Markers of growth and nutrition in children with acquired chylothorax post CHD surgery

Abstract

Background:

Acquired chylothorax is an established complication of CHD surgery, affecting 2–9% of patients. CHD places a child at risk for failure to thrive, with subsequent chylothorax imposing additional risk.

Objective:

We conducted a retrospective chart review to ascertain quantitative markers of nutrition and growth in children affected by chylothorax following CHD surgery between 2018 and 2022 compared to controls.

Methods:

We utilised electronic medical record system, EPIC, at Children’s Hospital, New Orleans, targeting subjects < 18 years old who underwent CHD surgery between 2018 and 2022 and developed a subsequent chylothorax. Study subjects were identified using the 10th revision of the International Classification of Diseases codes (ICD-10 codes: J94.0, I89.8, and J90.0). Each chylothorax case (n = 20) was matched by procedure type and age to a control with no chylothorax (n = 20). Data were recorded in REDCap and analysed using SPSS.

Results:

After removal of outliers, we analysed 19 total matched pairs. There was no statistical difference in growth velocity (p = 0.12), weight change (operation to discharge) (p = 0.95), weight change (admission to discharge) (p = 0.35), Z-score change (operation to discharge) (p = 0.90), Z-score change (admission to discharge) (p = 0.21), serum protein (p = 0.88), or serum albumin (p = 0.82). Among cases, linear regression demonstrated no significant association between maximum chylous output and growth velocity (p = 0.91), weight change (operation to discharge) (p = 0.15), or weight change (admission to discharge) (p = 0.98).

Conclusions:

We did not observe statistically significant markers of growth or nutrition in children with chylothorax post-CHD surgery compared to those without chylothorax. Multisite data collection and analysis is required to better ascertain clinical impact and guide clinical practice.

Introduction

CHD affects nearly 1% of all births in the United States of America per year, with twenty-five percent of cases requiring surgery within the first year of life. ^1–3 CHD in infants and children is associated with failure to thrive, malnutrition, and poor health outcomes, which require specialised treatment and nutritional support. ^4,5 Acquired chylothorax is a well-established complication of CHD surgery, affecting 2–9% of patients, where chylous fluid leaks into the pleural space. ^6–9 Chylothorax is believed to increase the risk of malnutrition and poor growth due to a loss of proteins, fatty soluble vitamins, lipids, and electrolytes during the chylous effusion. ^10–12 Taken together, acquired chylothorax in infants and children imposes additional risk to an already vulnerable patient population.

Suboptimal nutrition and failure to thrive are significant consequences of acquired chylothorax post CHD surgery, but serial data on nutritional markers and how certain markers respond to treatment and nutritional support are scarce. ^13,14 A recent systematic review on nutritional markers in infants with chylothorax found a paucity of studies focused on this issue, with only four studies focused on growth and nutritional markers in children with chylothorax post-CHD surgery. ¹⁴ While there are studies focused on establishing standard feeding and treatment protocols, few have attempted to investigate the nutritional consequences of these interventions. ^10,15 The lack of studies investigating the nutritional implications of chylothorax has created a critical knowledge gap for clinicians to tailor enteral feeding and chylothorax treatment post-CHD surgery.

Our objective was to ascertain quantitative markers of nutrition and growth in infants and children affected by chylothorax compared to controls, following CHD surgery. We sought to identify markers of growth and nutrition that may be impacted by chylothorax compared to children post-CHD surgery without development of chylothorax.

Materials and methods

We conducted a retrospective chart review of subjects < 18 years of age who underwent CHD surgery at Children’s Hospital, New Orleans between 2018 and 2022. The range of cardiac procedures patients underwent included Tetralogy of Fallot, Bidirectional Glenn, Fontan, and Norwood procedures, as well as aortic arch, right ventricular outflow tract, left to right shunt, and anomalous pulmonary venous return repairs. Each case was identified as a subject with post-operative diagnosis of chylothorax. Each case was matched 1:1, by procedure and age, to a control who received CHD surgery at Children’s Hospital, New Orleans but did not develop chylothorax. A system for classifying the risk of death associated with CHD surgery developed by the Society of Thoracic Surgeons – European Association for Cardio-Thoracic Surgery (STAT Mortality Category score) was calculated for each case based on procedure types to determine whether there were any differences in mortality risk between the two groups.

