Cardiac Ultrasound Findings in Infants with Severe (Hurler Phenotype) Untreated Mucopolysaccharidosis (MPS) Type I.

BACKGROUND: Serious cardiac valve disease and left ventricular hypertrophy occur in most untreated older children with severe mucopolysaccharidosis type I. Although it is assumed that early intervention prevents these processes, evaluation of cardiac findings in these infants has not yet been reported. METHODS: We reviewed echocardiograms of 13 untreated infants < 1 year of age with severe mucopolysaccharidosis type I who had undergone evaluation for hematopoietic cell transplantation. We recorded left ventricular chamber dimensions, septal and posterior wall thicknesses, ventricular function, and aortic sinus diameters. We evaluated mitral and aortic valves for increased thickness, regurgitation, and stenosis. RESULTS: Average age (7M, 6F) was 221 (range 25-347) days. Left ventricular chamber dimension was ≥2 SD of normal in 3/13; wall thicknesses were ≥2 SD of normal in 2/13 infants. Systolic function was normal. Mitral valves were thickened in all infants; mitral regurgitation was present in 9/13, but significant in only three infants. Aortic valves were thickened in 10/13, but no infant had significant aortic regurgitation. Neither mitral nor aortic stenosis occurred. Aortic roots were dilated to ≥2 SD of normal in 5/13. CONCLUSIONS: Characteristic cardiac features of severe mucopolysaccharidosis type I can be seen in infancy. Mitral and aortic valve thickening are nearly universally present, even in the youngest infants. In 20-30 % of infants, other abnormalities such as left ventricular dilation, increased wall thickness, and mild mitral/aortic regurgitation may occur. Aortic root dilation is a frequent finding. Early intervention with enzyme replacement therapy may minimize the incidence and severity of cardiac findings in these infants. SUMMARY: Serious cardiac valve disease and left ventricular hypertrophy occur in most untreated older children with severe mucopolysaccharidosis type I. Although it is assumed that early intervention prevents these processes, evaluation of cardiac findings in these infants has not yet been reported. In our study of 13 infants with severe untreated MPS I < 1 year of age, mitral and aortic valve thickening was nearly universally present and aortic root dilation was frequent. Despite this, we found a lower incidence of left ventricular hypertrophy and both a lower incidence and milder expression of mitral and aortic valve dysfunction than previously reported in older children. These findings suggest that earlier intervention, including neonatal screening, may be of benefit to children with severe MPS I.

Increased longevity and metabolic correction following syngeneic BMT in a murine model of mucopolysaccharidosis type I.

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive inherited disease caused by deficiency of the glycosidase α-L-iduronidase (IDUA). Deficiency of IDUA leads to lysosomal accumulation of glycosaminoglycans (GAG) heparan and dermatan sulfate and associated multi-systemic disease, the most severe form of which is known as Hurler syndrome. Since 1981, the treatment of Hurler patients has often included allogeneic BMT from a matched donor. However, mouse models of the disease were not developed until 1997. To further characterize the MPS-I mouse model and to study the effectiveness of BMT in these animals, we engrafted a cohort (n=33) of 4-8-week-old Idua(-/-) animals with high levels (88.4±10.3%) of wild-type donor marrow. Engrafted animals displayed an increased lifespan, preserved cardiac function, partially restored IDUA activity in peripheral organs and decreased GAG accumulation in both peripheral organs and in the brain. However, levels of GAG and GM3 ganglioside in the brain remained elevated in comparison to unaffected animals. As these results are similar to those observed in Hurler patients following BMT, this murine-transplantation model can be used to evaluate the effects of novel, more effective methods of delivering IDUA to the brain as an adjunct to BMT.

Open-lung biopsy guides therapy in children.

