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Ann Thorac Surg 2004;78:1688-1695
© 2004 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, Philadelphia, Pennsylvania, USA
b Division of Cardiology, Philadelphia, Pennsylvania, USA
c Division of Cardiac Anesthesiology, Philadelphia, Pennsylvania, USA
d Division of Biostatistics and Epidemiology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
Accepted for publication April 20, 2004.
* Address reprint requests to Dr Lodge, Duke University Medical Center, Box 3340, Durham, NC, USA 27710
andrew.lodge{at}duke.edu
Presented at the Fiftieth Annual Meeting of the Southern Thoracic Surgical Association, Bonita Springs, FL, Nov 13–15, 2003.
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Abstract |
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METHODS: Medical records of 18 patients admitted after 1997 were reviewed (group B) and compared with the previous group of 73 patients admitted between 1984 and 1997 (group A). Data were analyzed using a Cox proportional hazards model.
RESULTS: Median age at first operation was the same for both groups. The incidence of obstructed total anomalous pulmonary venous connection was not significantly different between groups (29% versus 33%, p = 0.70). Early survival is significantly improved for group B compared with group A (p = 0.015). Only group and younger age at initial operation were found to be risk factors for mortality. In the current group, 5 patients have undergone superior cavopulmonary connection with one death, 3 have undergone Fontan completion with no deaths, and heart or heart-lung transplantation was performed in 5 patients with two deaths.
CONCLUSIONS: Early survival in patients with single ventricle and total anomalous pulmonary venous connection has improved significantly in recent years, but intermediate survival is still approximately 50%. Selective management using staged reconstructive surgery and transplantation may result in improved survival. Further study may identify risk factors for mortality and improve selection of appropriate patients for each therapy.
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Introduction |
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Material and Methods |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDISCUSSIONReferences |
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Data were collected retrospectively by reviewing each patient's chart. The families of surviving patients were contacted and asked to complete a questionnaire and give consent for a review of outside medical records if indicated. When a patient had not been seen recently at the Children's Hospital of Philadelphia and the questionnaire information was incomplete, attempts were made to obtain outside records for review.
Data were analyzed for 91 children treated between July 1, 1984, and May 30, 2003. Data analysis involved three distinct phases. Phase 1 consisted of summarizing the data using measures of central tendency, variability, and association, calculation of frequency tables, and graphing relevant categorical variables for the group as a whole and for the two groups to be compared: patients treated before January 1, 1998 (n = 73, group A) and those treated after January 1, 1998 (n = 18, group B). These eras were selected to allow us to compare our current results with those reported previously. Phase 2 consisted of comparison tests between the two treatment groups for clinically important anatomic, perioperative, and survival status variables. Kaplan-Meier survival curves were graphed, and survival probabilities were compared for the two treatment groups using a Cox proportional hazards regression model. For these analyses, children were censored at the time of death or were withdrawn alive at the point of last contact. Survival time was defined as age in days with date of birth taken to be time zero. In Phase 3, 15 different single covariate Cox proportional hazards models were specified and tested for significance. Any single covariate model with a p value less than 0.15 was considered as a candidate for inclusion in the multiple covariate models. Because of the exploratory nature of the study and efforts to find the best combination of risk factors for death in these samples, several different multiple covariate models were specified and tested for fit. Hazard ratios, nested log likelihood ratios, and Wald statistic values were all used to help guide final model selection. Data were analyzed using STATA 8.0 (STATA Corp, College Station, TX).
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Results |
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Patient Characteristics
Relevant descriptive characteristics of the patient groups are shown in Table 1. The only statistically significant difference between groups was the higher incidence of obstructed pulmonary venous return at the second operation in group B. Heterotaxy syndrome was present in 68 of the patients (75%). Heterotaxy was slightly more prevalent in group B, although this difference did not reach statistical significance. The anatomic subtypes of TAPVC in both groups as well as the total cohort are also displayed in Table 1. Although there is a slightly higher percentage of supracardiac TAPVC and fewer cases of cardiac TAPVC in the more recent group, these differences were not statistically significant (p = 0.49 by Fisher's exact test). Overall, the distribution of types of TAPVC is not different from that expected in isolated TAPVC. In group A, 25 patients (34%) were dependent on the ductus arteriosus for pulmonary blood flow, and 23 patients (32%) were ductus dependent for systemic blood flow. In group B, 9 patients (50%) had ductus-dependent pulmonary circulation, and 3 patients (17%) had ductus-dependent systemic circulation. Only 14 patients in group A and 1 patient in group B had hypoplastic left heart syndrome, and only 19 patients in group A and 3 patients in group B underwent a stage I Norwood reconstruction as the first operative procedure. There was no statistically significant difference in the incidence of obstructed TAPVC or the proportion of patients undergoing a systemic-to-pulmonary artery shunt or repair of the TAPVC during the initial operation.