After obtaining study approval from our internal institutional review board, we utilised our electronic medical record system, EPIC, to identify cases using relevant International Classification of Diseases codes (ICD-10 codes: J94.0 (chylous effusion), I89.8 (chylothorax), and J90.0 (pleural effusion)). Each chylothorax diagnosis was confirmed with a pleural fluid triglyceride level ≥ 110 mg/dL. A participant flow chart outlines the screening and inclusion criteria in Figure 1. Data were abstracted from each chart, including serum lab values, chylous effusion variables, and growth parameters. The collected data were stored and managed electronically using REDCap hosted by Tulane University. Thirty percent of data were cross-checked by another research staff member to ensure data accuracy and integrity. The data were analysed via SPSS.

Figure 1. Participant flow chart.

Growth parameters collected included height, weight, and Centers for Disease Control and Prevention (CDC) growth percentiles at the following time points: 1) admission, 2) procedure, and 3) discharge. Total volume of blood products transfused, days on total parenteral nutrition, and doses of plasmalyte, received during admission were also collected as covariates to subjects’ weight measurements. The markers of nutrition collected were 1) serum total protein and 2) serum albumin. The chylothorax parameters collected included: 1) chylous triglyceride levels and 2) maximum daily chylous output in millilitres per kilogram per day. Additional health outcomes of interest were collected including post-operative complications, days on ventilation, length of stay, and mortality. Mortality was defined as within one year of follow-up.

Among cases, Shapiro–Wilk test confirmed normality of growth and nutrition parameters including: growth velocity, weight change, weight-for-length z-score change, serum protein, and serum albumin. Weight-for-length Z-scores were calculated based on the World Health Organization (WHO) calculator for infants < 24 months of age only. Student’s t-test was used to compare the aforementioned growth and nutrition parameters between cases and controls. Two-sample t-test was also used to compare the volume of blood products received, days on total parenteral nutrition, and doses of plasmalyte between cases and controls. Linear regression was used to ascertain the association between maximum chylous output with both growth velocity and weight change. Mann–Whitney U-Test was conducted to compare chylous triglyceride levels in cases with no weight gain or weight loss compared to subjects with weight gain over the hospital course.

Results

One case and one control were removed as outliers due to growth parameters greater than two standard deviations from the mean, yielding 19 total matched pairs. There was no differences in demographics, including age, sex, race, ethnicity, noted between the cases and controls, nor were there any significant differences between congenital heart disease, procedure types, or STAT categories noted (Table 1).

Table 1. Demographics

Abbreviations: arterial switch operation (ASO); Blalock–Thomas–Taussig shunt (BT shunt); extracorporeal membrane oxygenation (ECMO); right ventricular outflow tract (RVOT); transposition of the great arteries (TGA); total anomalous pulmonary venous return (TAPVR).

The most common CHD diagnoses included left to right shunts (53% cases vs. 58% controls), single ventricle physiology (53% each), and right ventricle outlet obstruction (32% cases vs. 27% controls). Forty-seven percent of chylothorax cases had two or more lesions, compared to 63% of controls. The most common surgical procedures were left to right shunt repairs (37% cases vs. 42% controls), Fontan procedures (21% cases vs. 16% controls), and Tetralogy of Fallot repairs (21% each). Additionally, 84% of cases and 89% of controls required two or more procedures, with 74% of cases versus 80% of controls receiving concomitant cavopulmonary bypass. Finally, 21% of chylothorax cases received extracorporeal membrane oxygenation, compared to 11% of controls (p = 0.08) (Table 1).

Hospital outcomes and growth and nutritional outcomes are outlined in Table 2. When comparing cases to controls, there was no difference in growth velocity (p = 0.12), weight change (operation to discharge) (p = 0.95), weight change (admission to discharge) (p = 0.35), weight-for-length Z-score change (operation to discharge) (p = 0.90), weight-for-length Z-score change (admission to discharge) (p = 0.21), serum protein (p = 0.88), or serum albumin (p = 0.82). Failure to thrive (defined as a weight for age that falls below the 5th percentile on multiple occasions) was identified in eight chylothorax patients and five case controls using CDC growth percentiles (p = 0.16). ¹⁶ Among cases alone, linear regression demonstrated no significant association between maximum chylous output with growth velocity (p = 0.91), weight change (operation to discharge) (p = 0.15), or weight change (admission to discharge) (p = 0.98). Six cases of chylothorax satisfied criteria of a high-volume chylous effusion, defined as > 19.99 ml/kg/day, with a mean of 16.2 ml/kg/day and a standard deviation of 11.7. No statistical change was seen in chylous triglyceride level between cases with no net weight gain/loss nor in cases with net weight gain over their respective hospital course (p = 0.733).

