1. The Optimal Timing of Stage-2-Palliation after the Norwood Operation: A Multi-Institutional Analysis from the CHSS
CHSS Fall Work Weekend
November 19, 2016
James M. Meza, MD and Jake Jaquiss, MD (Study PI), for the Optimal Timing of Stage 2 Working Group

2. Overview Background, Rationale, Hypothesis
Study Population and Characteristics
Outcomes and Risk Factors
Determinants of Timing of Stage-2-Palliation
Optimal Timing – Methods and Results
Effect of interval procedures – Methods and Results
Interpretation and Clinical Implications

3. Mortality during Staged Palliation
Survival through single ventricle palliation = 50-70%
Mortality after Norwood and before Stage-2-Palliation (S2P) remains high
Timing of S2P is physician modifiable
Effect of timing not well understood

4. Timing of S2P is a Complex Decision
Earlier S2P
Reduce volume load on systemic ventricle
Eliminate shunt-associated risks
Normalize coronary blood flow in those with BT shunt
Normalize pulmonary vascular flow and pressure
Underdevelopment of pulmonary vasculature
Failure of PVR to decrease
Later S2P
Growth of infant and pulmonary vasculature
Potentially decreased resource utilization
Increased exposure to risks of Norwood-associated physiology

5. Hypothesis An optimal timing exists
Norwood
S2P
Fontan ?
An optimal timing exists
Is based on patient-specific characteristics

6. Study Population & Characteristics

7. Patient Data Source
Data Source = CHSS Critical Left Ventricular Outflow Tract Obstruction Registry
Neonate ≤ age 30 days at admission to a CHSS institution
2005 onward
AV & VA concordance
Precludes an adequate systemic cardiac output through the aortic valve
Study inclusion criteria
Initial Norwood operation

8. Study Population 924 with an initial procedure, 72 excluded
CHSS LVOTO
N=924
Eligible
N=852
Initial procedure
N=702
Norwood
N=534
924 with an initial procedure, 72 excluded
852 included, 702 had an initial operation, 83 had an initial catheter procedure, 13 died before initial procedure , 54 alive without surgical information
534 Norwoods of the 702

9. Demographic Characteristics
Overall Cohort
(N=534)
Sex, male
66% (346)
Prenatal diagnosis
73% (383)
Prenatal intervention
1% (4)
Gestational age (weeks)
39.0 (38-39)
Birth weight (kg)
3.2 ( )
Low birth weight (< 2.5 kg)
16% (87)
Genetic abnormality
7% (41)
White race
84% (363)

10. Institutional Diagnoses
Overall Cohort
(N=534)
Hypoplastic left heart syndrome
92% (493)
Critical aortic stenosis
2% (13)
Aortic valve atresia
0.6% (4)
Mitral stenosis
0.2% (2)
Mitral atresia
Coarctation of the aorta
1% (3)
Interrupted aortic arch
2% (11)
Hypoplastic aortic arch

11. Echocardiographic Data
Overall Cohort
(N=534)
Aortic atresia/mitral atresia
28% (151)
Aortic atresia/mitral stenosis
18% (96)
Aortic stenosis/mitral atresia
1% (5)
Aortic stenosis/mitral stenosis
16% (84)
Isolated aortic atresia
2% (13)
Isolated aortic stenosis
7% (38)
Isolated mitral atresia
2% (11)
Isolated mitral stenosis
2% (8)
Other
3% (16)
Bilateral SVC
5% (19)

12. Outcomes and Risk Factors

13. Outcomes after Norwood

14. Norwood Operative Characteristics
Overall Cohort
(N=534)
Age at Norwood (days)
6.0 (0-48)
Shunt type
MBTS
49% (263)
RVPA conduit
50% (268)
Central shunt
1% (3)
Weight at Norwood (kg)
3.2 ( )
Elapsed time on CPB (min)
149.9 ± 45.9
Modified cerebral perfusion
91% (349)
Duration of circulatory arrest (min)
8.0 ( )

15. Hazard Model for Death after Norwood
Probability of Survival
Red line is parametric model, circles are KM estimates, dashed lines are 70% CL
Months since Norwood

16. Multivariable Model Candidate covariates = baseline, demographic, clinical through end of Norwood

17. Death after Norwood

18. Outcomes after S2P

19. Age at S2P Median = 5.1 (4.3–6.2) months Range = 1.7-17.2 months
154 days ( )
Range = months
days
Not normally distributed

21. Hazard Model for Death after S2P
Probability of Survival
Red line is parametric model, circles are KM estimates, dashed lines are 70% CL
Months since S2P

