Pediatric dysautonomia: Much-maligned, often overmedicated, but not as complex as you think.

Dysautonomia is an increasingly recognized yet still poorly understood disease within the field of pediatrics. Symptoms, including dizziness, headaches, fatigue, joint pain, anxiety, and intolerance of heat or cold, are often significant and difficult to sort, especially in terms of their relation to each other. This often leads to referral to multiple subspecialists, who then proceed to treat seemingly familiar symptoms in kind. In the authors' experience, this leads to more frustration on the part of the patients and their physicians when symptom improvement does not follow (or can even worsen). On the other hand, by understanding the pathophysiology, treatment success is possible by directing therapies toward the root causes and just as importantly, enlisting the patient in a daily treatment plan. In the text that follows, we hope to convey these viewpoints by highlighting an involved case, discussing the pathophysiology, outlining the usual evaluation, and finally describing our approach to treatment.

The utility of cardiac magnetic resonance imaging in post-Fontan surveillance.

OBJECTIVE: Gated cardiac MRI offers the most detailed and accurate noninvasive method of assessing cardiac anatomy, particularly in patients with complex congenital heart disease. The proposed benefits of using cMRI as a routine screening tool in the Fontan population include early recognition of asymptomatic, postoperative anatomic and physiologic changes. In 2011, we therefore instituted at our center a recommended practice of cMRI screening in patients with Fontan physiology at 3 and 8 years post-Fontan operation. The purpose of this study was to determine the impact of this standardized practice of cMRI screening on the clinical management of a Fontan population. DESIGN: We retrospectively reviewed charts from our institutional Fontan database to determine which patients were eligible for cMRI under the current guidelines and who underwent imaging from November 2002 to June 2015. We reviewed the frequency of cMRI and number of changes in management based on the results. Statistical significance was determined using a chi-square test. RESULTS: There were 141 cMRIs performed on 121 patients who met inclusion criteria. The odds of a change in management were significantly greater after clinically indicated cMRI compared to screening cMRI (OR = 3.79, 95% CI: 1.48-9.66, P = .004). There were near significant odds of change in management if the cMRI occurred <8 years after Fontan regardless of whether it was for screening or clinically indicated purposes (OR = 2.43, 95% CI: 0.97-6.08, P = .052). The most frequent change in management was referral for catheterization with pulmonary artery angioplasty. CONCLUSIONS: There is an important role for cMRI in routine surveillance of post-Fontan patients. Screening cMRI performed less than 8 years after Fontan palliation offers increased utility compared to studies performed later. The optimal timing of such imaging after Fontan palliation remains unclear.

Risk factors for major adverse events late after Fontan palliation.

OBJECTIVE: Risk factors for major adverse events late after Fontan palliation are unknown. Prior studies have suggested ventricular function and morphology as important risk factors. The aim of this study is to (1) characterize the late major adverse event profile in adult Fontan patients and (2) identify additional risk factors that may contribute to adverse outcomes. DESIGN AND SETTING: A retrospective review of all adult patients >15 years post-Fontan seen at a tertiary academic center was conducted. Clinical, laboratory, cardiac data, and abdominal imaging were collected via chart review. Major adverse events (death, cardiac transplantation, or listing) were identified, and timing of events was plotted using Kaplan-Meier methods. Univariate and multivariate logistic regression was used to determine independent predictors of late-term events. RESULTS: A total of 123 adult Fontan patients were identified (mean time post-Fontan 22.4 years [±4.4]). Major adverse events occurred in 19/123 patients (15%). In this 15-year survivor cohort, transplant-free survival rates were 94.6%, 82.9%, and 59.8% at 20, 25, and 30 years postoperation, respectively. Modes of death were Fontan failure with preserved function (4), congestive heart failure with decreased function (2), sudden death (2), thromboembolic event (1), post-Fontan conversion (2), and posttransplant (2). No differences in adverse outcomes were found based on morphology of the systemic ventricle, Fontan type, or systolic ventricular function. On the other hand, features of portal hypertension (OR 19.0, CI 4.7-77.3, P < .0001), presence of a pacemaker (OR 13.4, CI 2.6-69.8, P = .002), and systemic oxygen desaturation (OR 0.86, CI 0.75-0.98, P = .02) were risk factors for major adverse events in the multivariate analysis. CONCLUSIONS: In adult Fontan patients surviving >15 years post-Fontan, portal hypertension, oxygen desaturation, and need for pacemaker were predictive of adverse events. Traditional measures may not predict late-term outcomes in adult survivors; further study of the liver's role in late outcomes is warranted.

