Kathryn Dodds

Use of Oral Budesonide in the Management of Protein-Losing Enteropathy After the Fontan Operation

BACKGROUND Intestinal inflammation is a component of the pathophysiology of protein-losing enteropathy after the Fontan operation. Oral controlled-release budesonide is 90% metabolized at first pass through the liver, has high enteric anti-inflammatory activity and relatively low systemic effects, and may be an ideal agent for use in treating this disease. METHODS Budesonide was administered to 9 patients (4 male) with protein-losing enteropathy after the Fontan operation. The median interval between the Fontan operation and diagnosis of protein-losing enteropathy was 4 years (range, 0.1 to 13.3). Prior interventional therapy included pulmonary artery stent (1), fenestration (3), pacemaker placement (3) and Fontan revision (2). Prior medical therapy included oral prednisone (5), heparin (4), sildenafil (2), infliximab (1), and octreotide (1), all without persistent success. The starting daily dose of budesonide was 9 mg for patients 4 years old or older, and 6 mg for patients less than 4 years of age. RESULTS Mean serum albumin level 3 months before starting budesonide was 1.9 g/dL (range, 1 to 2.4 g/dL). Serum albumin level improved in all patients within 6 months of starting budesonide (mean 2.9 g/dL; range, 2.2 to 3.8 g/dL). Albumin levels of 3 g/dL or more were achieved in 8 of 9 patients within a median of 4.3 months (range, 2 to 25). Side effects included Cushingoid features and osteoporosis (3), infection requiring antibiotic treatment (5), and acne exacerbation (1). Weaning from high initial dose to a lower dose was possible with sustained effect; however, discontinuation of budesonide resulted in recurrence of hypoalbuminemia. CONCLUSIONS Oral budesonide is an effective therapy for treating protein-losing enteropathy after the Fontan operation. To maintain response, low-dose therapy must be continued.

Percutaneous Lymphatic Embolization of Abnormal Pulmonary Lymphatic Flow as Treatment of Plastic Bronchitis in Patients With Congenital Heart Disease

Background— Plastic bronchitis is a potentially fatal disorder occurring in children with single-ventricle physiology, and other diseases, as well, such as asthma. In this study, we report findings of abnormal pulmonary lymphatic flow, demonstrated by MRI lymphatic imaging, in patients with plastic bronchitis and percutaneous lymphatic intervention as a treatment for these patients. Methods and Results— This is a retrospective case series of 18 patients with surgically corrected congenital heart disease and plastic bronchitis who presented for lymphatic imaging and intervention. Lymphatic imaging included heavy T2-weighted MRI and dynamic contrast-enhanced magnetic resonance lymphangiogram. All patients underwent bilateral intranodal lymphangiogram, and most patients underwent percutaneous lymphatic intervention. In 16 of 18 patients, MRI or lymphangiogram or both demonstrated retrograde lymphatic flow from the thoracic duct toward lung parenchyma. Intranodal lymphangiogram and thoracic duct catheterization was successful in all patients. Seventeen of 18 patients underwent either lymphatic embolization procedures or thoracic duct stenting with covered stents to exclude retrograde flow into the lungs. One of the 2 patients who did not have retrograde lymphatic flow did not undergo a lymphatic interventional procedure. A total of 15 of 17(88%) patients who underwent an intervention had significant symptomatic improvement at a median follow-up of 315 days (range, 45–770 days). The most common complication observed was nonspecific transient abdominal pain and transient hypotension. Conclusions— In this study, we demonstrated abnormal pulmonary lymphatic perfusion in most patients with plastic bronchitis. Interruption of the lymphatic flow resulted in significant improvement of symptoms in these patients and, in some cases, at least temporary resolution of cast formation.