22. Variables – post-Norwood
Weights (z-score)
Norwood, echo, cath, clinic, S2P
Echo
AVVR
RV Function
Cath
PVR
QpQS
PA stenosis
PA hypoplasia
Chromosomal abnormality/genetic syndrome
Shunt type and size
Geographic region of S2P
Season of S2P
Bilateral SVC
Post-Norwood Course
Hospital LOS after Norwood
Length of mechanical ventilation after Norwood
Failed extubation after Norwood
Home oxygen
Tracheostomy
Respiratory illness
Unplanned readmission pre-S2P and LOS
Delayed S2P?
Diagnosis of NEC
Diagnosis of GERD
Interval cath and operative procedures
Inpatient vs. outpatient status at time of Stage 2
Limits of documentation
Mechanical ventilation at time of Stage 2
Pre-S2P clinic visit
O2 sats at pre-op clinic

23. Post-Norwood Course Overall Cohort (N=534)
Overall Cohort
(N=534)
Length of Norwood hospitalization (days)
25 (16-40)
Length of mechanical ventilation
7 (5-11)
Required re-intubation after Norwood
7% (37)
Required readmission for respiratory infection
5% (25)
Required home oxygen
5% (27)
Required tracheostomy
1% (3)
Diagnosis of necrotizing enterocolitis
12% (64)
Diagnosis of gastro-esophageal reflux
30% (158)

24. Pre-S2P Cardiac Catheterization
Overall Cohort
(N=534)
Age at pre-S2P catheterization (days)
 118 (84-154)
Interval from catheterization to S2P (days)
28 (12-58)
Weight (kg)
5.5 ( )
Weight-for-age z-score
-1.1 ( )
Pulmonary vascular resistance (Wood units)
1.9 ( )
QpQs
1.0 ( )
Coarctation
15% (79/534)
Moderate-severe RPA stenosis
15% (80)
Moderate-severe RPA hypoplasia
10% (54)
Moderate-severe LPA stenosis
17% (89)
Moderate-severe LPA hypoplasia
13% (67)

25. Pre-S2P Echocardiogram
Overall Cohort
(N=534)
Age at echocardiogram (days)
96 (28 – 139)
Interval from echocardiogram to S2P (days)
40 (11-107)
Weight (kg)
4.6 ( )
Weight-for-age z-score
-1.2 ( )
Moderate-severe RV dysfunction
10% (51/534)
Moderate-severe AVV regurgitation
22% (117/534)

26. Pre-S2P Clinic Visit Overall Cohort (N=534) Age at clinic visit (days)
Overall Cohort
(N=534)
Age at clinic visit (days)
121 (93-157)
Interval from clinic visit to S2P(days)
28 (12-58)
Weight (kg)
5.4 ( )
Weight-for-age z-score
-1.1 (-2.2 – 0.1)
Oxygen saturation (%)
80 (76-83)

27. Model for Death after S2P

28. Determinants of Timing of S2P

29. Determinants of Timing
Linear regression
Outcome = age at S2P
Candidate covariables – all from 1st two models

30. Determinants of Age at S2P

31. Determinants of Age at S2P

32. Analyzing Staged Procedures and Optimal Timing

33. Staged Procedures Conditional survival analysis [ CS = S(t|s) ]
Norwood
S2P
4-Years
Model 1
Model 2
Conditional survival analysis [ CS = S(t|s) ]
Use both models
Predict survival to day of S2P, then 2nd model for S2P for four years
Accounts for all patients!

34. Survival After Norwood%

35. Survival after Norwood, through S2P%

36. Survival through S2P Probability of Survival Months since Norwood
Survival at 4 years = 71±5%
Probability of Survival
COHORT AVERAGE
Months since Norwood

37. Analyzing Timing Age at S2P identified as risk factor
Parametric model = mathematical equation
Nomogram of survival vs. Age at S2P

38. post-Norwood Survival
Optimal Timing, by Age
Risk-adjusted, 4-Year,
post-Norwood Survival
Age at S2P (months)
“Cohort average”

39. Timing, by Age, with RV Dysfunction
No RV Dysfunction
Risk-adjusted, 4-Year,
post-Norwood Survival
RV Dysfunction
Age at S2P (months)

40. Timing, by Age, by Shunt Type
RVPA Conduit
Risk-adjusted, 4-Year,
post-Norwood Survival
MBTS
Age at S2P (months)

41. Optimal Timing, by Age Across various risk profiles
Low risk
Average-risk
Risk-adjusted, 4-Year,
post-Norwood Survival
High risk
Age at S2P (months)

42. post-Norwood Survival
Optimal Timing, by WAZ
Risk-adjusted, 4-Year,
post-Norwood Survival
Weight-for-Age Z-score
at the pre-S2P cath
“Cohort average”

43. Timing, by WAZ, with RV Dysfunction
No RV Dysfunction
RV Dysfunction
Risk-adjusted, 4-Year,
post-Norwood Survival
Weight-for-Age Z-score
at the pre-S2P cath

