- Email: [email protected]
Survival After Norwood Procedure in High-Risk Patients
Journal Pre-proof Survival After Norwood Procedure in High Risk Patients Jena Tanem, MS, APNP, Nancy Rudd, MS, APNP, Jennifer Rauscher, MSN, APNP, Ann Scott, MS, APNP, Michele A. Frommelt, MD, Garick D. Hill, MD PII:
S0003-4975(19)31359-1
DOI:
https://doi.org/10.1016/j.athoracsur.2019.07.070
Reference:
ATS 33007
To appear in:
The Annals of Thoracic Surgery
Received Date: 27 February 2019 Revised Date:
8 July 2019
Accepted Date: 23 July 2019
Please cite this article as: Tanem J, Rudd N, Rauscher J, Scott A, Frommelt MA, Hill GD, Survival After Norwood Procedure in High Risk Patients, The Annals of Thoracic Surgery (2019), doi: https:// doi.org/10.1016/j.athoracsur.2019.07.070. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons
1 High Risk Norwood Survival
Survival After Norwood Procedure in High Risk Patients Running Head: High Risk Norwood Survival
Jena Tanem, MS, APNP1, 2, Nancy Rudd, MS, APNP1, 2, Jennifer Rauscher, MSN, APNP1, 2, Ann Scott, MS, APNP1, 2, Michele A. Frommelt, MD1, 2, Garick D. Hill, MD1, 2
1
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
2
Division of Cardiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
Presentations: Oral presentation American Academy of Pediatrics Conference November 2018, Orlando FL-Jena Tanem MS, APNP
Classifications: Pediatric, CHD, CHD (hypoplastic left heart syndrome, Norwood operation), Cardiac, Neonate
Corresponding Author: Jena Tanem MS, APNP Children’s Hospital of Wisconsin 9000 Wisconsin Ave Milwaukee WI 53226 Email: [email protected]
2 High Risk Norwood Survival Abstract Background: Multiple single ventricle populations are noted to be at increased risk for mortality following the Norwood Procedure. Pre-operative risk factors include low birth weight (LBW), restrictive/intact atrial septum, obstructed pulmonary veins, ventricular dysfunction and atrioventricular valve (AVV) regurgitation. We report outcomes of the Norwood procedure in standard and high risk patients in the recent era.
Methods: All patients born with Hypoplastic Left Heart Syndrome (HLHS) between 2006 and 2016 who underwent a Norwood procedure at our institution were included. Retrospective review of patient data was performed and Kaplan-Meier analysis was used to evaluate survival between groups.
Results: The cohort included 177 patients. Fifty patients were determined high risk preoperatively: LBW (n=18), ventricular dysfunction/AVV regurgitation (n=13), intact or restrictive atrial septum/obstructed anomalous pulmonary venous return (n=14), and multiple factors (n=5). There were 2 (1.6%) deaths prior to Glenn in the standard risk group with a total of 10 (20%) from the high risk groups (p<0.0001). One year survival differed greatly between groups with highest being standard risk at 89% and lowest in the intact septum/obstructed veins group at 54%. There was a significant difference between groups in long term survival (p<0.001).
Conclusions: Outcomes following the Norwood procedure have improved for standard risk patients. Those with pre-operative risk factors account for the majority of early mortality following the Norwood procedure. This high risk status does not resolve after Glenn, as longer term survival continues to diverge from the standard risk group.
3 High Risk Norwood Survival
Abbreviations HLHS- Hypoplastic Left Heart Syndrome SV- Single Ventricle LBW-Low Birth Weight AVV-Atrioventricular Valve DORV-Double Outlet Right Ventricle DILV- Double Intlet Left Ventricle PA- Pulmonary Artery BT- Blalock Taussig
4 High Risk Norwood Survival Hypoplastic Left Heart Syndrome (HLHS) and other single ventricle (SV) variants with aortic arch hypoplasia remain a difficult population to manage throughout their lifespan. The initial surgical palliation, the Norwood Procedure, is typically performed in the first few days to two weeks of life and aims to relieve systemic obstruction and balance circulation using an artificial shunt as a constant and controlled source of pulmonary blood flow (1-2 ). Prior to the first reported successful Norwood procedure in 1980 the diagnosis of HLHS was universally fatal (3). Since that time there have been refinements in surgical technique and enhanced bedside monitoring, and as a result, surgical survival has dramatically improved over time (4). The Society of Thoracic Surgery database, which includes most centers in North America, reported hospital survival after Norwood as 85.7% from 2013-2016 (5). Outpatient interstage (time period between Norwood and Glenn palliation) survival has likewise improved, thanks in large part to the development and widespread utilization of interstage home monitoring programs. Historically mortality was as high as 10-15% during this time period; in the recent era however, the National Pediatric Cardiology Quality Improvement Collaborative reports 94.7% survival to stage 2 palliation for those discharged home during the interstage period (6
Previous studies have identified numerous single ventricle populations at increased risk for mortality. These pre-operative risk factors include those with low birth weight (LBW), restrictive or intact atrial septum, ventricular dysfunction and atrioventricular valve (AVV) regurgitation (7-15 ). It remains unclear whether survival has improved for these high risk patient populations in both the short and longer term. We sought to report outcomes of the Norwood procedure in high risk patients and compare these results to standard risk patients in the recent era.
Patients and Methods Approval of this study was obtained from the hospital’s Institutional Review Board and patient consent was waived for this retrospective study. All patients born with HLHS or single ventricle variants that included aortic hypoplasia between January 2006 and December 2016 who underwent a Norwood
5 High Risk Norwood Survival procedure at Children’s Hospital of Wisconsin were included. Patients with single ventricle variants that did not undergo Norwood were excluded. Two patients lost to follow up were not included; these patients were transferred to their referring institution when deemed ready for Norwood palliation discharge with no further follow up information available. Demographic and operative data were collected. There were 4 high risk groups created based on pre-operative findings of: 1) LBW, defined as birth weight of ≤2500 grams, 2) an intact or restrictive atrial septum, defined as having a mean echo gradient of > 8 mmHg (using echo closest to but before Norwood procedure), or obstructed anomalous pulmonary venous return (septum/veins group), 3) ≥moderate AVV regurgitation and/or ≥ moderate ventricular dysfunction (using echo closest to but before Norwood procedure) (dys/insuff group) and 4) those with multiple of these high risk co-morbidities (multiple group). The primary outcome of interest was transplant-free survival.
Statistical Analysis Groups were compared in univariate analysis using Fisher’s exact test for categorical data and KruskalWallis test for continuous data with Dunn’s test to identify which groups were significantly different. Kaplan-Meier analysis was used to evaluate survival between groups. Statistical analyses were performed using Stata IC 15 (Stata Corp, College Station TX) with p<0.05 considered significant.
Results There were 177 patients included in the cohort. Overall, 99 (56%) were male and 128 (72%) were White/Caucasian, 19 (11%) were Black/African American and 19 (11%) Hispanic. Most patients, 141 (80%), were prenatally diagnosed. Predominant diagnoses were HLHS in 119 (67%), Double outlet right ventricle (DORV) in 19 (10%), and Double inlet left ventricle (DILV) in 15 (8%). Median gestational age at birth was 38.8 weeks (range: 30.3-41) with a median birth weight of 3105 grams (range: 1240-4430). There were a total of 19 patients with genetic diagnoses;9 patients had heterotaxy syndrome, 4 had
6 High Risk Norwood Survival Turner's syndrome and 6 had other genetic diagnoses of unknown significance. Other organ system anomalies requiring treatment or subspecialty follow up were present in 20 patients (11%).
