European Journal of Cardio-thoracic Surgery 22 (2002) 82–89 www.elsevier.com/locate/ejcts

Risk factors for mortality after the Norwood procedureq

J. William Gaynora,*, William T. Mahleb, Mitchell I. Cohenb, Richard F. Ittenbachc, William M. DeCamplia, James M. Stevend, Susan C. Nicolsond, Thomas L. Spraya Downloaded from https://academic.oup.com/ejcts/article/22/1/82/516394 by guest on 28 September 2021 aDivision of Cardiothoracic Surgery, The Cardiac Center at The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Suite 8527, Philadelphia, PA 19104, USA bDivision of Cardiology, The Cardiac Center at The Children’s Hospital of Philadelphia, Philadelphia, PA, USA cDivision of Biostatistics and Epidemiology, The Cardiac Center at The Children’s Hospital of Philadelphia, Philadelphia, PA, USA dDivision of Cardiac Anesthesiology, The Cardiac Center at The Children’s Hospital of Philadelphia, Philadelphia, PA, USA Received 18 September 2001; received in revised form 7 March 2002; accepted 22 March 2002

Abstract Objectives: Recent studies have suggested that survival following the Norwood procedure is influenced by anatomy and is worse for patients with hypoplastic left heart syndrome (HLHS), particularly aortic atresia (AA), as compared to other forms of functional single ventricle and systemic outflow tract obstruction. The current study was undertaken to evaluate our recent experience with the Norwood procedure and to evaluate potential predictors of operative and 1-year mortality. Methods: A retrospective study of risk factors for operative and 1-year mortality in 158 patients undergoing the Norwood procedure between January 1, 1998 and June 30, 2001. Results: HLHS was present in 102 patients (70 with AA) and other forms of functional single ventricle with systemic outflow tract obstruction in the remaining 56. Operative survival was 77% (122/158), 78% for patients with HLHS and 75% for patients with other diagnoses. Multivariable analysis identified birth weight (odds ratio (OR) 0.18/kg, 95% confidence limit (CL) 0.08–0.42, P , 0:001), associated cardiac anomalies (OR 4.45, 95% CL 1.50–13.2, P ¼ 0:001), total support time (OR 1.02/min, 95% CL 1.01–1.03, P ¼ 0:004), and extracorporeal membrane oxygena- tion (ECMO) or ventricular assist device (VAD) support (OR 17.8, 95% CL 4.40–71.0, P , 0:001) as predictors of operative mortality. The anatomic diagnosis (HLHS versus non-HLHS) was not a predictor of mortality, P ¼ 0:6). The Kaplan–Meier survival estimate at 1 year was 66% (95% CL 58–73%) and was not different for patients with HLHS compared to non-HLHS, P ¼ 0:5. For patients who have survived the Norwood procedure, survival to 1 year was 86% (95% CL 78–91%). Presence of an extra-cardiac anomaly or genetic syndrome (OR 2.70, 95% CL 0.98–7.41%, P ¼ 0:05) and presence of an additional cardiac defect (OR 3.99, 95% CL 1.67–9.57, P ¼ 0:002) were predictors of worse survival in the first year of life. Conclusions: The Norwood procedure is currently being applied to a heterogeneous group of patients. Operative and 1-year survival are equivalent for patients with HLHS and those with other cardiac defects. The presence of additional cardiac or extra-cardiac anomalies are predictors of poor outcome. q 2002 Elsevier Science B.V. All rights reserved.

Keywords: Hypoplastic left heart syndrome; Norwood procedure

1. Introduction improved anesthetic management [2,3]. Despite the conti- nuing improvement in outcomes, the early survival for The Norwood procedure was introduced as first stage patients with functional single ventricle and systemic reconstructive surgery for patients with hypoplastic left outflow tract obstruction is significantly poorer than that heart syndrome (HLHS) and has subsequently been applied for other cardiac defects which require neonatal repair. A to many cardiac defects characterized by the presence of a variety of factors have been suggested as possible predictors functional single ventricle with systemic outflow tract of operative mortality including anatomic diagnosis, aortic obstruction [1]. Outcome following Norwood reconstruc- atresia (AA), additional cardiac defects, low birth weight, tion has improved significantly secondary to modifications prematurity, associated non-cardiac anomalies and genetic in the surgical technique, improved perioperative care, and syndromes, and recently post-natal diagnosis of the cardiac defect [3–10]. Recent studies also have suggested that the q outcome following the Norwood procedure for HLHS, Presented at the joint 15th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 9th Annual Meeting of the European particularly AA, is worse than for other forms of single Society of Thoracic Surgeons, Lisbon, Portugal, September 16–19, 2001. ventricle with systemic outflow tract obstruction [5,10]. In * Corresponding author. Tel.: 11-215-590-2708; fax: 11-215-590-2715. addition to the increased operative mortality, there is a E-mail address: [email protected] (J.W. Gaynor).

