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Ann Thorac Surg 2007;84:581-586
© 2007 The Society of Thoracic Surgeons
a Department of Cardiac Surgery, Children’s Hospital Boston, Boston, Massachusetts
b Department of Cardiology, Children’s Hospital Boston, Boston, Massachusetts
Accepted for publication April 2, 2007.
* Address correspondence to Dr Bacha, Department of Cardiac Surgery, Children’s Hospital Boston, Harvard Medical School, 300 Longwood Ave, Bader 273, Boston, MA 02115 (Email: emile.bacha{at}cardio.chboston.org).
Presented at the Forty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 29–31, 2007.
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Abstract |
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Methods: We retrospectively identified all neonates with a diagnosis of HLHS and I/HRAS who underwent stage I palliation at Children’s Hospital Boston between January 2001 and December 2006. Chart review enabled analysis of patient and procedural variables.
Results: All 32 patients underwent left atrial decompression in utero or postnatally before surgery. Fourteen patients (44%) underwent fetal intervention, either atrial septoplasty (n = 9) or aortic valvuloplasty (n = 5). Twenty-nine of the 32 patients had postnatal left atrial hypertension and underwent transcatheter atrial septoplasty as neonates before surgery; 3 did not require postnatal atrial septoplasty after successful fetal atrial septoplasty. After stage I, hospital survival was 69% (22 of 32). Need for shunt revision (p = 0.02) and for extracorporeal membrane oxygenation use (p < 0.001) were associated with hospital mortality. Survival at 6 months was 69% for patients who had fetal intervention, and 38% for those who were treated only postnatally (p = 0.2).
Conclusions: Surgical outcome for patients with HLHS and I/HRAS continues to improve. Prenatal decompression of the left atrium may be associated with greater hospital survival. Proposed effects of fetal intervention on lung pathology and longer-term survival are subjects for future study in this unique group of patients.
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Introduction |
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The purpose of this review is to explore the impact of newly introduced fetal therapies, to summarize recent surgical outcome for patients with HLHS and IAS at our center, and to identify predictors of survival to hospital discharge.
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Material and Methods |
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As part of a larger review of current outcomes of stage I palliation for HLHS, we retrospectively identified all newborns presenting to the Children’s Hospital Boston, in the last 6 years, with a diagnosis of HLHS associated with I/HRAS. This period coincided with the inception of our fetal cardiac interventional program, and the development of our capability to perform in utero atrial septoplasty [8, 9]. All infants with HLHS and I/HRAS managed at our center were identified, and those who underwent stage I surgical palliation between January 2001 and December 2006 were included in this review.
The study group consisted of patients who had the classical presentation of HLHS with I/HRAS or restrictive atrial septum in conjunction with consistent echocardiographic findings, as well as patients who were predicted to have this presentation by prenatal echocardiography. Thus, study patients included neonates with severe hypoxemia and hemodynamic instability requiring emergent or urgent transcatheter left atrial decompression, as well as neonates whose prenatal echocardiograms showed (1) an intact atrial septum or small atrial septal defect with absent or obstructed decompression and (2) dilated pulmonary veins and (3) prominent flow reversal or to-and-fro flow in the pulmonary veins [10, 11].
Starting in 2001, fetuses prenatally diagnosed with HLHS and I/HRAS were offered fetal intervention for left atrial decompression, at the discretion of the fetal cardiologist. When fetal intervention was performed, it was carried out as previously described with creation of an atrial septal defect by direct septal puncture [9].
After postnatal catheterization, the patients were transferred to the intensive care unit, and taken to the operating room once clinically stable. Surgery consisted of neoaortic arch reconstruction and atrial septectomy. Pulmonary blood flow derived from either a modified Blalock-Taussig shunt (mBTS) or a right ventricle to pulmonary artery (RV to PA) conduit, based on the individual surgeon’s preference. A period of deep hypothermic circulatory arrest was used in 30 cases (94%), with selective antegrade cerebral perfusion utilized in some cases at the surgeon’s discretion.
The primary outcome variables were in-hospital mortality and interstage mortality, occurring between stage I palliation and bidirectional Glenn (BDG). Patient and procedural variables assessed for association with outcomes included prenatal diagnosis, fetal intervention, type of fetal intervention, anatomical subgroup, presence of coronary artery fistulae, age at surgery, weight at surgery, type of pulmonary blood flow supply, need for revision of pulmonary blood flow supply, cardiopulmonary bypass time, circulatory arrest time, and postoperative extracorporeal membrane oxygenation (ECMO) requirement.
Continuous variables were summarized as mean ± SD or median (range). Characteristics were compared for patients who died in-hospital after the stage I procedure versus those who survived until discharge using Fisher’s exact test for categorical variables, and either two-sample t test or the Wilcoxon rank sum test for continuous variables. Survival probabilities were estimated using the Kaplan-Meier method. Time to death was compared for patients with and without a fetal intervention using the log-rank test.
