Ghafry M, Sharathkumar A. Direct oral anticoagulants in pediatric venous thromboembolism: Review of approved products rivaroxaban and dabigatran. Front Pediatr<\/em>. 2022;10:1005098. doi:10.3389\/fped.2022.1005098\r\n\r\nDoyle AJ, Crowley MP, Hunt BJ. Perioperative management of antithrombotic treatment in children. Paediatr Anaesth<\/em>. 2019;29(5):405-413. doi:10.1111\/pan.13511\r\n\r\n”,”hint”:””,”answers”:{“dey42”:{“id”:”dey42″,”image”:””,”imageId”:””,”title”:”A.\tAndexanet alfa “,”isCorrect”:”1″},”dkxmk”:{“id”:”dkxmk”,”image”:””,”imageId”:””,”title”:”B.\tProthrombin complex concentrate”},”71n6k”:{“id”:”71n6k”,”image”:””,”imageId”:””,”title”:”C.\tIdarucizumab”}}}}}

{“questions”:{“4x49p”:{“id”:”4x49p”,”mediaType”:”image”,”answerType”:”text”,”imageCredit”:””,”image”:””,”imageId”:””,”video”:””,”imagePlaceholder”:””,”imagePlaceholderId”:””,”title”:”Authors: J. O\u2019Doherty, MB, ChB AND M. Gangadharan, MD, FAAP, FASA – Children\u2019s Memorial Hermann Hospital, University of Texas Health Science Center, Houston, TX \r\n\r\nA full-term newborn girl is diagnosed with truncus arteriosus. A transthoracic echocardiogram reveals a main pulmonary trunk arising from the truncus arteriosus, which divides into right and left pulmonary arteries. According to the Collett and Edwards classification, which type of truncus arteriosus does this child have? “,”desc”:”EXPLANATION \r\nTruncus arteriosus (TA) is a cyanotic congenital cardiac abnormality characterized by a single arterial trunk supplying the aorta, pulmonary arteries, and coronary arteries. This rare condition represents one to three percent of all cardiac defects. In almost all cases, a large ventricular septal defect is present in the infundibular septum, along with a single truncal valve that is most commonly tri-leaflet.\r\n\r\n\r\nThe Collett and Edwards classification (see Figure 1) categorizes TA into four types based on the pattern of origin of the pulmonary arteries, which are as follows: \r\n\u2022\tType I is characterized by a main pulmonary artery originating from the truncus, which then divides into the left and right branch pulmonary arteries. \r\n\u2022\tType II is characterized by an absent main pulmonary artery segment. Instead, the right and left pulmonary arteries arise separately from the posterior aspect of the truncus with their origins close to each other. \r\n\u2022\tType III is identical to Type II, except with widely separated origins of the pulmonary arteries. \r\n\u2022\tType IV is now recognized as a distinct clinical diagnosis, pulmonary atresia with major aortopulmonary collaterals, and is no longer considered to be a form of TA. \r\n\r\n\r\nThe classification system proposed by Van Praagh and Van Praagh (see Figure 1) divides TA into four types, including the following: \r\n\u2022\tType A1, which is identical to Collett and Edwards Type I TA. \r\n\u2022\tType A2, which mirrors Collett and Edwards Type II and III TA. \r\n\u2022\tType A3 is characterized by one pulmonary artery arising from the truncus, while a second pulmonary artery is supplied by the ductus arteriosus or originates from a systemic artery. \r\n\u2022\tType A4 includes cases with aortic arch abnormalities including hypoplasia, coarctation, and\/or interruption. \r\n\r\n\r\nFigure 1: Classification Systems of Truncus Arteriosus\r\n\r\n \r\n\r\n\r\n\r\nIt is also important to characterize the cardiac anatomy of these patients, including the anatomy and function of the truncal valve and the arrangement of the coronary arteries, as these features can significantly impact surgical outcomes. The truncal valve may be normal, regurgitant, or, rarely, stenotic. The truncal valve is tri-leaflet in most cases of TA, but can also be quadricuspid, bicuspid, pentacuspid, or unicomissural, in order of decreasing frequency. Truncal valves with moderate to severe regurgitation are usually repaired at the time of complete surgical correction.