Table 2. Growth and nutrition outcomes

Data are presented as mean ± standard deviation. *Shapiro–Wilk test confirmed normality of the variables including Growth Velocity, Weight Change (Operation to Discharge), Weight Change (Admission to Discharge), Maximum Chylous Output. Due to mortality prior to discharge, n = 18 chylothorax and n = 17 control cases were included in the following growth parameter measurements”. **Weight for length z-score calculated based on WHO calculator for infants <24 months of age only. ****Two-sample usual t-test with independent samples was conducted with two-tailed p-values reported. SD was reported with a 95% confidence interval.

Fluid covariates to subjects’ weight measurements are listed in Table 2. The mean value of transfused blood products (packed red blood cells, cryoprecipitate, fresh frozen plasma, platelets, and salvaged red blood cells) per chylothorax case was 582.3 ml (range: 0–1738 ml), and 957.8 ml (range: 277–3586 ml) per control case (p = 0.14). Twelve chylothorax patients received total parenteral nutrition for a mean of 15.75 days, compared to seven control cases who received total parenteral nutrition for a mean of 14.43 days (p = 0.90). Appendix A outlines differences in the duration of different feeding methods, days achieving goal feeds (≥ 100kcal/kg/day), and changes in weights between chylothorax and control patients who received total parenteral nutrition during hospitalisation. The average change in weight during consecutive days not receiving caloric goal on enteral feeds was significantly lower (p = 0.038) in chylothorax cases (mean −28.2g/day) than control cases (mean 20.8 g/day). Per hospital protocol, most patients were not given anything by mouth (made NPO) for the entirety of their parenteral nutrition. Patients often transitioned to tube feeds before eventually attempting oral nutrition. Due to the inherent variability amongst nutrition regiments and limited sample size, our data lacked enough power to determine potential significance between study groups. While these variables were not included in our primary objectives, they were added for comparison. Eighty-four percent of chylothorax patients received conservative treatment, defined as median chain triglycerides and/or modified fat formulas (e.g., Enfaport, Vivonex, Neocate, and Pregestimil), whereas most control patients received standard infant formulas (fortified EBM, Pediasure, Similac Sensitive, and Total Comfort). Five chylothorax patients (26.3%) received a single dose of plasmalyte compared to nine control patients (47.4%) (p = 0.19). Additionally, four chylothorax cases received IVIG infusions while zero controls did.

Regarding hospital outcomes displayed in Table 2, the mean length of stay for chylothorax cases was significantly longer (p < 0.01) than that of the control cases [mean, 35.78 days (standard deviation, ± 8.21 days) versus mean, 16.58 days (standard deviation, ± 3.71 days)]. Additionally, 26% of chylothorax cases ended in mortality, whereas only 10% of control cases had the same outcome (p < 0.05). Mortality occurred post-surgery prior to discharge in 1/5 chylothorax cases and 2/2 control cases. The median STAT mortality category for both groups was category 2. Both groups also had a mean score of 2.53 with a standard deviation of ± 1.27 for chylothorax cases and ± 1.43 for controls (p = 1.00).

Discussion

With nearly one-fourth of infants with univentricular heart defects satisfying failure to thrive criteria within the first year of life, ¹⁷ a clear understanding of the implications of CHD and its complications on early growth and nutrition is imperative. Our study is the first to develop a more comprehensive picture of growth and nutrition markers in children with and without chylothorax development post-CHD surgery. Contrary to previous studies, weight measurements and Z-scores were collected and analysed at multiple timepoints allowing more accurate and reliable representations of growth than discrete measurements. Z-scores were incorporated into our analysis to describe a subject’s growth relative to the population mean using the standard deviation of the population of interest, allowing for more accurate ascertainment of growth over the study period. ¹⁸ The fluid covariate data revealed a greater degree of fluid resuscitation in the control group, which may indicate the chylothorax cases were fluid restricted. Differences in mean transfused volumes are worth considering when using weight as a marker for nutrition. The significant difference in weight gain between chylothorax and control cases during enteral feeds post total parenteral nutrition highlights how vital it is to optimise nutrition in chylothorax patients post CHD surgery, since the data indicate they are at greater risk of inadequate weight gain. Accurate representation of growth is crucial to determine adequate caloric intake in CHD infants with increased risk for failure to thrive. In this already vulnerable population, failure to thrive adds to the risk of long-term cognitive delay and poor neurodevelopmental outcomes. ^5,19

