Interstage Weight Gain Is Associated With Survival After First-Stage Single-Ventricle Palliation - NPC-QIC
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Interstage Weight Gain Is Associated
With Survival After First-Stage
Single-Ventricle Palliation
Charles F. Evans, MD, John D. Sorkin, MD, PhD, Danielle S. Abraham, MPH,
Brody Wehman, MD, Sunjay Kaushal, MD, PhD, and Geoffrey L. Rosenthal, MD, PhD
Division of Cardiac Surgery, Department of Surgery, Division of Gerontology and Geriatric Medicine, Department of Medicine,
Department of Epidemiology and Public Health, and Division of Pediatric Cardiology, Department of Pediatrics, University of
CONGENITAL HEART
Maryland School of Medicine, Baltimore, Maryland
Background. Low birth and operative weight have single-ventricle palliation between June 2008 and
been identified as risk factors for death after first-stage January 2015. Patients who underwent a hybrid operation
single-ventricle palliation. We hypothesize that weight (n [ 132) or were lost to follow-up (n [ 11) were
gain after the first-stage operation is associated with excluded. Transplant-free interstage survival was 90%
transplant-free interstage survival to admission for the (1,228 of 1,358). The mean weight gain was 2.5 (SD, 1.0)
second-stage operation. kg. Adjusted for age at the time of each measurement, the
Methods. We used historical data from the National number of measurements, age at discharge from the first-
Pediatric Cardiology Quality Improvement Collaborative stage operation, sex, diagnosis, postoperative arrhythmia,
database to conduct a longitudinal study to assess the postoperative complications, and discharge antibiotic
association between weight gain and transplant-free therapy, each 100-g increase in weight was associated
interstage survival. The primary predictor was weight with an odds ratio of transplant-free interstage survival of
gain. The primary outcome was transplant-free survival. 1.03 (95% confidence limit, 1.01, 1.05).
We constructed a repeated-measures logistic regression Conclusions. After first-stage single-ventricle pallia-
model using the general estimating equation method to tion, interstage weight gain is significantly associated
examine the association between weight gain and with transplant-free interstage survival.
transplant-free interstage survival.
Results. The study population included 1,501 infants (Ann Thorac Surg 2017;104:674–80)
who were discharged alive from the first-stage Ó 2017 by The Society of Thoracic Surgeons
S ingle-ventricle defects, including hypoplastic left
heart syndrome, are rare and occur in approximately
2 to 3/10,000 live births; they are also uniformly fatal if
in June 2013 [9]. In an effort to improve overall survival,
recent research has begun to explore factors associated
with survival during the interstage period.
untreated [1, 2] Operative death from the first-stage Low birth weight and low weight at the time of the first-
operation was formerly as high as 50%, but with stage operation have been identified as risk factors for
improved techniques and perioperative care, it has death after the first-stage single-ventricle palliation
dropped below 15% [1–4]. The mortality rate between the [10–12]. Likewise, low weight at the time of birth and at
first-stage and second-stage operation (the interstage the time of operation have been identified as risk factors
period) ranges from 2% to 15% [5, 6]. In the recent Single for death after the second-stage superior cavopulmonary
Ventricle Reconstruction trial, operative mortality or connection [13, 14]. Weight gain during the interstage
transplantation at 30 days was 12%, and the interstage period has been studied [15–17], but to date, no data are
mortality was 12% [7, 8]. Investigators from the National available to show that weight gain is associated with
Pediatric Cardiology Quality Improvement Collaborative interstage survival. Our goal was to assess the association
recently reported that interstage mortality dropped from between weight gain and transplant-free interstage sur-
9.5% (between April 2010 and May 2013) to 5.3% starting vival to admission for the second-stage superior
cavopulmonary connection or a two-ventricle repair. We
Accepted for publication Dec 19, 2016.
Presented at the American Heart Association Scientific Sessions, Orlando,
FL, Nov 7–11, 2015. The Supplemental Tables can be viewed in the online
Address correspondence to Dr Evans, Division of Cardiac Surgery,
version of this article [http://dx.doi.org/10.1016/
Department of Surgery, University of Maryland School of Medicine, 110 S j.athoracsur.2016.12.031] on http://www.annalsthoracic
Paca St, 7th Flr, Baltimore, MD 21201; email: cevans@smail.umaryland. surgery.org.
edu.
Ó 2017 by The Society of Thoracic Surgeons 0003-4975/$36.00
Published by Elsevier Inc. http://dx.doi.org/10.1016/j.athoracsur.2016.12.031Ann Thorac Surg EVANS ET AL 675
2017;104:674–80 WEIGHT GAIN AND INTERSTAGE SURVIVAL
hypothesized that interstage weight gain would be asso- our analyses are the odds of transplant-free survival to
ciated with transplant-free interstage survival. admission for the second-stage operation for each 100-g
weight gain.
