Donald A. Girod

Cardiovascular Effects of Atomoxetine in Children, Adolescents, and Adults

AbstractBackground: Atomoxetine is a highly specific presynaptic inhibitor of the noradrenaline (norepinephrine) transporter that was recently approved in the US for the treatment of patients with attention-deficit/hyperactivity disorder (ADHD). Adverse effects on the cardiovascular system, including abnormalities in heart rate, blood pressure, or cardiac rhythm have been associated with several noradrenergic medications. Objective: To further elucidate the magnitude and impact of blood pressure and pulse elevations in patients taking atomoxetine. Study Design: Short-term cardiovascular safety in children, adolescents, and adults with ADHD was assessed in five randomised, double-blind trials (duration up to 10 weeks) with atomoxetine (n = 612) or placebo (n = 474). Long-term cardiovascular safety in children and adolescents (n = 169) was assessed in patients who entered an open-label extension or a blinded continuation following short-term treatment. Methods: Adverse events, blood pressure, sitting pulse, and electrocardiograms (ECGs) were collected throughout the trials. QT intervals were corrected for heart rate by a data-specific correction factor (QTcD; derived from baseline ECGs) as well as standard methods. Results: Atomoxetine treatment was associated with small but statistically significant increases in mean systolic blood pressure in adults and diastolic blood pressure in children and adolescents. Mean pulse rate increased for all atomoxetine treatment groups. The increases in blood pressure and pulse tended to occur early in therapy, stabilised, and returned toward baseline upon drug discontinuation. There was no significant difference between atomoxetine and placebo treatment groups in change in QTcD interval for all study populations. Palpitations in the adult patient population were the only significant cardiovascular adverse event (p = 0.037) occurring more frequently in the atomoxetine treatment group (3.7%) than in the placebo group (0.8%). Discontinuations due to cardiovascular-related events were very uncommon in the adult group, and did not occur in the child/adolescent group. Conclusion: While atomoxetine has noradrenergic activity, increases in pulse and blood pressure were small and of little, if any, clinical significance. Atomoxetine was not associated with QT interval prolongation. Cardiovascular effects of atomoxetine were minimal, and atomoxetine was well tolerated in short- and long-term studies.

Surgical management of complete atrioventricular septal defects: A twenty-year experience

Creation of a competent left atrioventricular valve is a cornerstone in surgical repair of complete atrioventricular septal defects. To identify risk factors for mortality and failure of left atrioventricular valve repair and to determine the impact of cleft closure on postoperative atrioventricular valve function, we retrospectively analyzed hospital records of 203 patients between January 1974 and January 1995. Overall early mortality was 7.9%. Operative mortality decreased significantly over the period of the study from 19% (4/21) before 1980 to 3% (2/67) after 1990 (p = 0.03). Ten-year survival including operative mortality was 91.3% +/- 0.004% (95% confidence limit): all survivors are in New York Heart Association class I or II. Preoperative atrioventricular valve regurgitation was assessed in 203 patients by angiography or echocardiography and was trivial or mild in 103 (52%), moderate in 82 (41%), and severe in 18 (8%). Left atrioventricular valve cleft was closed in 93% (189/203) but left alone when valve leaflet tissue was inadequate and closure of the cleft might cause significant stenosis. Reoperation for severe postoperative left atrioventricular valve regurgitation was necessary in eight patients, five of whom initially did not have closure of the cleft and three of whom had cleft closure. Six patients had reoperation with annuloplasty and two patients required left atrioventricular valve replacement. Five patients survived reoperation and are currently in New York Heart Association class I or II. On most recent evaluation assessed by angiography or echocardiography (a mean of 59 months after repair), left atrioventricular valve regurgitation was trivial or mild in 137 of the 146 survivors (94%) examined; none had moderate or severe left atrioventricular valve stenosis. By multiple logistic regression analysis, strong risk factors for early death and need for reoperation included postoperative pulmonary hypertensive crisis, immediate postoperative severe left atrioventricular valve regurgitation, and double-orifice left atrioventricular valve. These results indicate that complete atrioventricular septal defects can be repaired with low mortality and good intermediate to long-term results. Routine approximation of the cleft is safe and has a low incidence of reoperation for left atrioventricular valve regurgitation.

