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Evolution of the Norwood operation outcomes in patients with late presentation
Journal Pre-proof Evolution of the Norwood Operation Outcomes in Patients with Late Presentation Mohamed F. Ismail, Ahmed F. Elmahrouk, Amr A. Arafat, Tamer E. Hamouda, Bayan A. Alshaikh, Mohammad S. Shihata, Ahmed A. Jamjoom, Osman O. Al-Radi PII:
S0022-5223(19)33096-X
DOI:
https://doi.org/10.1016/j.jtcvs.2019.07.154
Reference:
YMTC 15349
To appear in:
The Journal of Thoracic and Cardiovascular Surgery
Received Date: 13 February 2019 Revised Date:
5 July 2019
Accepted Date: 11 July 2019
Please cite this article as: Ismail MF, Elmahrouk AF, Arafat AA, Hamouda TE, Alshaikh BA, Shihata MS, Jamjoom AA, Al-Radi OO, Evolution of the Norwood Operation Outcomes in Patients with Late Presentation, The Journal of Thoracic and Cardiovascular Surgery (2019), doi: https://doi.org/10.1016/ j.jtcvs.2019.07.154. 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. Copyright © 2019 Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery
1
Evolution of the Norwood Operation Outcomes in Patients with Late
2
Presentation
3 4 5
Mohamed F. Ismail1,2, Ahmed F. Elmahrouk1, Amr A. Arafat3, Tamer E. Hamouda1,4, Bayan A. Alshaikh5, Mohammad S. Shihata1, Ahmed A. Jamjoom1, and Osman O. Al-Radi 1,6,
6 7 8 9 10 11 12 13 14
1.
2. 3. 4. 5. 6.
Division of Cardiac Surgery, Cardiovascular Department, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia. Cardio-thoracic Surgery Department, Mansoura University, Mansoura, Egypt. Cardiothoracic Surgery Department, Tanta University, Tanta, Egypt. Cardio-thoracic Surgery Department, Benha University, Benha, Egypt. Cardiac Surgery, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia Cardiac Surgery Section, Department of Surgery, King Abdulaziz University, Jeddah, Saudi Arabia.
15
Conflict of interest: None
16
Funding: None
17
Word Count:
18
Manuscript: ~3500
19
Ethical committee approval: (Reference Number IRB 2016-61, CVD-J/237/38)
20
Corresponding author:
21
Osman O. Al-Radi, MBBS, MSc, FRCSC,
22
MBC J-16, P.O. Box:40047, Jeddah 21499, Saudi Arabia.
23
E-mail: [email protected]
24 25 26 27 28 29
1
30
Abstract
31
Objectives: We present the evolution of Norwood operation outcomes and practice
32
pattern changes over 15 years from a single institution in Saudi Arabia. We intended to
33
identify time-trends in patient selection, procedural details, and outcome predictors over
34
time.
35
Methods: Patients who underwent a Norwood operation (n= 145) between 2003 and
36
2018 with the use of a Blalock-Taussig shunt (BT group; n= 72), right ventricle to
37
pulmonary artery shunt (Sano group; n= 66), or a primary cavo-pulmonary shunt (CPS
38
group; n=7), were included. The study outcomes were operative mortality, long-term
39
survival, and multistate transition to CPS, Fontan, and death.
40
Results: Median age was 29 days. Predictors of operative mortality were lower weight
41
(p= 0.026), and longer bypass time (p= 0.014), whereas, age and type of shunt were
42
not. Predictors of improved long-term survival were higher weight at operation
43
(p=0.0016), later era (p=0.006) and shorter bypass time (p=0.001). The multistate
44
model revealed that lower weight patients were more likely to undergo Sano vs. BT (p
45
<0.001), and if BT was chosen in such patients, they were more likely to die (p =0.027).
46
The likelihood of receiving Sano shunt was three-fold higher in the recent era (p=
47
0.003).
48
Conclusions: Improved outcomes of the Norwood operation are evident in the recent
49
era and with Sano shunt, especially in smaller weight patients. Late presentation or
50
older age is not a contraindication to Norwood operation. The incorporation of a primary
51
CPS at stage one operation is feasible in selected patients.
52 53
Word count: 247/250
54 55
Keywords: Norwood operation; Sano shunt; BT shunt; Cavo-pulmonary connection;
56
HLHS.
57 58 59 60
2
61 Center message
62 63 64
Sano shunt is associated with improved outcomes, especially in smaller patients.
65
CPS, as a component of the initial Norwood operation, is feasible in patients with low
66
pulmonary vascular resistance.
67 68
Characters+ spaces= 194/200
69 Central figure
70
71 72
The effect of era and type of shunt on long-term survival after the Norwood operation.
73
Characters +spaces= 90/90
74 75 76 77 3
78 79
Perspective statement
80
The current outcomes of the Norwood operation warrant offering the treatment to most
81
patients with hypoplastic left heart syndrome and similar lesions even with delayed
82
presentation. The use of Sano shunt was associated with improved outcomes.
83
Utilization of the CPS as a component of the initial Norwood operation is feasible and
84
safe in carefully selected patients with low pulmonary vascular resistance.
85 86
Characters+ spaces= 405/405
87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108
4
109 110 Introduction
111 112 113
The Norwood operation is the mainstay of initial palliation for Hypoplastic Left Heart
114
Syndrome (HLHS) and other single ventricle lesions with inadequate left side cardiac
115
structures. Since the introduction of the Norwood procedure, several shunt types were
116
described with variable outcomes. (1-3) Early in the development of Norwood
117
procedure, large right ventricle (RV) to pulmonary artery (PA) conduit/shunt was
118
attempted as a source of pulmonary blood flow after the Norwood procedure. (4) This
119
technique was abandoned in favor of a modified Blalock-Taussig shunt (BT), with a
120
polytetrafluoroethylene (PTFE) tube connecting the subclavian artery and the
121
pulmonary artery.
122
modification of the Norwood procedure by placing a larger PTFE graft between the right
123
ventricle and the pulmonary arteries but not as large as the original Norwood RV-PA
124
conduits. (6)
(5) Decades later, in 2003 Sano and colleagues reported a
125 126
Right ventricle to pulmonary artery conduit (Sano) may be associated with improved
127
operative outcomes, but the long-term survival and ventricular function could be
128
affected because of the ventriculotomy. In a propensity score-matched study, (7)
129
patients with a Sano shunt had better survival compared to BT shunt, and right
130
ventricular function was not different. In another series, RV function was lower after the
131
first stage with a BT shunt compared to Sano shunt; however, RV function improved
132
after the second and third stages of palliation. (8) Ventricular arrhythmia occurred more
133
frequently after Sano shunt, which correlated with late mortality in those patients. (9)
134
Despite the improved results of the Norwood procedure recently, heart failure and listing
135
for transplant are common after the procedure. (10)
136
The consistent performance and acceptable outcomes of the Norwood operation have
137
not been reported outside the developed countries. (11) Unique challenges exist in this
138
setting, mainly delayed diagnosis and presentation, and physiologic consequences of
139
unprotected pulmonary blood flow. We sought to present the evolution of the Norwood
5
140
operation, practice changes, and outcomes over 15 years from a single institution in
141
Saudi Arabia. Moreover, we intended to identify time-trends in patient selection,
142
procedural details, and outcomes as well as predictors of success or failure over follow-
143
up time. Patients and Methods
144 145
Study population:
146
The study included all patients who underwent Norwood procedure (n= 145) at King
147
Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia, between March
148
2003 and March 2018. Indications for the Norwood operation were HLHS, HLHS
149
variants, other univentricular anomalies with coarctation, and/or arch hypoplasia, and
150
severe forms of the Shone’s complex. Data are part of the Congenital Cardiac Surgery
151
Database (CCSdb) available at www.ccsdb.org and were populated prospectively.
152
Study design:
153
This is a retrospective cohort study in which the prospectively collected data in the
154
computerized surgical database were augmented with retrospective chart review and
155
direct or phone interview to assure currency of follow-up, which was completed in 98%
156
of patients within 6 months of the study date. The patients were grouped based on the
157
type of shunt used to provide pulmonary blood flow into three groups. The “BT” group
158
received
159
Polytetrafluorethylene (PTFE), the “Sano” group received a right ventricle to pulmonary
160
artery shunt also made of PTFE but larger size and the “CPS” group received a superior
161
cavo-pulmonary shunt (CPS) during the Norwood operation as the sole source of
162
pulmonary blood flow. A CPS was only used if there was objective evidence of very low
163
pulmonary vascular resistance and high pulmonary blood flow (Qp) to systemic blood
164
flow (Qs) ratio despite unrestricted pulmonary blood flow. This was confirmed both
165
clinically and by invasive catheterization. Patients were offered a primary CPS if they
166
had low weight for age, and arterial oxygen saturation by non-invasive oximetry > 95%
167
on room air, and Qp/Qs ≥ 2.3:1 or higher by invasive cardiac catheterization.
168
The Institutional Research Ethics Committee of King Faisal Specialist Hospital and
169
Research Center Jeddah approved the study protocol. (Reference Number IRB 2016-61,
170
CVD-J/237/38)
a
modified
BT
shunt
using
a
synthetic
tube
graft
made
of
6
171 172
Follow-up and study outcomes:
173
The operative outcomes, including the use of extracorporeal membrane oxygenation
174
(ECMO) and death during hospitalization of any cause, were studied. Surviving patients
175
were followed in an outpatient setting every 2 to 6 weeks until the second stage
176
palliation and less frequently thereafter. Families of patients lost to follow-up were
177
contacted to ascertain their vital status and wellbeing. All interventions and subsequent
178
operations were recorded and included in the analysis. Cardiac catherization performed
179
prior to second and third stage operations were examined.
180 181
Operative technique:
182
A median sternotomy was done in all patients, full exposure of the aorta including the
183
arch, and proximal part of the descending aorta was achieved. Cannulation of the main
184
pulmonary artery, aorta, innominate artery either directly or through a PTFE graft was
185
used for arterial perfusion.
