Abstract
Background
Low birth and operative weight have been identified as risk factors for death after first-stage single-ventricle palliation. We hypothesize that weight gain after the first-stage operation is associated with transplant-free interstage survival to admission for the second-stage operation.
Methods
We used historical data from the National Pediatric Cardiology Quality Improvement Collaborative database to conduct a longitudinal study to assess the association between weight gain and transplant-free interstage survival. The primary predictor was weight gain. The primary outcome was transplant-free survival. We constructed a repeated-measures logistic regression model using the general estimating equation method to examine the association between weight gain and transplant-free interstage survival.
Results
The study population included 1,501 infants who were discharged alive from the first-stage single-ventricle palliation between June 2008 and January 2015. Patients who underwent a hybrid operation (n = 132) or were lost to follow-up (n = 11) were excluded. Transplant-free interstage survival was 90% (1,228 of 1,358). The mean weight gain was 2.5 (SD, 1.0) kg. Adjusted for age at the time of each measurement, the number of measurements, age at discharge from the first-stage operation, sex, diagnosis, postoperative arrhythmia, postoperative complications, and discharge antibiotic therapy, each 100-g increase in weight was associated with an odds ratio of transplant-free interstage survival of 1.03 (95% confidence limit, 1.01, 1.05).
Conclusions
After first-stage single-ventricle palliation, interstage weight gain is significantly associated with transplant-free interstage survival.
Single-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 untreated [1, 2] Operative death from the first-stage operation was formerly as high as 50%, but with improved techniques and perioperative care, it has dropped below 15% [1–4]. The mortality rate between the first-stage and second-stage operation (the interstage period) ranges from 2% to 15% [5, 6]. In the recent Single Ventricle Reconstruction trial, operative mortality or transplantation at 30 days was 12%, and the interstage mortality was 12% [7, 8]. Investigators from the National Pediatric Cardiology Quality Improvement Collaborative recently reported that interstage mortality dropped from 9.5% (between April 2010 and May 2013) to 5.3% starting 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.
Low birth weight and low weight at the time of the first-stage operation have been identified as risk factors for death after the first-stage single-ventricle palliation [10-12]. Likewise, low weight at the time of birth and at the time of operation have been identified as risk factors for death after the second-stage superior cavopulmonary connection [13, 14]. Weight gain during the interstage period has been studied [15-17], but to date, no data are available to show that weight gain is associated with interstage survival. Our goal was to assess the association between weight gain and transplant-free interstage survival to admission for the second-stage superior cavopulmonary connection or a two-ventricle repair. We hypothesized that interstage weight gain would be associated with transplant-free interstage survival.
Patients and Methods
The University of Maryland School of Medicine Institutional Review Board approved this study (protocol HP-00064137).
Study Cohort
We used historic data from the National Pediatric Cardiology Quality Improvement Collaboration (NPC-QIC) database to conduct a longitudinal study of the association between interstage weight gain and transplant-free interstage survival after the first-stage single-ventricle palliation. The NPC-QIC maintains a patient registry that monitors survivors of single-ventricle palliative operations. Patients in the registry come from 56 centers in 31 states and Washington, D.C. Enrollment is open to all patients with a single-ventricle defect who were discharged alive after the first-stage operation. The parents or guardians of the children provide informed consent before enrollment in the registry. Once enrolled, patients are monitored from birth to discharge from the second-stage superior cavopulmonary connection. The data are checked periodically for quality and housed in a secure server at Cincinnati Children's Hospital Medical Center.
Study Outcomes
Our primary outcome was transplant-free interstage survival (yes or no), which was defined as survival without heart transplantation to hospital admission for the second-stage superior cavopulmonary connection or a two-ventricle repair. Children who survived to admission for the second-stage operation were considered to have met the primary outcome. Children who died, were not considered second-stage candidates, or underwent heart transplantation did not meet the primary outcome of transplant-free interstage survival. Our primary predictor was weight gain, starting at the time of discharge from the first-stage operation and subsequently determined at clinic visits, readmissions, and at the time of the second-stage operation.