Analyses started with linear regression using the gen-
Patients and Methods eral estimating equation method to examine the bivariate
The University of Maryland School of Medicine Institu- association between predictor variables and weight gain.
tional Review Board approved this study (protocol Variables considered included sex, race, ethnicity, gesta-
HP-00064137). tional age, birth weight, primary cardiac diagnosis, sec-
ondary cardiac diagnosis, the presence of a genetic
Study Cohort syndrome or organ system abnormality, the number of
We used historic data from the National Pediatric Car- preoperative risk factors, the need for a heart catheteri-
diology Quality Improvement Collaboration (NPC-QIC) zation, extracorporeal membrane oxygenation, reopera-
CONGENITAL HEART
database to conduct a longitudinal study of the associa- tion, other procedures, the occurrence of a postoperative
tion between interstage weight gain and transplant-free arrhythmia or a postoperative complication, the need for
interstage survival after the first-stage single-ventricle medication at discharge, the route of feeding at discharge,
palliation. The NPC-QIC maintains a patient registry that and the strategy and frequency of home monitoring.
monitors survivors of single-ventricle palliative opera- An arrhythmia was a postoperative rhythm abnormal-
tions. Patients in the registry come from 56 centers in 31 ity requiring treatment and included sinus bradycardia,
states and Washington, D.C. Enrollment is open to all reentrant supraventricular tachycardia, ectopic atrial
patients with a single-ventricle defect who were dis- tachycardia, atrial flutter or fibrillation, chaotic atrial
charged alive after the first-stage operation. The parents rhythm, junctional ectopic tachycardia, second-degree or
or guardians of the children provide informed consent third-degree atrioventricular block, and ventricular
before enrollment in the registry. Once enrolled, patients tachycardia or fibrillation. Precise definitions of the other
are monitored from birth to discharge from the second- categories can be found in Supplemental Table 1.
stage superior cavopulmonary connection. The data are We modeled the association between weight gain and
checked periodically for quality and housed in a secure the predictor variable, as well as the interaction between
server at Cincinnati Children’s Hospital Medical Center. the predictor variable and time, taking into account cor-
relation of weight measurements within patients and the
Study Outcomes clustering of patients by clinical center. From that model,
Our primary outcome was transplant-free interstage we reported the mean discharge weight and the esti-
survival (yes or no), which was defined as survival mated change in weight (g/wk) for different levels of the
without heart transplantation to hospital admission for given predictor variable. We restricted the analysis of the
the second-stage superior cavopulmonary connection or association between predictor variables and weight gain
a two-ventricle repair. Children who survived to admis- to observations collected during the first 60 weeks of age,
sion for the second-stage operation were considered to which limited the disproportionate effect of outlying
have met the primary outcome. Children who died, were observations on estimates of weight gain. We captured
not considered second-stage candidates, or underwent 99.8% of observations.
heart transplantation did not meet the primary outcome Analyses continued with logistic regression analyses to
of transplant-free interstage survival. Our primary pre- examine the bivariate association between the predictor
dictor was weight gain, starting at the time of discharge variables and interstage survival to the second-stage
from the first-stage operation and subsequently deter- operation. The odds ratios produced are the odds of
mined at clinic visits, readmissions, and at the time of the transplant-free survival to admission for the second-stage
second-stage operation. operation for a given category of the predictor variable
compared with the reference category. Colinearity be-
Statistical Methods tween weight and age at the time of measurement as well
We used repeated-measures logistic regression to model as weight gain and the number of measurements per
the odds of survival to the second-stage operation. We patient was examined.
