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Eur J Cardiothorac Surg 2003;23:735-742
© 2003 Elsevier Science NL
a Division of Cardiothoracic Surgery, University of Colorado Health Sciences Center and the Children's Hospital, Denver, CO, USA
b Division of Pediatric Cardiology, University of Colorado Health Sciences Center and the Children's Hospital, Denver, CO, USA
c Department of Preventative Medicine and Biometrics, University of Colorado Health Sciences Center and the Children's Hospital, Denver, CO, USA
Received 23 October 2002; received in revised form 8 February 2003; accepted 12 February 2003.
* Corresponding author. Tel.: +1-303-861-6624; fax: +1-303-764-8022
e-mail: mitchell.max{at}tchden.org
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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120 days before heart transplantation were assessed. Patients undergoing transplantation after standard management (control group) were compared to patients having a prior pulmonary blood flow limiting procedure (PAB group). Results: Of 16 identified patients, one crossed over to stage I Norwood on day 185 and died post-operatively. Fifteen patients were transplanted at age 120 days (control group n=9, PAB group n=6). Four PAB patients had open PA band placement. Two PAB patients underwent experimental percutaneous bilateral internal pulmonary artery flow limiting device insertion. The PAB group mean age at banding was 141±54 days, and mean interval from PAB to transplant was 35±31 days (range 1.5–68 days). No differences in age at transplant, weight at transplant, warm graft ischemia time or total graft ischemia time were detected between groups. Mean times of mechanical ventilation (control 143±69 h vs. PAB 44±13 h), inhaled nitric oxide (control 126±70 h vs. PAB 37±9 h), inotropic support (control 171±64 h vs. PAB 87±17 h), intensive care unit (ICU) stay (control 8.3±2.7 days vs. PAB 4.5±1.4 days), and hospital stay (control 10.4±3.9 days vs. PAB 7.0±1.1 days) were all lower in the PAB group (P<0.05 all comparisons). Two control patients died, three required extracorporeal membrane oxygenation (ECMO), and six did not tolerate primary chest closure. No PAB patient died or required ECMO. All PAB patients tolerated primary chest closure. All PAB patients had widely patent branch pulmonary arteries with no re-interventions to date. All hospital survivors remain alive (mean follow-up, control 50.2 months, PAB 11.5 months). Conclusions: Pre-transplant mechanical limitation of pulmonary blood flow simplified management and reduced morbidity for HLHS patients undergoing heart transplantation at ages 4 months. This strategy extends the permissible transplant waiting time in older infants with HLHS.
Key Words: Heart transplant • Hypoplastic left heart syndrome • Pulmonary artery band • Pulmonary hypertension
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Gibbs and associates first reported the combination of ductus arteriosus stenting and open bilateral branch pulmonary artery banding for the palliation of HLHS [15]. However, mortality was high and follow-up was limited. Other authors have described ductus arteriosus stenting alone as a bridge to transplantation for HLHS [16]. Recently, Akintuerk et al. reported a new strategy for HLHS treatment consisting of percutaneous ductus arteriosus stenting and open bilateral pulmonary artery banding in the newborn period followed by delayed arch reconstruction and bi-directional cavopulmonary shunt (i.e. combined stage I and II Norwood) [17]. This group also reported a similarly palliated HLHS patient who underwent successful delayed cardiac transplantation [17].
Our center began offering heart transplantation for babies with HLHS in 1990. In recent years, waiting list times in excess of 4 months have become increasingly frequent for these infants. Despite the routine use of milrinone and nitric oxide, the perioperative management of HLHS patients transplanted in this age range is often problematic due to elevated pulmonary vascular resistance. Right ventricular failure requiring support with extracorporeal membrane oxygenation (ECMO) is not uncommon [9]. Some experimental models of secondary pulmonary hypertension indicate that rapid biochemical changes occur when the underlying cause of the disease is eliminated leading to prompt normalization of pulmonary vascular function [18,19]. We hypothesized that mechanically restricting branch pulmonary artery blood flow in older infants with HLHS might allow salvage of infants who have endured prolonged severe pulmonary overcirculation but had not yet developed fixed pulmonary hypertension. Secondly, we theorized that this strategy might extend the safe waiting time for older infants with HLHS. The purposes of this study were: (1) to assess the impact of prior mechanical limitation of branch pulmonary artery blood flow on infants with HLHS undergoing heart transplantation at ages 4 months; and (2) to determine if this strategy could extend the safe waiting time for transplantation in older infants with HLHS.