Statistical Methods
We used repeated-measures logistic regression to model the odds of survival to the second-stage operation. We used the general estimating equation method of Liang and Zieger to account for the serial autocorrelation of repeated observations (ie, weights) obtained from the same child and for the correlation of children treated at the same clinical site [18]. The model thus included three levels: it recognized that multiple measurements of weight (level 1) were clustered within patients (level 2), who were in turn clustered within centers (level 3). We used the quasi-likelihood under the independence model criterion statistic to select the best covariance structure from four a priori identified covariance structures: unstructured, independent, exchangeable, and first-order autoregressive. The odds ratios produced by our analyses are the odds of transplant-free survival to admission for the second-stage operation for each 100-g weight gain.
Analyses started with linear regression using the general estimating equation method to examine the bivariate association between predictor variables and weight gain. Variables considered included sex, race, ethnicity, gestational age, birth weight, primary cardiac diagnosis, secondary cardiac diagnosis, the presence of a genetic syndrome or organ system abnormality, the number of preoperative risk factors, the need for a heart catheterization, extracorporeal membrane oxygenation, reoperation, other procedures, the occurrence of a postoperative arrhythmia or a postoperative complication, the need for medication at discharge, the route of feeding at discharge, and the strategy and frequency of home monitoring.
An arrhythmia was a postoperative rhythm abnormality requiring treatment and included sinus bradycardia, reentrant supraventricular tachycardia, ectopic atrial tachycardia, atrial flutter or fibrillation, chaotic atrial rhythm, junctional ectopic tachycardia, second-degree or third-degree atrioventricular block, and ventricular tachycardia or fibrillation. Precise definitions of the other categories can be found in Supplemental Table 1.
We modeled the association between weight gain and the predictor variable, as well as the interaction between the predictor variable and time, taking into account correlation of weight measurements within patients and the clustering of patients by clinical center. From that model, we reported the mean discharge weight and the estimated change in weight (g/wk) for different levels of the given predictor variable. We restricted the analysis of the association between predictor variables and weight gain to observations collected during the first 60 weeks of age, which limited the disproportionate effect of outlying observations on estimates of weight gain. We captured 99.8% of observations.
Analyses continued with logistic regression analyses to examine the bivariate association between the predictor variables and interstage survival to the second-stage operation. The odds ratios produced are the odds of transplant-free survival to admission for the second-stage operation for a given category of the predictor variable compared with the reference category. Colinearity between weight and age at the time of measurement as well as weight gain and the number of measurements per patient was examined.
To build the final model, we started with all predictor variables that were significantly associated (p < 0.05) with the primary predictor (weight gain) or with the outcome (transplant-free interstage survival). We manually removed predictors one at a time, starting with the predictor that had the highest p value, and then reevaluated the model with the remaining predictors. If the parameter estimate for the association between weight gain and transplant-free interstage survival changed by more than 10%, we added the predictor back into the model; otherwise, we left it out. We continued removing predictors in this fashion until the only remaining predictors were those we thought were clinically relevant, were associated with both the primary predictor and the outcome in bivariate analysis, or were significant at p of less than 0.05. Finally, we constructed an alternative model, adjusting for the same covariates, where those who received a heart transplant were considered interstage survivors.
All analyses were two-sided. A p value of less than 0.05 was considered significant. All analyses were performed using SAS 9.3 software (SAS Institute Inc, Cary, NC).
Results
The study population included 1,501 infants from 55 different centers who were discharged alive after the first-stage operation between June 2008 and January 2015. Patients who underwent a hybrid procedure (n =14; 132) and those who were lost to follow-up during the interstage period (n =14; 11) were excluded, leaving 1,358 children. The total number of weight measurements for the 1,358 patients in the analysis was 12,402. The median number of weight measurements per patient was 9 (interquartile range, 6 to 12). The median duration of the interstage period was 20 weeks (interquartile range, 17 to 24 weeks).