used the general estimating equation method of Liang To build the final model, we started with all predictor
and Zieger to account for the serial autocorrelation of variables that were significantly associated (p < 0.05) with
repeated observations (ie, weights) obtained from the the primary predictor (weight gain) or with the outcome
same child and for the correlation of children treated at (transplant-free interstage survival). We manually
the same clinical site [18]. The model thus included three removed predictors one at a time, starting with the pre-
levels: it recognized that multiple measurements of dictor that had the highest p value, and then reevaluated
weight (level 1) were clustered within patients (level 2), the model with the remaining predictors. If the parameter
who were in turn clustered within centers (level 3). We estimate for the association between weight gain and
used the quasi-likelihood under the independence transplant-free interstage survival changed by more than
model criterion statistic to select the best covariance 10%, we added the predictor back into the model;
structure from four a priori identified covariance struc- otherwise, we left it out. We continued removing pre-
tures: unstructured, independent, exchangeable, and dictors in this fashion until the only remaining predictors
first-order autoregressive. The odds ratios produced by were those we thought were clinically relevant, were676 EVANS ET AL Ann Thorac Surg
WEIGHT GAIN AND INTERSTAGE SURVIVAL 2017;104:674–80
associated with both the primary predictor and the The associations between selected predictors and
outcome in bivariate analysis, or were significant at p of transplant-free interstage survival to admission for the
less than 0.05. Finally, we constructed an alternative second-stage operation are summarized in Table 2 and
model, adjusting for the same covariates, where those Supplemental Table 3. Predictors associated with higher
who received a heart transplant were considered inter- odds of survival included a diagnosis of hypoplastic left
stage survivors. heart syndrome with aortic stenosis and mitral stenosis
All analyses were two-sided. A p value of less than 0.05 compared with aortic atresia and mitral atresia, and
was considered significant. All analyses were performed digoxin at the time of discharge. Predictors associated
using SAS 9.3 software (SAS Institute Inc, Cary, NC). with reduced odds of survival were more numerous and
included any major organ system abnormality, the use of
a Damus-Kaye-Stansel procedure with a modified
Blalock-Taussig shunt, the need for extracorporeal
Results
CONGENITAL HEART
membrane oxygenation, the need for a reoperation, any
The study population included 1,501 infants from 55 postoperative arrhythmia, and two or more postoperative
different centers who were discharged alive after the first- complications. The need for chlorothiazide, enalapril,
stage operation between June 2008 and January 2015. antibiotics, and benzodiazepines was associated with
Patients who underwent a hybrid procedure (n ¼ 132) reduced odds of interstage survival.
and those who were lost to follow-up during the inter- The final multivariable model included all 1,358
stage period (n ¼ 11) were excluded, leaving 1,358 chil- patients and was adjusted for the age of the patient at the
dren. The total number of weight measurements for the time of each weight measurement, the number of weight
1,358 patients in the analysis was 12,402. The median measurements per patient, the age at discharge from the
number of weight measurements per patient was 9 first-stage operation, sex, the primary cardiac diagnosis,
(interquartile range, 6 to 12). The median duration of the postoperative arrhythmia, postoperative complications,
interstage period was 20 weeks (interquartile range, 17 to and the use of antibiotics at discharge (Table 3). In the
24 weeks). final adjusted model, each 100 g of weight gain was
Most of the patients were boys (62%), and the most significantly associated with transplant-free interstage
common diagnosis was hypoplastic left heart syndrome survival (odds ratio, 1.03; 95% confidence limits, 1.01,
with aortic and mitral atresia (34%). The most common 1.05).
operation was the Norwood operation with a right In the alternative model, where patients who received a
ventricle–to–pulmonary artery shunt (61%). The median heart transplant were considered interstage survivors,
age at operation was 5 days (interquartile range, 4 to 8 each 100-g weight gain was significantly associated with
days). interstage survival (odds ratio, 1.03; 95% confidence
A postoperative arrhythmia was documented in 30%, limits, 1.01, 1.05).
and at least one postoperative complication occurred in
57%. The median length of stay was 28 days (interquartile
range, 19 to 46 days). Comment
Table 1 includes the mean discharge weight (kg) and the This longitudinal cohort study examined the association
mean weight gain (g/wk) for different levels of each of the between weight gain and transplant-free interstage sur-
listed variables. The mean weight at hospital discharge vival to admission for the second-stage operation after
from the first-stage operation was 3.66 (SD, 0.68) kg, and first-stage palliation of a single-ventricle defect. The
the mean weight gain during the interstage period was 142 average interstage weight gain was 2.5 (SD, 1.0) kg, and
g/wk (95% confidence limit, 138, 146 g/wk). The median 90% survived the interstage period to the second-stage
age at the second-stage operation was 21 weeks (inter- operation. The final multivariable model adjusted for
quartile range, 18 to 25 weeks). age of the patient at the time of each weight measure-
Variables in the bivariate analyses associated with ment, the number of weight measurements per patient,
reduced weight gain included female sex, a major organ the age at discharge from the first-stage operation, post-
system abnormality, increasing number of preoperative operative arrhythmia, and the need for antibiotics at
risk factors, the need for a postoperative heart catheteri- discharge and showed each 100-g weight gain during the
zation, the need for postoperative procedures, post- interstage period was associated with a 3% increase in the
operative complications, and feeding route. Details of the odds of survival. In an alternative model, where patients
association between baseline predictors and weight gain who received a heart transplant were considered inter-
are presented in the Supplemental Table 2. stage survivors, each 100-g weight gain was associated
Among the 1,228 patients (90%) who survived the with a 3% increase in the odds of survival. We predict
interstage period without the need for heart trans- from the model presented above and World Health
plantation, 1,222 were admitted for the second-stage Organization growth curves that the odds of survival are
operation, and 6 had a two-ventricle repair. Among the 12% better for girls and 10% better for boys in the 75th
130 (10%) not admitted for the second-stage operation or percentile than in the 25th percentile of weight gain
a two-ventricle repair, 88 died, 20 were considered not between the first and fifth month of life [19].