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2. Materials and methods |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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120 days, or were listed and survived to ages 120 days were identified. All patients with HLHS who underwent procedures to mechanically limit branch pulmonary artery blood flow regardless of age were also identified. Medical records were examined retrospectively, outcomes were determined, and a separate research database was compiled eliminating all identifying information. Patients undergoing transplantation after standard pretransplant medical management form the control group. Patients undergoing branch pulmonary artery flow limiting procedures before transplantation form the PAB group. This study was approved by the Colorado Multiple Institutional Review Board. Informed consent was obtained for all percutaneous pulmonary flow limiting procedures under a separate investigational protocol approved by the Colorado Multiple Institutional Review Board.
2.2. HLHS pretransplant protocol
Neonatal management of HLHS was as previously described [8]. Briefly, PGE1 infusion was initiated upon suspicion of cyanotic congenital heart disease, and the diagnosis of HLHS was confirmed echocardiographically. Hypoxic ventilation (17% FiO2/83%FiN2) was used to maintain elevated pulmonary vascular resistance and preserve systemic perfusion. Mechanical ventilation, inotropes, and diuretics were weaned as soon as possible and medications were minimized. When room air ventilation was well tolerated (age 4–6 weeks) patients were discharged for outpatient management. PGE1 was infused continuously until the time of transplantation. Atrial septal defects were left moderately restrictive (goal<2.5 m/s Doppler estimation) to reduce pulmonary blood flow and maintain systemic perfusion. Balloon and or blade atrial septostomy was performed for sustained saturations less than 60% and or atrial septal defect gradients greater than 2.5 m/s. After 1999, percutaneous ductus arteriosus stents (Protege, Sulzer IntraTherapeutics, St. Paul, MN) were placed using unilateral femoral venous access thereby eliminating the need for PGE1 infusion and long-term intravenous access. Ductus stenting was initially performed in older infants (age 5–7 months) and with experience was performed just prior to initial hospital discharge (approximately 6 weeks) to simplify outpatient management. Pulmonary reactivity was routinely assessed at clinic visits by determining the response of systemic oxygen saturation to supplemental O2 challenge. Atrial level shunting was monitored by systemic saturation and serial echocardiographic examinations.
2.3. Mechanical limitation of pulmonary blood flow
As of the year 2000, open bilateral pulmonary artery banding was performed by median sternotomy initially for patients not transplanted within 7 months. With experience the age at banding was progressively lowered to 3.5 months. PTFE bands (2 mm, IMPRA, Inc., Tempe AZ) were placed at the branch pulmonary artery origins and tightened to reduce pulmonary artery pressure to 50% of simultaneously measured systemic arterial pressure. Right pulmonary artery pressures were measured distal to the band directly with a three French catheter. Distal left pulmonary artery pressures were determined with a three French catheter passed into the left pulmonary artery from a purse-string suture on the opposite wall of the pulmonary trunk. Patients were extubated within 1–2 days and discharged home to continue waiting (Fig. 1 ). More recently, bilateral intravascular branch pulmonary artery flow limiting devices were used to achieve ‘internal banding’ (Fig. 2
). These devices were custom manufactured for this purpose and were placed via percutaneous femoral venous approach. The design goal, verified in a preclinical in vivo animal model, was a pressure drop yielding distal mean pulmonary artery pressures of 20 mmHg (unpublished data). Balloon and or blade atrial septostomy was performed to achieve non-restrictive atrial communication after open pulmonary artery banding or concurrently with placement of internal flow limiting devices.
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2.6. Definitions and statistical analysis
Surgical mortality was defined as death occurring within 30 days of transplant. Waiting list mortality was defined as death in listed or de-listed patients not undergoing heart transplantation. Total graft ischemia time was measured from donor aortic clamping to graft reperfusion. Warm graft ischemia time was measured from removal from cold storage to graft reperfusion. Categorical variables considered were surgical mortality, ECMO, and open chest management. Continuous variables considered were age at transplant, weight at transplant, total graft ischemia time, warm graft ischemia time, cardiopulmonary bypass time, circulatory arrest time, duration of mechanical ventilation, hours on nitric oxide, hours of inotropic support, ICU stay, and hospital stay. Fisher's exact test was used to compare categorical variables. Non-parametric Wilcoxon Rank-Sum test was used to compare continuous variables. Statistical analysis was performed with S Plus version 4.5 (Mathsoft, Inc. Seattle, WA).
