It is well known that the prognosis of patients with complex heart disease and heterotaxy syndrome is very poor. Each isomerism has characteristic cardiac anatomical abnormalities. Almost without exception, patients with a right isomerism have obstruction of the pulmonary outflow tract, as well as common mixing situations, and pulmonary atresia is present in two-fifths of cases
]. More patients with a right isomerism commonly have obstructed anomalous pulmonary venous connection and occasionally they have serious extracardiac anomalies
]. In contrast to a right isomerism, heart disease in a left isomerism may be relatively mild and a review showed only one-third had complex cyanotic heart disease with a univentricular heart
]. Interestingly, Asians show a higher prevalence of heterotaxy syndrome compared to Westerners
] and our series showed 35.5% (39/110) of heterotaxy in Fontan candidates excluded an operative mortality.
We can easily understand that most of our patients were patients with right isomerism and the most of the first palliative procedures were BT shunts. In some cases of well-balanced hemodynamic condition with adequate pulmonary outflow tract obstruction, the first palliation of BCPS is possible. In our study BCPS as a 1st palliation was performed in 30.8% of the total and more in the survival group. It could be the reason that the age of the 1st palliation in survival group was older than that of mortality group. We do not have any special policy about the timing of BCPS with heterotaxy syndrome.
There were various reasons revealed for death. Because much interstage mortality occurred outside of our hospital, it was difficult to find a cause of death for each case. The state of the spleen and the extracardiac anomalies in heterotaxy syndrome may be important risk factors for mortality. In general, a greater frequency of fulminating and fatal septicemia is possible in a right isomerism and that is the reason for the strong recommendation of pneumococcal and H. influenza vaccines. The most frequent cause of interstage death in our patients was infection but we did not have an isolated organism in the six patients who died due to severe infection. Even though infection was also the most important cause of interstage mortality in the non heterotaxy group, infection control and prevention is very important in heterotaxy syndrome with a functional single ventricle in the interstage period.
We had 7 patients who died of unknown sudden causes or arrhythmia (43.8%) among whom only 1 patient had been prescribed antiarrhythmic agents. The causes of interstage mortality in HLHS patients have been extensively studied and it has been described that a preoperative or postoperative history of arrhythmia was associated with a sudden, unexpected interstage mortality
]. In our study, most of the arrhythmias were detected in ICU care after the palliation. There were no serious arrhythmias that needed to be corrected immediately. We managed significant post-operative arrhythmias medically after immediate post-operative period. In some instances of right isomerism bilateral sinus node activity is present and in left isomerism, true sinus rhythm is less common. In many patients, a progressive slowing of the heart rate has been noted with advanced age, leading to the need for placement of a permanent pacemaker
]. Even though previous arrhythmia history was not a significant risk factor in our study, we were not sure if some of fatal arrhythmia that had not been detected happened to the patients of sudden death.
We also should have an interest in shunt occlusion in patients who underwent BT shunt as 1st palliation. For the prevention of an unexpected sudden interstage death, a comprehensive outpatient program using home pulse-oximetry and daily weight monitoring is useful, but the results were disappointing because interstage mortality did not decrease even with vigilant outpatient monitoring
]. For the prevention of the thrombosis after shunt operation, aspirin for 6 month after the operation or till the next palliation is usually accepted in our center.
Feeding difficulties after single ventricle palliation are frequently encountered because of a lack of preoperative feeding continued postoperatively, poor oromotor skills or gastroesophageal reflux. In heterotaxy syndrome, gastrointestinal malformation and feeding difficulties are more frequent and associated with aspiration-related death. Interestingly, Hebson et al. reported that neonates undergoing single ventricle palliation who required a gastrostomy and fundoplication were at increased risk of interstage mortality
]. They suggested feeding difficulty as a marker for an increased risk of interstage mortality. We did not realize the importance of the gastrointestinal malformation and feeding difficulties in heterotaxy syndrome until recently, when frequent vomiting was confirmed from malrotation in one patient. Nowadays we carry out gastrointestinal evaluation in patients with oral feeding difficulties after operation. Unfortunately we cannot provide the complete data of gastrointestinal abnormalities in our series. We suspected aspiration associated with feeding might contribute sudden death in one or two patients. However the interstage mortality in the patients was significantly associated with the body weight at discharge after the major palliative surgery.