1010-7940/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S1010-7940(02)00198-7 J.W. Gaynor et al. / European Journal of Cardio-thoracic Surgery 22 (2002) 82–89 83 persistent incidence of death; often sudden and unexplained, who are not candidates for further reconstructive surgery. during the first year of life among patients who survive the Thus, need for eventual transplantation is not considered initial hospitalization [11]. The current study was underta- failure of the newborn treatment protocol. The Norwood ken to evaluate our recent institutional experience with the procedure was performed by four surgeons and several Norwood procedure in patients with HLHS and other forms modifications were utilized during the study period. A stan- of functional single ventricle with systemic outflow tract dard Norwood operation was defined as atrial septectomy, obstruction and to evaluate potential predictors of operative right modified Blalock–Taussig shunt, division of the main and 1-year mortality. pulmonary artery with side-to-side anastomosis to the diminutive ascending aorta without aortic transection, and homograft patch augmentation of the ascending aorta and 2. Methods arch (Standard). In some patients, transection of both the aorta and pulmonary artery was performed with a side-to- The cardiac surgery and cardiac intensive care unit data- side anastomosis of the proximal divided vessels. The distal Downloaded from https://academic.oup.com/ejcts/article/22/1/82/516394 by guest on 28 September 2021 bases of The Children’s Hospital of Philadelphia were ascending aorta and arch were augmented with a homograft reviewed to identify all patients undergoing the Norwood patch and an end-to-end anastomosis performed between procedure between January 1, 1998 and June 30, 2001, as the distal aorta and the proximal great vessels (‘Double- well as those with similar cardiac defects (functional single Barrel’). A variety of other techniques were each utilized ventricle with systemic outflow tract obstruction) who did in a small number of patients including direct anastomosis not undergo surgery. Anatomic diagnosis was based on of the divided main pulmonary artery to the aortic arch, with review of echocardiography, operative findings, and or without anterior patch augmentation; use of a homograft autopsy reports. HLHS was defined as normal segmental tube interposition graft to connect the main pulmonary anatomy {S,D,S}, intact ventricular septum, aortic and artery to the aortic arch, and conversion to a Norwood mitral atresia or stenosis, and hypoplasia of the left ventricle type operation following previous coarctation repair (LV). Patients with double outlet right ventricle, mitral atre- (‘Other’). Repair of associated cardiac defects was sia, and aortic arch obstruction were also considered to have performed as appropriate. Delayed sternal closure was not HLHS. Patients with HLHS were further classified accord- routinely used. Support with extracorporeal membrane ing to the presence or absence of AA. Other forms of func- oxygenation (ECMO) or a ventricular assist device (VAD) tional single ventricle with systemic outflow tract was utilized when the patient could not be separated from obstruction, such as unbalanced atrioventricular canal cardiopulmonary bypass (CPB) or during resuscitation defects (AVC) and single LV with transposition of the following a cardiac arrest. great arteries, were classified as non-HLHS (Table 1). Follow-up status was determined by review of the medical 2.1. Statistical methods records and contact with the referring cardiologist. The study was approved by the Institutional Review Board at Data were analyzed and compared for four groups of The Children’s Hospital of Philadelphia. children: the entire cohort of children undergoing the At our institution, patients with functional single ventricle Norwood procedure; the cohort of children who were opera- and systemic outflow tract obstruction, including HLHS, tive survivors (survival to hospital discharge and at least 30 undergo staged surgical reconstruction. Primary cardiac days post-operatively); the subgroup of children with transplantation is not utilized. The Norwood procedure is HLHS; and in this subgroup, those with and without AA. performed in the neonatal period followed by superior cavo- Patient and operative variables were assessed as potential pulmonary connection at approximately 6 months of age predictors of operative (hospital discharge and at least 30 and a Fontan procedure at 18–24 months of age. Transplan- days after surgery) and 1-year mortality (Table 2). Data are tation is reserved for patients who develop significant presented as medians and ranges. ventricular dysfunction or AV valve regurgitation and Data analysis involved three phases. Phase I consisted of computation and evaluation of basic descriptive statistics Table 1 (e.g. central tendency, variability, association) to assist Cardiac defects other than HLHSa with the data exploration and understanding. Phase II Cardiac defect n Value Percent (%) consisted of two separate logistic regressions with operative survival as the outcome interest (one for the whole cohort of Unbalanced AVC 23/56 41 patients and the other for patients with HLHS only). Finally, Tricuspid atresia with TGA 5/56 9 TGA {S,L,L}, DILV, coarctation 9/56 16 Phase III of data analysis consisted of four separate survival TGA {S,D,D} with hypoplastic LV 5/56 9 analyses, all with 1-year survival as the outcome of interest: VSD with mitral atresia or stenosis 5/56 9 one analysis for the entire cohort of patients; one for the Other 9/56 16 patients who survived the initial operation; one for patients a AVC, atrioventricular canal defect; TGA, transposition of the great with HLHS only; and, finally, one analysis for the subgroup arteries; DILV, double inlet left ventricle; VSD, ventricular septal defect. of patients with HLHS who survived the initial operation. 84 J.W. Gaynor et al. / European Journal of Cardio-thoracic Surgery 22 (2002) 82–89