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Cavopulmonary Shunt and Fontan Procedures
Twenty-nine (36%) of the 81 patients who underwent surgery have undergone a cavopulmonary shunt. Six of these were performed as the initial operation, and 23 were performed after an initial palliative procedure. Twenty (69%) of these patients survived. Early survival was 62% in group A and 88% in group B (n = 6). Twenty-four patients (30% of the patients who underwent surgery) have undergone a Fontan operation. Median age at the time of Fontan operation was 34 months (range, 11 to 105 months). Sixteen (67%) of these patients survived. There have been two late deaths after the Fontan procedure. Survival after the Fontan procedure was 62% in group A (n = 21) and 100% in group B (n = 3).
Transplantation
Six transplants were performed in 5 patients in this series. All patients receiving transplants were in the more recent group. There were five heart transplants and one heart-lung transplant. Two patients underwent primary heart transplantation. The other 3 underwent transplantation as a salvage procedure for a failed earlier procedure. All 3 of the latter patients had pulmonary venous obstruction at the time of heart or heart-lung transplantation. No patient has undergone transplantation for a failed Fontan. Of the patients who underwent transplantation, 3 (60%) are still alive, including both patients who underwent primary heart transplants, with an average follow-up of 15 months.
Follow-Up Data From Patient Survey
Survey data are available from 17 of the 22 surviving patients. These patients are taking an average of 5.7 medications at 91 months of age. Of the 10 school-aged children, 3 attend regular schools and are in regular classes, 2 receive supplemental education or are in special classes in regular schools, and 5 are in specialized schools. Nine children missed a total of 161 school days in the last school year (average, 18 days). Ninety-eight (68%) of the missed days (average, 11 days per patient) were missed as a result of a cardiac condition. The current overall state of health of surviving patients as described by the family or patient was excellent in 7 patients, good in 6 patients, fair in 2 patients, and poor in 0 patients (data not available for 2 patients completing the questionnaire). Limitations to physical activity as assessed by the patient or parent were none in 6 patients, slight in 7 patients, and significant in 4 patients. The majority of patients were described to be in good or excellent health with no limitation or slight limitations in their physical activities. A variety of medical or social problems were described in the surviving patients, the most common of which were arrhythmias, speech impairment, or some level of learning disability (Fig 3). It was common for the patients to require the care of other professionals. Surviving patients are seen by an average of two specialists in addition to their pediatrician and cardiologist, most commonly a speech therapist (Fig 4). Six patients are not seen by any of these specialists, although 5 of these 6 have not yet reached school age.
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Comment |
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Other treatment options for single ventricle patients include medical treatment only, which has a dismal prognosis, and cardiac transplantation. The survival for pediatric heart transplantation is improving. Operative mortality has recently been reported to be less than 10% [7, 8], and survival is reported to be 78% to 89% after 1 year [7, 9, 10]. Certain groups have even suggested that, from a survival standpoint, transplantation is a better option than palliative surgery for children with hypoplastic left heart syndrome [11]. This has led some to recommend it as the preferred therapy for single ventricle patients. Although in some ways attractive, this therapeutic option is obviously limited by a shortage of donor organs and involves lifelong immunosuppressive therapy with its attendant risks and expense.
Given the previously reported dismal survival of single ventricle patients with TAPVC with conventional staged palliative surgery, we began to consider these patients for primary heart transplantation. Although transplantation in these patients involves the additional challenge of the pulmonary venous anastomosis in the face of abnormal anatomy, this is not an insurmountable problem as techniques for the repair of TAPVC have improved. This is supported by a report from Razzouk and colleagues [12] that demonstrated good results after transplantation in patients with functional single ventricle lesions and TAPVC. Recently we have treated 2 patients with a functional single ventricle and TAPVC with primary cardiac transplantation. We undertook this review to determine whether there had been improvement in survival in this patient group in the recent era with standard staged surgical palliation, and whether risk factors within this group could be identified that might lead to a more rational selection of patients for staged surgery versus transplantation.