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3. Results |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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120 days. Waiting list mortality occurred in one HLHS patient in this age range who crossed over to stage I surgical palliation at age 185 days and died post-operatively. These 16 patients were all listed for transplantation after June 1995. Nine patients undergoing transplantation had unrestricted pulmonary blood flow for 120 days or longer prior to transplant (control group). Eight control patients underwent standard pretransplant HLHS management with intravenous PGE1 infusion, and one control patient underwent prior ductus arteriosus stenting without a pulmonary blood flow limiting procedure. Six patients underwent ductus arteriosus stent placement followed by mechanical limitation of pulmonary blood flow prior to transplant (PAB group). Four PAB patients underwent open bilateral pulmonary artery banding, and two PAB patients underwent percutaneous placement of bilateral internal pulmonary artery flow limiting devices. Four other patients with HLHS underwent pulmonary blood flow limiting procedures (two open, two percutaneous) but were not included in the PAB group: two of these patients were transplanted at ages less than 120 days (n=2), one remained listed and was less than 120 days old at the study endpoint, and one patient with HLHS, cor triatriatum and total right lung aplasia underwent open left pulmonary artery band placement at 2 weeks of age but died 5 weeks later while remaining listed. There were no other mortalities in banded HLHS patients awaiting transplant. No complications occurred following ductus arteriosus stenting or pulmonary flow limiting procedures in the PAB group. The PAB group mean hospital stay following banding (open and percutaneous) was 3.3±3.4 days. The mean interval from PDA stent to band placement was 76±52 days (range 5–131 days). The mean interval from PDA stent to transplant was 112±52 days (range 20–179 days). The mean banding to transplant interval was 35±31 days and ranged from 1.5 to 64 days in patients undergoing open pulmonary artery bands while the intervals from percutaneous bilateral internal pulmonary artery flow limiting device implantation to transplant for the two patients who underwent this procedure were 6 days and 68 days.
The general medical states of the control and PAB groups immediately preceding transplantation were similar. Two of nine control patients were inpatients compared to one of six PAB patients. Both control patients managed as inpatients were transplanted prior to the development of our outpatient HLHS management protocol. The PAB patient who was an inpatient was transplanted 36 h following band placement. Baseline room air oxygen saturations immediately preceding transplantation ranged from 58 to 70% in the control group and 58–75% in the PAB group. Atrial septostomies were required in three of nine controls, and were performed so as to achieve mild restriction at the ASD. All PAB patients underwent atrial septostomies to achieve non-restrictive defects shortly after or concurrently with pulmonary blood flow limiting procedures. All controls had mildly or moderately restrictive atrial septal defects (range 1.6–3.0 m/s) assessed at the most recent echocardiogram prior to transplant. Medication requirements were similar except for PGE1 usage in 8/9 control patients. ACE inhibitors were perscribed in 4/9 controls vs. 3/6 PAB patients, and chronic diuretics were used in 5/9 controls vs. 3/6 PAB patients.
Table 1 summarizes the management and outcomes of all patients who underwent transplantation. No differences in age at transplant and weight at transplant were detected between groups. Table 2 lists intra-operative comparisons between the control and PAB groups. There were eight males and one female in the control group, and five males and one female in the PAB group. Blood types in the control group were O in six patients and A in three patients. All PAB patients were blood type O. At transplantation, no patient in the PAB group required branch pulmonary artery reconstruction. Aortic reconstruction in the PAB group differed from the control group only by the need for ductus arteriosus stent extraction.
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There were no late deaths in either group. The control group mean follow-up was 50.2 months. The PAB group mean follow-up was 11.5 months. Follow-up echocardiograms demonstrated widely patent aortic arches and branch pulmonary arteries in all patients. No patient in either group has required intervention for aortic arch obstruction or branch pulmonary artery stenosis.