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Results |
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Anatomy
Anatomy consisted of mitral stenosis with aortic atresia (MS/AA) in 9 patients, and mitral and aortic atresia (MA/AA) and mitral and aortic stenosis (MS/AS) in 8 patients each. The remaining 7 patients had anatomic variants, predominantly double-outlet right ventricle with mitral atresia (n = 3). Twelve patients had an IAS whereas 20 patients had a highly restrictive atrial septum.
Procedures
Nine neonates underwent fetal atrial septoplasty (all met criteria for restrictive atrial septum prenatally [Fig 1]). After this intervention, 3 did not require further preoperative enlargement of the atrial septal defect at birth. Five patients with restrictive atrial septum underwent fetal aortic valvuloplasty. A fetal atrial septoplasty was not done in those 5 patients in an attempt to promote left-sided structures growth. All 5 needed urgent atrial decompression after birth. Including those 5, a total of 23 neonates had only postnatal atrial septoplasty. Thus, 29 (23 plus 6 who had also fetal septoplasty) of the 32 patients (91%) underwent urgent or semiurgent transcatheter atrial septoplasty postnatally, before surgical palliation. An atrial stent was used in 14 of 29. The 3 patients who did not require postnatal transcatheter atrial septoplasty had adequate fetal opening of the atrial septum (1 with fetal atrial stent).
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Mean cardiopulmonary bypass time was 176 ± 64 minutes, mean cross-clamp time was 58 ± 33, and mean circulatory arrest time was 45 ± 22 minutes. The chest was initially left open in 26 patients (81%) after surgical palliation and was closed after a median of 3 days (range, 2 to 5).
Postoperative management to augment pulmonary blood flow included inhaled nitric oxide in 4 patients. Five patients (5 of 32, 16%), all with a mBTS, required shunt revision. Acute shunt thrombosis occurred in 1 patient. In the other 4 patients requiring shunt revision, excessive pulmonary blood flow prompted anatomic reduction of the shunt. Of 10 patients (31%) supported postoperatively with ECMO, 8 died. Indications for ECMO included inability to wean from cardiopulmonary bypass (n = 3), cyanosis (n = 3), low cardiac output state (n = 2), acute shunt thrombosis (n = 1), and coronary ischemia (n = 1).
Hospital Survival
None of the studied patient-specific variables were associated with hospital survival. Ten patients died in the hospital after stage I palliation, resulting in a hospital survival of 69%. Median hospital stay was 25 days (range, 8 to 87) for the 22 survivors. Revision of the systemic-to-pulmonary shunt (p = 0.02), and postoperative ECMO requirement (p < 0.001) were associated with increased hospital mortality (Table 1). Of the 4 patients requiring shunt reduction, only 1 survived to hospital discharge (versus 21 of 28 who did not require shunt reduction; p = 0.08). There was a trend toward higher mortality among patients of the anatomical subtype MS/AA (p = 0.09). Furthermore, the mortality was 80% (4 of 5) when coronary fistulae were present with MS/AA, and was significantly higher compared with the rest of the study group (p = 0.04).
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Interstage and Midterm Survival
Sixteen of the 22 stage I survivors (73%) underwent a BDG at a median of 151 days after stage I (range, 99 to 285). Interstage mortality occurred in 5 of 22 patients (23%) at a median of 97 days postoperatively (range, 19 to 152), and exclusively in patients who had a mBTS (Table 2). Thus, 17 of 32 patients (53%) survived to BDG. There was no hospital mortality associated with BDG. Kaplan-Meier estimate of survival to 6 months of age was 49% overall, and was not significantly higher for patients who had fetal intervention (69%) as opposed to those who were treated only postnatally (38%, p = 0.2; Figs 2 and 3).
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Pulmonary Vein Anomalies
Pulmonary venous anomalies (defined by autopsy findings in 5, need for surgery or transcatheter intervention on the pulmonary veins in 3, and either echocardiographic gradient of greater than 5 mm Hg, angiographic findings, or surgical observation in the remaining 3) were present in 11 of the 32 patients (34%) included in this study. Eight of the 15 patients (53%) who died before having a BDG had pulmonary venous anomalies (p = 0.02). An additional patient (cited above) with pulmonary vein stenosis died late after Fontan.
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Comment |
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In an ongoing effort to increase understanding of HLHS and IAS, we undertook the current review, attempting to determine survival rates and predictors of survival in more recent years. We found that among 32 infants having stage I palliation for HLHS with IAS at our institution between 2001 and 2006, hospital survival was 69%. This finding suggests improved survival relative to the preceding decade.