Most of the patients were boys (62%), and the most common diagnosis was hypoplastic left heart syndrome with aortic and mitral atresia (34%). The most common operation was the Norwood operation with a right ventricle–to–pulmonary artery shunt (61%). The median age at operation was 5 days (interquartile range, 4 to 8 days).
A postoperative arrhythmia was documented in 30%, and at least one postoperative complication occurred in 57%. The median length of stay was 28 days (interquartile range, 19 to 46 days).
Table 1 includes the mean discharge weight (kg) and the mean weight gain (g/wk) for different levels of each of the listed variables. The mean weight at hospital discharge from the first-stage operation was 3.66 (SD, 0.68) kg, and the mean weight gain during the interstage period was 142 g/wk (95% confidence limit, 138, 146 g/wk). The median age at the second-stage operation was 21 weeks (interquartile range, 18 to 25 weeks).
Table 1. Baseline Predictors and Their Association With Weight Gain.
| Predictor | n (%) | Mean (SD) Discharge Weight in kg | Mean (95% CL) Weekly Weight Gain in g | p |
|---|---|---|---|---|
| Total number of subjects | 1358 | 3.66 (0.68) | 142 (138, 146) | |
| Sex | <0.01 | |||
| Male | 843 (62) | 3.73 (0.69) | 149 (144, 154) | |
| Female | 514 (38) | 3.60 (0.64) | 132 (124, 139) | |
| Not available | 1 (<1) | … | … | |
| Diagnosis | 0.11 | |||
| Hypoplastic left heart | ||||
| Aortic atresia, mitral atresia | 459 (34) | 3.63 (0.63) | 148 (143, 154) | |
| Aortic atresia, mitral stenosis | 256 (19) | 3.56 (0.65) | 146 (136, 156) | |
| Aortic stenosis, mitral atresia | 44 (3) | 3.57 (0.63) | 147 (133, 161) | |
| Aortic stenosis, mitral stenosis | 222 (16) | 3.75 (0.78) | 135 (124, 147) | |
| Other single ventricle defect | 371 (27) | 3.73 (0.69) | 136 (128, 144) | |
| Not available | 6 (<1) | … | … | |
| Operative procedure | 0.38 | |||
| Norwood with RV-PA shunt | 823 (61) | 3.72 (0.69) | 144 (139, 150) | |
| Norwood with modified BT shunt | 469 (35) | 3.62 (0.66) | 138 (130, 146) | |
| DKS with modified BT shunt | 44 (3) | 3.68 (0.76) | 132 (116, 148) | |
| Other | 16 (1) | 3.98 (0.81) | 144 (136, 154) | |
| Not available | 6 (<1) | … | … | |
| Any arrhythmia | 0.14 | |||
| No | 954 (70) | 3.65 (0.68) | 144 (140, 149) | |
| Yes | 404 (30) | 3.68 (0.67) | 137 (128, 145) | |
| Postoperative complications | <0.01 | |||
| 0 | 579 (43) | 3.50 (0.58) | 147 (141, 154) | |
| 1 | 356 (26) | 3.70 (0.67) | 148 (141, 155) | |
| ≥2 | 423 (31) | 3.89 (0.74) | 129 (122, 137) | |
| Antibiotics at discharge | 0.06 | |||
| No | 1251 (92) | 3.65 (0.67) | 144 (139, 148) | |
| Yes | 107 (8) | 3.83 (0.77) | 125 (110, 141) |
BT = Blalock-Taussig; CL = confidence limit; DKS = Damus-Kaye-Stansel; PA = pulmonary artery; RV = right ventricle.