\r\n\r\n\r\nIn most cases, the right and left coronary arteries arise from their respective ostia on the right anterolateral and left posterolateral surface of the truncus. However, coronary artery anomalies are frequently associated with TA. Approximately 27% of patients have a left dominant system. The left anterior descending artery is often small, and the right coronary artery conal branch is more prominent, with large branches supplying the right ventricular outflow tract. This is important because the repair often involves the placement of a valved conduit from the right ventricle to the pulmonary artery.\r\n\r\n\r\nVariations in coronary anatomy can significantly impact surgical outcomes. In a recent single-center, retrospective review, 34 of 107 patients undergoing truncus arteriosus repair had at least one coronary lesion, which was defined as either a single coronary, ostial stenosis, intramural coronary course or juxta commissural origin of coronaries. Patients with one or two coronary lesions had similar 5-year survival, 80% and 83%, respectively. However, patients with three coronary lesions had a 5-year survival of 24% (p = 0.003). Furthermore, there was a trend towards improved 5-year survival if interventions were performed to treat coronary artery abnormalities. \r\n\r\n\r\nGenetic syndromes associated with truncus arteriosus are another consideration. A significant proportion of patients, 30 to 40 %, will have Chromosome 22q11.2 Deletion syndrome. These patients are 2.4 times more likely to have an aortic arch anomaly than those without this syndrome. Right aortic arch with mirror-image branching represents another common finding, occurring in 21 to 36 % of patients with TA. The ductus arteriosus is absent in 50% of patients with TA. However, the ductus arteriosus is typically present in patients with TA and a hypoplastic aortic arch anomaly. \r\n\r\n\r\nThe patient described in the vignette has a main pulmonary artery trunk arising from the truncus which divides into right and left pulmonary arteries, which is classified as Collett and Edwards Type I truncus arteriosus.\r\n\r\n\r\n\r\n \r\nREFERENCES \r\n\r\nParikh R, Eisses M, Latham GJ, Joffe DC, Ross FJ. Perioperative and Anesthetic Considerations in Truncus Arteriosus. Semin Cardiothorac Vasc Anesth<\/em>. 2018;22(3):285-293. doi:10.1177\/1089253218778826\r\n\r\n\r\nMenon SC, Cabalka AK, Dearani JA. Truncus Arteriosus. In: Shaddy RE, Penny DJ, Cetta F, Feltes TF, Mital S, eds. Moss and Adams\u2019 Heart Disease in infants, children and adolescents including the fetus and young adult<\/em>. 10th Edition. Philadephia, PA. Wolters Kluwer; 2022: 1009-1019\r\n\r\n\r\nBonilla-Ramirez C, Ibarra C, Binsalamah ZM, et al. Coronary Artery Anomalies Are Associated With Increased Mortality After Truncus Arteriosus Repair. Ann Thorac Surg<\/em>. 2021;112(6):2005-2011. doi:10.1016\/j.athoracsur.2020.08.082\r\n”,”hint”:””,”answers”:{“uho7t”:{“id”:”uho7t”,”image”:””,”imageId”:””,”title”:”A.\tType I”,”isCorrect”:”1″},”8cl68″:{“id”:”8cl68″,”image”:””,”imageId”:””,”title”:”B.\tType II”},”863q9″:{“id”:”863q9″,”image”:””,”imageId”:””,”title”:”C.\tType III”},”jpklg”:{“id”:”jpklg”,”image”:””,”imageId”:””,”title”:”D.\tType IV “}}}}}

{“questions”:{“p25o8”:{“id”:”p25o8″,”mediaType”:”image”,”answerType”:”text”,”imageCredit”:””,”image”:””,”imageId”:””,”video”:””,”imagePlaceholder”:””,”imagePlaceholderId”:””,”title”:”Authors: Morgan Ulloa, MD AND Kristin Richards, MD; University of Southern California, Children\u2019s Hospital Los Angeles, Los Angeles, CA \r\nMeera Gangadharan, MBBS, FAAP, FASA, UT Health, Children\u2019s Memorial Hermann Hospital, Houston, Texas \r\n\r\nA 14-year-old boy with a history of orthotopic heart transplantation receives the following medications: mycophenolate mofetil, tacrolimus, and prednisone. A recent comprehensive metabolic panel reveals an increase in his plasma creatinine from baseline. Which of the following immunosuppressant medications is MOST likely responsible for this laboratory finding?