ST2 predicts risk of unplanned readmission within one year after pediatric congenital heart surgery

Abstract

Objectives:

Approximately 10% to 20% of children are readmitted after congenital heart surgery. Very little is known about biomarkers as predictors of risk of unplanned readmission following pediatric congenital heart surgery. Novel cardiac biomarker ST2 may be associated with risk of unplanned readmission. ST2 concentrations are believed to reflect cardiovascular stress and fibrosis. Our objective was to explore the relationship between pre- and postoperative ST2 biomarker levels and risk of readmission within one year after congenital heart surgery.

Methods:

We prospectively enrolled pediatric patients <18 years of age who underwent at least one congenital heart operation at Johns Hopkins Hospital from 2010 – 2014. Plasma samples were collected immediately prior to surgery and at the end of bypass. We used Kaplan-Meier survival analysis and multivariable Cox regression models adjusting for variables used in the Society of Thoracic Surgeons (STS) Congenital Heart Surgery Database mortality risk model.

Results:

In our cohort (N=145), there were 39 children with readmissions within 365 days. The median time to unplanned readmission was 54 days (IQR: 10 – 153). Kaplan-Meier analysis demonstrated a significant difference across terciles of pre- and post-operative ST2 biomarker levels. After adjustment, elevated serum levels of ST2 measured preoperatively and postoperatively were associated with increased risk of readmission (hazard ratio range 2.5 to 3.7, all p<0.05).

Conclusions:

Elevated levels of ST2 are significantly associated with increased risk of unplanned readmission within one-year after pediatric congenital heart surgery. Novel serum biomarker ST2 can be used for risk stratification or estimating postsurgical prognosis.

Introduction

Readmission after operations for congenital heart defects (CHD) has significant implications for patient care. Readmission rates for congenital heart surgery vary between 8.7% and 15%.^1,2 Outcomes after operations for CHD have improved significantly in terms of operative mortality over the past two decades. With an overall decline in mortality to 2.8%, the focus has shifted to quality improvement, such as morbidity and readmissions reduction.^3,4 Beyond their financial impact, readmissions may further increase the psychosocial burdens, financial distress, and overall life disruption for pediatric patients and their families.^5–7

Reasons for long-term unplanned readmission following congenital heart surgery have not been studied extensively.^8,9 A single-center study suggested that pleural effusions, inflammation and infection, and cardiac related problems are among the major causes of readmission after congenital heart surgery.¹⁰ Beyond clinical risk factors, novel biomarkers may also play a role in predicting long-term unplanned readmission after congenital heart surgery. While multiple studies have shown that soluble suppression of tumorigenicity (ST2) is predictive of hospitalization and death in adults with heart failure, remarkably little is known about clinical predictors of unplanned readmission in pediatric cardiac care.^11–18 Although studies have established its roles in immune system regulation and the inflammatory response, it is unknown if this novel cardiac biomarker is associated with unplanned hospital readmission within one year following congenital heart surgery.

To better understand, and potentially reduce unplanned readmissions, prediction models have been developed to aid clinicians in identifying those at greatest risk of adverse events.^19,20 However there has been little emphasis on prediction of unplanned readmission within one-year following congenital heart surgery in children. The goal of this study was to evaluate the relationship between cardiac biomarker ST2 and one-year unplanned hospital readmission among children undergoing congenital heart surgery.

Patients and Methods

This is a single center retrospective analysis of a longitudinal cohort consisting of 244 consecutive patients who underwent at least one congenital cardiac operation, with cardiopulmonary bypass, at Johns Hopkins Children’s Center from 2010 to 2014. Patient, procedural, and outcome data were collected. The cohort was limited to children with biomarker information collected in association with the initial congenital heart surgery operation for each admission (index operation; N = 174). We excluded children with unknown prematurity status, patients weighing 2.5 kg or less at the time of surgery, patients that were aged > 18 years old at the time of surgery, and patients with missing preoperative or postoperative biomarker measurements (N=12). Finally, our cohort was limited to children who had at least one unplanned readmission (N=145). Unplanned readmissions were independently adjudicated by two pediatric cardiologists. The Committee for the Protection of Human Subjects at Dartmouth College and Johns Hopkins University (Institutional Review Board) approved this study for the prospective cohort with parental consent.