Variables in the bivariate analyses associated with reduced weight gain included female sex, a major organ system abnormality, increasing number of preoperative risk factors, the need for a postoperative heart catheterization, the need for postoperative procedures, postoperative complications, and feeding route. Details of the association between baseline predictors and weight gain are presented in the Supplemental Table 2.
Among the 1,228 patients (90%) who survived the interstage period without the need for heart transplantation, 1,222 were admitted for the second-stage operation, and 6 had a two-ventricle repair. Among the 130 (10%) not admitted for the second-stage operation or a two-ventricle repair, 88 died, 20 were considered not candidates for further intervention, and 22 underwent heart transplantation.
The associations between selected predictors and transplant-free interstage survival to admission for the second-stage operation are summarized in Table 2 and Supplemental Table 3. Predictors associated with higher odds of survival included a diagnosis of hypoplastic left heart syndrome with aortic stenosis and mitral stenosis compared with aortic atresia and mitral atresia, and digoxin at the time of discharge. Predictors associated 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 membrane oxygenation, the need for a reoperation, any postoperative arrhythmia, and two or more postoperative complications. The need for chlorothiazide, enalapril, antibiotics, and benzodiazepines was associated with reduced odds of interstage survival.
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) | <0.01 |
| 1-week increase in age | … | … | 0.97 (0.95, 0.98) | <0.01 |
| Age in weeks at discharge from first stage | … | … | 0.99 (0.98, 1.01) | 0.51 |
| Sex | 0.24 | |||
| Male | 769 (91) | 74 (9) | Reference | |
| Female | 459 (89) | 55 (11) | 0.80 (0.56, 1.16) | |
| Diagnosis | 0.03 | |||
| Hypoplastic left heart | ||||
| Aortic atresia, mitral atresia | 416 (91) | 43 (9) | Reference | |
| Aortic atresia, mitral stenosis | 222 (87) | 34 (13) | 0.68 (0.42, 1.09) | |
| Aortic stenosis, mitral atresia | 37 (84) | 7 (16) | 0.55 (0.23, 1.30) | |
| Aortic stenosis, mitral stenosis | 211 (95) | 11 (5) | 1.98 (1.00, 3.92) | |
| Other single ventricle defect | 336 (91) | 35 (9) | 0.99 (0.62, 1.59) | |
| Operative procedure | 0.04 | |||
| Norwood with RV-PA shunt | 755 (92) | 68 (8) | Reference | |
| Norwood with modified BT shunt | 418 (89) | 51 (11) | 0.74 (0.50, 1.08) | |
| DKS with BT shunt | 35 (80) | 9 (20) | 0.35 (0.16, 0.76) | |
| Other | 14 (88) | 2 (12) | 0.63 (0.14, 2.83) | |
| Any arrhythmia | 0.02 | |||
| No | 874 (92) | 80 (8) | Reference | |
| Yes | 353 (88) | 50 (12) | 0.64 (0.45, 0.94) | |
| Number of postoperative complications | <0.01 | |||
| 0 | 536 (93) | 43 (7) | Reference | |
| 1 | 326 (92) | 30 (8) | 0.87 (0.54, 1.42) | |
| ≥2 | 366 (87) | 57 (13) | 0.52 (0.34, 0.78) | |
| Antibiotics at discharge | <0.01 | |||
| No | 1142 (91) | 109 (9) | Reference | |
| Yes | 86 (80) | 21 (20) | 0.39 (0.23, 0.66) | |
BT = Blalock-Taussig; CL = confidence limit; DKS = Damus-Kaye-Stansel; OR = odds ratio; PA = pulmonary artery; RV = right ventricle.
The final multivariable model included all 1,358 patients and was adjusted for the age of the patient at the time of each weight measurement, the number of weight measurements per patient, the age at discharge from the first-stage operation, sex, the primary cardiac diagnosis, postoperative arrhythmia, postoperative complications, and the use of antibiotics at discharge (Table 3). In the final adjusted model, each 100 g of weight gain was significantly associated with transplant-free interstage survival (odds ratio, 1.03; 95% confidence limits, 1.01, 1.05).