Features of portal hypertension are associated with major adverse events in Fontan patients: the VAST study.

BACKGROUND: Chronic congestive hepatopathy is known to cause hepatic fibrosis and portal hypertension in patients post-Fontan operation for single ventricle palliation. The clinical significance of these findings is not clear. We hypothesized that features of portal hypertension would be significantly related to major adverse events. METHODS: A retrospective review of 73 adult and pediatric post-Fontan patients referred for a liver evaluation from 2001 to 2011 was performed. The relationship between features of portal hypertension (VAST score ≥2, 1 point each for Varices, Ascites, Splenomegaly or Thrombocytopenia) and a major adverse event (death, need for transplant, or hepatocellular carcinoma) was examined using logistic regression. RESULTS: 73 post-Fontan patients (30% female, 73% Caucasian, 66% systemic left ventricle (SLV), mean age 24±11 years, mean interval from Fontan 17±6 years) were included in analysis. Features of portal hypertension (VAST score ≥2) were present in 26 (36%), and there were 19 major adverse events: death (n=12), transplant (n=6), and HCC (n=1). A significant relationship was found between VAST score ≥2 and major adverse events (OR=9.8, 95% CI [2.9-32.7]). After adjusting for time since Fontan, SLV, age, hemoglobin and type of failure, VAST score ≥2 remained significant (OR=9.1, 95% CI [1.4-57.6]). CONCLUSION: Fontan patients with features of portal hypertension have a 9-fold increased risk for a major adverse event. Therapies targeted to manage clinical manifestations of portal hypertension, and early referral to heart transplant may help delay major adverse events. Future prospective studies are needed to confirm these findings.

Management of warfarin in children with heart disease.

Warfarin is an important therapy for children with heart disease. We assessed the impact of a computerized warfarin-dosing software program on measured INR values using a historical case-control design. Children (infant to 20 years of age) with cardiac disease managed with warfarin between September 1, 2006, and August 31, 2009 were included in the analysis. Warfarin therapy was tailored to specific underlying conditions based on consensus guidelines. Before the use of dosing software, medication adjustments were made by physicians using published guidelines. After software implementation, dosing adjustments were based on the software algorithm. There were 86 subjects in this analysis, and the most common indication for warfarin was prosthetic valve. Overall, the incidence of adverse bleeding events was 1.3% per patient-year. An analysis of patient-related factors associated with a low percentage of time within goal range demonstrated that both female sex (P = 0.048) and nonwhite race (P = 0.037) were significantly associated with less time in the target range. Use of the software program was associated with an increase in the percentage of time during which the INR was within the target range from 41.4 to 53.1% (P < 0.001). Incorporation of a computerized software program to assist dosing can improve the percentage of time that children with cardiac disease requiring warfarin remain within the target therapeutic range. Strategies to improve management and decrease sex and racial disparities in this population are needed.

Octopus papillary muscle associated with a left lateral accessory pathway.

Left ventricular papillary muscle abnormalities are rare malformations. They have been related to significant mitral valve dysfunction and left ventricular midcavitary obstruction. We report our experience with a young adult who presented with palpitations. An echocardiogram on the patient showed an "octopus-like" left ventricular papillary muscle. Subsequent electrophysiologic testing showed evidence of supraventricular tachycardia via a left lateral accessory pathway associated with the abnormal insertion of the papillary muscle attachments.

Impact of spironolactone on endothelial function in patients with single ventricle heart.