Biomarker Sample Collection

Pre and postoperative cardiac biomarker ST2 was the main exposures of interest in this study. Perioperative blood samples (heparinized plasma) were collected immediately prior to skin incision and in the operating room after decannulation from cardiopulmonary bypass. Samples were processed with the plasma aliquoted and stored at −80°C until assayed. Biomarkers were measured using a custom printed multiplex assay (Meso Scale Discovery) using commercial antibodies and calibrators (R&D Systems).

Main Outcome

The study endpoint was unplanned readmission within 365 days following discharge.

Statistical Analysis

Patient, clinical and procedural characteristics were compared with our composite endpoint using descriptive statistics. Differences in associations between the endpoint and various potential risk factors were compared using Pearson’s chi-square tests or Fisher’s exact test; continuous variables were compared with two-sample t-tests or Wilcoxon ranksum tests. Our observation window was three-years following congenital heart surgery, but we right-censored at one-year due to the lack of readmission events that were ascertained. All included patients had complete follow-up at one-year. The pre-and postoperative biomarkers were categorically modeled by tercile.

We used Kaplan-Meier survival analysis and Cox regression models to study the association of biomarker levels with freedom from unplanned readmission within one-year. Adjustment was carried out using the covariates used in on the Society of Thoracic Surgeons Congenital Heart Surgery Database Mortality Risk Model (STS-CHSD).²¹ Risk factors in the model include age (days) at surgery, weight (kilograms), any prior cardiothoracic operation (yes/no), any non-cardiac congenital anatomic abnormality (yes/no), any chromosomal abnormality or syndrome (yes/no), STAT mortality category, and presence of any STS-CHSD clinical preoperative risk factors. Preoperative risk factors were operationalized as a count variable based on the presence of the following preoperative factors: mechanical circulatory support, persistent shock at time of operation, renal dysfunction requiring dialysis, mechanical ventilation to treat cardiorespiratory failure, and preoperative neurological deficit. Given the limited number of outcome events, we aggregated all preoperative risk factors and dichotomized based on the presence of none or >1. The STAT mortality category is a risk stratification scoring system to categorize the complexity of surgery. Higher scores reflect more complex surgeries.²² This method of risk stratification is a widely accepted tool for the evaluation of differences in outcomes of surgery for congenital heart disease. The two patients missing STAT category information were excluded from the models. All other patients had complete congenital heart surgery admission information.

Results

Patient and pre-procedural characteristics are described in Table 1. In our cohort, 39 (26.9%) patients of 145 experienced at least one unplanned readmission within one-year from discharge. Children who were readmitted within one-year were younger, weighed less than children who were not readmitted, had significantly higher likelihood a preoperative complication and having a higher surgical STAT score. The median time to unplanned readmission was 54 days (IQR: 10 – 153). The most common reasons for unplanned readmissions were respiratory, gastrointestinal and infection complications.

Table 1.

Patient characteristics

Risk Factors	N = (145)	No readmission N = 106(%)	Readmission N = 39 (%)	p value
Age group1
Neonates	13	9 (8.5)	4 (10.3)
Infants	52	32 (30.2)	20 (51.3)
Children	80	65 (61.3)	15 (38.5)	0.042
Age, by month (median, IQR)		34.8 (5.2, 80.6)	7.4 (4.1, 48.7)	0.107
Gender
Female	54	36 (33.9)	18 (46.2)
Male	91	70 (66.1)	21 (54.8)	0.178
Weight
>10th percentile	133	99 (93.4)	34 (87.2)
<10th percentile	12	7 (6.6)	5 (12.8)	0.026
Weight, by kg (median, IQR)		12.3 (6, 21)	7.5 (5.2, 16.1)	0.147
Prematurity among neonates and infants
No	127	93 (87.7)	34 (87.2)
Yes	18	13 (12.3)	5 (12.8)	0.928
STAT Level
1	60	52 (49.1)	8 (20.5)
2	37	24 (22.6)	13 (33.3)
3	22	16 (15.1)	6 (15.4)
4	16	7 (6.6)	9 (23.1)
5	8	5 (4.7)	3 (7.7)
Missing	2	2 (100.0)	0 (0.0)	0.010
Prior cardiothoracic operation
No	133	98 (92.5)	35 (89.7)
Yes	12	8 (7.6)	4 (10.3)	0.600
Any non cardiac congenital anatomic abnormality
No	125	93 (87.7)	32 (82.1)
Yes	20	13 (12.3)	7 (17.9)	0.379
Chromosomal abnormality or syndrome
No	104	78 (73.6)	26 (66.7)
Yes	41	28 (26.4)	13 (33.3)	0.412
Any preoperative factor2
No	124	93 (87.7)	31 (79.5)
Yes	21	13 (12.3)	8 (20.5)	0.211
Cardiopulmonary bypass time, in minutes (mean, SD)		123.4 (73.9)	168.3 (84.2)	0.002
Cross clamp time, in minutes (mean, SD)		66.7 (54.3)	88.7 (71.4)	0.052

