Thomas M. Zellers

INHALED NITRIC OXIDE AND PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN

Background Persistent pulmonary hypertension of the newborn causes systemic arterial hypoxemia because of increased pulmonary vascular resistance and right-to-left shunting of deoxygenated blood. Inhaled nitric oxide decreases pulmonary vascular resistance in newborns. We studied whether inhaled nitric oxide decreases severe hypoxemia in infants with persistent pulmonary hypertension. Methods In a prospective, multicenter study, 58 full-term infants with severe hypoxemia and persistent pulmonary hypertension were randomly assigned to breathe either a control gas (nitrogen) or nitric oxide (80 parts per million), mixed with oxygen from a ventilator. If oxygenation increased after 20 minutes and systemic blood pressure did not decrease, the treatment was considered successful and was continued at lower concentrations. Otherwise, it was discontinued and alternative therapies, including extracorporeal membrane oxygenation, were used. Results Inhaled nitric oxide successfully doubled systemic oxygenation in 16 of 30 infants (53 percent), whereas conventional therapy without inhaled nitric oxide increased oxygenation in only 2 of 28 infants (7 percent). Long-term therapy with inhaled nitric oxide sustained systemic oxygenation in 75 percent of the infants who had initial improvement. Extracorporeal membrane oxygenation was required in 71 percent of the control group and 40 percent of the nitric oxide group (P=0.02). The number of deaths was similar in the two groups. Inhaled nitric oxide did not cause systemic hypotension or increase methemoglobin levels. Conclusions Inhaled nitric oxide improves systemic oxygenation in infants with persistent pulmonary hypertension and may reduce the need for more invasive treatments.

Enalapril Does Not Enhance Exercise Capacity in Patients After Fontan Procedure

BACKGROUND Angiotensin-converting enzyme inhibitors improve exercise capacity in adults with congestive heart failure by decreasing systemic vascular resistance and improving ventricular diastolic function. Patients who have undergone the Fontan procedure have decreased cardiac output, increased systemic vascular resistance, abnormal diastolic function, and decreased exercise capacity compared with normal people. METHODS AND RESULTS To test the hypothesis that afterload reduction therapy alters hemodynamic variables and augments exercise capacity in patients after a Fontan procedure, we compared the results of graded exercise with maximal effort from 18 subjects (14.5+/-6.2 years of age, 4 to 19 years after Fontan procedure) in a randomized, double-blind, placebo-controlled crossover trial using enalapril (0.2 to 0.3 mg x kg[-1] x d[-1], maximum 15 mg). Each treatment was administered for 10 weeks. Diastolic filling patterns at rest were assessed by Doppler determination of the systemic atrioventricular valve flow velocity at the conclusion of each therapy. No difference was detected in resting heart rate, blood pressure, or cardiac index. Diastolic filling patterns were also similar. Exercise duration was not different (6.4+/-2.6 [enalapril] versus 6.7+/-2.6 minutes [placebo]). The mean percent increase in cardiac index from rest to maximum exercise was slightly but significantly decreased in subjects after 10 weeks of enalapril therapy (102+/-34% [enalapril] versus 125+/-34% [placebo]; P<.02). At maximal exercise, cardiac index (3.5+/-0.9 [enalapril] versus 3.8+/-0.9 L x min[-1] x m2 [placebo]), oxygen consumption (18.3+/-9 [enalapril] versus 20.5+/-7 mL x min[-1] x kg[-1] [placebo]), minute ventilation (57.5+/-17 [enalapril] versus 55.4+/-19 L/min [placebo]), and total work (247+/-181 [enalapril] versus 261+/-197 W [placebo]) were not different. CONCLUSIONS We conclude that enalapril administration for 10 weeks does not alter abnormal systemic vascular resistance, resting cardiac index, diastolic function, or exercise capacity in patients who have undergone a Fontan procedure.

Comparison of surgical, stent, and balloon angioplasty treatment of native coarctation of the aorta: an observational study by the CCISC (Congenital Cardiovascular Interventional Study Consortium).