BACKGROUND: Open-lung biopsy is uncommon in children. Modern indications and outcomes are unknown. METHODS: This is a retrospective review of 64 open-lung biopsies (58 patients) from 1976 to 1996. Open-lung biopsies were used to grade vasculopathy in 8 patients (12% of 64) with pulmonary hypertension and in 10 patients (16% of 64) with combined pulmonary hypertension and lung parenchymal disease. Forty-six biopsies (72%) were obtained to diagnose parenchymal disease. Comparisons were made between biopsies performed from 1976 to 1989 and from 1990 to 1996. RESULTS: In the period 1990 to 1996, there were significantly more infants (p = 0.03), comorbid disease (p = 0.009), extracorporeal membrane oxygenation support (p < 10(-4)), and ventilator dependence (p = 0.05) and significantly less immunocompromise (p = 0.04). A definitive diagnosis was made in 43 of 64 cases (67%) and altered workup in 63 of 64 cases (98%). No correlation existed between Heath-Edwards grade of microangiopathy and catheterization data. Definitive diagnosis was most strongly associated with a nonimmunocompromised patient (p < 10(-4)). Although only one death (1.5%) was related to open-lung biopsy, the procedure was associated with a 30% inhospital mortality rate and an 11% morbidity rate. Of the 19 deaths, 1 patient died from the procedure, 13 died from their diseases, and 5 had support withdrawn. Death was associated with preoperative ventilator dependence (p < 10(-4)) and extracorporeal membrane oxygenation (p = 0.007). CONCLUSIONS: Pediatric open-lung biopsy commonly alters the diagnostic workup (98%). It is recommended for children who have been supported for 2 weeks by extracorporeal membrane oxygenation and for those with combined pulmonary hypertension and parenchymal lung disease. It is less useful in immunocompromised children.

Usefulness of surveillance endomyocardial biopsy after pediatric cardiac transplantation.

Endomyocardial biopsy remains the 'gold standard' for the diagnosis of acute rejection after cardiac transplantation, but few guidelines exist to determine the indications for its use in pediatric cardiac transplant recipients. To determine the usefulness of surveillance endomyocardial biopsy, 176 biopsies were reviewed from 12 patients, aged 0.5-16 (average 9.7) yr, maintained on cyclosporine, azathioprine and prednisone immunosuppression, and followed 2.8-45.5 (average 26.3) months after cardiac transplantation. Children old enough to cooperate (n = 6) underwent biopsy on nine occasions in the first 6 months after transplantation and quarterly thereafter. Children too young to cooperate (n = 6) underwent biopsy with general anesthesia on four occasions in the first 6 months after transplantation and every 6 months thereafter. Additional biopsies were performed as warranted by symptoms or noninvasive tests. A new episode of acute rejection was present in 13 biopsies (7%); continuing or resolving rejection in 19 others (11%). Remaining biopsies had no evidence of rejection (82 biopsies, 47%), had lymphocytic infiltrates insufficient for diagnosis (47 biopsies, 27%), were inadequate for diagnosis (14 biopsies, 8%), or were consistent with ischemia (1 biopsy, 0.5%). During the first 6 postoperative months, eight of 101 biopsies were positive for rejection, three occurring on routine surveillance biopsy. After 6 months, five of 75 biopsies showed a new episode of rejection, only one occurring on routine surveillance biopsy. Based on this data, it is concluded that: 1) episodes of rejection are relatively uncommon with triple drug immunosuppression; 2) surveillance biopsies in the first 6 months after cardiac transplantation may show unsuspected rejection; and 3) routine surveillance biopsies more than 6 months after cardiac transplantation are unlikely to show rejection in the absence of symptoms or other tests.

Echocardiographic-guided internal jugular venous cannulation in children with heart disease.