^1.Age group defined by days old at surgery: neonates: < 30 days; infants: >30 and < 365 days; children: > 365 and < 6570

^2.Any preoperative factor: Preoperative risk factors were operationalized as a count variable based on the presence of the following preoperative factors: mechanical circulatory support, persistent shock at time of operation, renal dysfunction requiring dialysis, mechanical ventilation to treat cardiorespiratory failure, and preoperative neurological deficit. Given the limited number of outcome events, we aggregated all preoperative risk factors and dichotomized based on the presence of none or >1.

Univariable Analyses

In the univariable analyses, pre-and postoperative ST2 were significantly associated with unplanned readmissions within one-year after congenital heart surgery. Preoperative middle and high tercile demonstrated a 3–4 fold greater hazard of unplanned readmission (HR: 2.94, 95% CI: 1.13–7.64; p: 0.027; HR: 3.82, 95% CI: 1.51–9.63, p: 0.005, respectively). Postoperative middle and high tercile also demonstrated significantly greater risk of unplanned readmission by one-year (HR: 3.32, 95% CI:1.18 – 9.31, p: 0.023; HR: 4.97, 95% CI: 1.86–13.27, p: 0.001). (Table 2)

Table 2.

Unadjusted and adjusted effects of preoperative and postoperative ST2 biomarker levels on risk of unplanned readmission within one-year

	Ng/mL	Free from readmission N (%)	Readmitted N (%)	Unadjusted		Adjusted*
				HR (95% CI)	P value	HR (95% CI)	P value
	Preoperative
ST2
1	0.46 – 1.49	43 (40.6)	6 (15.4)	REF		REF
2	1.50 – 2.69	34 (32.1)	14 (35.9)	2.94 (1.13 – 7.64)	0.027	3.11 (1.12 – 8.62)	0.029
3	2.70 – 106.33	29 (27.4)	19 (48.7)	3.82 (1.51 – 9.63)	0.005	2.96 (1.07 – 8.18)	0.049
	Postoperative
ST2
1	0.42 – 2.43	44 (41.5)	5 (12.8)	REF		REF
2	2.45 – 4.64	35 (33.0)	13 (33.3)	3.32 (1.18 – 9.31)	0.023	2.53 (0.86. – 7.47)	0.093
3	4.68 – 42.99	27 (25.5)	21 (53.9)	4.97 (1.86 – 13.27)	0.001	3.67 (1.23 – 10.95)	0.019

^*Risk factors in the model include: age (days) at surgery, weight (kilograms) at surgery, any prior cardiothoracic operation (yes/no), any non-cardiac congenital anatomic abnormality (yes/no), any chromosomal abnormality or syndrome (yes/no), STAT mortality category, and presence of any STS-CHSD clinical preoperative risk factors.

Adjusted analyses

Multivariable Cox proportional hazards regression analyses revealed serum levels of ST2 in the middle and high terciles of the population measured pre-and postoperatively were associated with increased risk of unplanned readmission (preoperative HR: 3.11, 95% CI: 1.12–8.62, p: 0.029; HR: 2.96, 95% CI: 1.07 – 8.18, p: 0.049; postoperative HR: 3.67, 95% CI: 1.23 – 10.95, p: 0.019). Postoperative serum levels in the middle tercile were not significantly associated with long-term risk of readmission. (Figure 1 and Figure 2)

Figure 1.

Kaplan-Meier curves for freedom from readmission by categories of preoperative ST2 biomarker levels. There is a significant association of elevated levels of preoperative ST2 and higher risk of readmission within one-year (log-rank: 0.006).

Figure 2.

Kaplan-Meier curves for freedom from readmission by categories of postoperative ST2 biomarker levels. There is a significant association of elevated levels of postoperative ST2 and higher risk of readmission within one-year (log-rank: 0.012).

Comment

To our knowledge, this is the first study to report the association of ST2 with risk of readmission within one-year for patients undergoing congenital heart surgery. There are limited clinical data on the relationship between ST2 and long-term outcomes following pediatric congenital heart surgery. Our findings demonstrate that higher levels of ST2 are associated with increased risk of readmission for pediatric patients undergoing congenital heart surgery.