Table 2 probability value from the survivor group. The more a logis- a Potential predictors of mortality tic model can distinguish between these groups, the closer Patient variables the area under the ROC curve will be to one [13]. Anatomic diagnosis (HLHS versus non-HLHS) Aortic atresia (for HLHS subgroup, yes or no) Age at admission for Norwood procedure 3. Results Prenatal diagnosis (yes or no) Presence of a genetic syndrome or major extra-cardiac anomaly Between January 1, 1998 and June 30, 2001, 158 infants (yes or no) underwent the Norwood procedure at The Children’s Hospi- Presence of additional cardiac defects tal of Philadelphia. During the same time period, 11 children (other than LSVC or interrupted IVC) Prematurity (,37 weeks gestational age) with suitable cardiac anatomy were admitted and did not Birth weight (kg) undergo surgery because of multiple congenital anomalies

or severe neurologic injury from a pre-hospital arrest. There Downloaded from https://academic.oup.com/ejcts/article/22/1/82/516394 by guest on 28 September 2021 Operative variables Year of surgery (1998–1999 versus 2000–2001) were 98 males and 60 females. The median birth weight was Age at surgery (days) 3075 g (range 1200–4625, n ¼ 156). Twenty-six children Surgeon (16%) were born prematurely (gestational age ,37 weeks, Weight at surgery (kg) range 28–36 weeks). A prenatal diagnosis of congenital Shunt size (3.0, 3.5, or 4.0 mm) heart disease had been made in 80 of the children (51%). Total support time (CPB time 1 DHCA time) CPB time (min) HLHS was present in 102 patients (70 with AA) and other DHCA time (min) diagnoses in 56 patients (Table 2). Significant associated Myocardial ischemia time (min) cardiac lesions, excluding persistent left superior vena Type of Norwood Reconstruction (standard, ‘Double-Barrel’, or other) cava and interrupted inferior vena cava, were present in Delayed sternal closure (yes or no) 33 children (21%) (Table 3). Significant extra-cardiac Need for post-operative ECMO or VAD support anomalies or genetic syndromes were present in 23 patients a HLHS, hypoplastic left heart syndrome; LSVC, left superior vena cava; (15%) (Table 3). The median age at admission to our insti- IVC, inferior vena cava; CPB, cardiopulmonary bypass; DHCA, deep tution for the Norwood procedure was 1 day (range 1–145). hypothermic circulatory arrest; ECMO, extracorporeal membrane oxyge- Five patients underwent surgery prior to the Norwood nation; VAD, ventricular assist device. procedure including atrial septectomy (2), coarctation repair (2), and coarctation repair with pulmonary artery banding One-year survival estimates were obtained from the (1). During the study period, no other children underwent Kaplan–Meier model. For survival analysis, the date of coarctation repair and pulmonary artery banding. The birth was considered as time zero. Logistic models were median age at the Norwood procedure was 5 days (range tested for fit using traditional chi-square goodness-of-fit 1–156). Sixteen children (10%) were 14 days of age or statistics with log likelihood and Wald tests serving as the greater at the time of surgery. The median weight at surgery basis for model comparisons. Similarly, Cox proportional was 3.04 kg (range 1.2–5.7). Thirty-seven children weighed hazard models were tested using chi-square goodness-of-fit 2.5 kg or less at the time of surgery (23%). Weight less than statistics and groups were compared using the log–rank test or equal to 2.5 kg at the time of surgery and/or an associated for equality of functions. Results are expressed as odds ratio anomaly (cardiac or extra-cardiac) was present in 73 (OR) with 95% confidence limits (CL). All hypotheses were patients (46%). A Standard Norwood procedure was tested at the a ¼ 0:01 level. The experiment-wise error rate performed in 115 patients, a ‘Double-Barrel’ procedure in was held constant at the a ¼ 0:05 level using Westfall and 28 patients, and ‘Other’ types in 15 patients. The median Young’s method for correlated endpoints [12]. Data were total support time (CPB time 1 deep hypothermic circula- analyzed using STATA 7.0 (Stata Corporation 2000, tory arrest (DHCA) time) was 88 min (range 60–295). The College Station, TX, USA). median CPB time alone was 43 min (range 37–233). The The area under the receiver operating characteristic median DHCA time was 44 min (range 1–116). The median (ROC) curve is a measure of the predictive accuracy of myocardial ischemia time was 45 min (range 20–125). the logistic model at different points of sensitivity and speci- Delayed sternal closure was utilized in 38 patients (24%). ficity (or 1 – specificity). The curve is generated by calcu- ECMO or VAD support was utilized in 18 patients (11%). lating the proportion of deaths predicted by the model among those who died as compared with the proportion of 3.1. Operative mortality deaths predicted by the model among those who survived for different threshold values. Threshold values used in The overall operative mortality was 36 patients (23%). these ROC curves are determined by the predicted probabil- Hospital survival for patients with HLHS was 78% (80/102) ities of death for each case in the logistic model. Thus, the and for non-HLHS patients was 75% (42/56). Among the area under the curve represents the probability that a sub-group of patients with HLHS, survival for patients with randomly chosen predicted probability value from the AA was 74% (52/70) and for patients with aortic stenosis death group exceeds that of a randomly chosen predicted was 87% (28/32). Hospital survival for patients weighing J.W. Gaynor et al. / European Journal of Cardio-thoracic Surgery 22 (2002) 82–89 85