\r\n”,”desc”:”EXPLANATION \r\nTacrolimus, also known as Prograf, FK506, or TAC, is a macrolide that is commonly utilized for the maintenance of immunosuppression in heart transplant recipients. The immunosuppressive properties of tacrolimus stem from its selective inhibition of calcineurin, which leads to decreased proliferation of T-lymphocytes and decreased production of interleukin 2 (IL-2), interleukin 3 (IL-3), interleukin 4 (IL-4), interferon gamma, CD40L, GM-CSF, and tumor necrosis factor alpha (TNF-alpha). It is a lipophilic medication that is predominantly metabolized by cytochrome P-450 CYP3A enzymes in the liver. Tacrolimus is eliminated via biliary excretion. The elimination half-life is dependent on the formulation (immediate-release versus extended-release). \r\n\r\nTacrolimus is known to be nephrotoxic. Renal injury is more likely with higher doses of the medication, liver disease, inhibition of cytochrome P-450 CYP3A (notably by grapefruit) leading to higher plasma levels of the medication and its active metabolites, pre-existing renal disease, and the concomitant use of other nephrotoxic agents such as non-steroidal anti-inflammatory drugs. The nephrotoxic effects can lead to either acute kidney injury, which can often be reversed with a reduction in the dose of the drug, or chronic progressive kidney disease, which may be irreversible and lead to end-stage renal disease. \r\n\r\nThe mechanism of tacrolimus nephrotoxicity is not entirely known but is believed to be similar to cyclosporine, another calcineurin inhibitor, with a longer history of use clinically and known nephrotoxic properties. The acute nephrotoxic effects of both medications are thought to be due to endothelial cell dysfunction in afferent and efferent glomerular arterioles, leading to vasoconstriction that limits renal blood flow and glomerular filtration. Pathological examination of renal tissue in patients with chronic progressive renal disease has demonstrated arteriopathy, tubular damage, glomerular damage, and interstitial fibrosis. These findings may be responsible for or worsen associated pathologic states, such as hypertension, that may then compound existing renal disease. Thrombotic microangiopathy is an additional mechanism by which tacrolimus may cause renal injury.\r\n\r\nThe primary approach to minimizing tacrolimus-associated nephrotoxicity is by limiting exposure to the medication. This can be accomplished with dose reduction, the addition of adjunctive immunosuppressive medications such as mycophenolate mofetil, avoidance of medications and substances that inhibit tacrolimus metabolism in the liver, avoidance of additional nephrotoxic agents and the management of physiologic states that may worsen renal disease such as hypertension. \r\n\r\nOther important side effects of tacrolimus include metabolic disturbances, such as hyperkalemia, hypophosphatemia, hypomagnesemia, metabolic acidosis secondary to reduced renal acid excretion, hypercalciuria, neurotoxicity (headaches, tremors, neuropathy, encephalopathy, seizures, posterior reversible encephalopathy syndrome), glucose intolerance, hyperuricemia, and gout. There is a published case report of bronchiolitis obliterans, which the authors believed was caused by tacrolimus in a 19-month-old heart transplant recipient. \r\n\r\nMycophenolate mofetil (MMF, CellCept, Myfortic), like its predecessor azathioprine, is an anti-metabolite medication that acts as a reversible, non-competitive inhibitor of inosine monophosphate dehydrogenase, thus inhibiting the synthesis of GMP and T cell and B cell function. Mycophenolate mofetil is used to decrease the dose of calcineurin inhibitors and, thereby, calcineurin inhibitor toxicity. The main adverse effects of MMF are hematologic (leukopenia, anemia, and thrombocytopenia) and gastrointestinal (diarrhea and vomiting).