Revision of the systemic-to-pulmonary shunt (p = 0.02), and postoperative ECMO requirement (p < 0.001) were associated with hospital mortality. At Children’s Hospital Boston, we have favored utilization of a mBTS in patients with HLHS and I/HRAS, in anticipation of elevated early postoperative pulmonary vascular resistance, and potentially exaggerated pulmonary vascular responsiveness. Recognition of pulmonary vascular and lymphatic abnormalites seen in this patient population, as well as our observance of progressive pulmonary vein stenosis in some cases, has reinforced this bias [2, 14]. Despite these numerous factors that might be expected to limit pulmonary blood flow, we found that pulmonary overcirculation can occur in these patients with HLHS and I/HRAS, necessitating shunt diameter reduction in 4 patients, 3 of whom did not survive hospitalization. Although the shunts were of uniform nominal diameter (3.5 mm), we speculate that variations in surgical technique (eg, placement at the proximal innominate artery) may have played a role. Clearly, some infants may require augmented pulmonary blood flow postoperatively to maintain oxygenation. However, the potential for a toll on systemic output and coronary perfusion should be recognized, as it may result in early mortality [3]. Furthermore, limited evidence exists that elevated pulmonary vascular resistance may normalize even in this vulnerable patient group [7]. Tailoring medical management with readily reversible therapies such as nitric oxide may be effective, and may incur less hemodynamic risk than presumptive augmentation of pulmonary blood flow by placement of a very proximal mBTS. The ongoing Single Ventricle Reconstruction Trial may help shed light on this important issue.
Increasingly, HLHS is diagnosed prenatally by fetal echocardiography, as it was in 84% of our patients. Given this high rate of fetal diagnosis in a small series of patients, we did not find prenatal diagnosis to be associated with improved survival. Uniquely, at our center, prenatal diagnosis of HLHS in association with a restrictive or intact atrial septum confers eligibility for a fetal intervention to open the atrial septum [9]. Successful prenatal intervention to decompress the left atrium may improve early postnatal cyanosis and mitigate some of the immediate postnatal mortality seen in this population. In our series, infants born after fetal intervention had a hospital survival of 79% of infants (11 of 14), compared with 61% of infants (11 of 18) treated only postnatally. Most of these fetal interventions were performed to create an atrial septal defect, although 5 fetuses had only aortic valve dilation prenatally [8]. Whether prenatal aortic valvuloplasty in these fetuses with HLHS augmented antegrade left atrial decompression remains uninvestigated.
Although anatomical subtype was not associated with surgical outcome, our findings suggest that there was a trend toward higher mortality among patients with MS/AA (p = 0.09). When coronary arterial fistulae were present, mortality was high (4 of 5, 80%). The question as to whether MS/AA anatomy with fistulae marks truly high risk subgroup of HLHS, and how this risk may be affected by I/HRAS physiology, is the subject of an ongoing review at our institution.
Follow-up of these 32 patients revealed a substantial rate of interstage mortality (23%), and further mortality even after Fontan completion. As might be expected in patients with HLHS and I/HRAS, developmental abnormalities of pulmonary vasculature and parenchyma continue to pose a risk to the palliated single-ventricle circulation.
Pulmonary vein anomalies, including a thickened vascular wall (primarily the intima and muscularis media), and vessel tortuosity or stenosis, which may be inapparent in the neonate, can develop over time. In our series, a significant association was found between the presence of pulmonary vein anomalies and death before BDG (8 of 15 patients, p = 0.02). Whereas fetal intervention for HLHS and I/HRAS can obviate the need for emergent left atrial decompression in some patients (3 in our series), and may allow for a more stable preoperative circulation in others, its benefit with regard to normalization of pulmonary vasculature remains, at this time, speculative.
In conclusion, hospital survival for patients with HLHS and I/HRAS continues to improve. When the diagnosis is made in utero, the left atrium can be decompressed prenatally, and successful fetal intervention may be associated with higher hospital survival. Proposed effects of fetal intervention on lung pathology and longer-term survival are subjects for future study in this group of patients.
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Discussion |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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I would like to congratulate Dr Vida and his team and colleagues at Boston Children’s Hospital for this excellent presentation and important contribution. This study clearly presents groundbreaking work, and the Boston team is to be congratulated. I would like to thank Dr Vida for sending me the manuscript ahead of time to review.
Your manuscript reports that for patients with hypoplastic left heart syndrome and intact atrial septum, survival at 6 months was 64% for patients who had fetal intervention and only 38% without fetal intervention. You conclude that surgical outcome for patients with hypoplastic left heart syndrome and intact atrial septum continues to improve. Prenatal decompression of the left atrium seems to be associated with higher survival. Other studies have shown that these patients with HLHS and intact atrial septum managed conventionally without fetal intervention are at extremely high risk with poor prognosis.