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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In recent years infants with HLHS requiring extended waiting times have become more common in our center. HLHS patients who have endured prolonged pulmonary overcirculation have presented particularly challenging transplant management problems. Our initial experience with percutaneous stenting of the ductus arteriosus and mechanical limitation of pulmonary blood flow in older HLHS infants demonstrates that transplant management is greatly simplified (Table 3). The transplant courses of our PAB patients mirrored the more smooth courses of patients with other diagnoses in which pulmonary hypertension is not a factor. This is remarkable considering that four PAB patients were older than 5 months at transplantation, and no other HLHS patients living beyond 5 months of age have survived at our center. Secondly, other experienced pediatric transplant centers have not reported successful transplantation for unpalliated HLHS patients beyond 6 months of age [3,10–14]. In contrast, three of our PAB patients were older than 6 months at transplantation. Our results indicate that this strategy extends the safe waiting time during which transplantation remains a viable option for patients with HLHS.
The primary limitation of this study is the small number of patients in each group. This factor limited the statistical power for detecting outcome differences, and it is not surprising that differences in mortality and ECMO requirements were not demonstrable. However, collective consideration of mortality, ECMO utilization, differences in open chest management, and the dramatically abbreviated postoperative courses of the PAB group suggest that prior mechanical limitation of pulmonary blood flow had a highly favorable impact on the safety of transplantation in older infants with HLHS. Conversely, small group sizes precluded demonstration of a statistical difference in age at transplant between the PAB group and control group. However, it is clinically relevant to note that three PAB patients were more than 200 days of age at transplant while the oldest control patient was 163 days old at transplant, and this patient died postoperatively. The second limitation of this study is the use of a non-concurrent control group. Several centers including ours have previously demonstrated that a learning curve is required to achieve excellent results with heart transplantation in young infants [8,10,12,23]. Because no patient in the current study underwent transplantation before 1995, all patients were treated after we had developed significant expertise in infant heart transplantation [8]. Therefore, the improved results in PAB patients are not likely due to an era effect. Thirdly, there were no changes in graft preservation methods, and the only change in perfusion technique was the tendency for reduced circulatory arrest time in more recent patients. Although the difference in circulatory arrest time in the PAB group approached significance (Table 2), circulatory arrest was also limited to arch reconstruction alone in four of the nine control patients, and graft total and warm ischemia times were similar. Consequently, perfusion changes do not reasonably account for the improvements observed in the PAB group. A fourth limitation is that eight of nine control patients required PGE1 infusions immediately prior to transplantation, and this was not necessary in the PAB patients. A deleterious effect of prolonged PGE1exposure cannot be excluded. Lastly, the medical management of posttransplant pulmonary hypertension was well established in our unit before the onset of the accrual period, and no changes in the perioperative management of pulmonary hypertension were made during the study.
Initial attempts to palliate neonates with HLHS with ductus arteriosus stenting and bilateral pulmonary artery banding had poor results [15]. More recently, Akintuerk et al. demonstrated that this strategy allowed temporary palliation and deferral of surgery for 4–6 months at which time aortic arch reconstruction and bi-directional cavopulmonary shunt were successfully combined in a single operation [17]. These authors also reported that eliminating pulmonary overcirculation allowed delayed heart transplantation in a patient with HLHS. Our series confirms that the suitable waiting period for transplantation in patients with HLHS can be safely extended beyond 7 months of age using a similar strategy.
There are significant differences in our palliative strategy compared to that of Akintuerk et al. Our initial objective was to salvage HLHS infants after prolonged waiting times. It then evolved to allow safe extension of waiting time in older infants and to lower their risk at transplantation. Although ages at catheter intervention were not stated, Akintuerk et al. report implies that stenting and banding were performed early in the neonatal time frame. In contrast, ductus arteriosus stenting was performed outside the neonatal period in our patients. Pulmonary artery banding was delayed for several months when it became apparent that individual patients were likely to experience extended waiting times. The older age at these interventions and shorter interval to subsequent surgery likely had a beneficial impact on management of the pulmonary arteries at transplantation in our patients compared to the difficulties Akintuerk et al. reported at combined stage I/II surgical palliation. Limiting pulmonary blood flow after several months of high flow has allowed good distal pulmonary artery growth. No patient in our series required more than simple branch pulmonary artery dilation at transplant, and no patient developed delayed pulmonary artery stenosis. Furthermore, no patient sustained phrenic nerve injury at transplantation. In contrast, three of nine patients reported by Akintuerk et al. required balloon dilation of either the banded pulmonary arteries or ductus stent while awaiting stage I/II surgical intervention. Combined stage I/II palliation was performed at intervals of 4–6 months, and extensive pericardial patch augmentation of the branch pulmonary arteries was required with one patient suffering phrenic nerve injury. Three of their eight surviving patients required early branch pulmonary artery stents. At the time of their report, no patient had undergone Fontan completion; consequently, the long-term consequences of pulmonary artery stents and extensive pericardial patch augmentation remain unclear. Because the longest interval between band placement and transplantation in our series was 68 days, the maximal interval before branch pulmonary artery problems are likely to occur following our strategy is unknown. Likewise the allowable time before the internal pulmonary artery flow limiting devices used in our patients are likely to complicate pulmonary artery reconstruction is also unknown.
