Comparison of Hybrid and Norwood Strategies in Hypoplastic Left Heart Syndrome

SURGERY | REVIEW

Hideyuki Kato, MD, Osami Honjo, MD, PhD, Glen Van Arsdell, MD, Christopher A. Caldarone, MD Division of Cardiovascular Surgery, Hospital for Sick Children, Labatt Family Heart Center

Received 12/12/2011, Reviewed 27/12/2011, Accepted 1/1/2012 Key words: Hybrid strategy, Norwood strategy, single ventricle, hypoplastic left heart syndrome DOI: 10.5083/ejcm.20424884.70

ABSTRACT CORRESPONDENCE

Current surgical palliation for neonates with single ventricle physiology includes Norwood-based Christopher A. Caldarone, MD, and Hybrid-based surgical strategies. When transplantation is not available, clinicians must choose Professor and Chair, Division of Cardiac Surgery, between these two strategies with distinctly different learning curves and risk profiles. The Norwood University of Toronto, strategy has evolved over several decades while the rising popularity of the Hybrid strategy is a Watson Family Chair in much more recent addition to our therapeutic options. Based upon the premise that avoiding cardio Cardiovascular Science – pulmonary bypass in the neonatal period and deferral of aortic arch reconstruction until a second Labatt Family Heart Center, stage procedure have an important influence on outcomes, the Hybrid strategy has compelling Hospital for Sick Children, theoretical advantages and disadvantages in comparison to the Norwood strategy. The purpose 555 University Avenue, of this review is to summarise the currently available data to support – or refute – the theoretical Toronto, Ontario, Canada, advantages of the Hybrid strategy within the context of the Norwood strategy. M5G 1X8 Tel: 416-813-6420 Fax: 416-813-7984 INTRODUCTION Interstage mortality between Stage I and Stage E-mail: christopher.caldarone@ II palliation is also significant (10.5 - 22%) [3, 6] sickkids.ca The Norwood-based strategy for single ventricle and may be influenced by chronic volume load- palliation has improved with technical innova- ing of the systemic ventricle [8], arrhythmias and tions and refinements over the last decades; shunt-related problems. These intrinsic prob- such as regional cerebral perfusion during aortic lems with the Norwood strategy have encour- arch reconstruction [1], placement of a right ven- aged the development of an alternative ‘Hybrid’ tricle-to-pulmonary artery (RV-PA) shunt rather strategy. than a systemic-to-pulmonary shunt [2, 3], and the concept of aggressive afterload reduction to The hybrid palliative strategy has evolved rap- maximise oxygen delivery following Norwood idly in the last decade [9, 10] and is based on the procedure [4, 5]. placement of bilateral pulmonary artery (PA) bands, stenting of the ductus arteriosus, and However, Norwood-based palliation continues atrial septostomy as Stage I palliation during the to have significant early and interstage mortal- neonatal period, followed by arch reconstruc- ity in the current era with the majority of deaths tion and bidirectional cavopulmonary shunt occurring in the peri-operative period after the as Stage II palliation at the age of four to six Norwood procedure [3, 6, 7]. After Stage I Nor- months. Stage I hybrid procedures avoid CPB, wood procedures, the presence of a systemic- cardioplegic arrest, and CPB-associated postop- to-pulmonary shunt contributes to the intrinsic erative systemic inflammatory response. instability of an ‘in-parallel’ circulation in which blood flow distribution may be altered sig- Furthermore, by deferring aortic arch recon- nificantly with perturbations in the ratio of sys- struction, the hybrid strategy avoids surgical temic to pulmonary vascular resistance and this alterations in cerebral blood flow (DHCA and/ vulnerability is compounded in the early post- or regional cerebral perfusion) in the neonatal operative period with post-cardioplegia related period when the brain may be more susceptible depression of cardiac output. Cardiopulmonary to neurologic injury [11]. Potential disadvan- bypass (CPB) and deep hypothermic circulation tages of hybrid palliation include obstruction of arrest (DHCA) contribute to a subsequent sys- the aortic isthmus by stent deployment, subse- temic inflammatory response which also has a quent coronary and cerebral malperfusion, and negative impact on the Norwood physiology in mechanical distortion of the branch pulmonary the early postoperative period. arteries. ISSN 2042-4884

