Thyroid Hormones Predict ICU Mortality After Cardiopulmonary bypass in Congenital Heart Disease Patients Under 3 Months Old

Backgroup: To study the effectiveness of thyroid hormones in predicting intensive care unit (ICU) mortality after cardiopulmonary bypass (CPB) in infants with congenital heart disease (CHD). Methods: We retrospective observational analyzed data from 133 patients under 3 months old who underwent cardiac surgery with CPB from June 2017 to November 2019. ICU mortality prediction was assessed by multivariate binary logistic regression analysis and area under the curve (AUC) analysis. Results: Non-survivors were younger (17.46±17.10 days vs. 38.63±26.87 days, P=0.006), with a higher proportion of neonates (9/13 vs. 41/120, P=0.017) and a higher proportion of individuals with Risk Adjustment in Congenital Heart Surgery-1 (RACHS-1) score ≥ 4 (8/13 vs. 31/120, P=0.020). No signicant difference was found in CPB and aortic cross-clamping (ACC) time. The levels of free triiodothyronine (FT3) (3.91±0.99 pmol/L vs. 5.11±1.55 pmol/L, P=0.007) and total triiodothyronine (TT3) (1.55±0.35 nmol/L vs. 1.90±0.57 nmol/L, P=0.032) were higher in survivors compared with non-survivors. In the ICU mortality prediction assessment, only FT3 was an independent mortality predictor and showed a good AUC (0.856 ± 0.040). Conclusion: FT3 was a powerful and the only independent predictor of ICU mortality in CHD infants under 3 months old after CPB.


Introduction
Congenital heart disease (CHD) is the most common congenital malformation among live births, accounting for approximately one-third of birth defects 1 . A systematic review showed that the prevalence of CHD increased from 0.6‰ in the 1930s to 9.1‰ at the end of the 20th century 2 . Cardiopulmonary bypass (CPB) is often used for surgery in complex CHD cases. However, hemodilution, hypothermia and ultra ltration during CPB have been identi ed as inducing a temporary hypothyroid state, especially in infants 3,4 .
The thyroid hormones triiodothyronine (T3) and thyroxin (T4) have permissive effects on β1-adrenergic receptors, which enhance heart contractility and reduce systemic vascular resistance 5,6 . Additionally, thyroid hormones increase preload and decrease afterload, leading to increase cardiac output 7 . Several studies have shown that the hypothyroid state, which affects the metabolism of myocardial energy, is associated with poor prognosis after cardiac surgery with CPB 8,9 . Correspondingly, thyroid hormone replacement therapy could provide clinical bene ts in infants undergoing CPB [8][9][10] .
A study was conducted to assess the effects of CPB on thyroid function in infants weighing less than 5 kg, and the results showed that low T3 and T4 were both predictors of high mortality 13 . Talwar et al 14 found that low levels of postoperative TT4 were correlated with postoperative morbidity, a prolonged postoperative course, and prolonged MV in open heart surgery with CPB. Since the levels of thyroid hormones play a critical role in recovery from cardiac surgery and thyroid hormones decreased after CPB, the preoperative level of thyroid hormones could be a predictor of ICU mortality after CPB in CHD patients. Therefore, we conducted a retrospective study to evaluate the effect of thyroid hormones in relation to survival in patients after cardiac surgery with CPB.

Methods
We retrospectively reviewed the medical records of patients with CHD under 3 months old in our hospital between June 2017 and November 2019. We excluded patients who were over 90 days old at the time of surgery, patients without CPB, patients with primary thyroid gland disease, and patients with trisomy 21 syndrome. Clinical data included gender; age; weight; Risk Adjustment in Congenital Heart Surgery-1 (RACHS-1) score 15

Statistical analysis
The statistical analysis was performed with SPSS version 20.0 software (Chicago, IL, USA). Continuous variables are expressed as the mean ± standard deviation, while categorical variables are summarized as frequencies and percentages. Comparisons between groups were made using unpaired Student's t-test for continuous variables and χ 2 or Fisher's exact test for categorical variables. Multivariate binary logistic regression analysis was further conducted to assess the independent ICU mortality predictors. Receiver operating characteristic (ROC) curves were generated to examine the variables for predicting ICU mortality, and the area under the curve (AUC) was calculated from the ROC curve. Youden's index, which maximized the sum of the sensitivity and speci city, was used to de ne the optimal cut-off value.
Statistical signi cance was de ned as P < 0.05.

Independent predictors of ICU mortality
Predictors with p-valves less than 0.1 were enrolled in the multivariate binary logistic regression analysis to determine the independent predictors of ICU mortality, except gender. As shown in Table 3, FT3 was the only independent predictor. Value of FT3 in predicting ICU morality ROC curves were constructed to examine the performance of FT3 as a predictor of ICU mortality (Fig. 1). The AUC was 0.856 ± 0.040, optimal cutoff value was 4.89 pmol/L, and sensitivity and speci city were 100% and 63.3%, respectively (Table 4).