\r\n\r\nPrednisone is a synthetic glucocorticoid pro-drug that is metabolized in the liver to prednisolone. Prednisone is utilized as an immunosuppressant medication and an anti-inflammatory medication. Although there are many undesirable side effects of glucocorticoid therapy, prednisone is not strongly associated with nephrotoxicity.\r\n\r\nThe correct answer is B. Renal toxicity is a major risk factor associated with the use of calcineurin inhibitor-type medications tacrolimus and cyclosporin. MMF and steroids are generally not associated with renal injury.\r\n\r\n\r\n\r\n\r\n \r\nREFERENCES \r\nHardinger K, Magee CC. Pharmacology of calcineurin inhibitors. In UpToDate, Connor RF (Ed), Wolters Kluwer. https:\/\/www.uptodate.com\/contents\/pharmacology-of-calcineurin-inhibitors Accessed on October 2, 2024.\r\n\r\nHardinger K, Brennan DC, Lam AQ. Cyclosporine and tacrolimus nephrotoxicity. In UpToDate, Connor RF (Ed), Wolters Kluwer. https:\/\/www.uptodate.com\/contents\/cyclosporine-and-tacrolimus-nephrotoxicity Accessed on October 3, 2024.\r\n\r\nKirpalani A, Teoh CW, Ng VL, Dipchand AI, Matsuda-Abedini M. Kidney disease in children with heart or liver transplant. Pediatr Nephrol<\/em>. 2021;36(11):3595-3605. doi:10.1007\/s00467-021-04949-5\r\n\r\nKarim F, Misra A, Sehgal S. Bronchiolitis obliterans organising pneumonia secondary to tacrolimus toxicity in a pediatric cardiac transplant recipient. Cardiol Young<\/em>. 2023;33(4):630-632. doi:10.1017\/S1047951122002049\r\n\r\nCrowley KL, Webber S. Immunosuppressive agents in pediatric heart transplantation. In: Munoz R, da Cruz EM, Vetterly CG, Cooper DS, Berry D, Eds. Handbook of Pediatric Cardiovascular Drugs<\/em>. 2nd Edition. London, UK: Springer-Verlag; 2014: pp 329-363.\r\n\r\n”,”hint”:””,”answers”:{“cvv25”:{“id”:”cvv25″,”image”:””,”imageId”:””,”title”:”A.\tMycophenolate mofetil “},”8xciu”:{“id”:”8xciu”,”image”:””,”imageId”:””,”title”:”B.\tTacrolimus “,”isCorrect”:”1″},”bqq8q”:{“id”:”bqq8q”,”image”:””,”imageId”:””,”title”:”C.\tPrednisone”}}}}}

{“questions”:{“p5z3o”:{“id”:”p5z3o”,”mediaType”:”image”,”answerType”:”text”,”imageCredit”:””,”image”:””,”imageId”:””,”video”:””,”imagePlaceholder”:””,”imagePlaceholderId”:””,”title”:”Authors: Clementine Vo, DO \u2013 Texas Children\u2019s Hospital\/Baylor College of Medicine, Houston, TX, USA AND\r\nDestiny F. Chau, MD – Arkansas Children\u2019s Hospital\/University of Arkansas for Medical Sciences, Little Rock, AR, USA \r\n\r\nA 16-year-old girl with a history of an unbalanced atrioventricular canal palliated with the Fontan procedure presents for cardiac catheterization due to ascites. Magnetic resonance imaging of the liver demonstrates hepatic fibrosis, and laboratory studies reveal hypoalbuminemia and elevated stool anti-trypsin levels. Which of the following diagnoses is the MOST likely cause of these clinical findings? \r\n”,”desc”:”EXPLANATION \r\nThe Fontan physiology creates a state of chronic venous hypertension that can lead to multi-system organ dysfunction, characterized by protein-losing enteropathy (PLE), plastic bronchitis, and Fontan-associated liver disease. PLE and plastic bronchitis are associated with lymphatic dysfunction and the leakage of protein-rich lymph fluid into luminal spaces adjacent to lymphatic vessels. The leakage of proteinaceous fluid into the intestinal lumen results in enteric protein loss, also known as PLE. Leakage of proteinaceous material into the bronchial tree causes plastic bronchitis with the formation of bronchial casts. Symptoms of plastic bronchitis include dyspnea, cough, wheezing, and, in severe cases, respiratory failure due to airway obstruction from the casts. The diagnosis is confirmed by bronchoscopy.