Critical heart disease in the neonate: Presentation and outcome at a tertiary care center

Objective: To define the modes of presentation, incidence of major organ dysfunction, predictors of hospital mortality, and adverse outcomes in neonates with critical heart disease admitted to a tertiary care center. Design: Retrospective chart review. Setting: A tertiary care pediatric cardiac intensive care unit and neonatal intensive care unit. Patients: The medical records for all neonates (≤30 days of age) with heart disease admitted to the cardiac intensive care unit or neonatal intensive care unit between October 1, 2002, and September 30, 2003, were reviewed. Interventions: None. Measurements and Main Results: A total of 190 neonates met inclusion criteria during this 1-yr period, of which 146 (77%) had at least one surgical procedure. Single ventricle heart disease was present in 42%. The most common mode of presentation was following a prenatal diagnosis (53%), followed by diagnosis in the newborn nursery (38%) and diagnosis after newborn hospital discharge (8%). The most common presenting findings in the newborn nursery were isolated murmur (38%) or cyanosis (32%), while circulatory collapse (38%) was the most common presentation after discharge. For the entire study cohort, 13% had a known genetic syndrome, 23% had a major noncardiac congenital anomaly, and 16% weighed <2.5 kg. The hospital mortality for the entire cohort was 7.4%. Risk factors associated with an increased risk of hospital mortality included younger age at admission, higher number of cardiopulmonary bypass runs, and need for postoperative cardiopulmonary resuscitation. Total hospital length of stay was >1 month in 17% of neonates. Conclusions: In patients with complex congenital heart disease, including nearly half with single ventricle heart disease, neonatal hospital mortality was 7%. These patients have a high frequency of multiple congenital anomalies, genetic syndromes, low birth weight, and prolonged length of stay.

Guidelines for the Outpatient Management of Complex Congenital Heart Disease

An increasingly complex group of children is now being followed as outpatients after surgery for congenital heart disease. A variety of complications and physiologic perturbations, both expected and unexpected, may present during follow-up, and should be anticipated by the practitioner and discussed with the patient and family. The purpose of this position article is to provide a framework for outpatient follow-up of complex congenital heart disease, based on a review of current literature and the experience of the authors.

End-organ consequences of the Fontan operation: liver fibrosis, protein-losing enteropathy and plastic bronchitis

The Fontan operation, although part of a life-saving surgical strategy, manifests a variety of end-organ complications and unique morbidities that are being recognised with increasing frequency as patients survive into their second and third decades of life and beyond. Liver fibrosis, protein-losing enteropathy and plastic bronchitis are consequences of a complex physiology involving circulatory insufficiency, inflammation and lymphatic derangement. These conditions are manifest in a chronic, indolent state. Management strategies are emerging, which shed some light on the origins of these complications. A better characterisation of the end-organ consequences of the Fontan circulation is necessary, which can then allow for development of specific methods for treatment. Ideally, the goal is to establish systematic strategies that might reduce or eliminate the development of these potentially life-threatening challenges.

Lean mass deficits, vitamin D status and exercise capacity in children and young adults after Fontan palliation

Objective We sought to evaluate body composition in children and young adults with Fontan physiology. Leg lean mass (LM) deficits correlate with diminished exercise capacity in other populations and may contribute to exercise limitations in this cohort. Methods This cross-sectional study included whole body dual energy X-ray absorptiometry scans in 50 Fontan participants ≥5 years, and measures of peak oxygen consumption (VO2) in 28. Whole body and leg LM (a measure of skeletal muscle) were converted to sex- and race-specific Z-scores, relative to age and stature, based on 992 healthy reference participants. Results Median age was 11.5 (range 5.1–33.5) years at 9.3 (1.1–26.7) years from Fontan. Height Z-scores were lower in Fontan compared with reference participants (−0.47±1.08 vs 0.25±0.93, p<0.0001). Body mass index Z-scores were similar (0.15±0.98 vs 0.35±1.02, p=0.18). LM Z-scores were lower in Fontan compared with reference participants (whole body LM −0.33±0.77 vs 0.00±0.74, p=0.003; leg LM −0.89±0.91 vs 0.00±0.89, p<0.0001). LM Z-scores were not associated with age or Fontan characteristics. Leg LM Z-scores were lower in vitamin D deficient versus sufficient Fontan participants (−1.47±0.63 vs −0.71±0.92, p=0.01). Median per cent predicted peak VO2 was 81% (range 13%–113%) and was associated with leg LM Z-scores (r=0.54, p=0.003). Conclusions Following Fontan, children and young adults are shorter than their peers and have significant LM deficits. Skeletal muscle deficits were associated with vitamin D deficiency and reduced exercise capacity. Future studies should examine the progression of these deficits to further understand the contribution of peripheral musculature to Fontan exercise capacity.