High risk groups There were 50 patients considered high risk preoperatively due to low birth weight (n=18), ventricular dysfunction or AVV regurgitation (n=13), intact or restrictive atrial septum or obstructed anomalous pulmonary venous return (n=14), or multiple factors (n=5). The multiple risk factor group consisted of 1 patient with LBW, restrictive/intact atrial septum and AVV regurgitation, 1 patient with LBW, AVV regurgitation and dysfunction, 1 patient with restrictive/intact atrial septum and dysfunction, 1 patient with obstructed anomalous veins and dysfunction and 1 patient with LBW and AVV regurgitation.
Comparison of pre-operative characteristics between high risk groups and the standard risk group can be seen in Table 1. Prenatal diagnosis for those in the dys/insuff group was significantly less (38%) as opposed to those in the standard risk group (85%). Mean age at Norwood procedure was 8.6 +6.7 days of age for the standard risk group, and significantly higher for those with LBW (17 +28.4 days), dys/insuff (11.7+5.3 days), and multiple group (12.6 +9.4 days). Pre-Norwood catheter or surgical intervention was performed in 20 (11.3%) patients, with the most common intervention being bilateral pulmonary artery (PA) banding (n=11). Other interventions included Aortic valvuloplasty (2), balloon atrial septostomy (1), coarctation repair (1), and multiple simultaneous interventions (5). No true hybrid interventions were performed; the 11 patients with bilateral PA banding were maintained on PGE until the time of their Norwood. There was no significant difference in rates of pre-Norwood intervention between groups.
Operative and post-operative comparisons between groups can be seen in Table 2. Median cardiopulmonary bypass time was 172 (IQR: 148-209) minutes and was significantly higher among the septum/veins group (201 with range of 181-238 minutes) and multiple risk group (245 with range of 191305 minutes). The median duration of days until chest closure was 4 (IQR:2-9) and was significantly
7 High Risk Norwood Survival higher among those with LBW (6.5 days), septum/veins (10.5 days) and multiple risk group (14 days). Duration of post-Norwood mechanical ventilation was 8 days among standard risk patient, longer in all high risk groups. The need for ECMO was 12% in those with standard risk, but significantly higher in the septum/veins group (57%) and in the multiple risk group (60%). Need for re-intervention, defined as any catheter or surgical intervention, was 61% in those with LBW, and 60% in the multiple group, significantly increased from 28% among those with standard risk. The most common re-intervention across all groups was shunt revision.
Median length of stay after Norwood for those discharged was 44 (IQR:28.5-56.5) days. For the standard risk group, 75% of patients were discharged home during the interstage period, whereas patients in the septum/veins or multiple risk groups were significantly less likely to be discharged during the interstage period, with 36% and 20% discharge rate respectively. All patients discharged home received home monitoring as a standard of care. Median age at Glenn by group was: 118 days for standard risk, 139 days for LBW group, 116 days for the dys/insuff group, 99 days for the septum/veins group, and 126 days for the multiple group. Two patients were ineligible for Glenn: one with intact atrial septum and required tracheostomy, and the other had pulmonary vascular disease that precluded Glenn. There were 2 (1.6%) deaths prior to Glenn in the standard risk group with a total of 10 (20%) from the high risk groups (p<0.0001). Of the patients who died, none were discharged home during the interstage period due to identified risk factors. The post Norwood deaths included: 4 from the LBW group, 4 from the septum/veins group, 1 from the dysf/insuff group, and 1 from the multiple group. Post-Glenn there were 6 deaths: 3 patients from the dysf/insuff group, 2 from the septum/veins group and 1 from the multiple group. Outcomes of the high risk groups can be seen in Figure 1. The high risk groups accounted for 83% of deaths prior to Glenn and 15 out of 24 (63%) deaths prior to 1 year of age.
The Kaplan-Meier transplant free survival curves for standard risk and each high risk group can be seen in Figure 2, with 1 and 5 year survival seen in Table 3. Survival at 1 year differed greatly between groups,
8 High Risk Norwood Survival with the highest survival being standard risk at 89%, and lowest among those in the septum/veins group at 54%. All groups saw a decline in survival at 5 years.
Comment This study confirms that outcomes following the Norwood procedure have dramatically improved in recent years. We demonstrate transplant-free survival for standard risk patients of 89% at 1 year and 81% at 5 years. Siffel et al., using a regional congenital defects registry data, previously demonstrated the improved outcomes between early and late eras in patients with HLHS with improvement from 0% survival to 1 year to 48% in the most recent era evaluated (1999-2005) (4). Despite improved survival in recent years, some pre-operative risk factors can significantly affect mortality including LBW, intact or restrictive atrial septum, ventricular dysfunction or AVV insufficiency (7-15 -13). Our study is unique in that we provide longer term outcomes in these groups in the contemporary time period. Additionally, we demonstrate that the groups with pre-operative risk factors account for a large proportion of mortality following the Norwood procedure. Of importance, this mortality risk does not resolve after Glenn, as high risk group survival continues to diverge from the standard risk group at 5 years.
Restrictive/intact atrial septum or obstructed pulmonary venous return is a well-established risk factor for single ventricle palliation (16-18 ). There is immediate risk associated with hypoxia and pulmonary edema after birth, increased risk from interventions required prior to Norwood and longer term risks of pulmonary vascular disease from left atrial hypertension during fetal life. These result in both a short and longer term increase in mortality (17). We demonstrated, as others have previously, (16 ) the more complicated operative and post-operative course of these patients as evidenced by the longer bypass time, period of time to chest closure and duration of mechanical ventilation. The majority of patients in the septum/veins group (57%) required ECMO prior to discharge from Norwood procedure. The majority (64%) of the patients in this group remained inpatient during the interstage period. As found with most patients who remained inpatient prior to Glenn, age at Glenn was earlier than the standard risk group.
9 High Risk Norwood Survival Decision to move forward with Glenn earlier was based on particularly tenuous clinical status and desire to have a more stable source of pulmonary blood flow. Previous studies have demonstrated poor survival in this cohort, reportedly 49% at 6 months of age and 43% at 2 years (17-18), in cohorts from 2001-2006 and 1999-2009 respectively. We confirmed that outcomes in this group remain poor. Our experience with prenatal intervention is limited, however we recognize that prenatal atrial septal intervention may be a means to improve outcome in this high risk group moving forward.
Similarly, LBW has repeatedly demonstrated additional risk for single ventricle patients (8,11,12,15,19,25 ). This increased risk can be attributed to multiple factors including prematurity and its associated co-morbidities, the technical challenges of smaller anatomic structures to repair, and limitations in the shunt sizes available. The smallest available BT shunt is 3.0 mm, which relative to weight is too large for many of these LBW neonates; this is an independent risk factor for mortality after shunt procedures (20-21). Kalfa et al. demonstrated good stage 1 palliation outcomes using primarily right ventricle to pulmonary artery shunts with an early operative mortality of 10.7% in patients weighing 1.32.5kg (22). This is far superior to earlier publications which reported early mortality of 30-45% ( 9,11). Kalfa et al. also advocated a strategy of primary Norwood (<2 weeks of age) rather than additional palliation to allow for growth (22 ). Similarly, Weinstein et al report comparable mortality rates between standard risk and LBW infants. They acknowledge the inherent technologic and physiologic risks, but suggest little benefit in delaying surgery to allow for growth (27). In addition, there is some data that suggests patients who have had bilateral PA bands placed prior to Norwood subsequently require earlier and repeat operative or catheter interventions on the PAs, adding to their overall risks for morbidity and mortality (28). For the aforementioned reasons, we have favored primary Norwood with Sano, reserving PA banding and continuation of prostaglandins for those ≤1.5 kg or with other comorbidities that required delayed Norwood. This group was also the oldest at the time of Glenn, however all high risk groups were older on average than the standard risk group, likely related to a combination of factors including: late diagnoses, organ dysfunction/overall clinical status, or need for additional interventions.