Recent research has demonstrated that novel cardiac biomarker ST2 is a strong and significant predictor of readmission and/or mortality for children following congenital heart surgery. In a recent study, children that were readmitted within 30-days of surgery exhibited elevated levels of postoperative ST2 and were associated with 4 to 7-times greater odds of readmission and/or mortality.¹⁷ In a separate study, the inclusion of ST2 to a readmission multi-marker panel model improved the prediction of readmission over patient characteristics and risk factors alone. The addition of biomarkers resulted in a statistically significant improvement in the performance of the prediction model from an AUROC of 0.719 to AUROC 0.805 (p=0.036).¹⁵ These findings strongly suggest that perioperative ST2 values are objective indicators of children at high risk of early death or readmission.

Novel cardiac biomarker ST2 signals myocardial fibrosis and remodeling that may provide additional benefit for the management of congenital heart disease.²³ ST2 is known to play a critical role in the regulation of the inflammatory and autoimmune response in the body.^11,12,24 Specifically in the heart, ST2 is expressed in both cardiomyocytes and cardiac fibroblasts that are induced either by biomechanical strain injury or angiotensin. Therefore, elevated levels of ST2 present as a response to myocardial stress, such as myocardial ischemia, neurohormonal activation or mechanical overload.^{18,19, 50}

Novel biomarker ST2 offers an advantage over the traditional biomarker B-type natriuretic peptide (BNP).¹⁸ In a recent study of two longitudinal pediatric cohorts, preoperative and postoperative values of NT-proBNP were not significantly associated with readmission or mortality following pediatric congenital heart surgery. While NT-proBNP is regularly used to predict readmission in adults after cardiac surgery, this biomarker does not have the same predictive value in a heterogenous population of children who receive surgery for CHD. ST2, unlike NT-proBNP, is not developmentally regulated and therefore not confounded by age.²⁵ Furthermore, the biologic and analytic variability of ST2 is much lower than BNP, suggesting that ST2 levels may be better in risk stratification and prognositication.^26,27

In this single-center observational study, we used a longitudinal cohort to assess the relationship of ST2 and unplanned readmission within one-year for patients undergoing congenital heart surgery. After adjustment, we found that patients in the middle and highest tercile of preoperative ST2 had 3-times the readmission risk after congenital heart surgery than patients in lowest tercile of the serum biomarker. Similarly, we found that patients in the highest tercile of postoperative ST2 had 2.5 – 3.7-times greater risk of readmission than those patients with lower levels of ST2 after surgery.

Our findings indicate that pre-and-postoperative ST2 values are associated with readmission in congenital heart surgery patients and could potentially be used as a tool to identify patients at higher risk of complications before surgery and at discharge. This study highlights the importance of assessing the true value of emerging cardiac fibrosis biomarkers beyond clinical risk factors, particularly in light of the American College of Cardiology/American Heart Association class II recommendation to include ST2 as an additive risk stratification biomarkers for acute and chronic heart failure in adults.²⁷

Limitations

This study has a few limitations. First, risk adjustment was initially performed using many, but not all, of the covariates from the contemporary version of the STS-CHSD mortality risk model, which is a method of adjusting for clinical and procedural case mix. Second, the relatively small proportion of patients with our endpoint after congenital heart surgery may have obfuscated some of the statistical associations between the biomarkers and our model covariates. Third, we included only patients for whom both pre-and post-operative samples had been collected. This approach may lead to sampling bias if biomarker collection was associated with congenital heart disease severity.

This study is the first to demonstrate that elevated pre-and post-operative levels of ST2 are significantly associated with increased risk of unplanned readmission within one-year after pediatric cardiac surgery. The ability to predict postoperative adverse outcomes from preoperative clinical data has significant implications for determining appropriate timing of surgery, assessing surgical alternatives and readiness for discharge after cardiac surgery. As a result, these cardiac biomarkers can be useful tools for risk stratification and improved patient care management. We recommend surgical teams include the clinical variables and biomarkers available to them in the model to identify the risk of readmission or death for each patient prior to discharge. Improved readmission risk models can provide case managers, therapists, and primary care providers a transitional care plan that is tailored to each individual patient to mitigate major adverse events and readmission. Future studies should further investigate the role of these cardiac biomarkers as well as well as other novel cardiac, renal and inflammatory biomarkers to improve prediction of adverse events following cardiac surgery.