Hepatic Fibrosis Is Universal Following Fontan Operation, and Severity is Associated With Time From Surgery: A Liver Biopsy and Hemodynamic Study

Background Congestive hepatopathy is a recognized complication of Fontan physiology. Data regarding the incidence of hepatopathy and risk factors are lacking. Methods and Results Liver biopsies and cardiac catherizations were performed as part of an evaluation offered to all patients ≥10 years after Fontan. Quantitative determination of hepatic fibrosis was performed using Sirius red staining with automated calculation of collagen deposition per slide (%CD). Biopsies from included subjects were compared to stained specimens from controls without known fibrotic liver disease. Patient characteristics, echocardiographic findings, and hemodynamic measures were evaluated as potential risk factors. The cohort consisted of 67 patients (31 female) at mean age of 17.3±4.5 years and mean time from Fontan of 14.9±4.5 years. Right ventricular morphology was present in 37 subjects. Median %CD by Sirius red staining was 21.6% (range 8.7% to 49.4%) compared to 2.6% (range 2.2% to 3.0%) in controls. There was a significant correlation between time from Fontan and degree of Sirius red staining (r=0.33, P<0.01). Serum liver enzymes and platelet count did not correlate with %CD. The median inferior vena cava pressure was 13 mm Hg (range 6‐24 mm Hg) and did not correlate with %CD. There was no difference in %CD based on ventricular morphology or severity of atrioventricular valve insufficiency. Conclusions In this cohort of predominantly asymptomatic children and adolescents electively evaluated after a Fontan operation, all exhibited evidence for hepatic fibrosis as measured by collagen deposition in the liver. Time from Fontan was the only factor significantly associated with collagen deposition. These findings demonstrate that liver fibrosis is an inherent feature of Fontan physiology and that the degree of fibrosis increases over time.

Prevalence and characterization of fibrosis in surveillance liver biopsies of patients with Fontan circulation.

The Fontan operation is a widely used palliative procedure in patients with single-ventricle anatomy that results in liver injury. As timely identification of liver fibrosis may result in management changes to Fontan patients, the aim of our study was to identify clinically meaningful semi quantitative/quantitative pathologic parameters for biopsy assessment. We performed a retrospective review of 74 liver needle biopsies from Fontan patients. Fibrosis was assessed using quantitative % collagen deposition by Sirius red image analysis, METAVIR, congestive hepatic fibrosis score, sinusoidal fibrosis score, and sinusoidal dilation score. Contemporaneous laboratory, hemodynamic, and ultrasound data were collected. Centrilobular and peri sinusoidal fibrosis was observed in all cases, with 39.2% high grade. Portal fibrosis was observed in 93.2%, with 36.2% high-grade (METAVIR F3-F4). Cirrhosis was observed in 5.4%. % Collagen deposition was increased over control tissue (P < .001) and correlated with time from Fontan (r = 0.3, P = .009) and prothrombin time (r = 0.25, P = .034). Mildly elevated prothrombin time/international normalized ratio was the only measure of liver function consistently associated with multiple high-grade fibrosis scores (METAVIR P = .046, sinusoidal fibrosis P = .018). Abnormal liver echotexture on ultrasound was associated with high-grade congestive hepatic fibrosis score (P = .03). Pathologic gradings and %CD correlated with each other (r = 0.48-0.8, P < .001). Hepatic fibrosis in Fontan patients in our study is universally present, appears to be time dependent, and correlates with few laboratory measurements of liver function. Careful assessment of needle liver biopsies lends a more meaningful measure of liver fibrosis in the Fontan patient than clinical and laboratory data, allowing for appropriate changes to patient management.

