Alan B. Lewis

The Treatment of Kawasaki Syndrome with Intravenous Gamma Globulin

We compared the efficacy of intravenous gamma globulin plus aspirin with that of aspirin alone in reducing the frequency of coronary-artery abnormalities in children with acute Kawasaki syndrome in a multicenter, randomized trial. Children randomly assigned to the gamma globulin group received intravenous gamma globulin, 400 mg per kilogram of body weight per day, for four consecutive days; both treatment groups received aspirin, 100 mg per kilogram per day, through the 14th day of illness, then 3 to 5 mg per kilogram per day. Two-dimensional echocardiograms were interpreted blindly and independently by two or more readers. Two weeks after enrollment, coronary-artery abnormalities were present in 18 of 78 children (23 percent) in the aspirin group, as compared with 6 of 75 (8 percent) in the gamma globulin group (P = 0.01). Seven weeks after enrollment, abnormalities were present in 14 of 79 children (18 percent) in the aspirin group and in 3 of 79 (4 percent) in the gamma globulin group (P = 0.005). No child had serious adverse effects from receiving gamma globulin. We conclude that high-dose intravenous gamma globulin is safe and effective in reducing the prevalence of coronary-artery abnormalities when administered early in the course of Kawasaki syndrome.

Comparison of shunt types in the Norwood procedure for single-ventricle lesions.

BACKGROUND The Norwood procedure with a modified Blalock-Taussig (MBT) shunt, the first palliative stage for single-ventricle lesions with systemic outflow obstruction, is associated with high mortality. The right ventricle-pulmonary artery (RVPA) shunt may improve coronary flow but requires a ventriculotomy. We compared the two shunts in infants with hypoplastic heart syndrome or related anomalies. METHODS Infants undergoing the Norwood procedure were randomly assigned to the MBT shunt (275 infants) or the RVPA shunt (274 infants) at 15 North American centers. The primary outcome was death or cardiac transplantation 12 months after randomization. Secondary outcomes included unintended cardiovascular interventions and right ventricular size and function at 14 months and transplantation-free survival until the last subject reached 14 months of age. RESULTS Transplantation-free survival 12 months after randomization was higher with the RVPA shunt than with the MBT shunt (74% vs. 64%, P=0.01). However, the RVPA shunt group had more unintended interventions (P=0.003) and complications (P=0.002). Right ventricular size and function at the age of 14 months and the rate of nonfatal serious adverse events at the age of 12 months were similar in the two groups. Data collected over a mean (+/-SD) follow-up period of 32+/-11 months showed a nonsignificant difference in transplantation-free survival between the two groups (P=0.06). On nonproportional-hazards analysis, the size of the treatment effect differed before and after 12 months (P=0.02). CONCLUSIONS In children undergoing the Norwood procedure, transplantation-free survival at 12 months was better with the RVPA shunt than with the MBT shunt. After 12 months, available data showed no significant difference in transplantation-free survival between the two groups. (ClinicalTrials.gov number, NCT00115934.)

Regression of coronary aneurysms in patients with Kawasaki syndrome.

Coronary aneurysms were demonstrated echocardiographically in 34 of 186 patients who presented with Kawasaki syndrome between 1979 and 1983. The aneurysms were confirmed by selective coronary angiography in 27 patients and by postmortem examination in one. The 27 surviving patients with proven aneurysms were followed for 2 to 40 months (mean 15), during which they received low dose (5 to 10 mg/kg) aspirin daily. Progressive improvement and resolution of aneurysms were observed by serial echocardiography in 18 patients and confirmed by angiography in 14. Coronary aneurysms persisted, however, in nine other patients for 14 to 40 months (mean 25.7). The incidence of aneurysm resolution was higher in children less than 1 year of age at the onset of the illness than in patients older than 1 year (100% vs 50%; p less than .001). Aneurysms were more likely to resolve in girls than in boys (100% vs 42%; p less than .001). Fusiform aneurysms tended to resolve more frequently than saccular lesions (80% vs 18%; p less than .025). Aneurysms located distally in the coronary arteries appear to regress more rapidly than proximal ones. We conclude that an age of less than 1 year at the onset of Kawasaki syndrome, female sex, and fusiform aneurysm morphology are significant factors that favor resolution of coronary artery aneurysms. However, important questions remain with regard to the long-term fate and functional capabilities of these healed lesions.