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Several institutions have reported a significant learning curve with The ratio of pulmonary to systemic blood flow (Qp/Qs) after Stage the hybrid strategy [9, 12, 13] and we have recently reported measur- I Norwood palliation was between 0.3 and 3.3 (mean 1.2±0.5) and, able trends toward improvement in outcomes, suggesting that in- despite bilateral pulmonary artery banding, the Qp/Qs ranged stitutional learning is an important component in the development from 0.4 to 5.7 (mean 1.7±1.0) after Stage I Hybrid palliation[14]. of this strategy. However, in the absence of post-cardioplegia deficits in myocardial performance, this level of overcirculation appears to be well toler- ated in Hybrid patients with normal myocardial reserve. It is impor- COMPARISON BETWEEN HYBRID AND tant to note, however, that this was an uncontrolled comparison NORWOOD STRATEGIES and the administration of vasodilators and inotropes was routinely used for the Norwood patients [15] and uncommonly used for the Early postoperative physiology after Stage I palliation Hybrid patients. The noted differences between the groups may have reflected the management strategy rather than differences in Pulmonary blood flow after Stage I palliation in Norwood and hy- the palliative strategies. brid patients is derived from systemic-to-pulmonary artery shunts with the objective of providing pulmonary blood flow which is suf- These data suggest that systemic afterload reduction such as milri- ficient for pulmonary gas exchange but controlled by the geometry none and phenoxybenzamine may be important in the early post- of the shunts/bands to prevent excessive volume loading of the operative period for post-Stage I Hybrid patients. Based on these heart. In Norwood patients an aorto-pulmonary or a RV-PA shunt findings, we have adopted a low threshold to employ systemic is used, whereas in hybrid patients banding of the proximal branch afterload reduction and inotropic support for neonates following pulmonary arteries is used to control pulmonary blood flow. Hybrid Stage I procedures – especially for those patients known to have diminished preoperative myocardial reserve. We also recog- The postoperative haemodynamics after first stage hybrid pallia- nize the potential for pulmonary overcirculation in patients with tion have not been extensively studied. As the hybrid strategy has diminished myocardial reserve and utilize standard intensive care evolved, avoidance of cardiopulmonary bypass was postulated to unit (ICU) measures to limit pulmonary blood flow in patients with better preserve myocardial function when compared to first stage evidence of inadequate distal oxygen delivery. Norwood palliation. Using respiratory spectrometry, we compared postoperative hemodynamics and oxygen delivery between Stage Survival I hybrid and Norwood patients and noted that the hybrid patients had higher systemic vascular resistance (SVR) during the first post- Several centers initially reported high mortality after Stage I Hybrid [9, 13] operative 48 hours after the Stage I procedure [14]. palliation . After a learning curve, outcomes tended to im- prove and were comparable with Norwood procedure in terms of This change was associated with lower cardiac output, low systemic mortality. Hospital survival after Stage I Hybrid palliation has been [10, 16, 17] blood flow (Qs) and oxygen delivery. Interestingly, despite bilateral reported ranging from 80 to 97% in more recent studies , PA banding, total pulmonary vascular resistance and pulmonary although some studies excluded high-risk patients from the anal- [18] blood flow (Qp) were not different between early postoperative ysis. In our recent hybrid and Norwood experience (Figure 1) , Hybrid and Norwood patients. we performed 47 hybrid procedures between 2004 and December 2010.

Figure 1: Clinical outcomes of patients who underwent Hybrid or Norwood strategy. Tx; cardiac transplantation (Citation from [18] with publisher’s permission)

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These hybrid patients consist of all neonates palliated with the Figure 2: Kaplan-Meier survival analysis comparing Hybrid and hybrid strategy excluding patients treated as a planned bridge to Norwood groups. There was no difference between the groups in 1 cardiac transplantation or critically ill patients who underwent the year survival. (Hybrid 68.5% vs. Norwood 64.3 %, p=0.88). hybrid procedure as a salvage strategy. During the same period, the Norwood procedure was performed in 63 patients.

There was no difference in mortality following Stage I palliation between the groups (Figure 1). Freedom from death or transplant after Stage II was comparable between two groups (Hybrid 88%vs. Norwood 84%, p=0.95) [18]. There was no significant difference in 1 year overall survival between two groups (Hybrid 68.5% vs. Nor- wood 64.3 %, p=0.88, Figure 2).