Patient growth during the interstage period is a crucial factor and studies have shown that weight gain in infants with HLHS is particularly challenging
]. The reasons for poor weight gain and low body weight are not clear in heterotaxy syndrome but may be multifactorial. Keller et al. demonstrated a somatic growth delay in patients with HLHS, particularly in the interstage period and also demonstrated that a low weight-for-z score was associated with poorer outcomes including more frequent interstage admission
]. We did not observed frequent admissions in our patient of interstage death and their feeding status, but the distribution of discharge patient body weight showed that 74.3% of our patients weighed less at discharge, below 25 percentile, while only 58.9% of our patients had their birth weight of below 25 percentile. A special nutritional and feeding program for growth restricted infants in the interstage period was required. With the special program, a higher weight gain allowed them to have next palliative treatment at shorter interval from the 1st palliative treatment
Residual anatomical lesions were not so common in our patients of interstage death but any undetectable minor anatomical problems, especially pulmonary venous obstruction and airway obstruction due to heart failure could contribute to the unexpected sudden death. The types of the 1st palliation were one of three, BT shunt, PAB and BCPS. As for BT shunt size, it depended on the patients’ body weight and surgical approach. Mostly 3.5 mm shunt via sternotomy or 4 mm shunt via lateral thoracotomy was used for our patients. In some cases we reduced the shunt size because of overflow after palliation. When it comes to PAB, external pulmonary artery banding via sternotomy is usual in our center. The strength of bandings is based on Trusler’s formula in single ventricle and is adjusted according to oxygen saturation using hemoclip.
The period before BCPS is accepted as the vulnerable period of sudden cardiac death in HLHS and interstage mortality in the period after the discharge from the first palliation and before BCPS persists at rates varying from 5% to 19%
]. Therefore from a HLHS study, the authors concluded that early BCPS at less than 4 month of age is safe in spite of a hospital course of longer duration
]. Our results in heterotaxy syndrome and functional single ventricle showed that the interstage mortality before BCPS was higher than that after BCPS and the cumulative survival of the patients who underwent BCPS as a 1st single ventricle palliation was much better than that of the patients whose 1st palliation were BTS or PAB. Therefore the BCPS as a 1st single ventricle palliation might be superior to BTS or PAB in terms of interstage mortality in heterotaxy syndrome with functional single ventricle and well balanced hemodynamics but further investigation is necessary.
The low oxygen saturation at discharge was one of the risk factors for the interstage mortality in heterotaxy syndrome with palliation for single ventricle. Shunt obstruction has been accepted as a major cause of cyanosis and sudden death in an infant with single ventricle physiology after palliation. Ohman et al. reported that home monitoring of oxygen saturation had the potential to detect some of the life-threatening shunt obstructions after BTS in infants with single-ventricle physiology
]. But we could not define the level of oxygen saturation of high risk for the interstage home monitoring of oxygen saturation.
Anomalous pulmonary venous drainage with obstruction in a single ventricle and heterotaxy syndrome is still a high risk for operative mortality
]. In our study, pulmonary venous stenosis at diagnosis was a significant risk factor of interstage mortality by multivariate Cox analysis. Our patients did not show severe pulmonary venous obstructions after the 1st palliation because pulmonary venous anomalies with obstruction are corrected at the initial stage by our policy. The repair of the pulmonary venous connection anomaly did not provoke a higher mortality than nonheterotaxy patients from some reports
], but our results showed that the existence of the pulmonary venous obstruction was an important factor for interstage mortality.
The post-operative course reflected by the duration of hospitalization, ICU stays and IV inotropes after palliation was important for interstage survival in our study. Residual atrioventricular valvular regurgitation was not a risk factor for our patients even though it was reported as a risk factor for late mortality in right isomerism
]. There was another report that described moderate atrioventricular valvular regurgitation and obstructed pulmonary venous anomaly as risk factors in right isomerism
]. We tried to correct atrioventricular valvular regurgitation over mild degree as soon as possible and many of correction were performed when BCPS was achieved.
The first limitation of our study is that it is a retrospective study. We tried to identify the mortality cases and the causes of death but we were unable to identify the exact causes of death for some cases that died at other hospitals or at home. We also were unable to identify the presence of a spleen in some patients with heterotaxy syndrome because some medical records were not complete. In general we hypothesized a right isomerism equaled asplenia and recommended preventive vaccination. The vaccination status also failed to be defined for each patient. We excluded a few patients alive that were waiting for BCPS or Fontan operation in a functional single ventricle that made slightly higher mortality rate. There are other important surgical factors that impact on the mortality, such as bypass time, shunt size, strength of banding and aortic regurgitation after palliation. We ignored to analyze some factors because of incompleteness and inaccuracy from old medical record. We focused several risk factors for interstage mortality in heterotaxy syndrome and further extensive investigation will be necessary in this recent period of developed surgical technique.
In summary, the interstage mortality in functional single ventricle and heterotaxy syndrome was much higher than the other non-heterotaxy group. Therefore more attention should be given to the prevention of interstage mortality in these patients.