Serum albumin is routinely measured during standard blood work, and the increased half-life reflects a dietary change over a three-week duration. Albumin is often considered a less reliable marker of nutrition than prealbumin because of its prolonged half-life and variability in patient with ascites, renal protein loss, liver disease, and inflammatory states. ^20,21 However, prealbumin levels drop rapidly in malnourished patients (half-life of two days) and normalise within ten days of adequate nutrition. ^22,23 Therefore, prealbumin measurements can potentially indicate whether a recent change in intervention or pathology may influence nutritional status and should be considered in lieu of albumin as a marker of nutritional status.

Children with CHD often have increased resting energy expenditure due to increased cardiac and respiratory effort. Inadequate energy intake from anorexia, early satiety, and feeding intolerance issues are also significant comorbid concerns. ²⁴ Current protein guidelines exist for infants with CHD, but they vary broadly and fail to consider the unique needs of infants with postoperative chylothorax. ^25,26 Serum total protein is a routine and affordable marker that can gauge a patient’s response to and tolerance of nutritional supplementation. It is worth noting that total protein synthesis is inhibited by proinflammatory states, which in and of themselves contribute towards malnutrition. These protein markers may potentially reflect the extent of inflammation in patients more so than the degree of malnutrition from a depletion in protein energy stores. ²⁷

Prolonged hospital length of stay and increased mortality are two potential consequences of acquired chylothorax post CHD surgery, which our data support. A 110-centre study determined a 1.4% to 2.9% estimated morality risk associated with STAT Category 2, and a 3.0% to 6.8% risk associated with STAT Category 3. With an average STAT score of 2.53, the morality rates seen in our patient population far surpass this study’s estimated risk. ²⁸ Previous studies found acquired chylothorax to be associated with longer length of stay, increased adjusted risk for in-hospital mortality and higher cost, regardless of procedure complexity. ^29,30 Our data support this finding. Extended length of stay have been shown to increase rates of nosocomial infections and long-term morbidity and mortality between 15 and 40%, which should be taken into considered in clinical practice and future studies. ^31–34

Our most notable limitation was our small sample size (n = 38). Increased sample size can be achieved for this rare complication via inter-institutional collaboration and multisite trials. Despite this, study inclusion criteria were developed to avoid convenience sampling. While case–control matching was manually performed, the patients were selected solely by closest age and shared procedure type. Greater length of stay noted in chylothorax cases may affect weight at the time of discharge and contribute to greater variability in collected growth metrics. Additional nutritional markers, including serum triglycerides, prealbumin, and fat-soluble vitamin levels, were not routinely collected at our institution and provide additional opportunities for future studies.

It would be reasonable to presume that damage to the thoracic duct and subsequent chylothorax would cause a drop in serum triglyceride levels, specifically long-chain triglycerides. ³⁵ This is of potential significance for infants and children since triglycerides are needed for energy reserves, cholesterol synthesis, and because long-chain triglycerides are considered essential for maturation of the developing brain, retina, and other organs in newborn infants. ³⁶ Future studies should seek to evaluate the relationship between chylothorax development and serum triglycerides. Finally, only six cases of chylothorax were considered high-volume chylothorax. While low output effusion is generally treated conservatively, high output effusions typically require more aggressive treatment. ³⁷ A larger sample size may have allowed stratification of low- and high-output cases.

Conclusion

Compared to controls, cases of chylothorax did not have statistically significant markers of growth or nutrition. For cases of chylothorax, maximum chylous output and chylous triglyceride level were not associated with markers of growth and nutrition in CHD patients with chylothorax. The increased length of stay and mortality seen in the chylothorax cases highlights the harmful impact this condition can have on CHD patients. The challenge of tailoring treatment for possible nutritional losses remains due to the paucity of comprehensive data on this topic.

Future studies should employ a multicentre, prospective study to facilitate an increase in sample size and power. We recommend that clinicians routinely measure key nutritional markers in serum and chylous output and record reliable growth metrics, since they are both relatively low-cost and lost-risk assessments that may improve medical management of these patients. Investigation is warranted on treatment methods (i.e., median chain triglycerides, total parenteral feeds, and surgery) and their influence on nutrition and growth, as well as morbidity and mortality. Multidisciplinary research and multicentre studies are needed to ascertain the clinical impact chylothorax has on the nutritional status of infants and children to better guide clinical practice.