Hemodynamics and pulmonary artery growth

Comparison of pre-Fontan catheterisation data between Hybrid and Norwood procedures is shown in Table 1[18]. There were no statistically significant differences in ventricular end-diastolic pressure and mixed venous saturation between the two groups. Mean PA pressures are also equivalent between the groups. There was, however, a non-significant trend toward larger Nakata index in the Norwood group compared with the Hybrid group. Both groups had equivalent PA growth and haemodynamics at the pre-Fontan catheterisation. These data suggest that the hybrid procedure leads to comparable candidates for the Fontan procedure.

Table 1: Comparison in pre-Fontan hemodynamics, pulmonary artery growth and ventricular function between Hybrid and Norwood groups.

AVVR = atrioventricular regurgitation; EDP = end diastolic pressure; LL = lower lobe; PA = pulmonary artery AVVR: none/trivial=1, mild=2, moderate=3, severe=4 Ventricular function: normal=1, mild impairment=2, moderate=3, severe=4 (Citation from [18] with publisher’s permission )

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Ventricular function and atrioventricular valve regurgitation Influence upon neurological development

Preservation of ventricular function and prevention of atrioven- Neurological development is a major concern with any treatment tricular valve regurgitation (AVVR) are critical determinants in the strategy for single ventricle palliation. The mean neurocognitive success of a single ventricle palliative strategy. These parameters test results in school-aged children with HLHS who underwent the may be jeopardised at many points in the Norwood single ventricle Norwood procedure or cardiac transplantation are significantly management strategy including: below population normative values [22]. In addition, pre-operative brain magnetic resonance imaging revealed that brains of HLHS 1) myocardial ischemia-reperfusion injury after cardioplegic arrest patients are smaller and less mature before surgery than patients at Norwood Stage I palliation, 2) volume overloading of the system- without congenital heart disease [23]. Thus, the impact on neuro- ic ventricle during the interstage period, and 3) impairment of the logical development is of critical importance for the single ventricle right ventricular function due to ventriculotomy at the site of con- strategies. struction of RV-PA conduits in Norwood patients treated with the Sano modification. On the other hand, the Hybrid procedure has The Hybrid strategy has a potential advantage in terms of preserva- potential for diminished myocardial function due to potential for tion of neurologic function in comparison to the Norwood strategy. restriction in coronary perfusion due to obstruction of retrograde By delaying aortic arch reconstruction until the second stage proce- aortic arch flow through the aortic isthmus after ductal stenting. dure at four-six months of age for Hybrid patients, there is indirect evidence suggesting that the delay may have a favorable impact on The influence of the obstruction of retrograde the neurological development. Galli et al reported that the devel- aortic arch on the Hybrid strategy opment of periventricular leukomalacia (PVL) after cardiac surgery is more prevalent in neonates compared with those at the age of Obstruction of retrograde aortic arch flow in patients with dimin- more than one month [11] suggesting age-related vulnerability to ished prograde aortic flow (e.g. aortic atresia) can be associated neurologic injury. PVL in preterm infants is associated with subse- with coronary and cerebral ischemia [19]. Obstruction can occur quent cerebral palsy, mental retardation, and learning disabilities. during the Hybrid Stage I procedure immediately after ductal stent Thus, there is an age-dependent window of vulnerability to brain deployment or the obstruction can develop in the interstage peri- injury [11] and the Hybrid strategy may have an advantage in delay- od due to progressive ingrowth of fibrous tissue as the site of inter- ing aortic arch reconstruction from the neonatal period to four-six section between the ductal stent and the aortic isthmus [13, 19, 20]. months of age. Objective demonstration of this advantage, however, will require a controlled clinical trial. Stoica et al. described a treatment strategy for patients with retrograde aortic arch malperfusion based upon surveillance, detec- In contrast to the age-related potential neurological advantage of tion, and catheter-based treatment including retrograde stenting the Hybrid strategy, there is a potential disadvantage with the Hy- of the aortic isthmus in the subset of patients in whom surveillance brid strategy. As mentioned above, the obstruction of retrograde resulted in detection of the stenosis. The strategy was associated aortic arch flow can limit cerebral blood flow for four to six months with a high incidence of death or transplantation among patients prior to arch reconstruction at the Stage II procedure and long peri- in whom retrograde aortic arch obstruction was treated – suggest- ods of limited cerebral blood flow may be detrimental to neurolog- ing that a treatment strategy may not be the optimal management ic development. If the reverse BT shunt can successfully maintain plan for addressing retrograde aortic arch obstruction [19]. Because arch perfusion, it may neutralise this problem. Further long term of the lack of success with a treatment strategy, the authors favour neurologic evaluation is required to compare the Norwood and Hy- the Norwood strategy for patients who are considered at risk for brid strategies in the context of neurologic function. retrograde aortic arch obstruction. Intubation time, intensive care unit stay and hospital stay As an alternative to a treatment-based strategy, we have developed a preventative strategy to address potential for retrograde aortic Another potential benefit of Hybrid procedure is that Hybrid pa- arch obstruction in Hybrid patients. In this strategy, we utilise the tients have shorter total intubation time, ICU stay, and hospital creation of prophylactic ‘reverse Blalock-Taussig (BT) shunts’ for length of stay (combined Stage I and II among survivors) [17, 24]. patients with restricted antegrade aortic flow and potential retro- Galantowicz et al. reported that 85% of Hybrid patients at both grade aortic arch obstruction [21]. Importantly, we have not needed Stage I and II were extubated in the first 24 hours [16]. Interestingly, to utilise retrograde stenting of the aortic isthmus as a treatment in our experience, we have noted a time-related tendency toward for arch malperfusion in any of the patients with a prophylactic re- improvement in the intubation time, the length of ICU stay, and verse BT shunt. The reverse BT shunt may have helped to neutralise hospital stay at the Hybrid Stage II, while concurrent Norwood pa- the risk of retrograde aortic arch obstruction. Because we have not tients did not have evidence of time-related improvements in these detected a significant survival disadvantage in the high-risk sub- parameters suggesting that we had reached a plateau in terms of set of patients with severely diminished prograde arch flow, we are refinement of the Norwood strategy[17] . continuing to utilise the reverse BT shunt as a prophylactic component of our hybrid management strategy in this high- risk group. Although there is less consumption of conventional measures of resource utilisation including intubation time, ICU stay, and hospital Ventricular function and AVVR were not different in a comparison length of stay in Hybrid strategy, unplanned reinterventions were of the hybrid and Norwood groups at the pre-Fontan evaluation more frequent in the Hybrid patients compared with the Norwood as shown in Table 1 (p-value = 0.7 and 0.27 respectively) [18]. These patients [18] (Hybrid 31.3% vs. Norwood 9.3%, p=0.016, Figure 3). data indicate that the Hybrid strategy has equivalent results with Any comparison of resource utilisation must include quantification Norwood strategy in terms of preservation of ventricular function of planned and unplanned hospital admissions, procedures and and atrioventricular valve function. interventions. Therefore, we are currently undertaking a study to examine total resource utilisation in a comparison of two palliative strategies.