186
drainage. Cardiopulmonary bypass (CPB) was established with systemic hypothermia
187
from 18° to 20°C. Antegrade cerebral perfusion was utilized in 111 patients (76.6%),
188
and no retrograde cerebral or distal aortic perfusion methods were used. Antegrade
189
cardioplegia was given through an aortic cannula or retrogradely into the aortic arch.
190
The pulmonary arteries were occluded to optimize systemic cooling and avoid
191
pulmonary edema. After cooling, the ductus arteriosus was divided. The coarctation was
192
excised if a significant posterior shelf was present. Aortic continuity was re-established
193
by direct aorta to aorta anastomosis posterolateral. The arch and descending aorta
194
were augmented with homograft tissue; bovine or equine pericardium. The main
195
pulmonary artery was divided and incorporated into the arch repair forming a Damus-
196
Kay-Stansel (DKS) connection. After arch reconstruction, the arch was perfused, and
197
the patient rewarmed. Atrial septectomy was done via a small right atrial incision. The
198
construction of a BT, Sano, or CPS shunt concluded the operation.
199
At the beginning of our experience, we tended to use BT shunt for all Norwood
200
procedures, and this practice was gradually changed, and Sano shunt gained more
201
popularity among the team. However, some surgeons are still using BT shunt if the
Cannulation of the right atrium was used for venous
7
202
aortic valve is not atretic, the ascending aorta and the origin of the brachiocephalic
203
artery are of good size.
204
In our current practice, Sano is preferred in lower weight patients; however, we do not
205
have a specific cut-off weight. Five surgeons contributed to the data set. Shunt type and
206
size were determined by the surgeon’s preference and experience. In the BT group, a
207
3.5- or 4-mm PTFE graft was anastomosed to the innominate artery and the pulmonary
208
artery confluence. In the Sano group, a size 5 or 6 PTFE graft was sutured to an
209
anterior ventriculotomy and the pulmonary artery confluence. The proximal anastomosis
210
was done with several different techniques including direct beveled anastomosis, direct
211
anastomosis with a pericardial hood, and with a ring reinforced conduit inserted into the
212
wall of the RV (Propaten; Gore-Tex; W. L. Gore & Associates, Inc, Flagstaff, Ariz). The
213
graft was placed on the left of the reconstructed arch in most patients. In the CPS
214
group; the superior vena cava (SVC) was divided and anastomosed to the right
215
pulmonary artery as a bidirectional cavo-pulmonary shunt. At the end of surgery; the
216
chest was left open if deemed necessary by the surgeon. No patients were extubated in
217
the operating room.
218
All patients were under continuous monitoring in the intensive care unit (ICU), by direct
219
arterial pressure, end-tidal CO2, and pulse oximetry. Arterial and venous blood gas
220
analyses were drawn in 2-3-hour intervals, and urine output was collected hourly.
221
Afterload reduction was achieved with milrinone infusion and occasional Nipride
222
infusion. When clinical stability was achieved, and laboratory findings were normalized,
223
delayed sternal closure was performed in the ICU. Repeated echocardiogram studies
224
were performed before discharge to assess anatomic and hemodynamic parameters.
225
Patients were discharged when clinically stable.
226
All patients were followed up by pediatric cardiologists. Cardiac catheterization was
227
performed for all patients before second-stage palliation to assess pulmonary vascular
228
resistance, pulmonary artery pressure, and Qp/Qs ratio. Anatomical problems were
229
carefully studied, and residual problems treated interventionally if possible. Second
230
Stage Palliation with a bidirectional CPS was undertaken within 3 to 9 months after
231
stage I palliation using a direct anastomosis between the SVC and the right pulmonary
8
232
artery. The previous shunt was divided, and Fontan completion (extracardiac;
233
fenestrated or not) was done between 2 and 5 years of age.
234
Statistical methods:
235
Categorical variables were presented as frequency and percentage. Continuous
236
variables were presented as 25th, 50th (median), and 75th quartiles, and the range was
237
used when appropriate. Operative outcomes, including in-hospital mortality of any
238
cause and ECMO use, were analyzed with Pearson test for categorical variables and
239
Kruskal-Wallis test for continuous variables. Multivariable logistic regression was used
240
to identify independent predictors of in-hospital mortality. Time-related survival was
241
studied using a multivariable Cox proportional hazard model. Survival plots were
242
generated using Kaplan-Meier methods, and 0.67% (1 standard deviation) error bands
243
were used to generate the shaded area with the log-log method. (12)
244
A multistate stage semi-Markov model was also used to examine the frequency of
245
transition of patients between 6 distinct states, namely Unoperated, BT, Sano, CPS,
246
Fontan, and Dead. Group differences and predictors of each transition were studied.
247
There were 11 possible transitions namely from birth to BT, Sano, CPS or death; from
248
BT to CPS or death; from Sano to CPS or death; from CPS to Fontan or death, and
249
from Fontan to death. Patients who died without surgery were not included in the study.
250
Therefore, the transition from birth to death was not applicable. The mstate package
251
(13, 14) of the R-project software was used.
252 253
A p-value of less than 0.05 was considered significant. All analyses were done using the
254
R-project statistical program (version 3.3.2, R Development Core Team, R Foundation
255
for Statistical Computing, Vienna, Austria- www.R-project.org).
256 Results
257 258
Preoperative and operative data:
259
One hundred and forty-five patients were included in the analysis. (Figure 1) The
260
median age at the Norwood operation was 29 days (range: 2 – 344). The type of shunt
261
in the initial Norwood operation was BT in 72, Sano in 66, and CPS in 7 patients. Five
262
surgeons performed the operations with varied practice lengths. CPS patients had 9
263
significantly higher weight (median:3.6 kg; p= 0.004). The Sano group had more
264
patients with aortic atresia and mitral atresia (p= 0.001), longer deep hypothermic
265
circulatory arrest (DHCA) time (p< 0.001), Table 1. The number of Norwood operations
266
performed annually, and the corresponding operative mortality changed over time from
267
4 cases in 2004 with 50% mortality to 15 cases in 2017 with 7% mortality, Figure 2.
268
Seven patients were candidates for a primary CPS after diagnostic cardiac
269
catheterization. Two patients had HLHS, and the third patient had HLHS and right atrial
270
isomerism. The fourth patient had mitral atresia (MA), coarctation of the Aorta (CoA)
271
and double outlet right ventricle; the fifth baby had MA, CoA and d transposition of great
272
arteries (dTGA). Patient number 6 was diagnosed with double inlet left ventricle, CoA
273
and aortic arch hypoplasia, and the last patient had tricuspid atresia, dTGA, and
274
interrupted aortic arch.
275
Patients thought to be potential candidates for a primary CPS underwent cardiac
276
catheterization. The Median pulmonary vascular resistance (PVR) for those patients on
277
room air was 2.1 woods unit (25th- 75th percentiles: 1- 3.6), and median Qp/Qs was 5.3
278
(25th- 75th percentiles: 2.5- 7.6).
279 280
Postoperative outcomes:
281
There was no difference in hospital stay (p= 0.548) and ECMO use (p= 0.324) among
282
the groups, Table 2. All-cause mortality in patients who required ECMO was 71.4% (n=
283
10; 9 of them were hospital mortality) in the BT group, and 88.9% in the Sano group (n=
284
8, 6 of them were hospital mortality).
285
Over the study period, operative mortality was 32% (23/72) in the BT group, 27%
286
(15/66) in the Sano group, and 0% (0/7) in the CPS group. Independent predictors of
287
operative mortality were lower weight (p= 0.026), and longer bypass time (p= 0.014).
288
Age and type of shunt were not significant predictors of operative mortality. Long-term
289
survival stratified by the shunt type and operation era is shown in figure 3. Independent
290
predictors of improved long-term survival were higher weight at operation (p= 0.0016),
291
later time era (2011-2018 vs. 2004-2012) (p= 0.006) and shorter bypass time (p=
10
292
0.001). There was no difference in the freedom from an arch or pulmonary artery/shunt
293
interventions among the groups (p= 0.931 and 0.358; respectively)
294
Multi-state transition model:
295
The frequency and predictors of the transition of patients between 6 distinct states,
296
namely Unoperated, BT, Sano, CPS, Fontan, and Dead, were evaluated. The
297
proportion of patients in each state at follow-up times is shown in figure 4. The
298
multistate model revealed that lower weight patients were more likely to undergo Sano
299
vs. BT or CPS (Hazard ratio (HR)= 2.4; 95% CI: 1.6- 3.7; p-value <0.001), and if BT was
300
chosen for lower weight patients they were more likely to die (HR=1.7; 95% CI: 1.1- 2.7;
301
p-value=0.027). Lower weight may also be associated with a higher risk of death in the
302
Sano group; however, this association did not reach statistical significance, p-
303
value=0.07. Moreover, the likelihood of receiving a Sano shunt was three-fold higher in
304
the recent time era versus the older time era (p-value=0.003), and the hazard of death
305
after a Norwood with Sano shunt improved in the recent time era (HR = 0.29; 95% CI:
306
0.11- 0.77; p-value= 0.01). The risk of death from a Norwood BT was also lower in the
307
recent time era; (HR=0.5; 95% CI: 0.2- 1.2); however, this did not reach the statistical
308
significance level (p-value =0.13). (Table 3) (Graphical abstract)
309
Discussion
310
The management of HLHS and similar lesions still presents a challenge, especially with
311
delayed presentation, and the optimal shunt for the first stage Norwood palliation is a
312
topic of ongoing research. BT Norwood had the drawback of diastolic runoff and
313
increased pulmonary blood flow, which was found to be associated with poor outcomes.
314
(15) Sano conduits were associated with good operative outcomes; however, the right
315
ventriculotomy may affect the long-term outcomes. (16) Therefore the long-term survival
316
benefit of Sano versus BT shunt is still debatable. Additionally, the optimal shunt type
317
for delayed presentation patients has not been studied in the literature.