OBJECTIVE: To determine if cannulation of the internal jugular vein (IJV) with echocardiographic guidance increases the success and decreases the complications of the procedure when performed in children with heart disease. DESIGN: Twenty-five consecutive pediatric patients with heart disease who underwent IJV cannulation with echocardiographic guidance between September 1986 and March 1992. SETTING: University hospital referral center serving a four-state area. PATIENTS AND OTHER PARTICIPANTS: Ambulatory patients were admitted for this procedure and then discharged at its completion; others included hospitalized patients. All patients were between the ages of 6 weeks and 21.8 years. All patients underwent IJV cannulation performed by a member of the Pediatric Cardiology Division at the University of Minnesota, Minneapolis. All patients either underwent heart transplant, and IJV access was obtained to perform an endomyocardial biopsy or had congenital heart disease, and the IJV was cannulated to perform a heart catheterization. Written consent was obtained either from the patient, if 18 years of age or older, or a parent or legal guardian. INTERVENTION: Cannulation of the IJV using echocardiographic guidance. MAIN OUTCOME MEASURES: Would IJV cannulation with echocardiographic guidance improve safety and diminish complications of the procedure when performed in pediatric patients with heart disease? We compared the results of our evaluation with published results in which echocardiographic guidance was not used. RESULTS: Cannulation of the IJV with echocardiographic guidance was performed successfully on 138 occasions in 25 pediatric patients. There were no lasting complications and no deaths using this method of venous access. CONCLUSIONS: As in the adult population, IJV cannulation with the assistance of echocardiography increases the success of the procedure and decreases the number of complications. Furthermore, echocardiographic guidance allows for repeated IJV cannulation in pediatric patients, regardless of age.

Outcome after referral for pediatric transplantation.

Although heart, heart-lung, or lung transplantation is performed in more than 200 children annually, the number of patients referred for such procedures is considerably greater, and little is known about the outcome of those referrals. To determine the outcome of pediatric transplant referrals we reviewed the follow-up of 31 patients evaluated at our institution for heart (24), heart-lung (three), or lung (four) transplantations between January 1991 and September 1992. Indications included hypoplastic left heart syndrome (seven patients), cardiomyopathy or myocarditis (seven patients), and postoperative congenital heart disease (10 patients) for heart transplantation; Eisenmenger's syndrome (three patients) for heart-lung transplantation; and primary pulmonary hypertension (two patients), broncho pulmonary dysplasia, and cystic fibrosis for lung transplantation. Only 14 of 31 referred patients were listed for transplantation; the remaining 17 patients either improved when medical therapy was maximized (nine patients), died within days of referral (three patients), refused (two patients), chose alternate surgery (one patient), were medically unacceptable (one patient), or are currently undecided (one patient). To date 7 of 14 patients listed have undergone successful heart transplantation; the remaining seven patients either improved and did not require transplantation (two patients), refused (one patient), died waiting (one patient), are currently awaiting a donor (one patient), or underwent Norwood procedure because of donor unavailability (two patients). Thus including patients who died before listing, only 14 of 31 referrals (45%) were deemed in need of a transplant.(ABSTRACT TRUNCATED AT 250 WORDS)

Results of a right ventricular outflow patch for pulmonary atresia with intact ventricular septum.

BACKGROUND: Although overall outcome has improved, pulmonary atresia with intact septum remains a difficult surgical and clinical problem. To determine whether an early right ventricular outflow patch will result in biventricular repair for this lesion, we reviewed the long-term follow-up (5.8 +/- 0.8 years) of 19 newborns who underwent repair between 1979 and 1990. METHODS AND RESULTS: An early right ventricular outflow patch was placed in 15 of 19 newborns; in the remaining four, this was preceded by an aortopulmonary shunt. Prostaglandin E1 infusion postoperatively eliminated the need for shunt in 14 of 15. Coronary sinusoids were ligated in three newborns. Based on right ventricular morphology, the newborns were divided into two groups: group 1 (tripartite, n = 9) and group 2 (bipartite and monopartite, n = 10). Before surgery, group 1 had significantly larger right ventricular volumes (23.6 +/- 3.7 versus 5.2 +/- 1.1 ml/m2, p < 0.002). Five-year survival was 79% for the entire series. Four infants, all group 2, died within 12 months of their initial surgery. Fourteen of 15 survivors (nine group 1 and five group 2) currently are acyanotic and New York Heart Association functional class I. A biventricular repair was achieved in 12 of 15, and three other children are awaiting evaluation. All 15 survivors had significant right ventricular and tricuspid annulus growth. CONCLUSIONS: Our data suggest that early placement of a right ventricular outflow patch in infants with pulmonary atresia and intact ventricular septum, regardless of right ventricular anatomy, results in an excellent chance for biventricular repair.