10 High Risk Norwood Survival
Patients with ventricular dysfunction or AVV insufficiency saw a decline in survival compared to those with standard risks. This is consistent with multiple other studies, including the Single Ventricle Reconstruction Trial, that have demonstrated these are indeed risk factors for mortality (14, 19, 23 ). Patients with AVV insufficiency or ventricular dysfunction were significantly less likely to have a prenatal diagnosis and this presentation likely contributed to their insufficiency and dysfunction noted on echo upon arrival to the hospital. While the Glenn operation is meant to offload the volume of the heart and inherently lessen AVV insufficiency, this is often not the result. Many patients have progressive insufficiency which can lead to decline in cardiac function, decreased cardiac output, and potentially endorgan injury which can all increase risk for mortality following Glenn (20). These patients continue to require close monitoring after the Glenn, as recovery of function is not always predictable.
As expected, patients with multiple risk factors had increased risk for mortality in the short term, and over time. Not only were these patients more likely to have increased bypass times, longer duration of intubation and more open chest days, but they were also more likely to require re-intervention (60%) and ECMO (60%). The SVR cohort had a 30 day post-Norwood ECMO rate of 8.9% with an additional eCPR rate of 6.6% ( though it is unclear how many patients overlapped) and a CPR rate of 22% (12). We feel our rate of ECMO, which included eCPR, pre-operative ECMO and ECMO used after 30 days, is therefore only slightly higher and this is likely due to survival of higher risk patients. Our CPR rate is actually lower than the SVR trial and this may be a result of increased or earlier ECMO use. Others have reported similar ECMO rates of 19-21% (29-30). The SVR cohort demonstrated a 75% survival for those who underwent Norwood in this population, but saw a decline to 35% survival at 3 years for those requiring CPR, and 26% survival at 3 years for those requiring ECMO (12). The high mortality rate among patients in this group is likely a combination of their inborn risk factors, as well as the threats associated with numerous surgical interventions and need for mechanical circulatory support.
11 High Risk Norwood Survival This study has limitations in that it was a single center, retrospective study with a limited number of patients. Patients who did not survive to Norwood procedure, whether in utero termination or demise, palliative care or post-natal diagnosis with death prior to presentation, were not included in this sample and therefore the population studied may be subject to bias. Additionally, as a tertiary care facility with a reputation for Norwood care, our sample may have been biased toward more high risk patients.
In conclusion, Norwood outcomes for standard risk patients have improved over the past decade. While outcomes have improved for those with high risk pre-operative characteristics, this group continues to account for a large majority of deaths following the Norwood procedure, and their increased risk persists in the longer term.
12 High Risk Norwood Survival References 1. Tweddell JS, Litwin SB, Thomas JP Jr, Mussatto K. Recent advances in the surgical management of the single ventricle pediatric patient. Pediatric Clin North Am 1999;46:465-80. 2. Alsoufi B. Management of the single ventricle and potentially obstructive system ventricular outflow tract, J Saudi Heart Assoc 2013; 25:191-202. 3. Norwood WI, Kirklin JK, Sanders SP. Hypoplastic left heart syndrome: experience with palliative surgery. Am J Cardiol. 1980; 45: 87-91. 4. Siffel C, Riehle-Colarusso T, Oster ME, Correa A. Survival of Children With Hypoplastic Left Heart Syndrome. Pediatrics. 2015; 136: e864-70. 5. Society of Thoracic Surgeons. Congenital Heart Surgery Database. Available at: https://www.sts.org/sites/default/files/documents/CHSD_ExecutiveSummary_Children_Spring2017.pdf. Accessed 11/20, 2017. 6. Anderson JB, Beekman RH,3rd, Kugler JD, et al. Improvement in Interstage Survival in a National Pediatric Cardiology Learning Network. Circ Cardiovasc Qual Outcomes. 2015; 8: 428-436. 7. Alsoufi B, Manlhiot C, Mahle WT, et al. Low-weight infants are at increased mortality risk after palliative or corrective cardiac surgery. J Thorac Cardiovasc Surg. 2014; 148: 2508-14.e1. 8. Alsoufi B, McCracken C, Ehrlich A, et al. Single ventricle palliation in low weight patients is associated with worse early and midterm outcomes. Ann Thorac Surg. 2015; 99: 668-676. 9. Curzon CL, Milford-Beland S, Li JS, et al. Cardiac surgery in infants with low birth weight is associated with increased mortality: analysis of the Society of Thoracic Surgeons Congenital Heart Database. J Thorac Cardiovasc Surg. 2008; 135: 546-551. 10. Hickey EJ, Nosikova Y, Zhang H, et al. Very low-birth-weight infants with congenital cardiac lesions: is there merit in delaying intervention to permit growth and maturation? J Thorac Cardiovasc Surg. 2012; 143: 126-36, 136.e1.
13 High Risk Norwood Survival 11. Pizarro C, Davis DA, Galantowicz ME, Munro H, Gidding SS. Stage I palliation for hypoplastic left heart syndrome in low birth weight neonates: can we justify it? Eur J Cardiothorac Surg. 2002; 21: 716720. 12. Tabbutt S, Ghanayem N, Ravishankar C, et al. Risk factors for hospital morbidity and mortality after the Norwood procedure: A report from the Pediatric Heart Network Single Ventricle Reconstruction trial. J Thorac Cardiovasc Surg. 2012; 144: 882-895. 13. Tweddell JS, Hoffman GM, Mussatto KA, et al. Improved survival of patients undergoing palliation of hypoplastic left heart syndrome: lessons learned from 115 consecutive patients. Circulation. 2002; 106: I82-9. 14. Ghanayem NS, Allen KR, Tabbutt S, et al. Interstage mortality after the Norwood procedure: Results of the multicenter Single Ventricle Reconstruction trial. J Thorac Cardiovasc Surg. 2012; . 15. Mahle WT, Spray TL, Wernovsky G, Gaynor JW, Clark BJ,3rd. Survival after reconstructive surgery for hypoplastic left heart syndrome: A 15-year experience from a single institution. Circulation. 2000; 102: III136-41. 16. Hehir DA, Dominguez TE, Ballweg JA, et al. Risk factors for interstage death after stage 1 reconstruction of hypoplastic left heart syndrome and variants. J Thorac Cardiovasc Surg. 2008; 136: 949, 99.e1-3. 17. Lowenthal A, Kipps AK, Brook MM, Meadows J, Azakie A, Moon-Grady AJ. Prenatal diagnosis of atrial restriction in hypoplastic left heart syndrome is associated with decreased 2-year survival. Prenat Diagn. 2012; 32: 485-490. 18. Vida VL, Bacha EA, Larrazabal A, et al. Hypoplastic left heart syndrome with intact or highly restrictive atrial septum: surgical experience from a single center. Ann Thorac Surg. 2007; 84: 581-5; discussion 586. 19. Sano S, Huang SC, Kasahara S, Yoshizumi K, Kotani Y, Ishino K. Risk factors for mortality after the Norwood procedure using right ventricle to pulmonary artery shunt. Ann Thorac Surg. 2009; 87: 178-85; discussion 185-6.