318
In this series, we compared three shunt types used for first stage Norwood palliation,
319
namely, BT, Sano, and CPS. The latter was used as a primary shunt type in patients
320
who presented late and had objective evidence of low pulmonary vascular resistance
321
despite the unrestricted pulmonary blood flow. During the study period, Sano conduits
322
were more commonly used in the recent era (2011-2018) compared to BT shunts. The
11
323
mortality improved markedly with the use of Sano shunts, but this also coincided with
324
the overall improved mortality in the recent era. Preoperatively, CPS patients were older
325
and had higher body weight compared to other groups, albeit still, they were small for
326
age as they presented later. The delayed presentation was due to deficiencies in
327
antenatal diagnosis and timely access to tertiary care facilities mainly because of
328
shortages of neonatal intensive care beds. Norwood centers are limited in our country
329
and children diagnosed with HLHS are started on prostaglandin then the referral system
330
is activated. The transfer may take several weeks.
331 332
Similar to what was reported by Mair and colleagues; (17) there was no difference in
333
total cardiopulmonary bypass and aortic clamp time between BT and Sano groups;
334
however, CPS group had significantly lower CPB and clamp times in our series. The
335
lower CPB and clamp time in CPS group could be attributed to the smaller numbers of
336
anastomoses in this group; additionally, there may be a surgeon effect as the surgeon
337
performed this approach has lower times in other groups too. The hospital stay was not
338
different among the groups, similar to what was reported in the literature. (3, 7, 18)
339
ECMO support for patients with HLHS after stage I palliation was increasingly used;
340
however, mortality remained high. (19) Early deployment of ECMO and careful
341
management to avoid complications might help improve survival. (20, 21) In a study of
342
149 infants who underwent a stage I reconstruction Tabbutt and associates did not
343
record any difference in ECMO support between the two shunt types (14% for BT group
344
and 13% in Sano group). (22) In our cohort, fourteen patients (19%) in the BT group
345
were subjected to ECMO due to hemodynamic instability compared to 9 patients in the
346
Sano group (15.3%); one-third of them survived to hospital discharge. On the other
347
hand, none of the CPS group required ECMO support post-Norwood. This difference
348
was found statistically non-significant because of the small sample.
349 350
Shunt type did not predict operative mortality in our series and lower birth weight and
351
longer bypass time were independent predictors of operative mortality. In addition, long-
352
term survival was not affected by the shunt type and higher weight at operation, later
353
era (2011-2018 vs. 2004-2012) and shorter bypass time predicted better long-term
12
354
survival. The Single Ventricle Reconstruction (SVR) trial randomized 555 patients
355
undergoing the Norwood procedure to receive either BT or Sano shunt, and their
356
primary endpoint was the incidence of mortality or cardiac transplantation. After 6 years,
357
Sano patients had better transplant-free survival but did not reach a significant level,
358
and no difference was found in hazard of death and catheter-based reintervention
359
between groups. (23)
360
The inter-stage period is recognized as a period of fragility with a high incidence of
361
sudden and unexpected death. (3) The multistate analysis showed that Sano was more
362
likely to be performed in lower birth weight patients, and when BT shunt was performed
363
in this subset of patients, the transition to death was significantly higher. Our current
364
practice does not recommend BT shunt in low weight babies (<2.7kg), atretic aortic
365
valve, small ascending aorta (<2.5 mm) or small origin of the brachiocephalic artery.
366
Further analysis of our data revealed that the hazard of death had significantly
367
decreased in the recent era, especially with Sano and CPS patients. This could be
368
attributed to the building experience, the more liberal use of ECMO support and
369
improvement of our referral system. In a study by Tabbutt and associates, (22) patients
370
with Sano returned earlier for their stage II palliation which could be explained by the
371
earlier development of pulmonary arteries following RV-PA conduit, which was
372
demonstrated in earlier studies. (2, 24, 25) On the other hand, Fiore and colleagues,
373
(26) found that the timing of the second stage palliation was similar with both shunts.
374
Sano shunt patients could come earlier to the second stage due to increasing cyanosis
375
secondary to narrowing at the proximal or distal conduit anastomosis, and the technique
376
of retaining the PTFE ring as a stent for the outflow anastomosis had prevented early
377
conduit failure. (27, 28)
378 379
The SVR trial reported an increased incidence for balloon dilation or stent placement in
380
the shunt or branch PAs in Sano group. (2) A study by Gist and colleagues (29)
381
reported no shunt or pulmonary artery intervention for the BT group and 15% for the
382
Sano group and they attributed this to the difficult access to the pulmonary artery for
383
intervention in this group. Mery and colleagues (30) explained the higher incidence of
384
central pulmonary artery stenosis in Sano patients by the anterior pull on the pulmonary
13
385
artery confluence by the conduit as the child grows. In our series, we found no
386
difference in the incidence of the pulmonary artery or shunt intervention between the BT
387
and Sano groups. None of the CPS patients required intervention. These results
388
indicate the feasibility and safety to perform CPS with first stage palliation in selected
389
patients presenting late and demonstrating low pulmonary vascular resistance.
390 391
Study limitations and strength:
392
The major limitation of the study is the retrospective nature of the study with the
393
selection and referral bias inherited to this study design. Different measured and
394
unmeasured patient characteristics could have affected the outcomes, and patient and
395
procedure risks were not equally distributed between the groups. However, we used
396
multivariable logistic and Cox regression analysis to adjust for the measured variables
397
and identify the predictors of mortality and long-term survival. Another limitation of the
398
study is the single center experience, and generalization of the results may be
399
problematic. However, the study presents a large experience in the management of
400
HLHS and variants over 15 years with complete follow-up in 98% of the patients. In
401
addition, the study presents CPS shunt as a primary shunt for the first stage Norwood
402
palliation in selected patients and shows its safety and feasibility in those patients.
403 404
Conclusions
405
Improved outcomes of the Norwood operation are evident in the more recent time era
406
and with more frequent utilization of the Sano shunt, especially in smaller weight
407
patients. Late diagnosis or older age should not be considered a contraindication to the
408
Norwood operation. Use of the CPS as a component of the initial Norwood operation is
409
feasible and may be safe in carefully selected patients with low pulmonary vascular
410
resistance. The current outcomes of the Norwood operation warrant offering the
411
treatment to most patients with hypoplastic left heart syndrome and similar lesions even
412
with delayed presentation.
413 414 415
14
416 417 418 419 420 421
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1. Graham EM, Zyblewski SC, Phillips JW, Shirali GS, Bradley SM, Forbus GA, et al. Comparison of Norwood shunt types: do the outcomes differ 6 years later? The Annals of thoracic surgery. 2010;90(1):31-5. 2. Ohye RG, Sleeper LA, Mahony L, Newburger JW, Pearson GD, Lu M, et al. Comparison of shunt types in the Norwood procedure for single-ventricle lesions. The New England journal of medicine. 2010;362(21):1980-92. 3. Ballweg JA, Dominguez TE, Ravishankar C, Gaynor JW, Nicolson SC, Spray TL, et al. A contemporary comparison of the effect of shunt type in hypoplastic left heart syndrome on the hemodynamics and outcome at Fontan completion. The Journal of thoracic and cardiovascular surgery. 2010;140(3):537-44. 4. Norwood WI, Lang P, Casteneda AR, Campbell DN. Experience with operations for hypoplastic left heart syndrome. The Journal of thoracic and cardiovascular surgery. 1981;82(4):511-9. 5. Barnea O, Austin EH, Richman B, Santamore WP. Balancing the circulation: theoretic optimization of pulmonary/systemic flow ratio in hypoplastic left heart syndrome. Journal of the American College of Cardiology. 1994;24(5):1376-81. 6. Sano S, Ishino K, Kawada M, Arai S, Kasahara S, Asai T, et al. Right ventricle-pulmonary artery shunt in first-stage palliation of hypoplastic left heart syndrome. The Journal of thoracic and cardiovascular surgery. 2003;126(2):504-9; discussion 9-10. 7. Wilder TJ, McCrindle BW, Phillips AB, Blackstone EH, Rajeswaran J, Williams WG, et al. Survival and right ventricular performance for matched children after stage-1 Norwood: Modified Blalock-Taussig shunt versus right-ventricle-to-pulmonary-artery conduit. The Journal of thoracic and cardiovascular surgery. 2015;150(6):1440-50, 52.e1-8; discussion 50-2. 8. Ruotsalainen HK, Pihkala J, Salminen J, Hornberger LK, Sairanen H, Ojala T. Initial shunt type at the Norwood operation impacts myocardial function in hypoplastic left heart syndrome. European journal of cardio-thoracic surgery. 2017;52(2):234-40. 9. Hall EJ, Smith AH, Fish FA, Bichell DP, Mettler BA, Crum K, et al. Association of Shunt Type With Arrhythmias After Norwood Procedure. The Annals of thoracic surgery. 2018;105(2):629-36. 10. Mahle WT, Hu C, Trachtenberg F, Menteer J, Kindel SJ, Dipchand AI, et al. Heart failure after the Norwood procedure: An analysis of the Single Ventricle Reconstruction Trial. The Journal of heart and lung transplantation. 2018;37(7):879-85. 11. Cao JY, Lee SY, Phan K, Ayer J, Celermajer DS, Winlaw DS. Early Outcomes of Hypoplastic Left Heart Syndrome Infants: Meta-Analysis of Studies Comparing the Hybrid and Norwood Procedures. World journal for pediatric & congenital heart surgery. 2018;9(2):224-33.