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HEALTHCARE BULLETIN | SURGERY

Figure 3: Freedom from unplanned reintervention after Stage II between Hybrid and Norwood groups at 3 years. Unplanned reintervention rate was higher in Hybrid group compared to Norwood group (31.3% vs. 9.3%, p=0.016). This data does not include unplanned reinterventions prior to Stage II (Citation from [18] with publisher’s permission).

CONCLUSIONS 2. Which strategy produces the better Fontan candidate?

Hybrid palliation is an evolving surgical strategy with comparable The Fontan procedure represents the convergence point for both survival to reported Norwood-based series. The Hybrid strategy management strategies. Parameters for this comparison include provides equivalent pre-Fontan haemodynamics and pulmonary haemodynamics, ventricular function, valvular competence and artery growth, preserves ventricular and atrioventricular valve pulmonary artery growth. function, and reduces resource utilisation. The comparative impact of the two different surgical strategies on neurological outcome is 3. Which strategy is associated with the most efficient use of not defined and should be a subject of prospective trials. resources when quantifying the entire resource burden from birth to Fontan procedure?

FUTURE DIRECTIONS If all other factors are equal, the superior strategy is the one that utilizes the least resources and poses the smallest burden on insti- Important questions to frame comparisons of the Hybrid and Nor- tutions and families. wood strategies include: Based on demonstration of equivalent survival, a prospective 1. Which strategy is associated with better long term randomised trial should be undertaken to compare the Norwood neurodevelopmental outcomes? and Hybrid strategies in the context of these three fundamental questions. There are compelling arguments for and against each strategy. In the past, the timing of arch intervention was immutable – and hypoplastic aortic arches required repair in the neonatal period. With the Hybrid strategy, it is now possible to defer aortic arch reconstruction and test the hypothesis that age is an important mediator of the vulnerability to injury after aortic arch reconstruction.

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