14 High Risk Norwood Survival 20. Alsoufi B, Gillespie S, Mori M, Clabby M, Kanter K, Kogon B. Factors affecting death and progression towards next stage following modified Blalock-Taussig shunt in neonates. Eur J Cardiothorac Surg. 2016; 50: 169-177. 21. Sasikumar N, Hermuzi A, Fan CS, et al. Outcomes of Blalock-Taussig shunts in current era: A single center experience. Congenit Heart Dis. 2017; 12: 808-814. 22. Kalfa D, Krishnamurthy G, Levasseur S, et al. Norwood Stage I Palliation in Patients Less Than or Equal to 2.5 kg: Outcomes and Risk Analysis. Ann Thorac Surg. 2015; 100: 167-173. 23. Shamszad P, Gospin TA, Hong BJ, McKenzie ED, Petit CJ. Impact of preoperative risk factors on outcomes after Norwood palliation for hypoplastic left heart syndrome. J Thorac Cardiovasc Surg. 2014; 147: 897-901. 24 Thakur V, Munk N, Mertens L, Nield LE. Does prenatal diagnosis of hypoplastic left heart syndrome make a difference? - A systematic review. Prenat Diagn. 2016; 36: 854-863. 25. Gelehrter, S., Fifer, C.G., Armstrong, A. et al. Outcomes of hypoplastic left heart syndrome in lowbirth-weight patients. Pediatr Cardiol (2011) 32: 1175. https://doi.org/10.1007/s00246-011-0053-2. 26. Ohye, R. Sleeper, L., Mahony, L. et al. Comparison of shunt types in the norwood procedure for single-ventricle lesions. New England Journal of Medicine (2010) 362: 1980-1992. DOI: 10.1056/NEJMoa0912461 27. Weinstein, S, Gaynor, W, Bridges, N, et al. Early survival of infants weighing 2.5 kilograms or less undergoing first-stage reconstruction for hypoplastic left heart syndrome. Cardiovascular Surgery (1999) 100: 167-170. 28. Davies, R, Radtke, W, Klenk, D, Pizzaro, C. Bilateral pulmonary arterial banding results in an increased need for subsequent pulmonary artery interventions. Journal of Thoracic and Cardiovascular Surgery. (2014) 147 (2): 706-712.
15 High Risk Norwood Survival 29. Debrunner, M., Porayette, P., Breinholt III, J.P., Turrentine, M., Cordes, T. Midterm survival of intants requiring postoperative extracorporeal membrane oxygenation after norwood palliation. Pediatr Cardiol. 2013 Mar; 34(3)570-5. 30. Ugaki S, Kasahara S, Kotani Y, et al. Extracorporeal membrane oxygenation following Norwood stage 1 procedures at a single institution. Artif Organs. 2010;34:898–903
16 High Risk Norwood Survival Table 1. Patient Characteristics by Risk Group Standard LBW Dys/Insuff Septum/veins Multiple P value risk (n=18) (n=13) (n=14) (n=5) (n=127) Male, n 76 (60%) 5 (28%) 6 (46%) 8 (57%) 4 (80%) 0.08 Race/ethnicity, n 0.1 White/Caucasian 92 (72%) 12 (67%) 9 (69%) 12 (86%) 3 (60%) Black/African 12 (9%) 5 (28%) 1 (8%) 1 (7%) American 16 (13%) 1 (6%) 1 (8%) 1 (7%) Hispanic 7 (6%) 2 (15%) 2 (40%) Other Prenatal diagnosis, n 108 (85%) 15 (83%) 5 (38%)† 11 (79%) 2 (40%) 0.001 Genetic syndrome, n 14 (11%) 2 (11%) 1 (8%) 2 (14%) 0 (0%) 0.98 Extracardiac anomaly, n 14 (11%) 4 (22%) 1 (8%) 0 (0%) 1 (20%) 0.28 Cardiac diagnosis, n HLHS 88 (69%) 10 (56%) 9 (69%) 10 (71%) 2 (40%) DORV 10 (8%) 1 (5%) 1 (8%) 2 (14%) 3 (60%) DILV 13 (10%) 2 (11%) Tricuspid atresia 8 (6%) 2 (11%) Unbalanced AVSD 6 (5%) 3 (17%) 2 (15%) Other 2 (2%) 1 (8%) 2 (14%) BT shunt 64 (50%) 5 (28%) 7 (54%) 7 (50%) 3 (60%) 0.4 Pre-Norwood intervention, 11 (9%) 3 (17%) 2 (15%) 3 (21%) 1 (20%) 0.2 n Mean Norwood age, days 8.6 (±6.7) 17 11.7 (±5.3)† 6.4 (±3.3) 12.6 0.005 (±SD) (±28.4)† (±9.4)† Mean gestational age, 38.7 35.6 38.7 (±1.4) 38.3 (±1.4) 38.2 0.0001 weeks (±SD) (±1.1) (±2.5)† (±1.7) Pre-Norwood characteristics between groups. P values obtained from Fisher’s exact test or KruskalWallis test. †indicates significant difference (p<0.05) compared to standard risk group. . AVSD atrioventricular septal defect, BT Blalock Taussig, DORV double outlet right ventricle, DILV double inlet left ventricle, HLHS hypoplastic left heart syndrome.
17 High Risk Norwood Survival Table 2. Operative Details by Risk Group Standard LBW (n=18) Dys/Insuff Septum/veins Multiple P risk (n=13) (n=14) (n=5) value (n=127) Bypass time, min 167 (142- 165 (152-224) 193 (165201 (181245 (191-305)† 0.006 (IQR) 201) 210)† 238)† Ventilation, days 8 (5-12) 16 (7-31)† 9 (7-13) 29 (10.527 (18.5-42.5)† 0.0002 (±SD) 35)† Open chest, days 3 (2-7) 6.5 (3-26.5)† 5 (3-7) 10.5 (3.514 (13.5-17)† 0.001 (±SD) 15.5)† Re-intervention, n 36 (28%) 11 (61%)† 1 (8%) 6 (43%) 3 (60%) 0.006 (%) ECMO, n (%) 15 (12%) 5 (28%) 2 (15%) 8 (57%)† 3 (60%)† <0.001 Discharged prior to 95 (75%) 10 (56%) 9 (69%) 5 (36%)† 1 (20%)† 0.003 Glenn, n (%) Survival to Glenn, n 125 (98%) 14 (78%)† 12 (92%) 10 (71%)† 4 (80%) <0.001 (%) Norwood operative and post-operative outcomes by group. P values obtained from Fisher’s exact test or Kruskal-Wallis test with post-hoc Dunn test. †indicates significant difference (p<0.05) compared to standard risk group.
18 High Risk Norwood Survival Table 3. Transplant Free Survival by Risk Group Survival 1 year 5 years Standard risk 89% (82-93) 81% (72-87) LBW
61% (35-79)
52% (26-73)
Dys/Insuff
84% (49-96)
56% (16-83)
Septum/Veins
54% (25-76)
46% (19-70)
Multiple
80% (20-97)
40% (5-75)
Transplant free survival by risk group at 1 and 5 years.
19 High Risk Norwood Survival Figure Legends Figure 1. Outcomes for high risk Norwood patients. Flow chart demonstrating outcomes for high risk patients. *Two patients were ineligible for Glenn: both with intact atrial septum and pulmonary vascular disease that precluded Glenn. †The post Norwood deaths included: 4 from LBW group, 4 from septum/veins group, 1 from dys/insuff group, and 1 from the multiple group. ‡Post-Glenn there were 6 deaths: 3 patients from dys/insuff group, 2 from the septum/veins group and 1 from the multiple group.