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12. THERNEAU TM, GRAMBSCH PM, FLEMING TR. Martingale-based residuals for survival models. Biometrika. 1990;77(1):147-60. 13. de Wreede LC, Fiocco M, Putter H. The mstate package for estimation and prediction in non- and semi-parametric multi-state and competing risks models. Computer methods and programs in biomedicine. 2010;99(3):261-74. 14. Putter H, Fiocco M, Geskus RB. Tutorial in biostatistics: competing risks and multi-state models. Statistics in medicine. 2007;26(11):2389-430. 15. Soo KW, Brink J, d'Udekem Y, Butt W, Namachivayam SP. Major Adverse Events Following Over-Shunting Are Associated With Worse Outcomes Than Major Adverse Events After a Blocked Systemic-to-Pulmonary Artery Shunt Procedure. Pediatric critical care medicine. 2018;19(9):854-60. 16. Frommelt PC, Gerstenberger E, Cnota JF, Cohen MS, Gorentz J, Hill KD, et al. Impact of initial shunt type on cardiac size and function in children with single right ventricle anomalies before the Fontan procedure: the single ventricle reconstruction extension trial. Journal of the American College of Cardiology. 2014;64(19):2026-35. 17. Mair R, Tulzer G, Sames E, Gitter R, Lechner E, Steiner J, et al. Right ventricular to pulmonary artery conduit instead of modified Blalock-Taussig shunt improves postoperative hemodynamics in newborns after the Norwood operation. The Journal of thoracic and cardiovascular surgery. 2003;126(5):1378-84. 18. Edwards L, Morris KP, Siddiqui A, Harrington D, Barron D, Brawn W. Norwood procedure for hypoplastic left heart syndrome: BT shunt or RV-PA conduit? Archives of disease in childhood Fetal and neonatal edition. 2007;92(3):F210-4. 19. Sherwin ED, Gauvreau K, Scheurer MA, Rycus PT, Salvin JW, Almodovar MC, et al. Extracorporeal membrane oxygenation after stage 1 palliation for hypoplastic left heart syndrome. The Journal of thoracic and cardiovascular surgery. 2012;144(6):1337-43. 20. Januszewska K, Stebel A, Malec E. Consequences of right ventricle-to-pulmonary artery shunt at the first stage for the Fontan operation. The Annals of thoracic surgery. 2007;84(5):1611-7. 21. ElMahrouk AF, Ismail MF, Hamouda T, Shaikh R, Mahmoud A, Shihata MS, et al. Extracorporeal Membrane Oxygenation in Postcardiotomy Pediatric Patients-15 Years of Experience Outside Europe and North America. The Thoracic and cardiovascular surgeon. 2019;67(1):28-36. 22. Tabbutt S, Dominguez TE, Ravishankar C, Marino BS, Gruber PJ, Wernovsky G, et al. Outcomes after the stage I reconstruction comparing the right ventricular to pulmonary artery conduit with the modified Blalock Taussig shunt. The Annals of thoracic surgery. 2005;80(5):1582-90; discussion 90-1. 23. Newburger JW, Sleeper LA, Gaynor JW, Hollenbeck-Pringle D, Frommelt PC, Li JS, et al. Transplant-Free Survival and Interventions at 6 Years in the SVR Trial. Circulation. 2018;137(21):2246-53. 24. Maher KO, Pizarro C, Gidding SS, Januszewska K, Malec E, Norwood WI, Jr., et al. Hemodynamic profile after the Norwood procedure with right ventricle to pulmonary artery conduit. Circulation. 2003;108(7):782-4.
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25. Caspi J, Pettitt TW, Mulder T, Stopa A. Development of the pulmonary arteries after the Norwood procedure: comparison between Blalock-Taussig shunt and right ventricularpulmonary artery conduit. The Annals of thoracic surgery. 2008;86(4):1299-304. 26. Fiore AC, Tobin C, Jureidini S, Rahimi M, Kim ES, Schowengerdt K. A comparison of the modified Blalock-Taussig shunt with the right ventricle-to-pulmonary artery conduit. The Annals of thoracic surgery. 2011;91(5):1479-84; discussion 84-5. 27. Baird CW, Myers PO, Borisuk M, Pigula FA, Emani SM. Ring-reinforced Sano conduit at Norwood stage I reduces proximal conduit obstruction. The Annals of thoracic surgery. 2015;99(1):171-9. 28. Bentham JR, Baird CW, Porras DP, Rathod RH, Marshall AC. A reinforced right-ventricleto-pulmonary-artery conduit for the stage-1 Norwood procedure improves pulmonary artery growth. The Journal of thoracic and cardiovascular surgery. 2015;149(6):1502-8.e1. 29. Gist KM, Barrett CS, Graham DA, Crumback SL, Schuchardt EL, Erickson B, et al. Pulmonary artery interventions after Norwood procedure: does type or position of shunt predict need for intervention? The Journal of thoracic and cardiovascular surgery. 2013;145(6):1485-92. 30. Mery CM, Lapar DJ, Seckeler MD, Chamberlain RS, Gangemi JJ, Kron IL, et al. Pulmonary artery and conduit reintervention rates after norwood using a right ventricle to pulmonary artery conduit. The Annals of thoracic surgery. 2011;92(4):1483-9; discussion 9.
519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 17
536 537 538 539 540 541 542
Tables and figures legends
543
Table1: Descriptive Statistics of preoperative and operative variables by type of shunt
544
(N=145).
545
Table 2: Descriptive Statistics of postoperative events by type of shunt (N=145).
546
Table 3: Multistate model: the effect of predictive factors; weight (top) and time era
547
(bottom) on transition probability (presented as a hazard ratio) between 6 distinct states
548
namely; Unoperated, BT, Sano, CPS, Fontan, and Dead.
549
Figure 1: The flowchart of patients included in the study
550
Figure 2: Operative mortality per year shown by shunt type; shunt.
551
Taussig shunt; Sano: Right ventricle to pulmonary artery shunt, CPS: Cavo-pulmonary
552
shunt)
553
Figure 3: Kaplan-Meier survival curve for the three shunt groups stratified by the time
554
era (2004- 2010 and 2011- 2018). Patients at risk are shown underneath the figure.
555
0.67% (1 standard deviation) error bands were used to generate the shaded area with
556
the log-log method.
557
(BT: Blalock Taussig shunt; Sano: Right ventricle to pulmonary artery shunt; CPS:
558
Cavo-pulmonary shunt).
559
Figure 4: The proportion of patients and the transition between 6 distinct states namely;
560
Unoperated, BT, Sano, CPS, Fontan, and Dead are shown in the y-axis versus follow-
561
up time in the x-axis. (BT: Blalock Taussig shunt; Sano: Right ventricle to pulmonary
562
artery shunt, CPS: Cavo-pulmonary shunt)
563
Graphical abstract: The flowchart of Norwood patients, the long-term survival, and the
564
interstage transition.
565
Video legend: Video presentation summarizing the study and explaining the indications
566
of Cavo-pulmonary shunt as first stage Norwood operation.
(BT= Blalock
18
567 568 569 570 571 572 573 574
Figure 1
575
576 577 578 579 580 581 582
19
583 584 585 586 587 588 589 590
Figure 2
591 592
20
593
Figure 3
594 595
21
596
Figure 4
597
22
Table1: Descriptive Statistics of preoperative and operative variables by type of shunt (N=145). N
BT
CPS
Sano
N=72
N=7
N=66
Gender: male
145 0.57
Age
145
18.00
143
2.8
(days)
Weight
(kg)
0.57
(41)
29.50
3.2
3.6
51.00
66.00 3.3
0.64
(4)
112.00
3.6
4.8
149.00
16.00 2.7
P-value 0.7161
(42)
26.00
3.0
3.3
46.75
0.0022 0.0042
Type of HLHS anatomy: AAMA
121
0.0011 0.17
(9)
0.14
(1)
0.45
(28)
AAMS
0.02
(1)
0.14
(1)
0.10
(6)
ASMA
0.15
(8)
0.00
(0)
0.13
(8)
ASMS
0.37
(19)
0.29
(2)
0.06
(4)
Other
0.29
(15)
0.43
(3)
0.26
(16)
145 0.29
(21)
1.00
(7)
0.86
(57)
A
145 0.67
(48)
0.29
(2)
0.33
(22)
B
0.25
(18)
0.00
(0)
0.11
(7)
C
0.00
(0)
0.00
(0)
0.09
(6)
Time Era: [2011,2018] Surgeon:
<0.0011 <0.0011
D
0.01
(1)
0.00
(0)
0.17
(11)
E
0.07
(5)
0.71
(5)
0.30
(20)
142
128.00
162.00
137
63.25
143
0.0
CPB time
(min)
185.00
68.50
73.00
79.00
84.50
127.50
32.00
35.00
70.50
49.75
66.00
165.75
<0.0012
Aortic clamp time
81.50
100.00
92.25
0.0122
(min)
DHCA time
(min)
Total circulatory arrest
0.0
7.5
19.0
24.0
34.5
2.0
36.0
65.0
<0.0012
145 0.028 (2)
0.85 (6)
0.39 (26)
<0.0011
145 0.95 (69)
0.28 (2)
0.60 (40)
<0.0011
Antegrade cerebral perfusion a
b c represent the 25th quartile a, the median b, and the 75th quartile c for continuous variables. N is the number of non-missing
values. Numbers after proportions are frequencies. Tests used: 1Pearson test; 2Kruskal-Wallis test. AAMA: Aortic Atresia with Mitral Atresia, AAMS: Aortic Atresia with Mitral Stenosis, ASMA: Aortic Stenosis with Mitral Atresia, ASMS: Aortic Stenosis with Mitral Stenosis. DHCA: Deep Hypothermic Circulatory Arrest. DHCA was included in the aortic clamp time but not part of the total bypass time.
Table 2: Descriptive Statistics of postoperative events by type of shunt (N=145). N Post-operative length of stay (Days) ECMO Arch intervention:
BT
CPS
Sano
N=72
N=7
N=66
140
10.75
145
0.19
145
25.00 (14)
39.25
26.00
31.00
0.00
(0)
34.50
11.00
0.14
22.00 (9)
0.83
(60)
0.86
(6)
0.82
(54)
Post Glenn balloon
0.00
(0)
0.14
(1)
0.00
(0)
Pre Glenn-balloon
0.11
(8)
0.00
(0)
0.12
(8)
Pre Glenn-CoA stent
0.06
(4)
0.00
(0)
0.06
(4)
None
P-value
38.00
0.5481 0.3242 0.0022
PA or shunt intervention:
144
None Pre Glenn-PA stent Pre Glenn-shunt stent Operative Outcome:
145
0.93
(67)
1.00
(7)
0.88
(57)
0.03
(2)
0.00
(0)
0.08
(5)
0.04
(3)
0.00
(0)
0.05
(3)
0.68
(49)
1.00
(7)
0.77
(51)
0.6352
0.1272
Alive a
b c represent the 25th quartile a, the median b, and the 75th quartile c for continuous variables.