Table 3. Adjusted Association Between Weight Gain and Transplant-Free Interstage Survival.
| Variable | Transplant-Free Interstage Survival OR (95% CL) | p |
|---|---|---|
| 100-g increase in weight | 1.03 (1.01, 1.05) | <0.01 |
| Measurements per patient, No. | 1.50 (1.40, 1.61) | <0.01 |
| 1-week increase in age | 0.89 (0.87, 0.92) | <0.01 |
| Age in weeks at discharge from first stage | 1.10 (1.05, 1.15) | <0.01 |
| Sex | 0.35 | |
| Male | Reference | |
| Female | 1.18 (0.83, 1.69) | |
| Diagnosis | 0.01 | |
| Hypoplastic left heart | Reference | |
| Aortic atresia, mitral atresia | 0.63 (0.39, 1.01) | |
| Aortic atresia, mitral stenosis | 0.53 (0.24, 1.15) | |
| Aortic stenosis, mitral atresia | 1.94 (0.99, 3.78) | |
| Aortic stenosis, mitral stenosis | 1.10 (0.69, 1.75) | |
| Other single-ventricle defect | ||
| Postoperative arrhythmia | 0.05 | |
| No | Reference | |
| Yes | 0.68 (0.47, 0.99) | |
| Complications, No. | 0.05 | |
| 0 | Reference | |
| 1 | 0.97 (0.60, 1.59) | |
| ≥2 | 0.59 (0.37, 0.93) | |
| Antibiotics at discharge | 0.01 | |
| No | Reference | |
| Yes | 0.46 (0.29, 0.75) |
CL = confidence limit; OR = odds ratio.
In the alternative model, where patients who received a heart transplant were considered interstage survivors, each 100-g weight gain was significantly associated with interstage survival (odds ratio, 1.03; 95% confidence limits, 1.01, 1.05).
Comment
This longitudinal cohort study examined the association between weight gain and transplant-free interstage survival to admission for the second-stage operation after first-stage palliation of a single-ventricle defect. The average interstage weight gain was 2.5 (SD, 1.0) kg, and 90% survived the interstage period to the second-stage operation. The final multivariable model adjusted for age of the patient at the time of each weight measurement, the number of weight measurements per patient, the age at discharge from the first-stage operation, postoperative arrhythmia, and the need for antibiotics at discharge and showed each 100-g weight gain during the interstage period was associated with a 3% increase in the odds of survival. In an alternative model, where patients who received a heart transplant were considered interstage survivors, each 100-g weight gain was associated with a 3% increase in the odds of survival. We predict from the model presented above and World Health Organization growth curves that the odds of survival are 12% better for girls and 10% better for boys in the 75th percentile than in the 25th percentile of weight gain between the first and fifth month of life [19].
Because operative death has been reduced since the Norwood operation was first described, reducing interstage death has become a major focus. Independent predictors of interstage death include ventricular dysfunction [6], perioperative arrhythmia [6, 20], an intact atrial septum [21], operation at age older than 7 days [21], use of a modified Blalock-Taussig shunt in patients with none or mild atrioventricular valve regurgitation [21], gestational age of less than 37 weeks [21], Hispanic ethnicity [21], the aortic atresia/mitral atresia subtype of hypoplastic left heart syndrome [21], and postoperative complications [8]. Our results confirm some findings of previous studies, specifically, that perioperative arrhythmia and postoperative complications are associated with interstage death. Unlike previous studies, we did not find an association between death and gestational age, Hispanic ethnicity, or hypoplastic left heart syndrome with aortic atresia and mitral atresia. We also showed that the need for antibiotics at discharge is associated with reduced interstage survival. We speculate that the need for antibiotics was a marker of a complicated postoperative course, which may be why it was associated with reduced survival. We added the number of weight measurements and age to the model to account for the fact that children who survived the interstage period had the opportunity to grow and those that did not obviously did not grow.