Figure 2. Transplant Free Survival by Risk Group. Kaplan-Meier transplant free survival curve with 95% confidence intervals for standard and high risk groups.
S0003-4975(19)31359-1
DOI:
https://doi.org/10.1016/j.athoracsur.2019.07.070
Reference:
ATS 33007
To appear in:
The Annals of Thoracic Surgery
Received Date: 27 February 2019 Revised Date:
8 July 2019
Accepted Date: 23 July 2019
Please cite this article as: Tanem J, Rudd N, Rauscher J, Scott A, Frommelt MA, Hill GD, Survival After Norwood Procedure in High Risk Patients, The Annals of Thoracic Surgery (2019), doi: https:// doi.org/10.1016/j.athoracsur.2019.07.070. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons
1 High Risk Norwood Survival
Survival After Norwood Procedure in High Risk Patients Running Head: High Risk Norwood Survival
Jena Tanem, MS, APNP1, 2, Nancy Rudd, MS, APNP1, 2, Jennifer Rauscher, MSN, APNP1, 2, Ann Scott, MS, APNP1, 2, Michele A. Frommelt, MD1, 2, Garick D. Hill, MD1, 2
1
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
2
Division of Cardiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
Presentations: Oral presentation American Academy of Pediatrics Conference November 2018, Orlando FL-Jena Tanem MS, APNP
Classifications: Pediatric, CHD, CHD (hypoplastic left heart syndrome, Norwood operation), Cardiac, Neonate
Corresponding Author: Jena Tanem MS, APNP Children’s Hospital of Wisconsin 9000 Wisconsin Ave Milwaukee WI 53226 Email: [email protected]
2 High Risk Norwood Survival Abstract Background: Multiple single ventricle populations are noted to be at increased risk for mortality following the Norwood Procedure. Pre-operative risk factors include low birth weight (LBW), restrictive/intact atrial septum, obstructed pulmonary veins, ventricular dysfunction and atrioventricular valve (AVV) regurgitation. We report outcomes of the Norwood procedure in standard and high risk patients in the recent era.
Methods: All patients born with Hypoplastic Left Heart Syndrome (HLHS) between 2006 and 2016 who underwent a Norwood procedure at our institution were included. Retrospective review of patient data was performed and Kaplan-Meier analysis was used to evaluate survival between groups.
Results: The cohort included 177 patients. Fifty patients were determined high risk preoperatively: LBW (n=18), ventricular dysfunction/AVV regurgitation (n=13), intact or restrictive atrial septum/obstructed anomalous pulmonary venous return (n=14), and multiple factors (n=5). There were 2 (1.6%) deaths prior to Glenn in the standard risk group with a total of 10 (20%) from the high risk groups (p<0.0001). One year survival differed greatly between groups with highest being standard risk at 89% and lowest in the intact septum/obstructed veins group at 54%. There was a significant difference between groups in long term survival (p<0.001).
Conclusions: Outcomes following the Norwood procedure have improved for standard risk patients. Those with pre-operative risk factors account for the majority of early mortality following the Norwood procedure. This high risk status does not resolve after Glenn, as longer term survival continues to diverge from the standard risk group.
3 High Risk Norwood Survival
Abbreviations HLHS- Hypoplastic Left Heart Syndrome SV- Single Ventricle LBW-Low Birth Weight AVV-Atrioventricular Valve DORV-Double Outlet Right Ventricle DILV- Double Intlet Left Ventricle PA- Pulmonary Artery BT- Blalock Taussig
4 High Risk Norwood Survival Hypoplastic Left Heart Syndrome (HLHS) and other single ventricle (SV) variants with aortic arch hypoplasia remain a difficult population to manage throughout their lifespan. The initial surgical palliation, the Norwood Procedure, is typically performed in the first few days to two weeks of life and aims to relieve systemic obstruction and balance circulation using an artificial shunt as a constant and controlled source of pulmonary blood flow (1-2 ). Prior to the first reported successful Norwood procedure in 1980 the diagnosis of HLHS was universally fatal (3). Since that time there have been refinements in surgical technique and enhanced bedside monitoring, and as a result, surgical survival has dramatically improved over time (4). The Society of Thoracic Surgery database, which includes most centers in North America, reported hospital survival after Norwood as 85.7% from 2013-2016 (5). Outpatient interstage (time period between Norwood and Glenn palliation) survival has likewise improved, thanks in large part to the development and widespread utilization of interstage home monitoring programs. Historically mortality was as high as 10-15% during this time period; in the recent era however, the National Pediatric Cardiology Quality Improvement Collaborative reports 94.7% survival to stage 2 palliation for those discharged home during the interstage period (6
Previous studies have identified numerous single ventricle populations at increased risk for mortality. These pre-operative risk factors include those with low birth weight (LBW), restrictive or intact atrial septum, ventricular dysfunction and atrioventricular valve (AVV) regurgitation (7-15 ). It remains unclear whether survival has improved for these high risk patient populations in both the short and longer term. We sought to report outcomes of the Norwood procedure in high risk patients and compare these results to standard risk patients in the recent era.
Patients and Methods Approval of this study was obtained from the hospital’s Institutional Review Board and patient consent was waived for this retrospective study. All patients born with HLHS or single ventricle variants that included aortic hypoplasia between January 2006 and December 2016 who underwent a Norwood
5 High Risk Norwood Survival procedure at Children’s Hospital of Wisconsin were included. Patients with single ventricle variants that did not undergo Norwood were excluded. Two patients lost to follow up were not included; these patients were transferred to their referring institution when deemed ready for Norwood palliation discharge with no further follow up information available. Demographic and operative data were collected. There were 4 high risk groups created based on pre-operative findings of: 1) LBW, defined as birth weight of ≤2500 grams, 2) an intact or restrictive atrial septum, defined as having a mean echo gradient of > 8 mmHg (using echo closest to but before Norwood procedure), or obstructed anomalous pulmonary venous return (septum/veins group), 3) ≥moderate AVV regurgitation and/or ≥ moderate ventricular dysfunction (using echo closest to but before Norwood procedure) (dys/insuff group) and 4) those with multiple of these high risk co-morbidities (multiple group). The primary outcome of interest was transplant-free survival.
Statistical Analysis Groups were compared in univariate analysis using Fisher’s exact test for categorical data and KruskalWallis test for continuous data with Dunn’s test to identify which groups were significantly different. Kaplan-Meier analysis was used to evaluate survival between groups. Statistical analyses were performed using Stata IC 15 (Stata Corp, College Station TX) with p<0.05 considered significant.
Results There were 177 patients included in the cohort. Overall, 99 (56%) were male and 128 (72%) were White/Caucasian, 19 (11%) were Black/African American and 19 (11%) Hispanic. Most patients, 141 (80%), were prenatally diagnosed. Predominant diagnoses were HLHS in 119 (67%), Double outlet right ventricle (DORV) in 19 (10%), and Double inlet left ventricle (DILV) in 15 (8%). Median gestational age at birth was 38.8 weeks (range: 30.3-41) with a median birth weight of 3105 grams (range: 1240-4430). There were a total of 19 patients with genetic diagnoses;9 patients had heterotaxy syndrome, 4 had
6 High Risk Norwood Survival Turner's syndrome and 6 had other genetic diagnoses of unknown significance. Other organ system anomalies requiring treatment or subspecialty follow up were present in 20 patients (11%).