OBJECTIVES The purpose of this study was to compare the safety and efficacy of surgical, stent, and balloon angioplasty (BA) treatment of native coarctation acutely and at follow-up. BACKGROUND Controversy surrounds the optimal treatment for native coarctation of the aorta. This is the first multicenter study evaluating acute and follow-up outcomes of these 3 treatment options in children weighing >10 kg. METHODS This is a multicenter observational study. Baseline, acute, short-term (3 to 18 months), and intermediate (>18 months) follow-up hemodynamic, imaging data, and complications were recorded. RESULTS Between June 2002 and July 2009, 350 patients from 36 institutions were enrolled: 217 underwent stent, 61 underwent BA, and 72 underwent surgery. All 3 arms showed significant improvement acutely and at follow-up in resting systolic blood pressure and upper to lower extremity systolic blood pressure gradient (ULG). Stent was superior to BA in achieving lower ULG acutely. Surgery and stent were superior to BA at short-term follow-up in achieving lower ULG. Stent patients had shorter hospitalization than surgical patients (2.4 vs. 6.4 days; p < 0.001) and fewer complications than surgical and BA patients (2.3%, 8.1%, and 9.8%; p < 0.001). The BA patients were more likely to encounter aortic wall injury, both acutely and at follow-up (p < 0.001). CONCLUSIONS Stent patients had significantly lower acute complications compared with surgery patients or BA patients, although they were more likely to require a planned reintervention. At short-term and intermediate follow-up, stent and surgical patients achieved superior hemodynamic and integrated aortic arch imaging outcomes compared with BA patients. Because of the nonrandomized nature of this study, these results should be interpreted with caution.

Stenting of Aortic Coarctation: Acute, Intermediate, and Long-Term Results of a Prospective Multi-Institutional Registry—Congenital Cardiovascular Interventional Study Consortium (CCISC)

Introduction: Since the 1980s, stent implantation has evolved as an important therapeutic strategy for coarctation of the aorta. However, available data is frequently flawed by short follow‐up, lack of adequate follow‐up imaging, and retrospective nature of data collection. Methods: Data was prospectively collected using a multicenter registry congenital cardiovascular interventional study consortium (CCISC). Between 2000 and 2009, 302 patients from 34 centers with a median weight of 58 kg underwent stent implantation for coarctation. Eligible patients (44%) completed intermediate follow‐up (3–18 months) with integrated imaging (cath, CT, MRI), whereas 21% completed long‐term follow‐up (>18–60 months). Procedural success was defined as UL/LL systolic gradient of less than 20 mm Hg, lack of significant recurrent obstruction, and freedom from unplanned repeat intervention. Results: Acute procedural success was 96%. Cumulative intermediate success was 86%, and cumulative long‐term success was 77%. Unplanned repeat interventions were required in 4%, and aortic wall complications were seen in 1% of patients (dissection n = 1 and aneurysm n = 3). Other adverse events (n = 15) occurred mainly acutely and included technical complications such as stent malposition (n = 9). At long‐term follow‐up, 23% of patients continued to have systolic blood pressure above the 95th centile, 9% had an upper‐to‐lower limb blood pressure gradient in excess of 20 mm Hg, and 32% were taking antihypertensive medication. Conclusions: This study documented acute, intermediate, and long‐term outcome data comparable or superior with other surgical or interventional series. However, even with successful initial stent therapy, patients continue to require long‐term follow‐up and have associated long‐term morbidity, relating to aortic wall complications, systemic hypertension, recurrent obstruction as well as need for repeat intervention.

Endothelium-dependent relaxations of piglet pulmonary arteries augment with maturation

ABSTRACT: To determine whether maturation alters endothelium-dependent responses in porcine pulmonary arteries, rings, with and without endothelium, of small pulmonary arteries taken from piglets of 3, 10, and 30 d of age were suspended in organ chambers filled with buffered salt solution, bubbled with 95% O2-5% CO2, and maintained at 37°C. These studies were performed in the presence of indomethacin (10−5 M) to inhibit prostaglandin synthesis. In rings without endothelium, potassium chloride (10−2 to 8.5 × 10−2 M) and histamine (10−9 to 10−5 M) caused concentration-dependent contractions. When normalized to maximal contractions achieved to each agonist, the concentration-effect curves to potassium chloride and histamine in rings without endothelium were similar at each age. Rings with endothelium showed a progressive shift to the right of the concentration-effect curve to histamine, possibly secondary to an increase in the basal release of, or responsiveness to, the endothelium-derived relaxing factor with maturation. Relaxations to sodium nitroprusside (10−9 to 10−5 M) were unaffected by age. In precontracted rings, acetylcholine (10−9 to 10−6 M), bradykinin (10−10 to 10−6 M), and the calcium ionophore A23187 (10−9 to 10−6 M) caused relaxations in rings with endothelium, but not in those without endothelium, which were greater at 10 and 30 d compared to 3 d; further augmentation at 30 d compared to 10 d was not observed. In rings without endothelium, changes in the responsiveness to nitric oxide (10−9 to 10−5 M), one of the proposed endothelium-derived relaxing factors, with age were comparable to those observed with endothelium-dependent relaxing agents. These studies demonstrate that endothelium-dependent relaxations increase with age, possibly due to changes in sensitivity of the smooth muscle to the endothelium-derived relaxing factor.