44. Timing, by WAZ, by Shunt Type
Risk-adjusted, 4-Year,
post-Norwood Survival
Weight-for-Age Z-score
at the pre-S2P cath
RVPA
MBTS

45. Optimal Timing, by WAZ Across various risk profiles
Risk-adjusted, 4-Year,
post-Norwood Survival
Weight-for-Age Z-score
at the pre-S2P cath
Low risk
Average-risk
High risk

46. Elective S2P

47. Indications for S2P

48. Operative Status vs. Age at S2P

49. Risk Factors in Elective Patients
Parameter Estimate ± STD
P-value
Reliability
RV dysfunction on pre-S2P echo,
moderate or severe
2.34 ± 0.54
<
73%
Younger age at S2P (days), natural
log transformation
1.74 ± 0.84
0.04
50%

50. post-Norwood Survival
Optimal Timing, by Age
Risk-adjusted, 4-Year,
post-Norwood Survival
Age at S2P (months)
“Elective average”

51. High-Risk Patients

52. Why does it appear that high-risk appear to do better with later S2P?
Regardless of age or WAZ – survival poor
Especially with early S2P
Cannot advocate non-intervention in the deteriorating “high-risk” infant
“Length time bias”
Highest risk patients die earlier – push down survival
Less high risk – survive longer to undergo later S2P

53. “High-Risk S2P” vs. Transplantation?
11 patients underwent heart transplantation after Norwood
All currently still alive
Can’t make a model, can only suggest this from descriptive statistics

55. Interval Procedures
Norwood
S2P
4-Years

56. Prevalence of Interval Procedures
Patients
Total procedures
# of Procedures
Survival after Norwood
Interval cardiac catheterization procedure
178
275
0-5
97%
Interval operation 68 86
0-3
68%

57. Methodology First analyzed for development of 2nd model
But occur during Norwood – S2P interval
Time-varying covariables
Modulated Renewal

58. Time-Varying Analysis
Parameter Estimate ± STD
P-value
Interval cardiac catheterization procedure
0.10 ± 0.25
0.70
Interval operation
0.69 ± 0.24
0.004

59. Effect of Interval Operations
Probability of Survival
Months since Norwood

60. Discussion, Implications, Conclusions

61. Low- and Average-Risk Patients
After 3-4 months and z-score > -2 for low and average risk patients
“Elective”
Patients are progressing early/being delayed for no reason
Younger age – risk factor
Converting some from elective non-elective?
Outgrowing shunts? Waiting for shunt complications

62. High-Risk Patients Survival is substantially reduced
A high risk patient at Norwood doesn’t become a better candidate after S2P (survival cost still seen)
Very poor survival with “early” S2P or low WAZ
No weight-for-age z-score, just like no age “maximizes” survival in these patients
Heart transplantation may maximize survival

63. Interval Procedures Low threshold for catheter-based procedures
If facing a non-elective S2P with intervenable pathology (e.g. shunt stenosis), try to bridge to a later, elective S2P
Operative procedures confer greater risk
Don’t avoid doing
Marker of more severe pathology and higher risk

64. Implications
Survival through staged procedures should be considered across all, not as individual discrete intervals
Active plan can be developed or modified for planning timing of S2P
This info can help with prioritization of rare hearts from transplantation – have an idea of who will fail staged palliation

65. THANK YOU

66. Median Age at S2P (months)†
Enrolled (n=534)*
Mortality after
Norwood (n=115)**
Reached S2P
(n=377)
Median Age at S2P (months)†
S2P (n=38)‡
Institution P 95
20% (19) 70
5.1 ( )
10% (7)
Institution I 63
30% (19) 40
6.3 ( )
15% (6)
Institution Q 52
12% (6) 43
4.8 ( )
9% (4)
Institution D 47 38
4.6 ( )
11% (4)
Institution T 36
19% (7) 29
6.1 ( )
14% (4)
Institution M 34
38% (13) 20
5.2 ( )
15% (3)
Institution F 30
20% (6) 22
3.2 ( )
14% (3)
Institution N
28% (8) 14
6.1 ( )
7% (1)
Institution H
0% (0) 21
4.0 ( )
10% (2)
Institution K
5.8 ( )
Institution A 19
42% (8) 11
6.3 ( )
9% (1)
Institution G 18
22% (4)
5.5 ( )
Institution S
35% (5) 7
4.0 ( )
14% (1)
Institution E 13
38% (5) 6
5.3 ( )
Institution B
36% (4)
4.8 ( )
17% (1)
Institution O 10
10% (1) 9
3.8 ( )
Institution L
11% (1) 8
5.6 ( )
Institution C
43% (3) 4
7.6 ( )
Institution J 2
6.8 ( )
Institution R 1
5.1 ( )
Institution U
3.2 ( )