Indomethacin therapy on the first day of life in infants with very low birth weight

To investigate the optimal timing for treatment of small premature infants, we performed a double-blind, controlled trial of indomethacin therapy on the first day of life in 104 infants weighing between 700 and 1300 gm. Infants were given indomethacin or placebo at a mean age of 15 hours. Eleven of the 56 infants given placebo developed large left-to-right shunts through a patent ductus arteriosus. In contrast, only two of the 51 infants given indomethacin developed large shunts (P less than 0.025). There were no significant differences in incidence of surgical ligation, duration of oxygen therapy, duration of endotracheal intubation, days required to regain birth weight, or incidence of complications. However, the power of the tests of significance was low because of the small number of patients. Thus, although the incidence of large left-to-right ductus shunts was decreased in the indomethacin group, morbidity was not otherwise altered for the entire group of patients, possibly because of the relatively low incidence (21%) of large shunts in the placebo group. We conclude that although treatment with indomethacin on the first day of life appears to be safe, there is little advantage to its use in centers where the incidence of large shunts through a patent ductus arteriosus is relatively low.

Cor Triatriatum: Clinical Presentation and Surgical Results in 12 Patients

Twelve patients with cor triatriatum have been seen at our institution since 1979. The clinical presentation, diagnostic evaluation, and surgical results are outlined in this retrospective review. Operation is the treatment of choice for this rare congenital cardiac defect. One patient died 1 day before scheduled operation, and 2 patients died postoperatively, yielding a surgical mortality rate of 17% and an overall mortality rate of 25%. Resection of the obstructing atrial membrane was performed using hypothermic cardiopulmonary bypass in all cases. Left atriotomy was performed in 6 patients, and right atriotomy was performed in 7. The two postoperative deaths occurred in patients who had serious associated cardiac defects. Associated anomalies include atrial septal defect, persistent left superior vena cava, and partial anomalous pulmonary venous return. The postoperative course has been excellent in all 9 surviving patients; all remain asymptomatic. Cor triatriatum is amenable to surgical repair with excellent results when diagnosed early and when not complicated by other severe cardiac anomalies.

Heparinization for prevention of thrombosis following pediatric percutaneous arterial catheterization.

SummaryOne thousand three hundred and sixteen consecutively catheterized infants and children were evaluated prospectively for femoral artery thrombosis following percutaneous cardiac catheterization. One hundred units/kg heparin bolus was given to 649 patients after arterial puncture (group A). A supplementary 50 units/kg of heparin bolus was given to 381 patients 75 minutes later, followed by a continuous heparin infusion if pulses were decreased (group B). Two hundred forty-one patients were managed similarly except the first supplementary bolus was given 45 minutes after initial heparinization, if necessary, and the second bolus and continuous infusion were begun 45 minutes later, if necessary (group C). Arterial thrombosis was diagnosed if pulses were not equal to those of the unused extremity 6 hours following catheterization.The overall incidence of arterial thrombosis was 0.8%. No statistically significant (p<.05) differences occurred related to the heparinization method used. However, absence of thrombosis in the last 241 consecutive patients (group C) and in the last 480 patients of groups B and C weighing more than 10 kg approaches significance (p<.1). Incidence of thrombosis was less than in previous studies (p<.0005 to .05). This study indicates that a very low incidence of arterial thrombosis can be achieved with systemic heparinization.

Right ventricular systolic function in adolescents and young adults after mustard operation for transposition of the great arteries

This study evaluates long-term ( > 10 years since surgery) right ventricular (RV) systolic function in patients who had previously undergone intraatrial baffle surgery for transposition of the great arteries. Studies suggest these patients are clinically stable and lead satisfactory lifestyles, but long-term ventricular performance is not known. Radionuclide angiocardiography was used to estimate RV ejection fraction in 58 patients a mean of 14 years after the Mustard operation. Repeat studies were performed in 32 patients. The absolute RV ejection fraction of 0.53 +/- 0.10 in our patients did not differ from normal values. Nine patients had a value < 0.42, placing them > 2 SDs below normal. Repeat RV ejection fraction decreased from 0.54 +/- 0.11 to 0.51 +/- 0.11 (p < 0.1) in 32 patients, and > 0.10 in 6. Thus, RV ejection fraction was abnormal in 9 of 58 patients (16%) evaluated > 10 years after a Mustard operation. Repeat studies demonstrate worsening in at least 6 of 32 patients (19%). These postoperative Mustard patients require continued evaluation, even in the absence of overt symptomatology.

Cross-sectional echocardiographic visualization of the stenotic pulmonary valve.