BACKGROUND: Mid-term survivors of the Fontan procedure are at risk for progressive heart failure, and endothelial dysfunction is thought to contribute to this process. Aldosterone antagonism has been shown to improve survival in adults with heart failure and the effects are mediated in part by changes in endothelial function. In the present study, we sought to determine if a short course of spironolactone improves endothelial function and alters serum cytokine profiles in adolescents and adults with single ventricle heart. METHODS: Subjects had baseline assessment of flow-mediated dilation and cytokine profiles (C-reactive protein, interleukin-6, interleukin-1b, interleukin-10, tumor necrosis factor-alpha). They were started on spironolactone 25 mg once a day and uptitrated to 50 mg once daily. After 4 weeks, flow-mediated dilation and cytokine profiles were re-evaluated. RESULTS: Ten subjects (median age 28 years) were enrolled and completed the protocol. The median flow-mediated dilation at baseline was 9.1% and did not change significantly after 4 weeks of spironolactone 7.6%, P = .46. There was mild elevation in serum cytokine profiles and only interleukin-1b decreased significantly with therapy, 0.39 to 0.23 pg/mL, P = .04. CONCLUSIONS: In this small study, a short course of spironolactone did not improve endothelial function or alter the majority of serum cytokine levels. Whether single ventricle patients might realize other potential benefits of aldosterone antagonism such as reduced cardiac fibrosis remains to be determined.

Endothelin receptor antagonists improve exercise tolerance and oxygen saturations in patients with Eisenmenger syndrome and congenital heart defects.

Patients with Eisenmenger syndrome experience substantial morbidity and decreased survival rates. In advanced cases, lung transplantation with cardiac repair or heart-lung transplantation is often the only option. The efficacy of endothelin receptor antagonists in Eisenmenger syndrome, which has similar pathophysiology to idiopathic pulmonary hypertension, remains unknown.We retrospectively studied adults with congenital heart disease and Eisenmenger syndrome who were treated with endothelin receptor antagonists. Analysis included chart reviews of clinical evaluations, oxygen saturation levels, functional class, 6-minute walk distances, and pulmonary artery pressures. In the 24 patients studied, Eisenmenger syndrome was caused by ventricular septal defect (6 patients), atrial septal defect (5), atrioventricular canal defect (3), complex congenital heart disease (9), and patent ductus arteriosus (1).Eisenmenger syndrome was treated with bosentan (21 patients) and sitaxsentan (3 patients). On average, therapy lasted 19 +/- 12 months. Subsequently, mean 6-minute walk distances improved from 226 +/- 159 m to 351 +/- 113 m (P = 0.004), and World Health Organization functional class improved > or =1 grade (P < 0.0001). Oxygen saturations increased on therapy from 80.5% to 87% (P < 0.0001). Pulmonary arterial systolic pressures decreased from 97 +/- 21 mmHg to 78 +/- 27 mmHg, and mean pressures from 59 +/- 16 mmHg to 47 +/- 17 mmHg (both P < 0.0001). Neither major complications from therapy nor changes in pulmonary capillary wedge pressure occurred.Endothelin receptor antagonists may play an important role in improving 6-minute walk distance, oxygen saturation, pulmonary artery pressures, and symptoms in adults who have congenital heart defects and Eisenmenger syndrome.

Effect of beta blockers (carvedilol or metoprolol XL) in patients with transposition of great arteries and dysfunction of the systemic right ventricle.

This study evaluated the effects of beta blockers (carvedilol and metoprolol XL) on New York Heart Association functional class and systemic right ventricular (RV) function in patients with complete transposition of the great arteries who had systemic RV dysfunction late after atrial inflow correction. A significant improvement in New York Heart Association functional class was found after 4 months of therapy with beta blockers. Functional recovery was significant mostly in those patients with pacemakers who received higher maintenance doses of carvedilol. RV end-diastolic area was significantly greater in untreated patients at the end of the follow-up period, whereas it was unchanged in treated patients. In conclusion, beta blockers prevent RV remodeling, with a concomitant improvement in exercise tolerance in patients with complete transposition of the great arteries and systemic RV dysfunction.

Exceptional survival: double inlet left ventricle presenting with aortic dissection.

Adult survival with unoperated univentricular heart is unusual, particularly into the latter decades. Survival is most common in balanced circulations, such as double inlet left ventricle with moderate pulmonary stenosis. We describe a woman who presented with an aortic dissection and previously unrecognized univentricular heart.

Thoracoscopic approach to epicardial lead implantation in adult patients with previous congenital cardiac surgery.