\r\n\r\nSigns and symptoms of PLE include progressive central and peripheral edema, ascites, and often diarrhea. PLE affects up to 13% of Fontan patients, typically within ten years of the Fontan procedure. Factors predisposing to PLE include altered intestinal mucosal perfusion, low cardiac output, a selective increase in mesenteric vascular resistance, a proinflammatory state altering gut membrane permeability, and low heparan sulfate proteoglycans in the enterocyte membrane resulting in reduced enteral protein transport and increased luminal protein loss. Protein loss results in severe hypoalbuminemia and low serum oncotic pressure, leading to edema. The gold standard for PLE diagnosis is an elevated 24-hour stool alpha-1 antitrypsin clearance. PLE may also be diagnosed with a single stool sample with an elevated alpha-1 antitrypsin level concurrent with serum hypoalbuminemia and generalized edema with no other cause. Chronic protein loss is associated with a multitude of clinical sequelae, such as poor tissue integrity and impaired wound healing, coagulation factor deficiency resulting in coagulopathy and thromboembolic complications, hypoalbuminemia leading to secondary hypocalcemia, and low immunoglobulin levels resulting in immunodeficiency.\r\n\r\nPLE management focuses on reducing chronic venous hypertension by optimizing Fontan hemodynamics and improving nutritional intake. Medical management includes diuretics to reduce fluid overload, albumin to restore oncotic pressure, steroids to reduce inflammation, aldosterone antagonists and\/or heparin to stabilize the proteoglycan layer of the gut, and pulmonary vasodilators to reduce chronic venous congestion. Lymphatic interventions may reroute the lymphatic flow to provide a measure of symptomatic relief and improvement in quality of life. Heart transplantation is the last resort and appears to be effective for symptom relief. However, patients with PLE are often poor candidates due to chronic protein wasting and poor nutritional status and may not survive the waiting period or the transplantation procedure. The prognosis is grim, with 50% mortality within the first five years after diagnosis. \r\n\r\nThe patient in the stem has elevated stool alpha-antitrypsin, hypoalbuminemia, and ascites, which are diagnostic for PLE. Therefore, PLE is the most likely cause of the clinical presentation described in the stem. Plastic bronchitis is not the correct answer, as it is characterized by respiratory symptoms and the presence of airway casts. Although hypoalbuminemia and ascites are both signs of hepatic dysfunction in Fontan-associated liver disease (FALD), the MRI demonstrates fibrosis rather than cirrhosis, a classic finding in FALD. Additionally, FALD is not usually associated with significant hepatic synthetic impairment.\r\n\r\n\r\n \r\nREFERENCES \r\nRychik J, Atz AM, Celermajer DS, et al. Evaluation and management of the child and adult with Fontan circulation: A scientific statement from the American Heart Association. Circulation<\/em>. 2019;140(6):e234-e284. \r\n\r\nMackie AS, Veldtman GR, Thorup L, Hjortdal VE, Dori Y. Plastic bronchitis and protein-losing enteropathy in the Fontan patient: Evolving understanding and emerging therapies. Can J Cardiol<\/em>. 2022;38(7):988-1001. doi:10.1016\/j.cjca.2022.03.011\r\n\r\nJohn AS, Johnson JA, Khan M, Driscoll DJ, Warnes CA, Cetta F. Clinical outcomes and improved survival in patients with protein-losing enteropathy after the Fontan operation. J Am Coll Cardiol<\/em>. 2014;64(1):54-62. doi: 10.1016\/j.jacc.2014.04.025. PMID: 24998129.\r\n\r\nStout KK, Daniels CJ, Aboulhosn JA, et al. 2018 AHA\/ACC guideline for the management of adults with congenital heart disease: Executive summary: A report of the American College of Cardiology\/American Heart Association task force on clinical practice guidelines [published correction appears in J Am Coll Cardiol. 2019.14;73(18):2361]. J Am Coll Cardiol<\/em>. 2019;73(12):1494-1563. doi:10.1016\/j.jacc.2018.08.1028\r\n\r\n”,”hint”:””,”answers”:{“1jyk6”:{“id”:”1jyk6″,”image”:””,”imageId”:””,”title”:”A.\tPlastic bronchitis”},”bedeu”:{“id”:”bedeu”,”image”:””,”imageId”:””,”title”:”B.\tProtein-losing enteropathy”,”isCorrect”:”1″},”rz5a2″:{“id”:”rz5a2″,”image”:””,”imageId”:””,”title”:”C.\tFontan-associated liver disease”}}}}}