Table 3 analysis for the HLHS patients alone ðn ¼ 102Þ, the only Associated cardiac lesions and associated major extra-cardiac anomalies or characteristics which increased the risk of operative death genetic syndromes were lower birth weight, longer total support time, and Associated cardiac lesions (n ¼ 33)a ECMO or VAD support (Table 4). The presence of AA Interrupted aortic arch (4) was not a predictor of operative death ðP ¼ 0:3Þ. The area Moderate–severe tricuspid regurgitation or AV valve regurgitation (9) under the ROC curve yielded a predictive accuracy of 89%. Total anomalous pulmonary venous return (3) Partial anomalous pulmonary venous return (3) Intact atrial septum or restrictive atrial septal defect (6) Anomalous origin of the right subclavian artery from the descending 3.3. Follow-up aorta (6) Anomalous origin of either subclavian artery from the pulmonary artery For the 108 patients born prior to June 30, 2000, follow- (2) up to death or at least 1-year of age is complete for 102 of Complete heart block (1) 108 patients (94%). For the remaining six patients, a median Downloaded from https://academic.oup.com/ejcts/article/22/1/82/516394 by guest on 28 September 2021 Sinus node dysfunction (1) of 337 days follow-up is available (range 84–358). For the Associated major extra-cardiac anomalies or genetic syndromes 50 patients born after June 30, 2000, complete follow-up to ¼ (n 23) death or till July 1, 2001 is available for 38 of the 50 patients Chromosomal abnormalities/trisomy (5) Ellis-van Creveld Syndrome (1) (76%). For the remaining 12 patients, a median of 208 days Meningomyelocele (1) of follow-up is available (range 20–308). A superior cavo- Congenital diaphragmatic hernia (1) pulmonary connection has been performed in 92 of the 123 Duodenal atresia (2) patients who survived the initial operation. Ninety were Oral–Digital–Facial Syndrome (1) performed during the first year of life at a median age of Omphalocele (1) Rectal–vaginal fistula (1) 190 days (range 119–308). Two patients underwent an Malrotation (1) unstaged Fontan procedure at greater than 1 year of age. Jacbobsen Syndrome (1) Orthotopic cardiac transplantation was performed during Cleft palate (1) the first year following the Norwood procedure in three Craniosynostosis (1) patients. CHARGE Syndrome (1) Biliary atreisa (1) There were 15 deaths during the first year of life among Other (4) the 122 children (12%) who survived the Norwood proce- dure; 11 occurred prior to the superior cavopulmonary a More than one additional lesion was present in two children. connection, one at the time of the superior cavopulmonary connection at another institution, and three following super- 2.5 kg or less at the time of surgery was 62% (23/37), ior cavopulmonary connection. Among the 11 deaths prior compared to 82% (99/121) for patients who weighed greater to superior cavopulmonary connection; eight were sudden than 2.5 kg. Hospital survival for patients with low weight at unexplained cardiac deaths, one was secondary to respira- the time of surgery (,2.5 kg) and/or an associated anomaly tory syncitial viral infection, one occurred during readmis- (cardiac or extra-cardiac) was 73% (53/73) compared to sion for shunt revision, and one was secondary to a 88% (75/85) for patients weighing greater than 2.5 kg cerebrovascular accident following cardiac catheterization. with no associated anomaly. Since January 1, 2000, mortal- Among the three deaths following superior cavopulmonary ity for this low-risk group has been 8% (3/38). Prenatal connection; two were sudden unexplained deaths and one diagnosis of congenital heart disease did not alter hospital occurred during readmission for take-down of the superior survival which was 77% (62/80) for patients with a prenatal cavopulmonary connection. diagnosis of congenital heart disease, compared to 77% (60/ Table 4 78) for those with a post-natal diagnosis. Logistic regression model for operative mortalitya

3.2. Logistic regression models Variable Odds ratio 95% CL P value Entire cohort (n ¼ 158) In the multivariable analysis for the entire cohort, the Birth weight 0.18/kg 0.08–0.42 , 0.001 only characteristics which were associated with an Additional cardiac anomaly 4.45 1.50–13.2 0.007 increased risk of operative death were lower birth weight, Total support time 1.02/min 1.01–1.03 0.004 an associated cardiac anomaly, longer total support time, ECMO or VAD support 17.8 4.40–71.0 , 0.001 and ECMO or VAD support (Table 2). Birth weight and HLHS cohort (n ¼ 102) weight at surgery was similar for the cohort; however, inclu- Birth weight 0.20/kg 0.07–0.58 0.003 sion of birth weight resulted in a better fit of the model. Total support time 1.02/min 1.00–1.03 0.02 Anatomic diagnosis (HLHS versus non-HLHS) was not a ECMO or VAD support 25.5 4.75–137 , 0.001 predictor of mortality ðP ¼ 0:6Þ. The area under ROC curve a ECMO, extracorporeal membrane oxygenation; VAD, ventricular assist yielded a predictive accuracy of 87%. In the multivariable device. 86 J.W. Gaynor et al. / European Journal of Cardio-thoracic Surgery 22 (2002) 82–89