Staged repair of interrupted aortic arch and ventricular septal defect in infancy.

Staged repair of interrupted aortic arch and ventricular septal defect was carried out in 20 infants from 1979 through 1990. Among the important associated cardiac defects were transposition of the great arteries, truncus arteriosus, and anomalous origin of the right pulmonary artery. The first stage, usually consisting of the placement of an 8- or 10-mm polytetrafluoroethylene graft, pulmonary artery banding, and ligation of the patent ductus arteriosus, resulted in 20 survivors (100%) There were two interim deaths (10%) before the second stage of ventricular septal defect closure and pulmonary artery band removal, which had 15 survivors (83%, 15/18). Because the major morbidity and mortality early in this experience could be traced to leaving the pulmonary artery band on too long, early removal (within 2 to 3 months) was begun. Since 1985, 8 (100%) of 8 infants have survived both stages and are now doing well. Because of the relatively large polytetrafluoroethylene graft, only 1 child (aged 9 years) has experienced substantial late aortic arch obstruction and undergone placement of an 18-mm Dacron graft without difficulty. Of interest is the finding that in only 1 (5%) of the 20 patients has major (greater than or equal to 40-mm Hg gradient) left ventricular outflow tract obstruction developed. In summary, the staged repair of interrupted aortic arch with ventricular septal defect has become very reliable despite the condition of the infant or major associated cardiac anomalies and can be recommended for infants at high risk for primary repair. More long-term information will be needed to determine which approach will be the best choice for the majority of infants.

Five-year experience with triple-drug immunosuppressive therapy in cardiac transplantation.

Although triple-drug immunosuppression with a combination of cyclosporine, prednisone, and azathioprine has been shown to improve short-term survival after cardiac transplantation, its long-term effects still are unknown. From December 1983 through December 1988, all patients (N = 139) who underwent orthotopic cardiac transplant at our institution received triple-drug immunosuppressant therapy. Follow-up averaged 32.2 +/- 15.8 months. Twenty-one patients died; 134 survived more than 30 days. Actuarial survival was 92% at 1 year, 85% at 3 years, and 78% at 5 years. Twenty-five episodes of acute graft rejection were diagnosed in 21 of the 139 recipients (0.18 episode per patient). In patients, the incidence of infection was 0.82 episode; 72% of infections were viral, with 10% due to cytomegalovirus. The incidence of coronary artery disease was 10% at 1 year, 25% at 3 years, and 36% at 5 years. Coronary artery disease was responsible for 60% of late deaths. Arterial hypertension developed in 81% of patients, despite relatively well-maintained renal function (serum creatinine, 1.7 +/- 0.3 mg/dl). Skeletal complications occurred in 15.8% and lymphoma in 1.4% of recipients. Complete long-term rehabilitation was achieved in all but two of the surviving patients. These data support the short- and long-term effectiveness of triple-drug therapy. This regimen reduces the incidence of rejection, infection, and lymphoma, as well as the degree of renal failure. However, the incidence of posttransplant coronary artery disease has not been reduced, and graft atherosclerosis represents the major cause of late graft failure and death.

Rejection and infection after pediatric cardiac transplantation.

Cardiac transplantation has only recently become an accepted therapeutic modality for children and adolescents with end-stage cardiomyopathy. Long-term survival, the incidence of rejection, and the incidence of infection are still being defined. From 1985 to 1989, 21 children aged 6 months to 19 years (average age, 11.2 years) underwent cardiac transplantation at our institutions. Eighteen survived the operative period and have been followed for 5 to 49 months (average follow-up, 24 months). All operative survivors have received triple-drug immunosuppression consisting of cyclosporine, azathioprine, and prednisone. During follow-up, 7 patients have been treated on 12 occasions for rejection as documented by endomyocardial biopsy. Eight (67%) of the 12 episodes of rejection occurred in the presence of subtherapeutic cyclosporine levels. Two of the 7 patients treated for rejection have subsequently died of ongoing cardiac rejection and arrhythmia. There have been no perioperative or late deaths from infection. Bacterial sepsis was identified and treated twice during follow-up, viral infections on five occasions, and fungal infection once. Actuarial 1-year survival and 3-year survival of the 18 operative survivors are 94% and 78%, respectively. In the first 7 months after cardiac transplantation, 73% of patients were free from rejection and 83% were free from serious bloodborne infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise response before and after termination of atrial tachycardia after congenital heart disease surgery.