Data from this report suggest that the mortality for surgical treatment of single ventricle lesions with TAPVC is not as high as it was before 1998. However, it is still higher than that for single ventricle lesions without TAPVC. Recent data suggest that hospital survival for hypoplastic left heart syndrome patients treated in the same era is better than 70% after the stage I Norwood procedure, and up to 100% after the bidirectional cavopulmonary shunt and Fontan procedure [2, 4, 13]. The data from our study suggest that the surgical procedures, including initial palliation, can be performed in these patients in the current era with a mortality similar to that reported for other single ventricle patients, but that overall intermediate-term survival for single ventricle patients with TAPVC is still only slightly better than 50%. Azakie and colleagues [14] recently reported a series of patients with atrial isomerism and heterotaxy undergoing the Fontan procedure with a surgical mortality of 13% and a 5-year survival of 83%. This series included patients with normal pulmonary venous drainage, and TAPVC was identified as a risk factor for mortality. Patients who did not survive to undergo a Fontan procedure were not included, so it is not possible to compare overall results between the two series. However, they concluded as we did that early and midterm outcomes after the Fontan procedure in these patients are improving.
As no specific management changes were used to treat the group B patients in this report other than primary transplantation in 2 of the patients, it is most likely that a better understanding of the physiology and perioperative management of the single ventricle patient are responsible for improving outcomes in both standard risk groups and this study population. Improvements in the areas of critical care and anesthesiology as well as in surgical techniques all are apt to play some role. Another important factor may be that all patients in the group B survived to undergo a surgical procedure, whereas 9 patients (12%) in group A did not. As this disease is uniformly fatal without surgery, improved ability to medically manage the patients before surgery will likely have an impact on survival.
Despite additional experience with this complex group of patients, it is still not possible to clearly identify risk factors for a poor outcome after surgery, or to determine the reasons for the better outcomes in group B. In fact, the risk factors may be less clear than they were previously. Obstructed TAPVC and the need for TAPVC repair at the time of the initial operation, which were risk factors for mortality in the original report, were factors that did not attain statistical significance with the addition of the more recently treated patients to the analysis. The distribution of anatomy and type of palliative procedure performed also did not seem to differ between the groups. It is worth noting that a majority of patients in this series had heterotaxy syndrome, including 94% of the patients in group B. Heterotaxy has been thought of as a risk factor for poor outcome. This was not found to be the case in this study. This is supported by other recent reports that showed that results of bidirectional cavopulmonary shunts and Fontan operations in patients with heterotaxy syndrome have improved in recent years [15, 16]. Younger age at the time of the initial surgery remains a significant risk factor. This most likely reflects the unstable nature of the patients who require earlier procedures. However, the median age at operation in this review was the same for both groups.
The lack of additional information predicting risk after surgery makes it difficult to make recommendations regarding staged palliation versus transplantation. Because of the small number of patients in the series that underwent transplantation and the fact that some of the patients underwent transplantation as a salvage procedure whereas some were primarily transplanted, it is impossible to compare the two subgroups, and this was not the intention of the study. Anatomic variation in the systemic and pulmonary venous return in these patients may add to the complexity of the heart transplantation procedure, but the same issues would exist for palliative operations. Experience with heart transplantation in these and similar patients demonstrates that with technical modifications, the individual patient anatomy can be overcome.
Data are now available on the long-term outcome for patients who undergo surgical procedures for single ventricle lesions [17, 18]. Many of these children have developmental delay, learning disabilities, and other issues requiring specialized care. Although perhaps not directly comparable, the follow-up data acquired in this study suggest that these problems exist in this group of patients to a similar extent. Although patients with a functional single ventricle and TAPVC who ultimately survive to Fontan operation can have a clinically good outcome, the need for special education and multiple medications in many may have significant quality-of-life and cost implications.
Several limitations of the current study must be discussed. It is a retrospective review, and therefore subject to the limitations inherent in all such studies. The patient population is somewhat heterogeneous, comprising a number of different anatomic diagnoses. Ideally one would perform a prospective randomized clinical trial with different groups for staged palliative surgery and transplantation. Given the infrequency of occurrence of this combination of lesions it is unlikely that such a study could ever be performed. The relatively small number of patients makes the identification of risk factors for mortality somewhat difficult as the statistical power to discern differences between groups is relatively low, and therefore defining a strategy to treat the individual patient is problematic.
In conclusion, survival for staged surgical palliation for single ventricle patients with TAPVC has improved in recent years to the point that this therapeutic approach is a reasonable one for this patient group. Procedures necessary before the second day of life can be expected to have a worse outcome, likely owing to patient factors that necessitate an earlier procedure. Long-term data on functional outcome suggest that these patients have a similar quality of life as other single ventricle patients staged to Fontan operation. Decisions for staged palliative surgery versus transplantation should be based on individual patient anatomy and institutional experience until more informative data are available.