Table 5 Cox proportional hazards regression for 1-year mortality

Variable Odds ratio 95% CL P value

Entire cohort (n ¼ 158) Extra-cardiac anomaly or 2.50 1.27–4.89 0.008 genetic syndrome Additional cardiac defect 3.24 1.82–5.79 , 0.001 Birth weight 0.51/kg 0.34–0.77 0.001 Total support time 1.01/min 1.01–1.02 , 0.001 ECMO or VAD support 5.89 2.95–11.8 , 0.001 HLHS cohort (n ¼ 102) Additional cardiac defect 3.08 1.54–6.18 0.002 Birth weight 0.44/kg 0.25–0.78 0.005 Downloaded from https://academic.oup.com/ejcts/article/22/1/82/516394 by guest on 28 September 2021 Total support time 1.01/min 1.00–1.01 0.008 Fig. 1. Kaplan–Meier survival estimate for entire cohort ðn ¼ 158Þ with ECMO or VAD support 4.99 2.37–10.5 , 0.001 95% CL. anomaly (cardiac and/or extra-cardiac) (48%, 95% CL 35– 3.4. Survival analysis 59%), P ¼ 0:0003 (Fig. 3). For patients who survived the Norwood procedure, survi- For the entire cohort, the Kaplan–Meier survival estimate val to 1 year was 86% (95% CL 78–91%). The only char- at 1 year was 66% (95% CL 58–73%) (Fig. 1). Survival at 1 acteristic which predicted 1-year mortality in the early year was not different for patients with HLHS (64%, 95% CL survivors were an additional cardiac defect (OR 3.99, 95% 54–73%) compared to non-HLHS (68%, 95% CL 54–79%), CL 1.67–9.57, P ¼ 0:002) or an extra-cardiac anomaly or P ¼ 0:6 (Fig. 2). In the multivariable analysis, the character- genetic syndrome (OR 2.70, 95% CL 0.98–7.41%, istics which predicted mortality in the first year of life for the P ¼ 0:05). Anatomic diagnosis was not a predictor of 1- entire cohort were lower birth weight, an associated cardiac year mortality. For the HLHS patients who survived the anomaly, an extra-cardiac anomaly or genetic syndrome, initial surgery, survival to 1 year was 83% (95%CL 72– longer total support time, and ECMO or VAD support 90%) and 92% (95% CL 76–97%) for non-HLHS patients, (Table 5). Among the HLHS cohort, characteristics which P ¼ 0:2. The only predictor of mortality during the first year predicted 1-year mortality were similar; lower birth weight, of life for the HLHS patients who survived the initial proce- an extra-cardiac anomaly, longer total support time, and dure was an extra-cardiac anomaly or genetic syndrome ECMO or VAD support (Table 5). In the univariable analy- (OR 5.27, 95% CL 1.12–24.7, P ¼ 0:035). sis, there was lower survival at 1 year for patients with AA (57%, 95% CL 44–68%), compared to those without AA (81%, 95% CL 62–91%), P ¼ 0:05. However, in the multi- 4. Discussion variable analysis, AA was not a predictor of mortality ðP ¼ 0:3Þ. Survival to 1 year of age was significantly greater The current study demonstrates that the Norwood proce- for patients weighing .2.5 kg at the time of the Norwood dure is being applied to a heterogeneous patient population procedure without an associated anomaly (cardiac and/or and outcomes continue to improve. The overall hospital extra-cardiac) (82%, 95% CL 71–89%), compared to the survival was 77%, despite a patient population with either survival of patients with weight #2.5 kg and/or an associated