Exercise Tolerance and Cardiorespiratory Response to Exercise Before and After the Fontan Operation

To determine the effect of the Fontan operation on exercise tolerance and cardiorespiratory response to exercise, we compared the preoperative and postoperative responses to graded exercise to maximal effort in 20 patients who underwent a modified Fontan procedure. The mean interval between preoperative and postoperative exercise testing was 1.8 years. Postoperatively, total work performed, duration of exercise, and maximal oxygen uptake were significantly increased. Although cardiac output increased during exercise, the response was subnormal, and stroke volume was unchanged. The heart rate and systolic blood pressure during maximal exercise were not significantly changed from preoperative values, but the diastolic blood pressures during rest and maximal exercise were significantly increased postoperatively. Systemic arterial blood oxygen saturation increased after the modified Fontan operation, but during exercise, a mild but significant desaturation occurred (93% compared with 90%). The ventilatory equivalent for oxygen decreased toward normal during exercise. The respiratory rate and oxygen consumption during resting remained unchanged from preoperative values. For this subset of patients, these data indicate that exercise tolerance improves, cardiac output and stroke volume responses to exercise are subnormal, and ventilatory response to exercise decreases toward normal after the modified Fontan operation.

Protein-Losing enteropathy after the modified fontan operation: Oral prednisone treatment with biopsy and laboratory proved improvement

Protein-losing enteropathy occurs in up to 10% of patients following the modified Fontan procedure. Treatment is still controversial. We describe a female adolescent who developed protein-losing enteropathy 4 years after a modified Fontan procedure. Treatment with oral prednisone attenuated the protein loss with subsequent normalization of her serum total protein and albumin levels. Discontinuation of prednisone therapy was associated with relapse, which was again treated successfully with low-dose oral prednisone. Small bowel biopsy-proved diagnosis with improvement, relapse, and improvement again are documented, as are other useful laboratory findings.

Balloon angioplasty for recurrent coarctation of the aorta in patients following staged palliation for hypoplastic left heart syndrome

After stage I palliation for hypoplastic left heart syndrome, recurrent coarctation occurred in 9 of 25 survivors (36%) requiring balloon angioplasty, predominantly from a prograde approach. Although angioplasty was initially successful in all patients, recoarctation occurred in 4 and repeat angioplasty was successful in 2.

Two-dimensional and Doppler echocardiography alone can adequately define preoperative anatomy and hemodynamic status before repair of complete atrioventricular septal defect in infants <1 year old

OBJECTIVES We sought to assess the ability of two-dimensional and Doppler echocardiography alone, without cardiac catheterization, to evaluate infants < 1 year of age for complete open heart repair of complete balanced atrioventricular (AV) septal defect. BACKGROUND Two-dimensional echocardiographic-Doppler examinations provide accurate anatomic detail in patients with AV septal defect. Lung biopsy data have shown that patients rarely develop significant inoperable pulmonary vascular disease before 7 months of age. Although calculated pulmonary arteriolar resistance is often elevated in young infants with this heart defect, this elevation rarely reflects significant pulmonary vascular changes in infants < 7 to 12 months of age. METHODS We performed a retrospective review of 34 patients who underwent complete repair of AV septal defect at our institution between January 1, 1988 and September 1, 1992. Some patients had both catheterization and echocardiographic-Doppler studies (group I, n = 16); others had only echocardiographic-Doppler studies (group II, n = 18). RESULTS The groups were comparable with regard to age at echocardiography and operation, days in the hospital, days with ventilatory and inotropic support and occurrence of postoperative pulmonary hypertension. One child (2.9%) died during the early postoperative period, and one child in each group (5.8%) died within the 1st year of life. Preoperative echocardiography allowed better detailing of anatomy, valve commitment and regurgitation than was possible with catheterization alone. Knowledge of preoperative pulmonary resistance did not alter the surgical decision or predict postoperative pulmonary hypertension. There was no apparent difference in mortality between the two groups (0 vs. 5.5%), but the small number of patients in each group provides for a very low power (beta = 0.04) calculation. This mortality rate is not different from that reported in recent studies. CONCLUSIONS Patients with AV septal defect can safely undergo surgical correction of this defect on the basis of echocardiographic-Doppler data alone.

Coarctation index: identification of recurrent coarctation in infants with hypoplastic left heart syndrome after the Norwood procedure

Assessment of recurrent coarctation after the Norwood procedure by routine measures is complicated by the unusual physiology caused by the presence of a modified Blalock-Tausig shunt with distal aortic arch obstruction. We present a new index that uses 2-dimensional measurement of the reconstructed aortic arch, which is highly sensitive and specific in identifying recurrent coarctation after the Norwood procedure in children with hypoplastic left heart syndrome.