High risk groups There were 50 patients considered high risk preoperatively due to low birth weight (n=18), ventricular dysfunction or AVV regurgitation (n=13), intact or restrictive atrial septum or obstructed anomalous pulmonary venous return (n=14), or multiple factors (n=5). The multiple risk factor group consisted of 1 patient with LBW, restrictive/intact atrial septum and AVV regurgitation, 1 patient with LBW, AVV regurgitation and dysfunction, 1 patient with restrictive/intact atrial septum and dysfunction, 1 patient with obstructed anomalous veins and dysfunction and 1 patient with LBW and AVV regurgitation.
Comparison of pre-operative characteristics between high risk groups and the standard risk group can be seen in Table 1. Prenatal diagnosis for those in the dys/insuff group was significantly less (38%) as opposed to those in the standard risk group (85%). Mean age at Norwood procedure was 8.6 +6.7 days of age for the standard risk group, and significantly higher for those with LBW (17 +28.4 days), dys/insuff (11.7+5.3 days), and multiple group (12.6 +9.4 days). Pre-Norwood catheter or surgical intervention was performed in 20 (11.3%) patients, with the most common intervention being bilateral pulmonary artery (PA) banding (n=11). Other interventions included Aortic valvuloplasty (2), balloon atrial septostomy (1), coarctation repair (1), and multiple simultaneous interventions (5). No true hybrid interventions were performed; the 11 patients with bilateral PA banding were maintained on PGE until the time of their Norwood. There was no significant difference in rates of pre-Norwood intervention between groups.
Operative and post-operative comparisons between groups can be seen in Table 2. Median cardiopulmonary bypass time was 172 (IQR: 148-209) minutes and was significantly higher among the septum/veins group (201 with range of 181-238 minutes) and multiple risk group (245 with range of 191305 minutes). The median duration of days until chest closure was 4 (IQR:2-9) and was significantly
7 High Risk Norwood Survival higher among those with LBW (6.5 days), septum/veins (10.5 days) and multiple risk group (14 days). Duration of post-Norwood mechanical ventilation was 8 days among standard risk patient, longer in all high risk groups. The need for ECMO was 12% in those with standard risk, but significantly higher in the septum/veins group (57%) and in the multiple risk group (60%). Need for re-intervention, defined as any catheter or surgical intervention, was 61% in those with LBW, and 60% in the multiple group, significantly increased from 28% among those with standard risk. The most common re-intervention across all groups was shunt revision.
Median length of stay after Norwood for those discharged was 44 (IQR:28.5-56.5) days. For the standard risk group, 75% of patients were discharged home during the interstage period, whereas patients in the septum/veins or multiple risk groups were significantly less likely to be discharged during the interstage period, with 36% and 20% discharge rate respectively. All patients discharged home received home monitoring as a standard of care. Median age at Glenn by group was: 118 days for standard risk, 139 days for LBW group, 116 days for the dys/insuff group, 99 days for the septum/veins group, and 126 days for the multiple group. Two patients were ineligible for Glenn: one with intact atrial septum and required tracheostomy, and the other had pulmonary vascular disease that precluded Glenn. There were 2 (1.6%) deaths prior to Glenn in the standard risk group with a total of 10 (20%) from the high risk groups (p<0.0001). Of the patients who died, none were discharged home during the interstage period due to identified risk factors. The post Norwood deaths included: 4 from the LBW group, 4 from the septum/veins group, 1 from the dysf/insuff group, and 1 from the multiple group. Post-Glenn there were 6 deaths: 3 patients from the dysf/insuff group, 2 from the septum/veins group and 1 from the multiple group. Outcomes of the high risk groups can be seen in Figure 1. The high risk groups accounted for 83% of deaths prior to Glenn and 15 out of 24 (63%) deaths prior to 1 year of age.
The Kaplan-Meier transplant free survival curves for standard risk and each high risk group can be seen in Figure 2, with 1 and 5 year survival seen in Table 3. Survival at 1 year differed greatly between groups,
8 High Risk Norwood Survival with the highest survival being standard risk at 89%, and lowest among those in the septum/veins group at 54%. All groups saw a decline in survival at 5 years.
Comment This study confirms that outcomes following the Norwood procedure have dramatically improved in recent years. We demonstrate transplant-free survival for standard risk patients of 89% at 1 year and 81% at 5 years. Siffel et al., using a regional congenital defects registry data, previously demonstrated the improved outcomes between early and late eras in patients with HLHS with improvement from 0% survival to 1 year to 48% in the most recent era evaluated (1999-2005) (4). Despite improved survival in recent years, some pre-operative risk factors can significantly affect mortality including LBW, intact or restrictive atrial septum, ventricular dysfunction or AVV insufficiency (7-15 -13). Our study is unique in that we provide longer term outcomes in these groups in the contemporary time period. Additionally, we demonstrate that the groups with pre-operative risk factors account for a large proportion of mortality following the Norwood procedure. Of importance, this mortality risk does not resolve after Glenn, as high risk group survival continues to diverge from the standard risk group at 5 years.
Restrictive/intact atrial septum or obstructed pulmonary venous return is a well-established risk factor for single ventricle palliation (16-18 ). There is immediate risk associated with hypoxia and pulmonary edema after birth, increased risk from interventions required prior to Norwood and longer term risks of pulmonary vascular disease from left atrial hypertension during fetal life. These result in both a short and longer term increase in mortality (17). We demonstrated, as others have previously, (16 ) the more complicated operative and post-operative course of these patients as evidenced by the longer bypass time, period of time to chest closure and duration of mechanical ventilation. The majority of patients in the septum/veins group (57%) required ECMO prior to discharge from Norwood procedure. The majority (64%) of the patients in this group remained inpatient during the interstage period. As found with most patients who remained inpatient prior to Glenn, age at Glenn was earlier than the standard risk group.
9 High Risk Norwood Survival Decision to move forward with Glenn earlier was based on particularly tenuous clinical status and desire to have a more stable source of pulmonary blood flow. Previous studies have demonstrated poor survival in this cohort, reportedly 49% at 6 months of age and 43% at 2 years (17-18), in cohorts from 2001-2006 and 1999-2009 respectively. We confirmed that outcomes in this group remain poor. Our experience with prenatal intervention is limited, however we recognize that prenatal atrial septal intervention may be a means to improve outcome in this high risk group moving forward.
Similarly, LBW has repeatedly demonstrated additional risk for single ventricle patients (8,11,12,15,19,25 ). This increased risk can be attributed to multiple factors including prematurity and its associated co-morbidities, the technical challenges of smaller anatomic structures to repair, and limitations in the shunt sizes available. The smallest available BT shunt is 3.0 mm, which relative to weight is too large for many of these LBW neonates; this is an independent risk factor for mortality after shunt procedures (20-21). Kalfa et al. demonstrated good stage 1 palliation outcomes using primarily right ventricle to pulmonary artery shunts with an early operative mortality of 10.7% in patients weighing 1.32.5kg (22). This is far superior to earlier publications which reported early mortality of 30-45% ( 9,11). Kalfa et al. also advocated a strategy of primary Norwood (<2 weeks of age) rather than additional palliation to allow for growth (22 ). Similarly, Weinstein et al report comparable mortality rates between standard risk and LBW infants. They acknowledge the inherent technologic and physiologic risks, but suggest little benefit in delaying surgery to allow for growth (27). In addition, there is some data that suggests patients who have had bilateral PA bands placed prior to Norwood subsequently require earlier and repeat operative or catheter interventions on the PAs, adding to their overall risks for morbidity and mortality (28). For the aforementioned reasons, we have favored primary Norwood with Sano, reserving PA banding and continuation of prostaglandins for those ≤1.5 kg or with other comorbidities that required delayed Norwood. This group was also the oldest at the time of Glenn, however all high risk groups were older on average than the standard risk group, likely related to a combination of factors including: late diagnoses, organ dysfunction/overall clinical status, or need for additional interventions.