Fig. 2. Kaplan–Meier survival estimate for entire cohort stratified by Fig. 3. Kaplan–Meier survival estimate for entire cohort ðn ¼ 158Þ stratified anatomic diagnosis (HLHS versus non-HLHS). by presence of risk factors (low weight and/or associated anomalies). J.W. Gaynor et al. / European Journal of Cardio-thoracic Surgery 22 (2002) 82–89 87 low weight at the time of surgery and/or an associated such as obstructed pulmonary venous drainage, total anom- anomaly (cardiac or extra-cardiac) present in 73 patients alous pulmonary venous connection, anomalous origin of (46%). Operative survival for patients without these risk the right subclavian artery; as well as operative factors factors was 88%, compared to 73% for those with one or such as prolonged CPB time [3–10]. Unlike the current more risk factors. During the study period, only 11 patients study, some studies have suggested that the cardiac diagno- presenting to our hospital with a suitable cardiac defect did sis remains a risk factor with less favorable outcomes for not undergo surgery suggesting that patients previously not patients with HLHS as compared to other cardiac defects. considered to be operative candidates are now undergoing Daebritz et al. [5] compared the results of the Norwood the Norwood procedure. Hospital survival for the patients operation for patients with HLHS and those with other with no significant associated anomalies now approaches malformations in 194 patients who underwent surgery that for other forms of critical congenital heart disease between 1990 and 1998. One hundred thirty-one patients which require surgical repair in the neonatal period, such had HLHS and 63 patients had other defects. In this study, as interrupted aortic arch, truncus arteriosus, and pulmonary the operative mortality was significantly greater for patients Downloaded from https://academic.oup.com/ejcts/article/22/1/82/516394 by guest on 28 September 2021 atresia with intact ventricular septum. Although anatomic with HLHS (37%) compared to those with other defects diagnosis (HLHS versus non-HLHS) was not a risk factor, (19%). One-year survival was also significantly lower for the presence of an associated cardiac defect was a predictor patients with HLHS (51%) compared to patients with other of operative mortality. As in previous studies, lower weight defects (71%). There was no difference in survival between remains a risk factor for operative mortality, although the the anatomic subgroups in the HLHS patients. outcome appears to be improving. A prenatal diagnosis of Low weight at the time of surgery has been identified as a the cardiac defect did not decrease the mortality risk, consis- predictor of mortality [3,4]. In 1999, Weinstein reported tent with previous studies from our institution [14]. In addi- outcome following the Norwood procedure for 67 patients tion to patient characteristics which increased risk, weighing #2.5 kg at the time of surgery between 1990 and operative factors such as prolonged total support time and 1997 with an operative mortality of 51% [4]. No variable the need for ECMO or VAD were associated with an could be correlated with increased mortality, although there increased risk of death in the multivariable analysis. was a trend toward increased mortality with increased CPB The early and late outcomes for children presenting with time and decreased ventricular function. The hospital survi- functional single ventricle and systemic outflow tract val for low weight infants of 62% in the current study obstruction, including HLHS, have improved significantly suggests that the prognosis may be improving. since the introduction of the Norwood procedure. Mahle et Of concern is the persistent incidence of death during the al. [2] reported outcomes of 840 patients who underwent the first year of life among patients who survived the initial Norwood procedure for HLHS between 1984 and 1999. The hospitalization. In the current study, 12% of the survivors overall 1-year survival was 51%, however, there was a of the initial procedure died prior to 1 year of age, most significant improvement in the mortality associated with before superior cavopulmonary connection. These deaths the Norwood procedure in recent years. Later year of are usually sudden and often unexplained. Mahle et al. surgery was associated with significantly improved survival. [11] evaluated the incidence of unexpected death among Operative survival for the period 1995–1998 was 71.4%. 536 patients with HLHS who survived the Norwood proce- Anatomic subtype was not a risk factor for death. Clancy dure. Unexpected death occurred in 4.1% of this large group et al. [8] assessed pre-operative predictors of operative of patients (22/536) at a median age of 79 days. A multi- mortality in a large group of neonates with congenital variable analysis demonstrated that perioperative arrhyth- heart disease. Patients with functional single ventricle and mias and earlier era of surgical procedure were associated systemic outflow tract obstruction had an increased opera- with an increased risk for unexpected death. No anatomic tive mortality (26%), compared to other defects. Predictors subtypes were found to be risk factors for death. In the of mortality in this group included presence of a genetic current study, most of the late deaths occurred prior to the syndrome, decreased Apgar score, and increased age at superior cavopulmonary connection; while mortality for this hospital admission. procedure is itself very low, 1/92 (1.1%). Multiple factors Many factors are likely responsible for the improvement may be responsible for the unexplained deaths, including in operative survival following the Norwood procedure coronary insufficiency, arrhythmia, ventricular dysfunction, including improved surgical techniques, improved perio- residual arch obstruction, pulmonary artery distortion, perative management, and improved anesthetic techniques. restrictive atrial septal defect, and inadequate pulmonary Despite the improving outcome, early survival for these blood flow. However, in the current study, the only predictor children is still significantly lower than for other forms of of mortality in the first year of life for those who survived heart disease, which require neonatal surgical intervention. the Norwood procedure was the presence of associated Factors which have been identified in multiple studies as anomalies (either cardiac or extra-cardiac). There was no potential predictors of mortality include low weight; difference in 1-year survival between patients with HLHS presence of associated extra-cardiac defects or chromoso- and other cardiac defects, however, there was a trend toward mal abnormalities; presence of additional cardiac defects poorer survival for patients with AA as is reported in other 88 J.W. Gaynor et al. / European Journal of Cardio-thoracic Surgery 22 (2002) 82–89 studies. In the current study, AA was not a predictor of operative and during the first year, is due to patient-related, mortality in the multivariable analysis suggesting it is linked rather than procedure-related variables, over which the to other risk factors such as lower birth weight or associated medical and surgical teams have little control. The outcome anomalies. Patients with AA may be at risk for sudden for low birth weight infants has improved, but low weight death, secondary to the lack of antegrade aortic flow and remains a risk factor for mortality. In low-risk patients (i.e. abnormal coronary artery flow patterns. Some studies have those weighing .2.5 kg without additional cardiac or non- suggested that patients with smaller ascending aortas have a cardiac anomalies), the early risk of surgery is 8%, which is worse outcome [6,7]. As operative survival continues to similar to other forms of critical heart disease requiring improve, it is important to identify patients at increased newborn surgical management. As operative survival risk for death after hospital discharge and determine if following the Norwood procedure continues to improve, it modification of the treatment protocol can improve survival. is difficult to justify either non-intervention or primary Associated cardiac defects have also been identified as transplantation. Inter-stage mortality remains a concern. risk factors for both operative and 1-year mortality in other The most important predictors of a poor outcome in the Downloaded from https://academic.oup.com/ejcts/article/22/1/82/516394 by guest on 28 September 2021 studies as well [3–10]. Unfortunately, not every study first year of life for patients who survive the initial hospita- reports the same defects. In the current study, associated lization are the presence of additional cardiac or extra- cardiac defects included interrupted aortic arch, anomalies cardiac defects. Additional studies are necessary to deter- of pulmonary venous connection, obstruction to pulmonary mine if changes in management strategy or patient selection venous drainage, anomalous origin of a subclavian artery, may reduce this risk. and atrioventricular valvar regurgitation. All of these have been implicated in other studies as predictors of mortality. Acknowledgements The finding that additional cardiac defects are risk factors for both operative and 1-year mortality suggests that cardiac We wish to acknowledge the contribution of the many transplantation could be a better treatment strategy for some other physicians, nurses, and other personnel who partici- of these patients. However, many of these patients, particu- pated in the care of these infants. In particular, we would larly those with obstruction to pulmonary venous drainage, like to thank Nancy D. Bridges, Gil Wernovsky, and Tom R. are difficult to stabilize medically while awaiting transplan- Karl for their significant contribution to the care of these tation. Because of the increasing scarcity of appropriate patients and in the preparation of this manuscript. donor organs as well as the mortality and morbidity while waiting for an organ, it is not clear that a strategy of primary transplantation would result in an improved outcome. Inter- References estingly, associated extra-cardiac anomalies and genetic syndromes were predictors of 1 year of survival but were [1] Norwood WI, Lang P, Hansen DD. Physiologic repair of aortic atresia not associated with increased operative mortality. Thus, – hypoplastic left heart syndrome. N Engl J Med 1983;308:23–26. even though these patients may survive the initial proce- [2] Mahle WT, Spray TL, Wernovsky G, Gaynor JW, Clark BJ. Survival after reconstructive surgery for hypoplastic left heart syndrome: a 15- dure, the mid-term outcome is less favorable. Changing year experience from a single institution. Circulation 2000;102(Suppl surgical treatment protocols are unlikely to improve III):III-136–III-141. outcome for this subgroup of patients, as they do not alter [3] Bove EL, Lloyd TR. Staged reconstruction for hypoplastic left heart the underlying syndrome. syndrome: contemporary results. Ann Surg 1996;224(3):387–395. There are several limitations to this study. The retrospec- [4] Weinstein S, Gaynor JW, Bridges ND, Wernovsky G, Montenegro LM, Godinez RI, Spray TL. Early survival of infants weighing 2.5 tive nature precludes identification of risk factors not kilograms or less undergoing first-stage reconstruction for hypoplastic entered into the model. The presence of an associated left heart syndrome. Circulation 1999;100(Suppl II):II-167–II-170. cardiac defect was a predictor of both operative and 1- [5] Daebritz SH, Nollert GDA, Zurakowski D, Khalil PN, Lang P, del year mortality, however, the number of patients with each Nido PJ, Mayer JE, Jonas RA. Results of Norwood stage I operation: defect is small and it is not possible to evaluate the impact of comparison of hypoplastic left heart syndrome with other malforma- tions. J Thorac Cardiovasc Surg 2000;119:358–367. each defect individually. In addition, there is a trend toward [6] Ishino K, Stu¨mper O, De Giovanni JJV, Silove ED, Wright JGC, worse outcomes for patients with AA, however, data on the Sethia B, Brawn WJ. The modified Norwood procedure for hypoplas- actual size of ascending aorta is not available. tic left heart syndrome: early to intermediate results of 120 patients In conclusion, the Norwood procedure is currently being with particular reference to aortic arch repair. J Thorac Cardiovasc applied to a heterogeneous group of patients with variable Surg 1999;117:920–930. [7] Poirier NC, Drummond-Webb JJ, Hisamochi K, Imamura M, Harri- results in certain subgroups. The early survival for patients son AM, Mee RBB. Modified Norwood procedure with a high-flow undergoing the Norwood procedure continues to improve, cardiopulmonary bypass strategy results in low mortality without late especially for patients of normal birth weight without asso- arch obstruction. J Thorac Cardiovasc Surg 2000;120:875–884. ciated anomalies. There is no difference in operative or 1- [8] Clancy RR, McGaurn SA, Wernovsky G, Spray TL, Norwood WI, year survival for patients with HLHS, compared to those Jacobs ML, Murphy JD, Gaynor JW, Goin JE. Preoperative risk-of- death predictors model in heart surgery with deep hypothermic circu- with other forms of functional single ventricle and systemic latory arrest in the neonate. J Thorac Cardiovasc Surg 2000;119:347– outflow tract obstruction. Much of the mortality risk, both 357. J.W. Gaynor et al. / European Journal of Cardio-thoracic Surgery 22 (2002) 82–89 89