Real-time, cross-sectional echocardiograms of the pulmonary valve were recorded in 22 patients with valvular pulmonary stenosis (VPS) (14 mild, eight moderate or severe) and 25 normal subjects. Normally during systole the pulmonary leaflet echoes moved rapidly apart and in the fully opened position lay parallel and in close apposition to the margins of the pulmonary artery. In 20 of 22 patients with VPS in whom the pulmonary valve was recorded the systolic configuration of the leaflets, opening pattern of the leaflet echoes, and presence of presystolic doming served to differentiate the stenotic valve from normal. In contrast M-mode recordings of the pulmonary valve were possible in only 12 of these 22 cases (seven mild and five moderate or severe) and suggested VPS in only the five cases with moderate or severe stenosis. Cross-sectional echocardiography offers a direct, noninvasive method for visualizing the stenotic pulmonary valve and should be an improvement over the indirect M-mode data.

Surgery for discrete subvalvular aortic stenosis: Actuarial survival, hemodynamic results, and acquired aortic regurgitation

Discrete membranous subaortic stenosis (DMSS) accounts for 8 to 30% of congenital left ventricular outflow obstruction. The immediate effectiveness of surgical resection of this discrete obstructing membrane has been well documented, but little has appeared regarding late clinical and hemodynamic follow-up. Fifty-three patients with DMSS underwent operation at our institution from 1957 to 1983. Most (78%) were symptomatic, 79% had left ventricular hypertrophy (LVH) by electrocardiogram, and 92% had roentgenographic evidence of cardiomegaly preoperatively. Catheterization revealed a mean preoperative left ventricular-aortic gradient of 89 mm Hg. Twenty-eight patients had associated aortic insufficiency (AI) on the initial aortogram. Seven patients acquired AI in the interim between the first and second preoperative catheterization. Our patients have been followed for up to 12 years postoperatively. There have been 2 early and 3 late deaths. (Actuarial analysis revealed 5- and 10-year survival of 95% and 83%, respectively.) Seventy-one percent of the previously symptomatic patients noted relief of their preoperative complaints, and 45% of those with LVH had a regression in voltage. Cardiomegaly as determined by chest roentgenogram decreased in 45%. The left ventricular-aortic gradient fell to an average of 35 mm Hg a year postoperatively. Surgical treatment of congenital subvalvular aortic stenosis is effective in reducing the preoperative symptoms and the left ventricular-aortic gradient. It appears that DMSS causes AI.

Transverse aortic wall tears in infants after balloon angioplasty for aortic valve stenosis: relation of aortic wall damage to diameter of inflated angioplasty balloon and aortic lumen in seven necropsy cases

Aortic wall tears resulting from rupture of dilating balloons in infants undergoing transluminal balloon angioplasty have not been previously recognized. A 2 day old infant had percutaneous transluminal balloon angioplasty to dilate a stenotic aortic valve, and after multiple balloon inflations the balloon burst. The infant died 2 days after undergoing transluminal balloon angioplasty and at necropsy a circumferential, transverse aortic wall tear was found. To test the hypothesis that rupture of appropriately sized balloons results in similar aortic wall tears, six unfixed, intact infant aortas were subjected to transluminal balloon angioplasty at necropsy: two infants had balloon rupture with inflated balloon diameter similar to that of the aorta, two had balloon rupture with an undersized balloon and two had dilation with an oversized balloon. Transverse wall tears occurred in aortas with similar aortic and balloon diameters; no aortic wall damage occurred with rupture of undersized balloons, and aortic rupture resulted from the use of oversized balloons. Thus, intimal-medial tears in the infant aorta may result from balloon bursting during angioplasty when aortic and inflated balloon diameters are similar.

Angiographic determination of arterial patency after percutaneous catheterization in infants and small children.

Patency of the femoral artery of infants and children who previously had percutaneous arterial catheterization at a weight of < 25 kg was studied angiographically. During the study period, 118 patients had repeat arterial catheterization, 48 from the opposite leg. Femoral artery occlusion was found in four patients, while 44 of the 48 studied from the opposite leg had complete patency. At the later study, all four with blockage were asymptomatic and possessed good pedal pulses, while two had decreased femoral pulsations. When events surrounding initial catheterization were retrospectively analyzed, three of four had decreased pedal pulsations beyond six hours. It is concluded that 3-8%percnt; of patients weighing < 25 kg have arterial occlusion after catheterization. This complication may be entirely asymptomatic, but these patients will require continued observation for possible late vascular problems.