N is the number of non-missing values. Numbers after proportions are frequencies. Tests used: 1Pearson test; 2Kruskal-Wallis test.
Table 3: Multistate model, predictors of transitions between states From\To Birth BT
BT 0.846 1.170 1.617 (0.3)
Hazard ratio for lower Weight (by 1 kg) CPS Fontan
Sano 1.573 2.398 3.654 (<0.001)
Death
0.587 1.091 2.031 (0.8)
NE
0.799 1.034 1.339 (0.8)
1.061 1.691 2.694 (0.027)
0.875 1.861 3.959
(0.107)
Sano CPS Fontan
From\To
0.942 2.137 4.852 (0.069) 0.602 0.840 1.173 (0.3)
0.551 1.223 2.715 (0.6) 0.152 0.455 1.357 (0.16)
BT 0.133 0.222 0.372 (<0.001)
Hazard ratio for time era [2013-2018] vs. [2003-2013) Sano CPS Fontan
Death
Birth * NE 1.454 2.954 5.999 (0.003) BT 0.706 1.437 2.924 (0.3) 0.204 0.501 1.234 (0.13) Sano 0.2210.8012.897 (0.7) 0.108 0.288 0.766 (0.013) CPS 0.554 1.909 6.581 (0.3) 0.055 0.238 1.039 (0.056) Fontan * States in left Colum indicate the “From” states and those in top row indicate the “To” state for each transition. Grey cells indicate invalid transitions. Each cell shows the effect of the predictor as a Hazard Ratio (HR) with 95% confidence intervals (CI) in subscripts, lower 95%CI HR higher 95%CI. Numbers between brackets represent p-values, significant p-values are shown in italic. NE: No events. * indicate that the number of cases and events are too small for reliable statistics.
S0022-5223(19)33096-X
DOI:
https://doi.org/10.1016/j.jtcvs.2019.07.154
Reference:
YMTC 15349
To appear in:
The Journal of Thoracic and Cardiovascular Surgery
Received Date: 13 February 2019 Revised Date:
5 July 2019
Accepted Date: 11 July 2019
Please cite this article as: Ismail MF, Elmahrouk AF, Arafat AA, Hamouda TE, Alshaikh BA, Shihata MS, Jamjoom AA, Al-Radi OO, Evolution of the Norwood Operation Outcomes in Patients with Late Presentation, The Journal of Thoracic and Cardiovascular Surgery (2019), doi: https://doi.org/10.1016/ j.jtcvs.2019.07.154. 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. Copyright © 2019 Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery
1
Evolution of the Norwood Operation Outcomes in Patients with Late
2
Presentation
3 4 5
Mohamed F. Ismail1,2, Ahmed F. Elmahrouk1, Amr A. Arafat3, Tamer E. Hamouda1,4, Bayan A. Alshaikh5, Mohammad S. Shihata1, Ahmed A. Jamjoom1, and Osman O. Al-Radi 1,6,
6 7 8 9 10 11 12 13 14
1.
2. 3. 4. 5. 6.
Division of Cardiac Surgery, Cardiovascular Department, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia. Cardio-thoracic Surgery Department, Mansoura University, Mansoura, Egypt. Cardiothoracic Surgery Department, Tanta University, Tanta, Egypt. Cardio-thoracic Surgery Department, Benha University, Benha, Egypt. Cardiac Surgery, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia Cardiac Surgery Section, Department of Surgery, King Abdulaziz University, Jeddah, Saudi Arabia.
15
Conflict of interest: None
16
Funding: None
17
Word Count:
18
Manuscript: ~3500
19
Ethical committee approval: (Reference Number IRB 2016-61, CVD-J/237/38)
20
Corresponding author:
21
Osman O. Al-Radi, MBBS, MSc, FRCSC,
22
MBC J-16, P.O. Box:40047, Jeddah 21499, Saudi Arabia.
23
E-mail: [email protected]
24 25 26 27 28 29
1
30
Abstract
31
Objectives: We present the evolution of Norwood operation outcomes and practice
32
pattern changes over 15 years from a single institution in Saudi Arabia. We intended to
33
identify time-trends in patient selection, procedural details, and outcome predictors over
34
time.
35
Methods: Patients who underwent a Norwood operation (n= 145) between 2003 and
36
2018 with the use of a Blalock-Taussig shunt (BT group; n= 72), right ventricle to
37
pulmonary artery shunt (Sano group; n= 66), or a primary cavo-pulmonary shunt (CPS
38
group; n=7), were included. The study outcomes were operative mortality, long-term
39
survival, and multistate transition to CPS, Fontan, and death.
40
Results: Median age was 29 days. Predictors of operative mortality were lower weight
41
(p= 0.026), and longer bypass time (p= 0.014), whereas, age and type of shunt were
42
not. Predictors of improved long-term survival were higher weight at operation
43
(p=0.0016), later era (p=0.006) and shorter bypass time (p=0.001). The multistate
44
model revealed that lower weight patients were more likely to undergo Sano vs. BT (p
45
<0.001), and if BT was chosen in such patients, they were more likely to die (p =0.027).
46
The likelihood of receiving Sano shunt was three-fold higher in the recent era (p=
47
0.003).
48
Conclusions: Improved outcomes of the Norwood operation are evident in the recent
49
era and with Sano shunt, especially in smaller weight patients. Late presentation or
50
older age is not a contraindication to Norwood operation. The incorporation of a primary
51
CPS at stage one operation is feasible in selected patients.
52 53
Word count: 247/250
54 55
Keywords: Norwood operation; Sano shunt; BT shunt; Cavo-pulmonary connection;
56
HLHS.
57 58 59 60
2
61 Center message
62 63 64
Sano shunt is associated with improved outcomes, especially in smaller patients.
65
CPS, as a component of the initial Norwood operation, is feasible in patients with low
66
pulmonary vascular resistance.
67 68
Characters+ spaces= 194/200
69 Central figure
70
71 72
The effect of era and type of shunt on long-term survival after the Norwood operation.
73
Characters +spaces= 90/90
74 75 76 77 3
78 79
Perspective statement
80
The current outcomes of the Norwood operation warrant offering the treatment to most
81
patients with hypoplastic left heart syndrome and similar lesions even with delayed
82
presentation. The use of Sano shunt was associated with improved outcomes.
83
Utilization of the CPS as a component of the initial Norwood operation is feasible and
84
safe in carefully selected patients with low pulmonary vascular resistance.
85 86
Characters+ spaces= 405/405
87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108
4
109 110 Introduction
111 112 113
The Norwood operation is the mainstay of initial palliation for Hypoplastic Left Heart
114
Syndrome (HLHS) and other single ventricle lesions with inadequate left side cardiac
115
structures. Since the introduction of the Norwood procedure, several shunt types were
116
described with variable outcomes. (1-3) Early in the development of Norwood
117
procedure, large right ventricle (RV) to pulmonary artery (PA) conduit/shunt was
118
attempted as a source of pulmonary blood flow after the Norwood procedure. (4) This
119
technique was abandoned in favor of a modified Blalock-Taussig shunt (BT), with a
120
polytetrafluoroethylene (PTFE) tube connecting the subclavian artery and the
121
pulmonary artery.
122
modification of the Norwood procedure by placing a larger PTFE graft between the right
123
ventricle and the pulmonary arteries but not as large as the original Norwood RV-PA
124
conduits. (6)
(5) Decades later, in 2003 Sano and colleagues reported a
125 126
Right ventricle to pulmonary artery conduit (Sano) may be associated with improved
127
operative outcomes, but the long-term survival and ventricular function could be
128
affected because of the ventriculotomy. In a propensity score-matched study, (7)
129
patients with a Sano shunt had better survival compared to BT shunt, and right
130
ventricular function was not different. In another series, RV function was lower after the
131
first stage with a BT shunt compared to Sano shunt; however, RV function improved
132
after the second and third stages of palliation. (8) Ventricular arrhythmia occurred more
133
frequently after Sano shunt, which correlated with late mortality in those patients. (9)
134
Despite the improved results of the Norwood procedure recently, heart failure and listing
135
for transplant are common after the procedure. (10)
136
The consistent performance and acceptable outcomes of the Norwood operation have
137
not been reported outside the developed countries. (11) Unique challenges exist in this
138
setting, mainly delayed diagnosis and presentation, and physiologic consequences of
139
unprotected pulmonary blood flow. We sought to present the evolution of the Norwood
5
140
operation, practice changes, and outcomes over 15 years from a single institution in
141
Saudi Arabia. Moreover, we intended to identify time-trends in patient selection,
142
procedural details, and outcomes as well as predictors of success or failure over follow-
143
up time. Patients and Methods
144 145
Study population:
146
The study included all patients who underwent Norwood procedure (n= 145) at King
147
Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia, between March
148
2003 and March 2018. Indications for the Norwood operation were HLHS, HLHS
149
variants, other univentricular anomalies with coarctation, and/or arch hypoplasia, and
150
severe forms of the Shone’s complex. Data are part of the Congenital Cardiac Surgery
151
Database (CCSdb) available at www.ccsdb.org and were populated prospectively.
152
Study design:
153
This is a retrospective cohort study in which the prospectively collected data in the
154
computerized surgical database were augmented with retrospective chart review and
155
direct or phone interview to assure currency of follow-up, which was completed in 98%
156
of patients within 6 months of the study date. The patients were grouped based on the
157
type of shunt used to provide pulmonary blood flow into three groups. The “BT” group
158
received
159
Polytetrafluorethylene (PTFE), the “Sano” group received a right ventricle to pulmonary
160
artery shunt also made of PTFE but larger size and the “CPS” group received a superior
161
cavo-pulmonary shunt (CPS) during the Norwood operation as the sole source of
162
pulmonary blood flow. A CPS was only used if there was objective evidence of very low
163
pulmonary vascular resistance and high pulmonary blood flow (Qp) to systemic blood
164
flow (Qs) ratio despite unrestricted pulmonary blood flow. This was confirmed both
165
clinically and by invasive catheterization. Patients were offered a primary CPS if they
166
had low weight for age, and arterial oxygen saturation by non-invasive oximetry > 95%
167
on room air, and Qp/Qs ≥ 2.3:1 or higher by invasive cardiac catheterization.