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DISCUSSION |
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I am curious about two things. First of all, inasmuch as in group A in your series you had a lot of nonsurvivors before surgery, meaning that those patients either were refused surgery or were in an era where they did not get the surgery, did you eliminate them from your analysis of death? It seems that they represented a fairly significant number.
The second question I have is regarding the management of these patients when they do present with single ventricle and total anomalous pulmonary venous connection. They are all going to Fontan procedures, and clearly one of the major complicating issues that would keep them from becoming good Fontan operations would be if their obstructed pulmonary venous return is proximal to the actual connection of the communicating vein. I am wondering whether you found in examining the patients who had the risk factor of being "young age" if that was because they were obstructed and so they needed surgery more quickly? Perhaps if you really look at that group you would find that obstructed pulmonary venous return was a risk factor and it just happened to present at a young age.
And the third question I have is in the patients who have anomalous pulmonary venous connection with a single ventricle, was it your policy to do anything about the anomalous pulmonary venous connection at the time of the palliative operation? That is, did you ligate the communicating vein in addition to creating a communication between the confluence and the atrium or did you leave it open to be dealt with at a later time to reduce the possibility of obstruction in the postoperative period?
Once again, a very complicated topic, and an excellent presentation; I am proud of you.
DR LODGE: Thank you, Dr Ungerleider, for your comments and questions. To answer your first question, in the first group, there were 9 patients who died before having any surgical procedure performed. There were also 3 patients in that group who underwent procedures not specific to the cardiac diagnosis, for example, pacemaker placement or the initiation of extracorporeal membrane oxygenation support. All those patients did poorly. We did run the analysis with those patients in and out of the group, but because they did factor into the overall picture of how patients with this condition do, we decided to leave them in the analysis for the data that we presented here.
In terms of your question about the obstruction of pulmonary venous return, we did find in the initial series that obstructed anomalous venous return was a risk factor for mortality. That did not come out as a risk factor for mortality in this update, and the reason for that may be improved techniques of repairing it. The incidence of obstruction was the same in both groups.
I think you are right that the patients who presented earlier with an obstructed pulmonary venous return are patients who did require their earlier procedures, and those were patients who did more poorly. There was no difference in the incidence of that problem between the two groups, however, so it probably does not explain the mortality difference between the groups.
And then just to answer your question about the timing of repair of the total anomalous pulmonary venous connection, that was based on individual patient anatomy and the degree of obstruction as assessed at the time. The timing of correction of the total anomalous pulmonary venous connection was variable, sometimes being performed at the first procedure and sometimes being performed later. If the total anomalous pulmonary venous connection was unobstructed, frequently it was left alone at the first operation. If total anomalous pulmonary venous connection repair was performed at the first operation, the connecting vein would usually be ligated.
DR W. STEVES RING (Dallas, TX): You are really to be congratulated on an excellent series of some very difficult patients here. Two groups that you have identified have particularly troubled us: one is the patients with obstructed total veins, the other is the group of the hypoplastic left heart with critical aortic stenosis or aortic atresia. And as you only had 18 patients in your second group, and there were only 4 patients with obstructed veins, if I am doing the math correctly, and I do not know how many of them would have been hypoplastic, probably only a couple, are you really powered sufficiently to say that there is not really much difference between the obstructed and the unobstructed veins in that second group of patients? What has been your experience in the outcome in the obstructed veins in the current era, and what has been your outcome with the hypoplastic left heart syndrome patients in the current era?
DR LODGE: You are right, there were only a small number of patients with those conditions in the recent series. There were only 2 patients with hypoplastic left heart syndrome in the recent group, so I think that is too small a group to really evaluate.
In terms of the statistical power, it is difficult to say with small numbers that there is no difference. We did not find a statistical difference in the study, but I do not think that we can say confidently that there would be no difference if we had a larger number of patients. Interestingly, the incidence of obstructed total anomalous pulmonary venous connection in the recent patients was similar to that in the older series of patients despite the improvement in survival, but there were, again, a small number of patients with that condition.
The patients in the more recent series actually presented more frequently with recurrent pulmonary venous obstruction, in other words, something that had to be dealt with at the second or third operation, and despite that, they seemed to do better overall as a group.
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  Y. Oshima, M. Yoshida, A. Maruo, C. Shimazu, T. Higuma, and T. Inoue Modified primary sutureless repair of total anomalous pulmonary venous connection in heterotaxy. Ann. Thorac. Surg., October 1, 2009; 88(4): 1348 - 1350. [Abstract] [Full Text] [PDF]
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