We studied exercise performance before and after conversion of atrial tachycardia to sinus rhythm, atrial bradycardia, or junctional rhythm in 10 patients 9-25 years of age 8-20 years after congenital heart disease surgery (complete transposition of the great arteries, seven of 10 patients). The same maximal cycle (five of 10 patients) or treadmill (five of 10 patients) exercise protocol was performed in atrial tachycardia and sinus rhythm 1-232 days after atrial tachycardia (mean, 34 days). Electrocardiogram, heart rate, and pulmonary gas exchange were recorded. Sinus rhythm exercise increased peak VO2 (mean, 28.7 [sinus rhythm] vs. 24.7 [atrial tachycardia], p less than 0.01), exercise time (p less than 0.01), and O2 pulse at rest (p less than 0.01) and at peak exercise (NS). Mean resting heart rate decreased from 109 to 70 beats/min (p less than 0.01). In atrial tachycardia, peak exercise heart rate was low (80-163 beats/min) because of fixed conduction (six of 10 patients) or high as conduction approached 1:1 (176-252 beats/min) (four of 10 patients). In sinus rhythm, rest to peak exercise heart rate increased in six of 10 patients (p less than 0.05). The data show improved exercise performance in sinus rhythm primarily because of improved heart rate adaptation to exercise, by either permitting increased heart rate response or eliminating excessively high heart rate with inadequate diastolic filling.

Echocardiographic versus cardiac catheterization diagnosis of infants with congenital heart disease requiring cardiac surgery.

The success of noninvasive preoperative evaluation of infants with congenital heart disease using cardiac ultrasound depends not only on diagnostic accuracy, but also on risk of morbidity and mortality as compared with infants who undergo cardiac catheterization. Fifty-six infants (age 10 weeks or younger) with coarctation of the aorta (n = 16), coarctation with ventricular septal defect (n = 12), valvar aortic stenosis (n = 10) or total anomalous pulmonary venous connection (n = 18) were examined. Thirty-one underwent noninvasive preoperative assessment and 25 underwent evaluation including cardiac catheterization. Age, level and duration of support, pH, renal function, mortality, complications of cardiac catheterization and errors of diagnosis were compared. Significant differences between the 2 groups were more frequent preoperative use of prostaglandin E1 and shorter hospital stay in the noninvasively evaluated coarctation group. Of the infants with coarctation and ventricular septal defect, 1 who had cardiac catheterization required renal transplantation and 1 evaluated noninvasively required surgery at age 3 months for mitral stenosis not discovered on preoperative evaluation. One noninvasively evaluated infant with total anomalous pulmonary venous connection had a stenotic communication between the pulmonary venous confluence and the left atrium not detected by ultrasound. Surgery was successful in the latter 2 infants. Noninvasive preoperative diagnosis of some infants with congenital heart disease can be performed without increasing the risk of operative morbidity and mortality. Eliminating cardiac catheterization reduces hospital costs, decreases total numbers of catheterizations performed and influences the structure of training programs.

Predictive value of lung biopsy in ventricular septal defect: long-term follow-up.

Although the Heath-Edwards classification has been used for more than 25 years to evaluate pulmonary vascular changes, its potential to predict the long-term course after successful ventricular septal defect closure has not been proved. Operative lung biopsy slides obtained at the time of closure from 57 infants and children who had been among the first survivors (between 1954 and 1960) of such surgery were graded in blinded fashion according to the Heath-Edwards classification system, and the resultant biopsy grade of each was compared with the eventual long-term outcome of each child. In 53 (93%) of the 57 cases, the Heath-Edwards system correlated well with long-term clinical or hemodynamic status of the patient. Grade IV changes were predictive of a usually fatal outcome, while grade I and II changes were generally benign. Death from pulmonary vascular disease occurred, however, in four children whose operative lung biopsy had been classified as either grade I or II, indicating that the focal nature of the higher Heath-Edwards grades, or human error, must be considered when this classification system is employed.