candidates for further intervention, and 22 underwent Because operative death has been reduced since the
heart transplantation. Norwood operation was first described, reducingAnn Thorac Surg EVANS ET AL 677
2017;104:674–80 WEIGHT GAIN AND INTERSTAGE SURVIVAL
Table 1. Baseline Predictors and Their Association With Weight Gain
Mean (SD) Discharge Mean (95% CL) Weekly
Predictor n (%) Weight in kg Weight Gain in g p
Total number of subjects 1358 3.66 (0.68) 142 (138, 146)
Sex678 EVANS ET AL Ann Thorac Surg
WEIGHT GAIN AND INTERSTAGE SURVIVAL 2017;104:674–80
Table 2. Association Between Predictors and Transplant-Free Interstage Survival
Transplant Free Interstage Survival
Predictor Yes (%) No (%) OR (95% CL) p
Total number of subjects 1228 (90) 130 (10)
100-gram increase in weight . . 0.99 (0.97, 1.01) 0.14
Number of measurements per subject . . 1.43 (1.32, 1.55)Ann Thorac Surg EVANS ET AL 679
2017;104:674–80 WEIGHT GAIN AND INTERSTAGE SURVIVAL
Table 3. Adjusted Association Between Weight Gain and Transplant-Free Interstage Survival
Transplant-Free Interstage Survival
Variable OR (95% CL) p
100-g increase in weight 1.03 (1.01, 1.05)680 EVANS ET AL Ann Thorac Surg
WEIGHT GAIN AND INTERSTAGE SURVIVAL 2017;104:674–80
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CONGENITAL HEART
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INVITED COMMENTARY
The National Paediatric Cardiology Quality Improvement of care in the interstage period, these data demonstrate
Collaborative (NPC-QIC; http://npcqic.org) is a multi- that we need to do something more for patients who, for
center initiative led by Cincinatti Children’s Hospital and whatever reason, are not gaining weight. Aggressive
created with the mission of standardizing care and reintervention for arch or shunt obstruction or, more
improving outcomes for infants with single-ventricle controversially, earlier performance of the stage 2 oper-
congenital heart disease. The group began in 2007 by ation may be beneficial in the subset of patients strug-
implementing practice change among participating in- gling to gain weight. Although data from the Pediatric
stitutions. Since then, outcomes have been monitored and Heart Network Infant Single Ventricle trial previously
studied through a registry that now encompasses data demonstrated higher procedural risk for those undergo-
from more than 2000 patients, and lessons learned from ing stage 2 at a younger age [2], a recent report from the
this research have driven further practice changes. NPC-QIC registry suggests similar outcomes and less
Evans and colleagues [1] interrogated the registry to interstage attrition among centers performing the stage 2
answer the question: Is interstage weight gain after stage 1 operation earlier [3].
palliation associated with improved survival? They iden-
tified 1358 patients undergoing non-hybrid stage 1 pallia- Ajay J. Iyengar, MBBS(Hons), PhD
tion operated over a 7-year period. An association between
Australia and New Zealand Fontan Registry
weight gain in the interstage period and survival (both
Murdoch Children’s Research Institute
overall and transplant-free) was shown in adjusted anal-
Flemington Rd
ysis that was not present in simple univariable analysis.
Parkville 3052
The magnitude of this gain is small but significant and
Melbourne, Australia
would not have been detected were it not for the quantity
email: ajayjiyengar@gmail.com
of longitudinal follow-up data within the registry.
The major limitation of this dataset is that it captures
only the fraction of patients who were discharged be-
References
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ventricle palliation. Ann Thorac Surg 2017;104:674–80.
predominant single ventricle morphology. Finally, the 2. Cnota JF, Allen KR, Colan S, et al. Superior cavopulmonary
effect of weight gain on the hospital mortality after stage 2 anastomosis timing and outcomes in infants with single
could not be analyzed. ventricle. J Thorac Cardiovasc Surg 2013;145:1288–96.
These limitations notwithstanding, to our knowledge 3. Hill GD, Rudd NA, Ghanayem NS, Hehir DA, Bartz PJ. Center
variability in timing of stage 2 palliation and association with
this is the first study to demonstrate an association interstage mortality: a report from the National Pediatric
between survival and weight gain between stages 1 and 2. Cardiology Quality Improvement Collaborative. Pediatr Car-
Although optimizing weight gain is already a major focus diol 2016;37:1516–24.
Ó 2017 by The Society of Thoracic Surgeons 0003-4975/$36.00
Published by Elsevier Inc. http://dx.doi.org/10.1016/j.athoracsur.2017.01.015You can also read