In 2002, the Children’s Hospital of Philadelphia reported that survival after stage I Norwood was 82% in low-risk patients. In the same study, they found that there was no difference in survival when comparing patients undergoing stage I for HLHS versus other lesions. Nevertheless, in soon to be published data from CHOP, the CHOP study reports that HLHS with intact or highly restrictive atrial septum remains a high-risk lesion. In a review of 38 patients with HLHS and intact or highly restrictive atrial septum, 30-day cumulative survival was only 38% among those with the most severe form of anatomical obstruction. Outcome was not improved with the strategy of aggressive early intervention immediately after birth for the neonate with the fetal diagnosis of intact atrial septum. Despite planned Caesarian section followed by immediate surgical or catheter-based intervention, outcome remained poor. In fact, no difference in outcome was seen in patients with prenatal versus postnatal diagnosis in this subset of patients. Hypoplastic left heart syndrome and intact atrial septum was found by the CHOP team to be a highly lethal condition despite prenatal diagnosis, and they recommended that fetal intervention should be considered in these high-risk fetuses. Because of this challenging problem, several groups, including your group, is investigating fetal intervention for this complex subset of patients. I have four questions for you.
First, what are your current indications and contraindications for fetal intervention in hypoplastic left heart syndrome? Second, should all patients with HLHS and intact atrial septum be referred for fetal intervention? Third, fetal dilatation of the aortic valve in these patients may lead to growth of the hypoplastic left ventricle; how many patients in Boston have undergone eventual biventricular repair after fetal intervention for hypoplastic left heart syndrome? And finally, despite successful fetal decompression of the obstructed atrial septum in HLHS, underlying pulmonary vascular disease may persist leading to problems at the time of stage II and stage III; have you seen this late problem and do you expect to?
Again, I would congratulate you for an excellent presentation of truly groundbreaking research. While discussing this paper with Carl Backer earlier, Carl stated that this presentation is a "landmark series where intervention has altered the natural history of congenital heart disease with fetal intervention." I congratulate you and the Boston team.
DR VIDA: Thank you, Dr Jacobs, for your questions. Concerning the first question, the current indications for a fetal procedure in a patient with hypoplastic left heart syndrome are two: one, the decompression of the left atrium in patients with intact or highly restrictive atrial-septal communication; and two, the dilation of the aortic valve to recruit the left ventricle for possible biventricular repair in the future. The contraindications for fetal intervention can be fetal or maternal. The presence of twin or multiple pregnancies, chromosomal anomalies, and associated extracardiac anomalies is an absolute fetal contraindication. The fetal position is also a relative contraindication. As far as the mother is concerned, we believe that intolerance to anesthesia, difficult airways, bleeding problems, or use of anticoagulation have to be considered general contraindications. As example, the mother of one of our patients had deep venous thrombosis during the pregnancy and owing to the use of heparin, it was not possible to achieve decompression of the left atrium in utero.
Regarding the second question, we think that every fetus with in-utero echocardiographic diagnosis of intact or highly restrictive flow in the pulmonary vein, in the absence of contraindication for fetal procedure, should be considered for fetal decompression of the pulmonary veins. We believe that this procedure could have early potential benefits for these patients as the relief of the profound cyanosis at birth in addition to promote hemodynamic stability. Furthermore we believe that fetal decompression could also be beneficial in the mid term, preventing damage of the pulmonary vasculature.
Regarding your third question, we were able to dilate the aortic valve in utero in 5 patients within this group. One of these patients has already had biventricular repair after a staged bidirectional Glen anastomosis, and 3 patients are still waiting for further evaluation after cavopulmonary shunts. One of the 5 patients died in hospital after stage I palliation after requiring ECMO support for overcirculation.
Pulmonary vein anomalies were present in 10 of the 32 patients (31%) in our series. Eight of these patients died before having a bidirectional Glen, and 1 additional patient died later after completing the Fontan operation. Thank you.
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Acknowledgments |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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References |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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This article has been cited by other articles:
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  N. Manning and N. Archer Fetal pulmonary venous Doppler flow patterns in hypoplastic left heart syndrome Heart, November 1, 2008; 94(11): 1374 - 1375. [Full Text] [PDF]
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 V. L. Vida, E. A. Bacha, A. Larrazabal, K. Gauvreau, A. L. Dorfman, G. Marx, T. Geva, A. C. Marshall, F. A. Pigula, J. E. Mayer, et al. Surgical outcome for patients with the mitral stenosis-aortic atresia variant of hypoplastic left heart syndrome. J. Thorac. Cardiovasc. Surg., February 1, 2008; 135(2): 339 - 346. [Abstract] [Full Text] [PDF]
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