168
The Institutional Research Ethics Committee of King Faisal Specialist Hospital and
169
Research Center Jeddah approved the study protocol. (Reference Number IRB 2016-61,
170
CVD-J/237/38)
a
modified
BT
shunt
using
a
synthetic
tube
graft
made
of
6
171 172
Follow-up and study outcomes:
173
The operative outcomes, including the use of extracorporeal membrane oxygenation
174
(ECMO) and death during hospitalization of any cause, were studied. Surviving patients
175
were followed in an outpatient setting every 2 to 6 weeks until the second stage
176
palliation and less frequently thereafter. Families of patients lost to follow-up were
177
contacted to ascertain their vital status and wellbeing. All interventions and subsequent
178
operations were recorded and included in the analysis. Cardiac catherization performed
179
prior to second and third stage operations were examined.
180 181
Operative technique:
182
A median sternotomy was done in all patients, full exposure of the aorta including the
183
arch, and proximal part of the descending aorta was achieved. Cannulation of the main
184
pulmonary artery, aorta, innominate artery either directly or through a PTFE graft was
185
used for arterial perfusion.
186
drainage. Cardiopulmonary bypass (CPB) was established with systemic hypothermia
187
from 18° to 20°C. Antegrade cerebral perfusion was utilized in 111 patients (76.6%),
188
and no retrograde cerebral or distal aortic perfusion methods were used. Antegrade
189
cardioplegia was given through an aortic cannula or retrogradely into the aortic arch.
190
The pulmonary arteries were occluded to optimize systemic cooling and avoid
191
pulmonary edema. After cooling, the ductus arteriosus was divided. The coarctation was
192
excised if a significant posterior shelf was present. Aortic continuity was re-established
193
by direct aorta to aorta anastomosis posterolateral. The arch and descending aorta
194
were augmented with homograft tissue; bovine or equine pericardium. The main
195
pulmonary artery was divided and incorporated into the arch repair forming a Damus-
196
Kay-Stansel (DKS) connection. After arch reconstruction, the arch was perfused, and
197
the patient rewarmed. Atrial septectomy was done via a small right atrial incision. The
198
construction of a BT, Sano, or CPS shunt concluded the operation.
199
At the beginning of our experience, we tended to use BT shunt for all Norwood
200
procedures, and this practice was gradually changed, and Sano shunt gained more
201
popularity among the team. However, some surgeons are still using BT shunt if the
Cannulation of the right atrium was used for venous
7
202
aortic valve is not atretic, the ascending aorta and the origin of the brachiocephalic
203
artery are of good size.
204
In our current practice, Sano is preferred in lower weight patients; however, we do not
205
have a specific cut-off weight. Five surgeons contributed to the data set. Shunt type and
206
size were determined by the surgeon’s preference and experience. In the BT group, a
207
3.5- or 4-mm PTFE graft was anastomosed to the innominate artery and the pulmonary
208
artery confluence. In the Sano group, a size 5 or 6 PTFE graft was sutured to an
209
anterior ventriculotomy and the pulmonary artery confluence. The proximal anastomosis
210
was done with several different techniques including direct beveled anastomosis, direct
211
anastomosis with a pericardial hood, and with a ring reinforced conduit inserted into the
212
wall of the RV (Propaten; Gore-Tex; W. L. Gore & Associates, Inc, Flagstaff, Ariz). The
213
graft was placed on the left of the reconstructed arch in most patients. In the CPS
214
group; the superior vena cava (SVC) was divided and anastomosed to the right
215
pulmonary artery as a bidirectional cavo-pulmonary shunt. At the end of surgery; the
216
chest was left open if deemed necessary by the surgeon. No patients were extubated in
217
the operating room.
218
All patients were under continuous monitoring in the intensive care unit (ICU), by direct
219
arterial pressure, end-tidal CO2, and pulse oximetry. Arterial and venous blood gas
220
analyses were drawn in 2-3-hour intervals, and urine output was collected hourly.
221
Afterload reduction was achieved with milrinone infusion and occasional Nipride
222
infusion. When clinical stability was achieved, and laboratory findings were normalized,
223
delayed sternal closure was performed in the ICU. Repeated echocardiogram studies
224
were performed before discharge to assess anatomic and hemodynamic parameters.
225
Patients were discharged when clinically stable.
226
All patients were followed up by pediatric cardiologists. Cardiac catheterization was
227
performed for all patients before second-stage palliation to assess pulmonary vascular
228
resistance, pulmonary artery pressure, and Qp/Qs ratio. Anatomical problems were
229
carefully studied, and residual problems treated interventionally if possible. Second
230
Stage Palliation with a bidirectional CPS was undertaken within 3 to 9 months after
231
stage I palliation using a direct anastomosis between the SVC and the right pulmonary
8
232
artery. The previous shunt was divided, and Fontan completion (extracardiac;
233
fenestrated or not) was done between 2 and 5 years of age.
234
Statistical methods:
235
Categorical variables were presented as frequency and percentage. Continuous
236
variables were presented as 25th, 50th (median), and 75th quartiles, and the range was
237
used when appropriate. Operative outcomes, including in-hospital mortality of any
238
cause and ECMO use, were analyzed with Pearson test for categorical variables and
239
Kruskal-Wallis test for continuous variables. Multivariable logistic regression was used
240
to identify independent predictors of in-hospital mortality. Time-related survival was
241
studied using a multivariable Cox proportional hazard model. Survival plots were
242
generated using Kaplan-Meier methods, and 0.67% (1 standard deviation) error bands
243
were used to generate the shaded area with the log-log method. (12)
244
A multistate stage semi-Markov model was also used to examine the frequency of
245
transition of patients between 6 distinct states, namely Unoperated, BT, Sano, CPS,
246
Fontan, and Dead. Group differences and predictors of each transition were studied.
247
There were 11 possible transitions namely from birth to BT, Sano, CPS or death; from
248
BT to CPS or death; from Sano to CPS or death; from CPS to Fontan or death, and
249
from Fontan to death. Patients who died without surgery were not included in the study.
250
Therefore, the transition from birth to death was not applicable. The mstate package
251
(13, 14) of the R-project software was used.
252 253
A p-value of less than 0.05 was considered significant. All analyses were done using the
254
R-project statistical program (version 3.3.2, R Development Core Team, R Foundation
255
for Statistical Computing, Vienna, Austria- www.R-project.org).
256 Results
257 258
Preoperative and operative data:
259
One hundred and forty-five patients were included in the analysis. (Figure 1) The
260
median age at the Norwood operation was 29 days (range: 2 – 344). The type of shunt
261
in the initial Norwood operation was BT in 72, Sano in 66, and CPS in 7 patients. Five
262
surgeons performed the operations with varied practice lengths. CPS patients had 9
263
significantly higher weight (median:3.6 kg; p= 0.004). The Sano group had more
264
patients with aortic atresia and mitral atresia (p= 0.001), longer deep hypothermic
265
circulatory arrest (DHCA) time (p< 0.001), Table 1. The number of Norwood operations
266
performed annually, and the corresponding operative mortality changed over time from
267
4 cases in 2004 with 50% mortality to 15 cases in 2017 with 7% mortality, Figure 2.
268
Seven patients were candidates for a primary CPS after diagnostic cardiac
269
catheterization. Two patients had HLHS, and the third patient had HLHS and right atrial
270
isomerism. The fourth patient had mitral atresia (MA), coarctation of the Aorta (CoA)
271
and double outlet right ventricle; the fifth baby had MA, CoA and d transposition of great
272
arteries (dTGA). Patient number 6 was diagnosed with double inlet left ventricle, CoA
273
and aortic arch hypoplasia, and the last patient had tricuspid atresia, dTGA, and
274
interrupted aortic arch.
275
Patients thought to be potential candidates for a primary CPS underwent cardiac
276
catheterization. The Median pulmonary vascular resistance (PVR) for those patients on
277
room air was 2.1 woods unit (25th- 75th percentiles: 1- 3.6), and median Qp/Qs was 5.3
278
(25th- 75th percentiles: 2.5- 7.6).
279 280
Postoperative outcomes:
281
There was no difference in hospital stay (p= 0.548) and ECMO use (p= 0.324) among
282
the groups, Table 2. All-cause mortality in patients who required ECMO was 71.4% (n=
283
10; 9 of them were hospital mortality) in the BT group, and 88.9% in the Sano group (n=
284
8, 6 of them were hospital mortality).
285
Over the study period, operative mortality was 32% (23/72) in the BT group, 27%
286
(15/66) in the Sano group, and 0% (0/7) in the CPS group. Independent predictors of
287
operative mortality were lower weight (p= 0.026), and longer bypass time (p= 0.014).
288
Age and type of shunt were not significant predictors of operative mortality. Long-term
289
survival stratified by the shunt type and operation era is shown in figure 3. Independent
290
predictors of improved long-term survival were higher weight at operation (p= 0.0016),
291
later time era (2011-2018 vs. 2004-2012) (p= 0.006) and shorter bypass time (p=
10
292
0.001). There was no difference in the freedom from an arch or pulmonary artery/shunt
293
interventions among the groups (p= 0.931 and 0.358; respectively)
294
Multi-state transition model:
295
The frequency and predictors of the transition of patients between 6 distinct states,
296
namely Unoperated, BT, Sano, CPS, Fontan, and Dead, were evaluated. The
297
proportion of patients in each state at follow-up times is shown in figure 4. The
298
multistate model revealed that lower weight patients were more likely to undergo Sano
299
vs. BT or CPS (Hazard ratio (HR)= 2.4; 95% CI: 1.6- 3.7; p-value <0.001), and if BT was
300
chosen for lower weight patients they were more likely to die (HR=1.7; 95% CI: 1.1- 2.7;
301
p-value=0.027). Lower weight may also be associated with a higher risk of death in the
302
Sano group; however, this association did not reach statistical significance, p-
303
value=0.07. Moreover, the likelihood of receiving a Sano shunt was three-fold higher in
304
the recent time era versus the older time era (p-value=0.003), and the hazard of death
305
after a Norwood with Sano shunt improved in the recent time era (HR = 0.29; 95% CI:
306
0.11- 0.77; p-value= 0.01). The risk of death from a Norwood BT was also lower in the
307
recent time era; (HR=0.5; 95% CI: 0.2- 1.2); however, this did not reach the statistical
308
significance level (p-value =0.13). (Table 3) (Graphical abstract)
309
Discussion
310
The management of HLHS and similar lesions still presents a challenge, especially with
311
delayed presentation, and the optimal shunt for the first stage Norwood palliation is a
312
topic of ongoing research. BT Norwood had the drawback of diastolic runoff and
313
increased pulmonary blood flow, which was found to be associated with poor outcomes.