10 High Risk Norwood Survival
Patients with ventricular dysfunction or AVV insufficiency saw a decline in survival compared to those with standard risks. This is consistent with multiple other studies, including the Single Ventricle Reconstruction Trial, that have demonstrated these are indeed risk factors for mortality (14, 19, 23 ). Patients with AVV insufficiency or ventricular dysfunction were significantly less likely to have a prenatal diagnosis and this presentation likely contributed to their insufficiency and dysfunction noted on echo upon arrival to the hospital. While the Glenn operation is meant to offload the volume of the heart and inherently lessen AVV insufficiency, this is often not the result. Many patients have progressive insufficiency which can lead to decline in cardiac function, decreased cardiac output, and potentially endorgan injury which can all increase risk for mortality following Glenn (20). These patients continue to require close monitoring after the Glenn, as recovery of function is not always predictable.
As expected, patients with multiple risk factors had increased risk for mortality in the short term, and over time. Not only were these patients more likely to have increased bypass times, longer duration of intubation and more open chest days, but they were also more likely to require re-intervention (60%) and ECMO (60%). The SVR cohort had a 30 day post-Norwood ECMO rate of 8.9% with an additional eCPR rate of 6.6% ( though it is unclear how many patients overlapped) and a CPR rate of 22% (12). We feel our rate of ECMO, which included eCPR, pre-operative ECMO and ECMO used after 30 days, is therefore only slightly higher and this is likely due to survival of higher risk patients. Our CPR rate is actually lower than the SVR trial and this may be a result of increased or earlier ECMO use. Others have reported similar ECMO rates of 19-21% (29-30). The SVR cohort demonstrated a 75% survival for those who underwent Norwood in this population, but saw a decline to 35% survival at 3 years for those requiring CPR, and 26% survival at 3 years for those requiring ECMO (12). The high mortality rate among patients in this group is likely a combination of their inborn risk factors, as well as the threats associated with numerous surgical interventions and need for mechanical circulatory support.
11 High Risk Norwood Survival This study has limitations in that it was a single center, retrospective study with a limited number of patients. Patients who did not survive to Norwood procedure, whether in utero termination or demise, palliative care or post-natal diagnosis with death prior to presentation, were not included in this sample and therefore the population studied may be subject to bias. Additionally, as a tertiary care facility with a reputation for Norwood care, our sample may have been biased toward more high risk patients.
In conclusion, Norwood outcomes for standard risk patients have improved over the past decade. While outcomes have improved for those with high risk pre-operative characteristics, this group continues to account for a large majority of deaths following the Norwood procedure, and their increased risk persists in the longer term.
12 High Risk Norwood Survival References 1. Tweddell JS, Litwin SB, Thomas JP Jr, Mussatto K. Recent advances in the surgical management of the single ventricle pediatric patient. Pediatric Clin North Am 1999;46:465-80. 2. Alsoufi B. Management of the single ventricle and potentially obstructive system ventricular outflow tract, J Saudi Heart Assoc 2013; 25:191-202. 3. Norwood WI, Kirklin JK, Sanders SP. Hypoplastic left heart syndrome: experience with palliative surgery. Am J Cardiol. 1980; 45: 87-91. 4. Siffel C, Riehle-Colarusso T, Oster ME, Correa A. Survival of Children With Hypoplastic Left Heart Syndrome. Pediatrics. 2015; 136: e864-70. 5. Society of Thoracic Surgeons. Congenital Heart Surgery Database. Available at: https://www.sts.org/sites/default/files/documents/CHSD_ExecutiveSummary_Children_Spring2017.pdf. Accessed 11/20, 2017. 6. Anderson JB, Beekman RH,3rd, Kugler JD, et al. Improvement in Interstage Survival in a National Pediatric Cardiology Learning Network. Circ Cardiovasc Qual Outcomes. 2015; 8: 428-436. 7. Alsoufi B, Manlhiot C, Mahle WT, et al. Low-weight infants are at increased mortality risk after palliative or corrective cardiac surgery. J Thorac Cardiovasc Surg. 2014; 148: 2508-14.e1. 8. Alsoufi B, McCracken C, Ehrlich A, et al. Single ventricle palliation in low weight patients is associated with worse early and midterm outcomes. Ann Thorac Surg. 2015; 99: 668-676. 9. Curzon CL, Milford-Beland S, Li JS, et al. Cardiac surgery in infants with low birth weight is associated with increased mortality: analysis of the Society of Thoracic Surgeons Congenital Heart Database. J Thorac Cardiovasc Surg. 2008; 135: 546-551. 10. Hickey EJ, Nosikova Y, Zhang H, et al. Very low-birth-weight infants with congenital cardiac lesions: is there merit in delaying intervention to permit growth and maturation? J Thorac Cardiovasc Surg. 2012; 143: 126-36, 136.e1.
13 High Risk Norwood Survival 11. Pizarro C, Davis DA, Galantowicz ME, Munro H, Gidding SS. Stage I palliation for hypoplastic left heart syndrome in low birth weight neonates: can we justify it? Eur J Cardiothorac Surg. 2002; 21: 716720. 12. Tabbutt S, Ghanayem N, Ravishankar C, et al. Risk factors for hospital morbidity and mortality after the Norwood procedure: A report from the Pediatric Heart Network Single Ventricle Reconstruction trial. J Thorac Cardiovasc Surg. 2012; 144: 882-895. 13. Tweddell JS, Hoffman GM, Mussatto KA, et al. Improved survival of patients undergoing palliation of hypoplastic left heart syndrome: lessons learned from 115 consecutive patients. Circulation. 2002; 106: I82-9. 14. Ghanayem NS, Allen KR, Tabbutt S, et al. Interstage mortality after the Norwood procedure: Results of the multicenter Single Ventricle Reconstruction trial. J Thorac Cardiovasc Surg. 2012; . 15. Mahle WT, Spray TL, Wernovsky G, Gaynor JW, Clark BJ,3rd. Survival after reconstructive surgery for hypoplastic left heart syndrome: A 15-year experience from a single institution. Circulation. 2000; 102: III136-41. 16. Hehir DA, Dominguez TE, Ballweg JA, et al. Risk factors for interstage death after stage 1 reconstruction of hypoplastic left heart syndrome and variants. J Thorac Cardiovasc Surg. 2008; 136: 949, 99.e1-3. 17. Lowenthal A, Kipps AK, Brook MM, Meadows J, Azakie A, Moon-Grady AJ. Prenatal diagnosis of atrial restriction in hypoplastic left heart syndrome is associated with decreased 2-year survival. Prenat Diagn. 2012; 32: 485-490. 18. Vida VL, Bacha EA, Larrazabal A, et al. Hypoplastic left heart syndrome with intact or highly restrictive atrial septum: surgical experience from a single center. Ann Thorac Surg. 2007; 84: 581-5; discussion 586. 19. Sano S, Huang SC, Kasahara S, Yoshizumi K, Kotani Y, Ishino K. Risk factors for mortality after the Norwood procedure using right ventricle to pulmonary artery shunt. Ann Thorac Surg. 2009; 87: 178-85; discussion 185-6.