Older clinical studies have demonstrated histologic reversal of pulmonary arteriopathy in patients with severe overcirculation following prolonged periods of pulmonary artery banding [24]. An intriguing observation we have noted is that pulmonary hypertension appears to improve very rapidly after mechanically limiting pulmonary blood flow in HLHS patients who have already endured sustained pulmonary overcirculation. Three of our PAB patients underwent transplantation within 15 days of banding (ages 214, 158 and 114 days at banding). We are unaware of any experimental work involving a model of secondary pulmonary hypertension caused by pulmonary overcirculation that has examined the time course of reversal of pulmonary vascular disease. However, studies in hypoxia-induced models of secondary pulmonary hypertension indicate that biochemical changes occur within days of eliminating hypoxia resulting in rapid normalization of pulmonary vascular structure [18,19]. These experimental studies and our clinical observations suggest that rapid amelioration of pulmonary hypertension may also occur in children with large left to right shunts when the shunt is eliminated or minimized within the time frame of our study. Planned investigations in an animal model of prolonged pulmonary overcirculation may validate our findings and further delineate the chronology and underlying mechanisms mediating changes in pulmonary vascular reactivity that appear to be associated with the acute elimination of excessive pulmonary blood flow.
Based on our experience we recommend that patients with HLHS who are listed for transplantation should undergo ductus arteriosus stent placement at between 4 and 6 weeks of age. Earlier stent placement should be considered earlier if another interventional catheterization procedure (i.e. atrial septostomy) is required. Mechanical limitation of pulmonary blood flow should be considered at 3–4 months. This strategy limits pulmonary artery manipulations to older patients who are more likely to present problems with pulmonary vascular reactivity and minimizes the potential for complicating pulmonary artery reconstruction at the time of transplantation. This strategy could also be used to facilitate delayed combined aortic arch reconstruction and bi-directional cavopulmonary shunt (stage I/II Norwood) without necessitating percutaneous interventions or major surgical intervention in the early neonatal period. Delaying percutaneous palliation (ductus stenting, internal flow limiters, and atrial septostomy) 4–6 weeks and minimizing the interval to combined stage I/II Norwood palliation (i.e. at the age of 3–3.5 months) would eliminate the need for repeat sternotomy and prevent pulmonary artery complications at the time of combined stage I/II surgical palliation. The major potential advantage of this strategy compared to commonly employed variations of stage I Norwood palliation is the elimination of a surgical systemic-pulmonary shunt thereby preventing the early post-operative challenges in managing pulmonary, systemic and coronary perfusion that contribute to mortality.
In conclusion, our results indicate that mechanical limitation of pulmonary blood flow in patients with HLHS who have waited for heart transplantation longer than 4 months improves the ease and safety of subsequent transplant management in these patients. This strategy extends the safe waiting time for older HLHS patients listed for transplantation who have endured prolonged pulmonary overcirculation. Although open pulmonary artery banding requires an additional surgical procedure and necessitates a repeat sternotomy at the time of transplantation, these negative aspects are more than offset by the improved results at transplantation in this age range. The development of a percutaneous method of limiting pulmonary blood flow in patients with HLHS should eliminate the need for open pulmonary artery banding and may favorably impact the management of younger patients with HLHS undergoing transplantation or staged palliation.
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Acknowledgments |
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Footnotes |
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References |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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