314
(15) Sano conduits were associated with good operative outcomes; however, the right
315
ventriculotomy may affect the long-term outcomes. (16) Therefore the long-term survival
316
benefit of Sano versus BT shunt is still debatable. Additionally, the optimal shunt type
317
for delayed presentation patients has not been studied in the literature.
318
In this series, we compared three shunt types used for first stage Norwood palliation,
319
namely, BT, Sano, and CPS. The latter was used as a primary shunt type in patients
320
who presented late and had objective evidence of low pulmonary vascular resistance
321
despite the unrestricted pulmonary blood flow. During the study period, Sano conduits
322
were more commonly used in the recent era (2011-2018) compared to BT shunts. The
11
323
mortality improved markedly with the use of Sano shunts, but this also coincided with
324
the overall improved mortality in the recent era. Preoperatively, CPS patients were older
325
and had higher body weight compared to other groups, albeit still, they were small for
326
age as they presented later. The delayed presentation was due to deficiencies in
327
antenatal diagnosis and timely access to tertiary care facilities mainly because of
328
shortages of neonatal intensive care beds. Norwood centers are limited in our country
329
and children diagnosed with HLHS are started on prostaglandin then the referral system
330
is activated. The transfer may take several weeks.
331 332
Similar to what was reported by Mair and colleagues; (17) there was no difference in
333
total cardiopulmonary bypass and aortic clamp time between BT and Sano groups;
334
however, CPS group had significantly lower CPB and clamp times in our series. The
335
lower CPB and clamp time in CPS group could be attributed to the smaller numbers of
336
anastomoses in this group; additionally, there may be a surgeon effect as the surgeon
337
performed this approach has lower times in other groups too. The hospital stay was not
338
different among the groups, similar to what was reported in the literature. (3, 7, 18)
339
ECMO support for patients with HLHS after stage I palliation was increasingly used;
340
however, mortality remained high. (19) Early deployment of ECMO and careful
341
management to avoid complications might help improve survival. (20, 21) In a study of
342
149 infants who underwent a stage I reconstruction Tabbutt and associates did not
343
record any difference in ECMO support between the two shunt types (14% for BT group
344
and 13% in Sano group). (22) In our cohort, fourteen patients (19%) in the BT group
345
were subjected to ECMO due to hemodynamic instability compared to 9 patients in the
346
Sano group (15.3%); one-third of them survived to hospital discharge. On the other
347
hand, none of the CPS group required ECMO support post-Norwood. This difference
348
was found statistically non-significant because of the small sample.
349 350
Shunt type did not predict operative mortality in our series and lower birth weight and
351
longer bypass time were independent predictors of operative mortality. In addition, long-
352
term survival was not affected by the shunt type and higher weight at operation, later
353
era (2011-2018 vs. 2004-2012) and shorter bypass time predicted better long-term
12
354
survival. The Single Ventricle Reconstruction (SVR) trial randomized 555 patients
355
undergoing the Norwood procedure to receive either BT or Sano shunt, and their
356
primary endpoint was the incidence of mortality or cardiac transplantation. After 6 years,
357
Sano patients had better transplant-free survival but did not reach a significant level,
358
and no difference was found in hazard of death and catheter-based reintervention
359
between groups. (23)
360
The inter-stage period is recognized as a period of fragility with a high incidence of
361
sudden and unexpected death. (3) The multistate analysis showed that Sano was more
362
likely to be performed in lower birth weight patients, and when BT shunt was performed
363
in this subset of patients, the transition to death was significantly higher. Our current
364
practice does not recommend BT shunt in low weight babies (<2.7kg), atretic aortic
365
valve, small ascending aorta (<2.5 mm) or small origin of the brachiocephalic artery.
366
Further analysis of our data revealed that the hazard of death had significantly
367
decreased in the recent era, especially with Sano and CPS patients. This could be
368
attributed to the building experience, the more liberal use of ECMO support and
369
improvement of our referral system. In a study by Tabbutt and associates, (22) patients
370
with Sano returned earlier for their stage II palliation which could be explained by the
371
earlier development of pulmonary arteries following RV-PA conduit, which was
372
demonstrated in earlier studies. (2, 24, 25) On the other hand, Fiore and colleagues,
373
(26) found that the timing of the second stage palliation was similar with both shunts.
374
Sano shunt patients could come earlier to the second stage due to increasing cyanosis
375
secondary to narrowing at the proximal or distal conduit anastomosis, and the technique
376
of retaining the PTFE ring as a stent for the outflow anastomosis had prevented early
377
conduit failure. (27, 28)
378 379
The SVR trial reported an increased incidence for balloon dilation or stent placement in
380
the shunt or branch PAs in Sano group. (2) A study by Gist and colleagues (29)
381
reported no shunt or pulmonary artery intervention for the BT group and 15% for the
382
Sano group and they attributed this to the difficult access to the pulmonary artery for
383
intervention in this group. Mery and colleagues (30) explained the higher incidence of
384
central pulmonary artery stenosis in Sano patients by the anterior pull on the pulmonary
13
385
artery confluence by the conduit as the child grows. In our series, we found no
386
difference in the incidence of the pulmonary artery or shunt intervention between the BT
387
and Sano groups. None of the CPS patients required intervention. These results
388
indicate the feasibility and safety to perform CPS with first stage palliation in selected
389
patients presenting late and demonstrating low pulmonary vascular resistance.
390 391
Study limitations and strength:
392
The major limitation of the study is the retrospective nature of the study with the
393
selection and referral bias inherited to this study design. Different measured and
394
unmeasured patient characteristics could have affected the outcomes, and patient and
395
procedure risks were not equally distributed between the groups. However, we used
396
multivariable logistic and Cox regression analysis to adjust for the measured variables
397
and identify the predictors of mortality and long-term survival. Another limitation of the
398
study is the single center experience, and generalization of the results may be
399
problematic. However, the study presents a large experience in the management of
400
HLHS and variants over 15 years with complete follow-up in 98% of the patients. In
401
addition, the study presents CPS shunt as a primary shunt for the first stage Norwood
402
palliation in selected patients and shows its safety and feasibility in those patients.
403 404
Conclusions
405
Improved outcomes of the Norwood operation are evident in the more recent time era
406
and with more frequent utilization of the Sano shunt, especially in smaller weight
407
patients. Late diagnosis or older age should not be considered a contraindication to the
408
Norwood operation. Use of the CPS as a component of the initial Norwood operation is
409
feasible and may be safe in carefully selected patients with low pulmonary vascular
410
resistance. The current outcomes of the Norwood operation warrant offering the
411
treatment to most patients with hypoplastic left heart syndrome and similar lesions even
412
with delayed presentation.
413 414 415
14
416 417 418 419 420 421
References
422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456
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12. THERNEAU TM, GRAMBSCH PM, FLEMING TR. Martingale-based residuals for survival models. Biometrika. 1990;77(1):147-60. 13. de Wreede LC, Fiocco M, Putter H. The mstate package for estimation and prediction in non- and semi-parametric multi-state and competing risks models. Computer methods and programs in biomedicine. 2010;99(3):261-74. 14. Putter H, Fiocco M, Geskus RB. Tutorial in biostatistics: competing risks and multi-state models. Statistics in medicine. 2007;26(11):2389-430. 15. Soo KW, Brink J, d'Udekem Y, Butt W, Namachivayam SP. Major Adverse Events Following Over-Shunting Are Associated With Worse Outcomes Than Major Adverse Events After a Blocked Systemic-to-Pulmonary Artery Shunt Procedure. Pediatric critical care medicine. 2018;19(9):854-60. 16. Frommelt PC, Gerstenberger E, Cnota JF, Cohen MS, Gorentz J, Hill KD, et al. Impact of initial shunt type on cardiac size and function in children with single right ventricle anomalies before the Fontan procedure: the single ventricle reconstruction extension trial. Journal of the American College of Cardiology. 2014;64(19):2026-35. 17. Mair R, Tulzer G, Sames E, Gitter R, Lechner E, Steiner J, et al. Right ventricular to pulmonary artery conduit instead of modified Blalock-Taussig shunt improves postoperative hemodynamics in newborns after the Norwood operation. The Journal of thoracic and cardiovascular surgery. 2003;126(5):1378-84. 18. Edwards L, Morris KP, Siddiqui A, Harrington D, Barron D, Brawn W. Norwood procedure for hypoplastic left heart syndrome: BT shunt or RV-PA conduit? Archives of disease in childhood Fetal and neonatal edition. 2007;92(3):F210-4. 19. Sherwin ED, Gauvreau K, Scheurer MA, Rycus PT, Salvin JW, Almodovar MC, et al. Extracorporeal membrane oxygenation after stage 1 palliation for hypoplastic left heart syndrome. The Journal of thoracic and cardiovascular surgery. 2012;144(6):1337-43. 20. Januszewska K, Stebel A, Malec E. Consequences of right ventricle-to-pulmonary artery shunt at the first stage for the Fontan operation. The Annals of thoracic surgery. 2007;84(5):1611-7. 21. ElMahrouk AF, Ismail MF, Hamouda T, Shaikh R, Mahmoud A, Shihata MS, et al. Extracorporeal Membrane Oxygenation in Postcardiotomy Pediatric Patients-15 Years of Experience Outside Europe and North America. The Thoracic and cardiovascular surgeon. 2019;67(1):28-36. 22. Tabbutt S, Dominguez TE, Ravishankar C, Marino BS, Gruber PJ, Wernovsky G, et al. Outcomes after the stage I reconstruction comparing the right ventricular to pulmonary artery conduit with the modified Blalock Taussig shunt. The Annals of thoracic surgery. 2005;80(5):1582-90; discussion 90-1. 23. Newburger JW, Sleeper LA, Gaynor JW, Hollenbeck-Pringle D, Frommelt PC, Li JS, et al. Transplant-Free Survival and Interventions at 6 Years in the SVR Trial. Circulation. 2018;137(21):2246-53. 24. Maher KO, Pizarro C, Gidding SS, Januszewska K, Malec E, Norwood WI, Jr., et al. Hemodynamic profile after the Norwood procedure with right ventricle to pulmonary artery conduit. Circulation. 2003;108(7):782-4.