[9] Tworetzky W, McElhinney DB, Reddy VM, Brook MM, Hanley FL, into the coronaries proximal to the takeoff of the shunt. In essence, this Silverman NH. Improved surgical outcome after fetal diagnosis of technique is similar to the standard Norwood operation that puts the coron- hypoplastic left heart syndrome. Circulation 2001;103:1269–1273. ary at the same risk of stenosis. One has to decide where exactly to implant [10] Jacobs ML, Blackstone EH, Bailey LL. Intermediate survival in the aorta and a circumferential suture line is necessary in a very diminutive neonates with AA: a multi-institutional study. J Thorac Cardiovasc ascending aorta. I think if one prefers this technique, there is no real disad- Surg 1998;116:417–431. vantage but I am not sure there is a real advantage either. [11] Mahle WT, Spray TL, Gaynor JW, Clark BJ. Unexpected death after My own personal prejudice is that in very tiny patients, a central shunt reconstructive surgery for hypoplastic left heart syndrome. Ann may be a better option than a modified Blalock–Taussig shunt using a 3 mm Thorac Surg 2001;761:61–65. central shunt in a 1.2–1.5 kg baby. [12] Zhang J, Quan H, Ng J, Stepanavage ME. Some statistical methods Dr H. Jalahi (Brisbane, Australia): When we looked into our own results for multiple endpoints in clinical trials. Control Clin Trials in Brisbane with a success rate of about 72%, there were a number of 1997;18:204–221. patients who had pre-operative pulmonary insufficiency of more than [13] Murph JM, Berwick DM, Weinstein MC, Borus JF, Budman SH, mild degree, mild to moderate. Have you encountered that problem, has Klerman GL. Performance of screening and diagnostic tests. Arch it been an issue in your group, and how did you handle those patients,