Transplantation-Free Survival and Interventions at 3 Years in the Single Ventricle Reconstruction Trial

Background— In the Single Ventricle Reconstruction (SVR) trial, 1-year transplantation-free survival was better for the Norwood procedure with right ventricle–to–pulmonary artery shunt (RVPAS) compared with a modified Blalock-Taussig shunt (MBTS). At 3 years, we compared transplantation-free survival, echocardiographic right ventricular ejection fraction, and unplanned interventions in the treatment groups. Methods and Results— Vital status and medical history were ascertained from annual medical records, death indexes, and phone interviews. The cohort included 549 patients randomized and treated in the SVR trial. Transplantation-free survival for the RVPAS versus MBTS groups did not differ at 3 years (67% versus 61%; P=0.15) or with all available follow-up of 4.8±1.1 years (log-rank P=0.14). Pre-Fontan right ventricular ejection fraction was lower in the RVPAS group than in the MBTS group (41.7±5.1% versus 44.7±6.0%; P=0.007), and right ventricular ejection fraction deteriorated in RVPAS (P=0.004) but not MBTS (P=0.40) subjects (pre-Fontan minus 14-month mean, −3.25±8.24% versus 0.99±8.80%; P=0.009). The RVPAS versus MBTS treatment effect had nonproportional hazards (P=0.004); the hazard ratio favored the RVPAS before 5 months (hazard ratio=0.63; 95% confidence interval, 0.45–0.88) but the MBTS beyond 1 year (hazard ratio=2.22; 95% confidence interval, 1.07–4.62). By 3 years, RVPAS subjects had a higher incidence of catheter interventions (P<0.001) with an increasing HR over time (P=0.005): <5 months, 1.14 (95% confidence interval, 0.81–1.60); from 5 months to 1 year, 1.94 (95% confidence interval, 1.02–3.69); and >1 year, 2.48 (95% confidence interval, 1.28–4.80). Conclusions— By 3 years, the Norwood procedure with RVPAS compared with MBTS was no longer associated with superior transplantation-free survival. Moreover, RVPAS subjects had slightly worse right ventricular ejection fraction and underwent more catheter interventions with increasing hazard ratio over time. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00115934.

Outcome of infants and children with dilated cardiomyopathy.

A review of 81 infants and children with dilated, poorly contracting left ventricles without associated structural abnormalities was undertaken to identify risk factors for poor outcome, which could be used in selecting candidates for cardiac transplantation. Significant atrial or ventricular dysrhythmias, or both, were detected on presentation or during follow-up in 24 patients. Arrhythmias were present in only 8 of 51 survivors (16%) but were detected in 16 of 30 patients (53%) who died (p less than 0.05). Patients dying suddenly were even more likely to have had documented dysrhythmias (8 of 11, p less than 0.05). Left ventricular shortening fraction was similar in survivors and nonsurvivors (14.9 +/- 1.0% vs 15.3 +/- 1.7%). Left ventricular end-diastolic pressure in 44 patients who had cardiac catheterization averaged 20.8 +/- 1.6 mm Hg. Left ventricular end-diastolic pressure was significantly higher in patients who died than in those who survived (29.5 +/- 2.2 vs 15.0 +/- 1.6 mm Hg, p less than 0.001). Analysis of actuarial survival revealed that mortality was highest during the first 6 months after presentation (19% mortality). Survival declined more gradually thereafter and was 70% at 2 years, 64% at 5 years and 52% after 11.5 years. Age at initial presentation did not have any significant impact on survival. However, left ventricular end-diastolic pressure greater than 25 torr was associated with a significantly increased mortality rate (p less than 0.05). Early cardiac transplantation should be considered in patients with markedly elevated left ventricular end-diastolic pressure or complex atrial or ventricular arrhythmias.

The effect of treatment with angiotensin-converting enzyme inhibitors on survival of pediatric patients with dilated cardiomyopathy.

SummaryOutcome in 81 pediatric patients with dilated cardiomyopathy was reviewed to assess whether treatment with angiotensin-converting enzyme (ACE) inhibitors affected survival. Age at onset was 3.6±0.6 years. Twenty-seven children (group 1) were treated with ACE inhibitors. Conventional therapy was used in the remaining 54 patients (group 2). There were no significant differences between the two groups in age at onset, left ventricular shortening fraction, left ventricular end-diastolic pressure, or mean pulmonary artery pressure. Patients treated with ACE inhibitors had a significantly better survival during the first year (p<0.05) with continuation of this trend throughout the second year (p=0.06). Beyond 2 years there was a tendency toward better survival in ACE inhibitor-treated patients, but the differences were no longer significant (p=0.14). These data, along with observations in adult patients with chronic cardiac failure, indicate that converting enzyme inhibitors have a beneficial effect on prolonging survival of infants and children with severe left ventricular dysfunction from dilated cardiomyopathy.

Clinical profile and outcome of restrictive cardiomyopathy in children

The clinical profile and outcome of idiopathic restrictive cardiomyopathy in a group of eight children are reviewed. There were six girls and two boys. Age at presentation was 4.0 +/- 2.6 years (range 1.3 to 9.5 years). All patients had evidence of congestive heart failure with systemic venous congestion. Right or left atrial enlargement was the most consistent ECG finding and was present in all patients. Left ventricular shortening fraction was normal in five patients, increased in two, and mildly reduced in one. The most striking echocardiographic feature was severe biatrial dilatation in the presence of normal or near-normal ventricular cavity dimensions. Marked elevation of left ventricular end-diastolic pressure was noted in all seven patients undergoing cardiac catheterization (34 +/- 7 torr; range 24 to 40 torr). Right ventricular end-diastolic pressure was elevated but significantly different from left ventricular pressure (18 +/- 7 torr; p less than 0.01). A characteristic early diastolic dip with a rapid rise to an elevated plateau (square root sign) was present in five of seven patients. Median survival was 1.4 years. Six patients died 0.2 to 7.0 years after they were initially seen. The actuarial survival rate 1.5 years after presentation was 44%, decreasing to 29% at 4 years. Restrictive cardiomyopathy has a worse prognosis in children than in adults. In part this may reflect the more advanced symptoms of congestive failure at initial presentation. Pediatric patients should be considered for early cardiac transplantation.