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499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518
25. Caspi J, Pettitt TW, Mulder T, Stopa A. Development of the pulmonary arteries after the Norwood procedure: comparison between Blalock-Taussig shunt and right ventricularpulmonary artery conduit. The Annals of thoracic surgery. 2008;86(4):1299-304. 26. Fiore AC, Tobin C, Jureidini S, Rahimi M, Kim ES, Schowengerdt K. A comparison of the modified Blalock-Taussig shunt with the right ventricle-to-pulmonary artery conduit. The Annals of thoracic surgery. 2011;91(5):1479-84; discussion 84-5. 27. Baird CW, Myers PO, Borisuk M, Pigula FA, Emani SM. Ring-reinforced Sano conduit at Norwood stage I reduces proximal conduit obstruction. The Annals of thoracic surgery. 2015;99(1):171-9. 28. Bentham JR, Baird CW, Porras DP, Rathod RH, Marshall AC. A reinforced right-ventricleto-pulmonary-artery conduit for the stage-1 Norwood procedure improves pulmonary artery growth. The Journal of thoracic and cardiovascular surgery. 2015;149(6):1502-8.e1. 29. Gist KM, Barrett CS, Graham DA, Crumback SL, Schuchardt EL, Erickson B, et al. Pulmonary artery interventions after Norwood procedure: does type or position of shunt predict need for intervention? The Journal of thoracic and cardiovascular surgery. 2013;145(6):1485-92. 30. Mery CM, Lapar DJ, Seckeler MD, Chamberlain RS, Gangemi JJ, Kron IL, et al. Pulmonary artery and conduit reintervention rates after norwood using a right ventricle to pulmonary artery conduit. The Annals of thoracic surgery. 2011;92(4):1483-9; discussion 9.
519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 17
536 537 538 539 540 541 542
Tables and figures legends
543
Table1: Descriptive Statistics of preoperative and operative variables by type of shunt
544
(N=145).
545
Table 2: Descriptive Statistics of postoperative events by type of shunt (N=145).
546
Table 3: Multistate model: the effect of predictive factors; weight (top) and time era
547
(bottom) on transition probability (presented as a hazard ratio) between 6 distinct states
548
namely; Unoperated, BT, Sano, CPS, Fontan, and Dead.
549
Figure 1: The flowchart of patients included in the study
550
Figure 2: Operative mortality per year shown by shunt type; shunt.
551
Taussig shunt; Sano: Right ventricle to pulmonary artery shunt, CPS: Cavo-pulmonary
552
shunt)
553
Figure 3: Kaplan-Meier survival curve for the three shunt groups stratified by the time
554
era (2004- 2010 and 2011- 2018). Patients at risk are shown underneath the figure.
555
0.67% (1 standard deviation) error bands were used to generate the shaded area with
556
the log-log method.
557
(BT: Blalock Taussig shunt; Sano: Right ventricle to pulmonary artery shunt; CPS:
558
Cavo-pulmonary shunt).
559
Figure 4: The proportion of patients and the transition between 6 distinct states namely;
560
Unoperated, BT, Sano, CPS, Fontan, and Dead are shown in the y-axis versus follow-
561
up time in the x-axis. (BT: Blalock Taussig shunt; Sano: Right ventricle to pulmonary
562
artery shunt, CPS: Cavo-pulmonary shunt)
563
Graphical abstract: The flowchart of Norwood patients, the long-term survival, and the
564
interstage transition.
565
Video legend: Video presentation summarizing the study and explaining the indications
566
of Cavo-pulmonary shunt as first stage Norwood operation.
(BT= Blalock
18
567 568 569 570 571 572 573 574
Figure 1
575
576 577 578 579 580 581 582
19
583 584 585 586 587 588 589 590
Figure 2
591 592
20
593
Figure 3
594 595
21
596
Figure 4
597
22
Table1: Descriptive Statistics of preoperative and operative variables by type of shunt (N=145). N
BT
CPS
Sano
N=72
N=7
N=66
Gender: male
145 0.57
Age
145
18.00
143
2.8
(days)
Weight
(kg)
0.57
(41)
29.50
3.2
3.6
51.00
66.00 3.3
0.64
(4)
112.00
3.6
4.8
149.00
16.00 2.7
P-value 0.7161
(42)
26.00
3.0
3.3
46.75
0.0022 0.0042
Type of HLHS anatomy: AAMA
121
0.0011 0.17
(9)
0.14
(1)
0.45
(28)
AAMS
0.02
(1)
0.14
(1)
0.10
(6)
ASMA
0.15
(8)
0.00
(0)
0.13
(8)
ASMS
0.37
(19)
0.29
(2)
0.06
(4)
Other
0.29
(15)
0.43
(3)
0.26
(16)
145 0.29
(21)
1.00
(7)
0.86
(57)
A
145 0.67
(48)
0.29
(2)
0.33
(22)
B
0.25
(18)
0.00
(0)
0.11
(7)
C
0.00
(0)
0.00
(0)
0.09
(6)
Time Era: [2011,2018] Surgeon:
<0.0011 <0.0011
D
0.01
(1)
0.00
(0)
0.17
(11)
E
0.07
(5)
0.71
(5)
0.30
(20)
142
128.00
162.00
137
63.25
143
0.0
CPB time
(min)
185.00
68.50
73.00
79.00
84.50
127.50
32.00
35.00
70.50
49.75
66.00
165.75
<0.0012
Aortic clamp time
81.50
100.00
92.25
0.0122
(min)
DHCA time
(min)
Total circulatory arrest
0.0
7.5
19.0
24.0
34.5
2.0
36.0
65.0
<0.0012
145 0.028 (2)
0.85 (6)
0.39 (26)
<0.0011
145 0.95 (69)
0.28 (2)
0.60 (40)
<0.0011
Antegrade cerebral perfusion a
b c represent the 25th quartile a, the median b, and the 75th quartile c for continuous variables. N is the number of non-missing
values. Numbers after proportions are frequencies. Tests used: 1Pearson test; 2Kruskal-Wallis test. AAMA: Aortic Atresia with Mitral Atresia, AAMS: Aortic Atresia with Mitral Stenosis, ASMA: Aortic Stenosis with Mitral Atresia, ASMS: Aortic Stenosis with Mitral Stenosis. DHCA: Deep Hypothermic Circulatory Arrest. DHCA was included in the aortic clamp time but not part of the total bypass time.
Table 2: Descriptive Statistics of postoperative events by type of shunt (N=145). N Post-operative length of stay (Days) ECMO Arch intervention:
BT
CPS
Sano
N=72
N=7
N=66
140
10.75
145
0.19
145
25.00 (14)
39.25
26.00
31.00
0.00
(0)
34.50
11.00
0.14
22.00 (9)
0.83
(60)
0.86
(6)
0.82
(54)
Post Glenn balloon
0.00
(0)
0.14
(1)
0.00
(0)
Pre Glenn-balloon
0.11
(8)
0.00
(0)
0.12
(8)
Pre Glenn-CoA stent
0.06
(4)
0.00
(0)
0.06
(4)
None
P-value
38.00
0.5481 0.3242 0.0022
PA or shunt intervention:
144
None Pre Glenn-PA stent Pre Glenn-shunt stent Operative Outcome:
145
0.93
(67)
1.00
(7)
0.88
(57)
0.03
(2)
0.00
(0)
0.08
(5)
0.04
(3)
0.00
(0)
0.05
(3)
0.68
(49)
1.00
(7)
0.77
(51)
0.6352
0.1272
Alive a
b c represent the 25th quartile a, the median b, and the 75th quartile c for continuous variables.
N is the number of non-missing values. Numbers after proportions are frequencies. Tests used: 1Pearson test; 2Kruskal-Wallis test.
Table 3: Multistate model, predictors of transitions between states From\To Birth BT
BT 0.846 1.170 1.617 (0.3)
Hazard ratio for lower Weight (by 1 kg) CPS Fontan
Sano 1.573 2.398 3.654 (<0.001)
Death
0.587 1.091 2.031 (0.8)
NE
0.799 1.034 1.339 (0.8)
1.061 1.691 2.694 (0.027)
0.875 1.861 3.959
(0.107)
Sano CPS Fontan
From\To
0.942 2.137 4.852 (0.069) 0.602 0.840 1.173 (0.3)
0.551 1.223 2.715 (0.6) 0.152 0.455 1.357 (0.16)
BT 0.133 0.222 0.372 (<0.001)
Hazard ratio for time era [2013-2018] vs. [2003-2013) Sano CPS Fontan
Death
Birth * NE 1.454 2.954 5.999 (0.003) BT 0.706 1.437 2.924 (0.3) 0.204 0.501 1.234 (0.13) Sano 0.2210.8012.897 (0.7) 0.108 0.288 0.766 (0.013) CPS 0.554 1.909 6.581 (0.3) 0.055 0.238 1.039 (0.056) Fontan * States in left Colum indicate the “From” states and those in top row indicate the “To” state for each transition. Grey cells indicate invalid transitions. Each cell shows the effect of the predictor as a Hazard Ratio (HR) with 95% confidence intervals (CI) in subscripts, lower 95%CI HR higher 95%CI. Numbers between brackets represent p-values, significant p-values are shown in italic. NE: No events. * indicate that the number of cases and events are too small for reliable statistics.