Gen Psychiatry 1987;44:550–555. please? Downloaded from https://academic.oup.com/ejcts/article/22/1/82/516394 by guest on 28 September 2021 [14] Mahle WT, Clancy RR, McGaurn SP, Goin JE, Clark BJ. Impact of Dr Spray: Pre-operative pulmonary insufficiency has not been common prenatal diagnosis on survival and early neurologic morbidity in above a mild degree; when a patient has excessive pulmonary blood flow neonates with the hypoplastic left heart syndrome. Pediatrics pre-operatively, sometimes functional pulmonary insufficiency will occur 2001;107:1277–1282. but this has not really been a problem late after the Norwood operation. I can only remember two patients in our overall experience with staged reconstruction who have required pulmonary valve surgery after staged Appendix A. Conference discussion reconstruction. Therefore, pulmonary insufficiency of the neoaorta seems to be quite rare. Tricuspid regurgitation is relatively common but rarely Dr C. Tchervenkov (Montreal, Canada): We are currently evaluating the requires surgical intervention. When tricuspid regurgitation does require outcome for the Norwood procedure at the level of the Congenital Heart intervention, it is usually present at birth and reflects anatomic abnormal- Surgeons Society in almost 700–800 patients, two-thirds of them with AA ities of the tricuspid valve or the papillary muscles. It is possible that as well as with aortic stenosis. I had the privilege to read probably more patients with severe tricuspid regurgitation at presentation are better served than half of the operative reports on these patients. One of the areas we tried by cardiac transplantation. to focus on is the handling of the coronary circulation of the ascending Dr S. Sano (Okayama, Japan): I presented my new technique in Toronto aorta, and although I unfortunately was not able to be at the analysis with and then have some comment about death after Norwood. And I think most Gene Blackstone because I was in Europe, but one of the things we are of the presentation you do and Edward Bove do are very much similar. You going to look at is the size of the ascending aorta and also the type of have a huge experience of Norwood, and I think the mortality is higher in a operation that was performed. low birth weight baby, small baby, and also a small ascending aorta, like I know that in your institution you have a very standard way of filleting aortic atresia. These are due to the coronary perfusion, malperfusion. So I open the ascending aorta down to the transected main pulmonary artery think my technique of RV–PA shunt is useful to these low birth weight stump and enlarge that to the homograft patch. But there are other ways of babies, especially small babies, and those with aortic atresia with very tiny handling the ascending aorta, and one is to simply leave it all the way down ascending aortas. What do you think of the RV–PA shunt? from the aortic arch unopened, another way, as performed by Roger Mee, is Dr Spray: I am intrigued by the use of an RV to PA shunt. While there are to, in many cases, divide it and transect it and implant it into the reconstruc- advantages to antegrade flow into the pulmonary arteries, it is also asso- tion. ciated with pulmonary insufficiency and requires an incision in the right A couple of questions. One, have you done a stratification of the patients ventricle, which is the systemic ventricle. I believe many surgeons still have with respect to the size of the ascending aorta, particularly in the cases that some concerns about making an incision in the systemic ventricle, however, there is AA with a small ascending aorta, 4 mm, 3 mm, less than 2, and when one reflects on your results, it is hard to say that RV function has been what is the outcome in these patients with respect to ascending aortic size? significantly altered. It would be valuable to see long term data of function Would you care to comment on the importance of these three various of the right ventricular free wall. techniques of reconstruction with respect to the coronary circulation, your I am intrigued that use of this technique may be beneficial in the very technique, the modified Norwood, the one where the ascending aorta is left small patient. Obviously, when one is operating on a 1.2 kg baby, shunt as a long coronary conduit from the aortic arch, as well as the technique of selection is difficult and antegrade flow may be more easily accomplished transection and implantation into the reconstruction? with your technique Dr Spray: Unfortunately, I can’t comment about the effect of aortic size Dr Sano: I have done six patients out of 18 less than 2.5 kg. I lost one. because it was not consistently measured in this entire cohort. I do, And the post-operative management is very much the same of the patient however, think that the size of the ascending aorta is an issue. Obviously, with like a 3.1 kg baby. This is completely different. when the ascending aorta is 1 mm in diameter, the technical issues of Dr Spray: One interesting thing to me is the fact that the mortality after reconstructing the aortic arch are more complicated and the risk of coronary the Norwood operation has fundamentally changed over the last 5 years. ischemia may be greater. The timing of mortality has also changed. Mortality usually doesn’t occur The reason the original Norwood operation involved opening the tiny in the first few days of after surgery now, but still occurs in the first 6 ascending aorta down to the origins of the coronary arteries was to augment weeks after the Norwood operation and may be from other associated the entire ascending aorta and arch and to maintain the maximum inflow abnormalities. Sudden cardiovascular collapse is rarely the cause of into the coronary arteries proximal to the takeoff of the shunt from the mortality, while it used to be the most common sequence of events innominate artery. I think that it is in general a bad idea to leave the tiny early after the first stage reconstruction. I do not know how much of ascending aorta with any significant length; the inflow into the common the early mortality was ischemia in the past and how much ischemia coronary artery. Because echo studies after the Norwood operation have contributes to the later mortality that we see today. I would love to be shown that flow in the coronaries is primarily systolic rather than diastolic able to do PET scan on every one of these infants and look at coronary after the first stage operation, I am worried about shunt runoff causing blood flow and perfusion, however, we have not been able to accomplish coronary ischemia. that yet in our own institution. Reimplantation of the diminutive ascending aorta into the proximal Dr Sano: In these 2 years I had no early deaths, no late deaths, no sudden pulmonary artery is another technique, which provides a more direct inflow deaths at all.