Management of pulmonary atresia with intact ventricular septum.

Infants with pulmonary atresia and intact ventricular septum pose a difficult clinical problem. Pulmonary valvotomy has been widely recommended for relief of the right ventricular obstruction, and most infants also have had an aortopulmonary shunt placed to ensure pulmonary blood flow. We have evolved a different approach that includes placement of a right ventricular outflow tract patch initially and continuation of prostaglandin E1 infusion postoperatively until the need for a shunt can be determined. We report here our management of 15 neonates with this diagnosis and suprasystemic right ventricular pressures. All of the infants were placed on a regimen of prostaglandin E1 before the operation to improve pulmonary blood flow, and all had an outflow patch placed early in life. Satisfactory postoperative right ventricular function, which would allow both outflow patching and ductus ligation, could be confidently predicted in only two of the 15 patients. For nine of the 15 an outflow patch was placed and prostaglandin was infused postoperatively to provide pulmonary blood flow until right ventricular function became adequate. Early in the series, three other infants were judged to need an aortopulmonary shunt in addition to decompression by an outflow patch, and one infant had only a shunt placed. Postoperatively, adequate pulmonary blood flow was present in all, and 11 of the 15 (73%) survived. Three of the deaths (average 2.8 days) after the outflow patch operation probably resulted from premature cessation of the prostaglandin infusion. One neonate with an outflow patch and a shunt died of myocardial ischemia because of coronary artery steal through right ventricular sinusoids. One late death occurred suddenly in the child with only a shunt, presumably because of an arrhythmia. The remaining survivors (10/15, 67%) are alive and have had complete repair. Study of these patients has also revealed that the definition of adequate right ventricular size needs to be more liberal. Five of the 10 surviving patients had a residual atrial septal defect with a right-to-left shunt at the ages of 1 to 3 years, but balloon occlusion of the atrial septal defect during cardiac catheterization revealed that the right ventricle in these patients was functionally adequate. These five children subsequently underwent closure of the atrial septal defect, and in two the aortopulmonary shunt was also taken down. In summary, correction was achieved in all survivors, in contrast to reported studies in which many patients are living with shunts.(ABSTRACT TRUNCATED AT 400 WORDS)

Repair of type B interruption of the aortic arch. Results and follow-up.

Surgical repair of type B interruption of the aortic arch and ventricular septal defect (VSD) in the newborn period is difficult and the optimal approach is controversial. We report here our early and late results using a two-staged approach in the repair of these lesions in seven consecutive neonates whose weights ranged from 2.9 to 3.8 kg and who were all less than 21 days of age. Each underwent aortic arch reconstruction off cardiopulmonary bypass with placement of a large (6 to 10 mm) polytetrafluoroethylene (PTFE) graft and pulmonary artery banding for interruption of the aortic arch (six) or extreme hypoplasia (one) of the arch. All seven (100%) survived the first-stage operation. No significant (greater than 10 mm Hg) conduit gradient was found in the seven patients studied 3 to 18 months postoperatively. One death occurred in a patient at 1 year of age with severe subaortic stenosis. Six patients subsequently underwent closure of VSD and removal of a pulmonary artery band, with five survivors (83%). The operative death occurred in an infant in whom pulmonary hypertension developed from an inadequate pulmonary artery band. One late death occurred at home when a tracheostomy tube, required because of severe tracheomalacia, became plugged. The long-term survival rate for completion of both stages is 57%. We conclude: (1) Aortic arch reconstruction and pulmonary artery banding can be reliably performed even in critically ill infants, and the 8 or 10 mm grafts should be adequate for several years. (2) Significant subaortic stenosis occurred in only one patient. (3) Pulmonary artery banding was the greatest source of difficulty, and distortion of the pulmonary arteries, inadequate banding, and compression of the trachea were all seen. Therefore, the staged repair will provide good results with this complex anomaly, and most of the problems associated with this approach may be eliminated by early second-stage repair.