Cause, timing, and location of death in the Single Ventricle Reconstruction trial

OBJECTIVES The Single Ventricle Reconstruction trial randomized 555 subjects with a single right ventricle undergoing the Norwood procedure at 15 North American centers to receive either a modified Blalock-Taussig shunt or right ventricle-to-pulmonary artery shunt. Results demonstrated a rate of death or cardiac transplantation by 12 months postrandomization of 36% for the modified Blalock-Taussig shunt and 26% for the right ventricle-to-pulmonary artery shunt, consistent with other publications. Despite this high mortality rate, little is known about the circumstances surrounding these deaths. METHODS There were 164 deaths within 12 months postrandomization. A committee adjudicated all deaths for cause and recorded the timing, location, and other factors for each event. RESULTS The most common cause of death was cardiovascular (42%), followed by unknown cause (24%) and multisystem organ failure (7%). The median age at death for subjects dying during the 12 months was 1.6 months (interquartile range, 0.6 to 3.7 months), with the highest number of deaths occurring during hospitalization related to the Norwood procedure. The most common location of death was at a Single Ventricle Reconstruction trial hospital (74%), followed by home (13%). There were 29 sudden, unexpected deaths (18%), although in retrospect, 12 were preceded by a prodrome. CONCLUSIONS In infants with a single right ventricle undergoing staged repair, the majority of deaths within 12 months of the procedure are due to cardiovascular causes, occur in a hospital, and within the first few months of life. Increased understanding of the circumstances surrounding the deaths of these single ventricle patients may reduce the high mortality rate.

Radionuclide Angiographic Evaluation of Ventricular Function in Isolated Congenitally Corrected Transposition of the Great Arteries

Eight asymptomatic patients (mean age 19 years, range 7 to 32) with congenitally corrected transposition of the great arteries (CCTGA) underwent equilibrium gated radionuclide angiocardiography at rest and during supine bicycle exercise to assess systemic (morphologic right) and pulmonary (morphologic left) ventricular function. Five patients had normal intracardiac hemodynamic values, 2 had trivial atrioventricular valve regurgitation and 1 patient had trivial pulmonary ventricular outflow tract obstruction. Average exercise duration was 11 +/- 1 minute, with limitation due only to fatigue. At peak exercise, heart rate increased 225% and systolic blood pressure 152% over the rest value. Pulmonary ventricular ejection fraction at rest was 51 +/- 3% (mean +/- standard error of the mean); it did not change significantly at peak stress, 53 +/- 2%. Systemic ventricular ejection fraction was 48 +/- 4% at rest and increased to 64 +/- 4% at peak exercise (p less than 0.01). Count-based volume changes for the pulmonary chamber showed no significant change in end-diastolic or systolic counts at peak exercise (109 +/- 8% and 106 +/- 9% of rest value, respectively). However, end-diastolic counts decreased 13% (87 +/- 3% of rest value) and end-systolic counts 34% (62 +/- 7% of rest value) at peak exercise in the systemic ventricle. These data suggest normal systemic and impaired pulmonary ventricular function in patients with congenitally corrected transposition of the great arteries unaccompanied by significant associated lesions. These findings have important clinical implications in the setting of complex congenital heart disease in patients in whom a morphologic right ventricle functions as the systemic pumping chamber. Despite the pulmonary ventricular dysfunction, symptoms were not apparent at rest or during exercise.

Administration of prostaglandin E1 in neonates with critical congenital cardiac defects

Prostaglandin E1 was administered to 12 neonates and young infants in whom pulmonary or systemic blood flow was entirely or significantly dependent upon persistent patency of the ductus arteriosus. Nine neonates responded favorably to PGE1 infusion; their mean age was 2.8 days. Three infants who failed to respond were 10 days, 14 days, and 9 weeks of age, respectively. Six neonates with right ventricular outflow obstruction had a mean increase in arterial PO2 of 136% following administration of PGE1. In three patients in whom systemic flow was ductus dependent, PGE1 infusion was followed by improvement in arterial blood pressure, peripheral perfusion, and urine output. Complications included pyrexia, vasodilatation, and myoclonic jerks (or focal seizures). Three side effects were easily reversible by decreasing the infusion rate or altering the site of administration. PGE1 is a highly effective agent in stabilizing critically ill neonates with ductus dependent congenital cardiac lesions.