Deficits in bone density and structure in children and young adults following Fontan palliation.

BACKGROUND Survival of patients with congenital heart disease has improved such that there are now more adults than children living with these conditions. Complex single ventricle congenital heart disease requiring Fontan palliation is associated with multiple risk factors for impaired bone accrual. Bone density and structure have not been characterized in these patients. METHODS Tibia peripheral quantitative computed tomography (pQCT) was used to assess trabecular and cortical volumetric bone mineral density (vBMD), cortical dimensions, and calf muscle area in 43 Fontan participants (5-33 years old), a median of 10 years following Fontan palliation. pQCT outcomes were converted to sex- and race-specific Z-scores relative to age based on >700 healthy reference participants. Cortical dimensions and muscle area were further adjusted for tibia length. RESULTS Height Z-scores were lower in Fontan compared to reference participants (mean ± SD: -0.29 ± 1.00 vs. 0.25 ± 0.93, p < 0.001); BMI Z-scores were similar (0.16 ± 0.88 vs. 0.35 ± 1.02, p = 0.1). Fontan participants had lower trabecular vBMD Z-scores (-0.85 ± 0.96 vs. 0.01 ± 1.02, p < 0.001); cortical vBMD Z-scores were similar (-0.17 ± 0.98 vs. 0.00 ± 1.00, p = 0.27). Cortical dimensions were reduced with lower cortical area (-0.59 ± 0.84 vs. 0.00 ± 0.88, p<0.001) and periosteal circumference (-0.50 ± 0.82 vs. 0.00 ± 0.84, p < 0.001) Z-scores, compared to reference participants. Calf muscle area Z-scores were lower in the Fontan participants (-0.45 ± 0.98 vs. 0.00 ± 0.96, p = 0.003) and lower calf muscle area Z-scores were associated with smaller periosteal circumference Z-scores (R = 0.62, p < 0.001). Musculoskeletal deficits were not associated with age, Fontan characteristics, parathyroid hormone or vitamin D levels. CONCLUSIONS Children and young adults demonstrate low trabecular vBMD, cortical structure and muscle area following Fontan. Muscle deficits were associated with smaller periosteal dimensions. Future studies should determine the fracture implications of these deficits and identify interventions to promote musculoskeletal development.

A Multifaceted Approach to the Management of Plastic Bronchitis After Cavopulmonary Palliation

BACKGROUND Plastic bronchitis is a rare, potentially life-threatening complication after Fontan operation. Hemodynamic alterations (elevated central venous pressure and low cardiac output) likely contribute to the formation of tracheobronchial casts composed of inflammatory debris, mucin, and fibrin. Pathologic studies of cast composition support medical treatment with fibrinolytics such as inhaled tissue plasminogen activator (t-PA). METHODS This was a retrospective case series of medical, surgical, and catheter-based treatment of patients with plastic bronchitis after cavopulmonary palliation. RESULTS Included were 14 patients (86% male, 93% white). Median age at Fontan operation was 2.7 years (range, 1.2 to 4.1 years), with median interval to plastic bronchitis presentation of 1.5 years (range, 9 days to 15.4 years). Cast composition was available for 11 patients (79%) and included fibrin deposits in 7. All patients were treated with pulmonary vasodilators, and 13 (93%) were treated with inhaled t-PA. Hemodynamically significant lesions in the Fontan pathway were addressed by catheter-based (n=9) and surgical (n=3) interventions. Three patients (21%) underwent heart transplantation. Median follow-up was 2.7 years (range, 0.6 to 8.7 years). Symptoms improved, such that 6 of 13 patients (46%) were weaned off t-PA. Rare or episodic casts are successfully managed with outpatient t-PA in most of the other patients. Of the 3 patients who underwent heart transplant, 2 are asymptomatic and 1 has recurrent casts in the setting of elevated filling pressures and rejection. CONCLUSIONS A systematic step-wise algorithm that includes optimization of hemodynamics, aggressive pulmonary vasodilation, and inhaled t-PA is an effective treatment strategy for patients with plastic bronchitis after cavopulmonary connection.