14 High Risk Norwood Survival 20. Alsoufi B, Gillespie S, Mori M, Clabby M, Kanter K, Kogon B. Factors affecting death and progression towards next stage following modified Blalock-Taussig shunt in neonates. Eur J Cardiothorac Surg. 2016; 50: 169-177. 21. Sasikumar N, Hermuzi A, Fan CS, et al. Outcomes of Blalock-Taussig shunts in current era: A single center experience. Congenit Heart Dis. 2017; 12: 808-814. 22. Kalfa D, Krishnamurthy G, Levasseur S, et al. Norwood Stage I Palliation in Patients Less Than or Equal to 2.5 kg: Outcomes and Risk Analysis. Ann Thorac Surg. 2015; 100: 167-173. 23. Shamszad P, Gospin TA, Hong BJ, McKenzie ED, Petit CJ. Impact of preoperative risk factors on outcomes after Norwood palliation for hypoplastic left heart syndrome. J Thorac Cardiovasc Surg. 2014; 147: 897-901. 24 Thakur V, Munk N, Mertens L, Nield LE. Does prenatal diagnosis of hypoplastic left heart syndrome make a difference? - A systematic review. Prenat Diagn. 2016; 36: 854-863. 25. Gelehrter, S., Fifer, C.G., Armstrong, A. et al. Outcomes of hypoplastic left heart syndrome in lowbirth-weight patients. Pediatr Cardiol (2011) 32: 1175. https://doi.org/10.1007/s00246-011-0053-2. 26. Ohye, R. Sleeper, L., Mahony, L. et al. Comparison of shunt types in the norwood procedure for single-ventricle lesions. New England Journal of Medicine (2010) 362: 1980-1992. DOI: 10.1056/NEJMoa0912461 27. Weinstein, S, Gaynor, W, Bridges, N, et al. Early survival of infants weighing 2.5 kilograms or less undergoing first-stage reconstruction for hypoplastic left heart syndrome. Cardiovascular Surgery (1999) 100: 167-170. 28. Davies, R, Radtke, W, Klenk, D, Pizzaro, C. Bilateral pulmonary arterial banding results in an increased need for subsequent pulmonary artery interventions. Journal of Thoracic and Cardiovascular Surgery. (2014) 147 (2): 706-712.
15 High Risk Norwood Survival 29. Debrunner, M., Porayette, P., Breinholt III, J.P., Turrentine, M., Cordes, T. Midterm survival of intants requiring postoperative extracorporeal membrane oxygenation after norwood palliation. Pediatr Cardiol. 2013 Mar; 34(3)570-5. 30. Ugaki S, Kasahara S, Kotani Y, et al. Extracorporeal membrane oxygenation following Norwood stage 1 procedures at a single institution. Artif Organs. 2010;34:898–903
16 High Risk Norwood Survival Table 1. Patient Characteristics by Risk Group Standard LBW Dys/Insuff Septum/veins Multiple P value risk (n=18) (n=13) (n=14) (n=5) (n=127) Male, n 76 (60%) 5 (28%) 6 (46%) 8 (57%) 4 (80%) 0.08 Race/ethnicity, n 0.1 White/Caucasian 92 (72%) 12 (67%) 9 (69%) 12 (86%) 3 (60%) Black/African 12 (9%) 5 (28%) 1 (8%) 1 (7%) American 16 (13%) 1 (6%) 1 (8%) 1 (7%) Hispanic 7 (6%) 2 (15%) 2 (40%) Other Prenatal diagnosis, n 108 (85%) 15 (83%) 5 (38%)† 11 (79%) 2 (40%) 0.001 Genetic syndrome, n 14 (11%) 2 (11%) 1 (8%) 2 (14%) 0 (0%) 0.98 Extracardiac anomaly, n 14 (11%) 4 (22%) 1 (8%) 0 (0%) 1 (20%) 0.28 Cardiac diagnosis, n HLHS 88 (69%) 10 (56%) 9 (69%) 10 (71%) 2 (40%) DORV 10 (8%) 1 (5%) 1 (8%) 2 (14%) 3 (60%) DILV 13 (10%) 2 (11%) Tricuspid atresia 8 (6%) 2 (11%) Unbalanced AVSD 6 (5%) 3 (17%) 2 (15%) Other 2 (2%) 1 (8%) 2 (14%) BT shunt 64 (50%) 5 (28%) 7 (54%) 7 (50%) 3 (60%) 0.4 Pre-Norwood intervention, 11 (9%) 3 (17%) 2 (15%) 3 (21%) 1 (20%) 0.2 n Mean Norwood age, days 8.6 (±6.7) 17 11.7 (±5.3)† 6.4 (±3.3) 12.6 0.005 (±SD) (±28.4)† (±9.4)† Mean gestational age, 38.7 35.6 38.7 (±1.4) 38.3 (±1.4) 38.2 0.0001 weeks (±SD) (±1.1) (±2.5)† (±1.7) Pre-Norwood characteristics between groups. P values obtained from Fisher’s exact test or KruskalWallis test. †indicates significant difference (p<0.05) compared to standard risk group. . AVSD atrioventricular septal defect, BT Blalock Taussig, DORV double outlet right ventricle, DILV double inlet left ventricle, HLHS hypoplastic left heart syndrome.
17 High Risk Norwood Survival Table 2. Operative Details by Risk Group Standard LBW (n=18) Dys/Insuff Septum/veins Multiple P risk (n=13) (n=14) (n=5) value (n=127) Bypass time, min 167 (142- 165 (152-224) 193 (165201 (181245 (191-305)† 0.006 (IQR) 201) 210)† 238)† Ventilation, days 8 (5-12) 16 (7-31)† 9 (7-13) 29 (10.527 (18.5-42.5)† 0.0002 (±SD) 35)† Open chest, days 3 (2-7) 6.5 (3-26.5)† 5 (3-7) 10.5 (3.514 (13.5-17)† 0.001 (±SD) 15.5)† Re-intervention, n 36 (28%) 11 (61%)† 1 (8%) 6 (43%) 3 (60%) 0.006 (%) ECMO, n (%) 15 (12%) 5 (28%) 2 (15%) 8 (57%)† 3 (60%)† <0.001 Discharged prior to 95 (75%) 10 (56%) 9 (69%) 5 (36%)† 1 (20%)† 0.003 Glenn, n (%) Survival to Glenn, n 125 (98%) 14 (78%)† 12 (92%) 10 (71%)† 4 (80%) <0.001 (%) Norwood operative and post-operative outcomes by group. P values obtained from Fisher’s exact test or Kruskal-Wallis test with post-hoc Dunn test. †indicates significant difference (p<0.05) compared to standard risk group.
18 High Risk Norwood Survival Table 3. Transplant Free Survival by Risk Group Survival 1 year 5 years Standard risk 89% (82-93) 81% (72-87) LBW
61% (35-79)
52% (26-73)
Dys/Insuff
84% (49-96)
56% (16-83)
Septum/Veins
54% (25-76)
46% (19-70)
Multiple
80% (20-97)
40% (5-75)
Transplant free survival by risk group at 1 and 5 years.
19 High Risk Norwood Survival Figure Legends Figure 1. Outcomes for high risk Norwood patients. Flow chart demonstrating outcomes for high risk patients. *Two patients were ineligible for Glenn: both with intact atrial septum and pulmonary vascular disease that precluded Glenn. †The post Norwood deaths included: 4 from LBW group, 4 from septum/veins group, 1 from dys/insuff group, and 1 from the multiple group. ‡Post-Glenn there were 6 deaths: 3 patients from dys/insuff group, 2 from the septum/veins group and 1 from the multiple group.
Figure 2. Transplant Free Survival by Risk Group. Kaplan-Meier transplant free survival curve with 95% confidence intervals for standard and high risk groups.