BACKGROUND: : Substantial technical challenges exist in placing transvenous pacing leads in the heterogeneous adult congenital heart disease patient population. Anatomical issues including occlusion of central veins, single ventricle physiology, and lack of transvenous access to systemic right ventricles, often require thoracotomy for epicardial lead placement. METHODS: : We assessed the feasibility of performing a totally thoracoscopic approach to epicardial pacing lead implantation in 10 adult patients (mean age 32.5 years) with congenital heart disease. The underlying cardiac anatomy consisted of transposition of the great arteries, status post (s/p) Mustard procedure (3); tricuspid atresia, s/p Fontan procedure (3); congenitally corrected transposition (1); Ebstein's anomaly, s/p tricuspid valve replacement (1); AV canal, s/p repair (1); and hypertrophic cardiomyopathy, s/p myomectomy (1). Twenty-six previous cardiac operations (mean 2.8 per patient) had been performed in this group. RESULTS: : Indications for thoracoscopic lead insertion included primary rhythm disturbances, progressive heart failure with a QRS>120 milliseconds, and an unapproachable coronary sinus or failed transvenous lead insertion. All patients underwent thoracoscopic implantation of 2 epicardial leads to the systemic ventricle and generator insertion. Intraoperative transesophageal echocardiography (TEE) was used in all cases, which facilitated port placement. Measurements at operation showed mean threshold of 2.0V (95% CI 0.9-3.1V at 0.5 milliseconds) and a mean impedance of 1259 Ohms (95% CI 418-2100). There were no procedural related complications and no patient required conversion to an open procedure. Seventy percent of patients were extubated immediately after the procedure and were discharged from the intensive care unit within 24 hours. There was 1 noncardiac death due to gastrointestinal ischemia. CONCLUSION: : Adults with congenital heart disease present significant challenges to pacing lead implantation including variability of the location of the systemic ventricle, coronary sinus anatomy, right-sided valve replacement, a small thoracic cavity, limited vascular access, and adhesions from prior cardiac procedures. Additionally, thoracoscopy has been previously considered a contraindication in this subgroup of patients. However, we have demonstrated that with careful preoperative planning and the assistance of TEE, a totally thoracoscopic approach to epicardial lead implantation is both feasible and safe.

Effects of pulmonary valve replacement on QRS duration and right ventricular cavity size late after repair of right ventricular outflow tract obstruction.

This study evaluated the effects of pulmonary valve replacement (PVR) on QRS duration and right ventricular (RV) cavity size in patients who had severe pulmonary regurgitation late after previous repair of RV outflow tract obstruction. A significant decrease in maximal QRS duration and RV end-diastolic volume was found after PVR. The change in QRS duration was most significant in patients with a baseline QRS > or =155 ms (176 +/- 15 to 160 +/- 18 ms, p <0.001). RV end-diastolic volume was significantly correlated with maximal QRS duration before (r = 0.93, p <0.0001) as well as after (r = 0.82, p <0.001) PVR. In patients with pulmonary regurgitation late after repair of RV outflow tract obstruction, PVR reduces maximal QRS duration with a concomitant decrease in RV volumes.

Initial experience with bosentan therapy in patients with the Eisenmenger syndrome.

Bosentan, an endothelin-1 antagonist that can be administered orally, has been shown to be effective in the treatment of idiopathic pulmonary arterial hypertension and may be of benefit to patients with the Eisenmenger syndrome. Nine patients with Eisenmenger's syndrome were treated with bosentan at a dose of 125 mg twice a day. After treatment with bosentan, 6 of 9 patients (67%) had an improvement in New York Heart Assocation classification of >/=1 grades (p = 0.03). Oxygen saturation levels increased from 79 +/- 5% to 88 +/- 6%, (p = 0.03). The side effects of bosentan therapy were minor; no significant changes in liver function tests were noted. These preliminary data suggest that oral administration of bosentan therapy for Eisenmenger's syndrome results in improved oxygenation and functional status with minimal side effects.

The neonate with suspected congenital heart disease.

Congenital heart disease (CHD) occurs in 8 per 1000 live births, with approximately one third of these neonates requiring intervention in the first month of life. Neonates with respiratory distress, cyanosis, feeding difficulties, low cardiac output, or dysmorphic syndromes commonly have CHD. Clinical suspicion increases in a symptomatic infant with a heart murmur, but the presence or absence of a murmur does not assure either the presence or absence of significant congenital heart disease. Infants suspected to have CHD may be divided into premature and term infants, as well as infants with duct-dependent pulmonary blood flow, infants with duct-dependent systemic blood flow, and infants with unrestricted pulmonary blood flow. This article will also address the specialized clinical situations of total anomalous pulmonary venous return, transposition of the great arteries, and hypoplastic left heart syndrome with intact atrial septum.