Growth in patients with single-ventricle defects has been a subject of interest and has been examined in several studies. A secondary analysis of the Pediatric Heart Network Infant Single Ventricle Enalapril trial examined growth from birth to age 14 months in 230 infants [22]. The main outcome measure was change in the weight-for-age z score. The study showed infants with single-ventricle defects, in aggregate, had an initial negative weight-for-age z score trajectory until age 2 months, when it leveled off and then increased gradually. A multivariable model found that younger age at study enrollment, greater gestational age, and nutrition with tube feeding were associated with a negative change in the weight-for-age z score during the interstage period. When we used repeated-measures linear regression with the general estimating equation method, rather than simple linear regression with change in the weight-for-age z score as the dependent variable, no association was seen between gestational age and weight. We also noted, however, that the need for a gastrostomy tube was associated with slower weight gain. Unfortunately, the database does not capture why gastrostomy tubes were used. They may have been used as a prophylactic measure or because of a complication that made enteral feeding a challenge.
A secondary analysis of the Single Ventricle Reconstruction Trial examined growth from birth to 3 years in 498 infants with hypoplastic left heart syndrome [23]. During the interstage period, the mean change in the weight-for-age z score was –0.08 (SD, 1.09). Higher birth weight, lower socioeconomic status, absence of pre-Norwood enteral feeding, use of a modified Blalock-Taussig shunt, increased number of interstage complications, and the method of feeding were independently associated with a mean decrease in the weight-for-age z score during the interstage period. Again, we noted that the need for a gastrostomy tube was associated with slower weight gain. We did not observe a significant association between shunt type and interstage weight gain. In contrast to the Single Ventricle Reconstruction Trial analysis, we saw that low birth weight (<2.5 kg) was not associated slower weight gain.
To our knowledge, this is the first study to show that interstage weight is associated with survival after the first-stage single-ventricle palliation. Its main strengths include a large sample size and detailed follow-up, which allowed collection and inclusion of multiple measures of weight. Previous reports using data from the NPC-QIC used change in the weight-for-age z score, which reduced the measure of growth to a single data point and only accounted for the difference between the first and last measurement. The NPC-QIC database includes many measurements per patient. We used raw weights in a repeated-measures logistic regression analysis, which allowed us to take advantage of the increased statistical power that resulted from analyzing all available weight measurements for each patient and also to account for the clustering of patients within centers.
The study has several limitations. First, there may be unmeasured covariates that confound the association between weight gain and interstage survival or covariates that have a complex association with interstage survival that were not recognized. In the course of the analysis, the effect of center volume and the era of operation were explored. Neither had an obvious association with interstage survival, however, that either could have a more subtle association is plausible.
Second, data on ventricular function and atrioventricular valve regurgitation were missing for more than 60% of patients and were thus not included in the analysis.
Third, because of the great number of covariates available, we combined some into broad categories instead of including them as individual covariates.
Fourth, the NPC-QIC data set contains retrospective, observational data that are voluntarily submitted from programs participating in the improvement collaborative. Limitations in the data may relate to patient selection bias, partial data sets for some patients, the heterogeneous composition of participating programs of different sizes and geographic locations, or a combination of these.
Finally, the NPC-QIC focuses primarily on patients with hypoplastic left heart syndrome, and therefore the results and conclusions may not be applicable to all patients who undergo first-stage single-ventricle palliation for other diagnoses.
Supplementary Material
Acknowledgments
Danielle S. Abraham is supported by the National Institute on Aging (grant T32-AG-000262).
Footnotes
Presented at the American Heart Association Scientific Sessions, Orlando, FL, Nov 7-11, 2015.
The Supplemental Tables can be viewed in the online version of this article [http://dx.doi.org/10.1016/j.athoracsur.2016.12.031] on http://www.annalsthoracicsurgery.org.
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