Discussion
To our best knowledge, the present study is the rst clinical retrospective analysis of the predictable value of thyroid hormones in patients with CHD undergoing CPB. In our study of 133 consecutive patients, we found that FT3 may be an independent predictor of ICU mortality based on multivariate binary logistic regression and ROC curves. Previous studies 16 have reported that low T3 was an independent predictor of ICU mortality, which is consistent with our nding. However, for CHD patients, especially children, RACHS-1 scores could predict ICU mortality, length of ICU stay and duration of MV [17][18][19][20] . In our study, compared with survivors, non-survivors had a higher RACHS-1 score. However, in the additional multivariate binary logistic regression, it was not an independent mortality predictor. We suggest that RACHS-1 scores on the basis of CHD subtype should not consider the relationship of year, weight, and levels of thyroid hormone as confounding factors 21 . Additionally, the small sample size of children with RACHS-1 scores of 5 or 6 may be another reason for the reduced statistical power. Although the CPB and ACC time were high in non-survivors, no signi cant difference was found compared with survivors, which demonstrates the improvement of cardiac surgery techniques and perfusion mode of CPB in China.
We found an interesting phenomenon in our study, namely, that all the non-survivors were male. This could be related to the preference for sons over daughters, which is very common in China. Thus, when a child is diagnosed with complex CHD, based on the gender, operative risk and economic status of the parents, girls may not have the opportunity to undergo the operation, especially in rural areas 22,23 . Due to this bias, we removed gender from the multivariate binary logistic regression.
Thyroid hormones have important effects on the cardiovascular system, such as increasing cardiac output and decreasing systemic vascular resistance, which are predictive of good outcomes 24,25 . However, several studies have veri ed that cardiac surgery with CPB induces a marked depression of thyroid hormones 14,26,27 . Researchers have found that low levels of T3 28 or T4 14 were correlated with postoperative morbidity in open heart surgery with CPB. A study was conducted to assess the effects of CPB on thyroid function in infants weighing less than 5 kg, and the results showed that low T3 and T4 were both predictors of high mortality 13 . Since postoperative low levels of thyroid hormones could lead to a poor prognosis, a preoperative increase in thyroid hormones may improve the prognosis. A multicenter randomized controlled trial (RCT) of T3 supplementation of patients undergoing heart surgery with CPB (TRICC) showed that T3 supplementation provides clinical advantages in patients younger than 5 months, but not in older patients 29 . Talwar et al 30 performed an RCT study of perioperative oral T4 in patients younger than 6 months who underwent open heart surgery with CPB and found that thyroid hormone levels reduced postoperative and that T4 supplementation reduced the duration of MV and ICU and hospital stays. Therefore, the preoperative level of thyroid hormones may predict the prognosis of patients with CHD undergoing CPB. Kumar et al 31 found that low T3 is an important marker of mortality in critically ill patients, while low T4 and TSH did not increase the predictability. In a large-scale prospective, observational study of unselected ICU patients, they found that FT3 was the most powerful and only independent predictor of ICU mortality among the thyroid hormone indicators 16 . However, Quispe et al 32 found that the FT3 level was not signi cantly different between survivors and nonsurvivors and was not a mortality predictor.
Our study showed that only FT3 is the independent predictor of ICU mortality with a good AUC. Thyroid hormones include T4, which represents the major form of circulating thyroid hormones (> 80%), and T3, which accounts for a small portion (< 20%) of circulating thyroid hormones and has a major biological effect on the heart. Moreover, the levels of TT3 and TT4 can be affected by the concentration of thyroxine-binding globulin (TBG) or the binding ability of TBG, which may be affected by several drugs, including furosemide and heparin 16 . In contrast, FT3 and FT4 were not affected in these conditions. Thus, the level of FT3 may be better than other thyroid hormones as a predictor of ICU mortality, which is consistent with our ndings.
Some limitations exist in our study. First, this was a retrospective study with a small sample size, which limited the statistical power. Therefore, additional cases need to be enrolled, and a prospective randomized multicenter study should be conducted. Second, patients with RACHS-1 scores of 5 or 6 are rare, which reduced the ability of RACHS-1 to predict ICU mortality in CHD children. Finally, we did not consider the relationship of thyroid hormones with albumin and dopamine, which may provide more robust evidence to assess the predominant predictor.

Conclusion
Thyroid hormones play an important role in the recovery of patients with CHD undergoing CPB, and FT3 level was the most powerful and only independent predictor of ICU mortality. Receiver operating characteristic curves for free triiodothyronine (FT3)