European Journal of Cardiovascular Medicine

Congenital heart disease (CHD) is one of the most common birth anomalies, affecting approximately 8–10 out of every 1000 live births globally, with many infants requiring corrective or palliative surgical intervention in early life [1]. Cardiopulmonary bypass (CPB) known to be associated with significant postoperative hormonal disturbances, including the phenomenon of "non-thyroidal illness syndrome" (NTIS) or "low T3 syndrome" [2]. This condition is characterized by reduced levels of triiodothyronine (T3) and thyroxine (T4), despite normal or low-normal thyroid-stimulating hormone (TSH) concentrations and is frequently observed after major pediatric cardiac surgeries [3].

Thyroid hormones play a crucial role in metabolic regulation, cardiovascular function, and neurodevelopment, particularly in infants [4]. Postoperative reductions in T3 and T4 may impair myocardial performance, prolong mechanical ventilation, and delay recovery, especially in neonates and infants with immature hypothalamic-pituitary-thyroid axis [5]. Several studies have investigated the potential of thyroid hormone supplementation in ameliorating these effects, aiming to improve hemodynamic stability, inotropic support requirement, and postoperative outcomes [6].

Oral thyroid hormone replacement is an appealing intervention due to its non-invasive nature and potential to prevent perioperative hormone derangements. However, the literature remains inconclusive regarding its efficacy, dosage, and safety profile in infants undergoing CPB [7]. Recent trials and meta-analyses have shown variable outcomes, with some studies indicating a significant reduction in low cardiac output syndrome and ICU stay, while others report negligible or no benefit [8–10].

Given the high incidence of postoperative NTIS and its association with adverse outcomes, further research is warranted to delineate the role of preemptive oral thyroid hormone therapy in this vulnerable population. This study aims to assess the effect of perioperative oral thyroid hormone administration on serum T3, T4, and TSH levels in infants undergoing congenital cardiac surgery under CPB, thereby evaluating its potential to improve perioperative endocrine balance and recovery.

After obtaining approval from the Institutional Ethics Committee (EC/Approval/03/C.Anae/13/06/2022), this prospective, randomized, double-blinded controlled trial was conducted at U.N. Mehta Institute of Cardiology and Research Centre, Ahmedabad, over a two-year period from June 2022 to June 2024.

A total of 100 infants aged ≤1 year undergoing open-heart surgery for congenital heart disease falling under RACHS-1 categories 2–5 were included in the study. Randomization was done using a computer-generated sequence and sealed envelope technique. Blinding was maintained for both the data collector and operating surgeon.

Inclusion Criteria

• Infants aged ≤1 year.
• Undergoing congenital cardiac surgery under cardiopulmonary bypass (CPB).
• Surgery categorized under RACHS-1 categories 2–5.

Exclusion Criteria

• Known thyroid or other endocrine disorders.
• Abnormal baseline thyroid profile.
• History of preoperative thyroid hormone therapy or radiation.
• Use of medications affecting thyroid function.
• Preoperative use of inotropes or circulatory support.
• Preoperative acute kidney injury (AKI).
• Down syndrome.
• Perioperative mortality.

Study Groups

• Group P (Placebo group, n = 50): Received no thyronorm.
• Group T (Treatment group, n = 50): Received oral thyronorm 10 mcg/kg 12 hours preoperatively and 5 mcg/kg once daily postoperatively for 4 days.

Preoperative Assessment

All infants underwent clinical and demographic evaluation a day prior to surgery. Data on age, sex, weight, CBC, electrolytes, renal and liver function tests, chest X-ray, ECG, and echocardiography were documented. Baseline serum T3, T4, and TSH levels were measured.

Anaesthetic and Surgical Protocol

All patients were premedicated and induced as per institutional protocols. Anaesthesia was induced with midazolam 0.03 mg/kg, ketamine 2 mg/kg, glycopyrrolate 0.01 mg/kg, and fentanyl 5 mcg/kg, followed by vecuronium 0.12 mg/kg for intubation. Monitoring included ECG, SpO₂, temperature, and invasive lines.

Standard CPB protocol was followed. Heparin (400 IU/kg) was administered. CPB circuit was primed with lactated Ringer’s and fresh blood to maintain a hematocrit of 25–30%. Cardioplegia was initiated after aortic cross-clamp and cooling to 32–33°C. Post-surgery, rewarming to 35–36°C, deairing, spontaneous sinus rhythm recovery, and weaning from CPB were performed. Protamine was used to reverse heparin.

Postoperatively, patients were shifted to ICU and received either thyronorm (5 mcg/kg) or placebo orally at 6, 24, 48, and 72 hours.

Postoperative Assessment

• Daily thyroid function tests (T3, T4, TSH).
• Ejection fraction (EF) via echocardiography.
• Mechanical ventilation duration, time to extubation, and ICU length of stay.
• Vasoactive inotropic score (VIS), calculated using:

VIS=dopamine (μg/kg/min)+dobutamine (μg/kg/min)+100xepinephrine dose (μg/kg/min)+100×norepinephrine (μg/kg/min)+10000vasopressin (ug/kg/min)+10×milrinone (mcg/kg/min)

• A ≥20% reduction in VIS was considered significant.
• Additional parameters: heart rate, mean arterial pressure, serum lactate, and mixed venous oxygen saturation.

Statistical Analysis

Data were analyzed using SPSS version 22. Quantitative data were presented as mean ± standard deviation, while categorical data were expressed in percentages. An independent sample t-test was used to compare continuous variables between groups. A p-value <0.05 was considered statistically significant.

Table 1 shows the baseline demographic characteristics of the two groups. The mean age in the thyronorm group was 6.66 ± 3.16 months compared to 6.42 ± 3.11 months in the placebo group, with no statistically significant difference (p = 0.6982). The mean weight was slightly higher in the thyronorm group (5.54 ± 2.22 kg) than in the placebo group (4.50 ± 1.29 kg), though not statistically significant (p = 0.54). Gender distribution was also similar between groups, with a p-value of 0.5839, indicating well-matched study populations.

Table 2 shows the serum T3 and T4 levels measured at preoperative baseline and at 6, 24, 48, and 72 hours postoperatively. Preoperative T3 values were similar between groups (p = 0.205). However, postoperative levels at 24, 48, and 72 hours were significantly higher in the thyronorm group compared to the placebo group, with p-values <0.001, demonstrating the efficacy of oral thyronorm in maintaining elevated T3 levels after surgery. For T4 levels preoperative values were not significantly different between the groups (p = 0.205), a marked and statistically significant elevation in T4 levels was observed in the thyronorm group at 24, 48, and 72 hours postoperatively (p <0.001 for all). This supports the role of thyronorm in boosting T4 levels during the postoperative phase.

The lactates between two groups preoperatively and at intervals of 6 hrs,24 hrs,48 hrs,72 hrs is 0.934,0.727,0.770,0.652,0. 8014.there was no difference between two groups. (Table 3) The mixed venous oxygen saturation between two groups preoperatively and at intervals of 6 hrs, 24 hrs ,48 hrs, 72 hrs is 0.806, 0.890, 0.998,0.711, 0. 955.there was no difference between two groups. (Table 4)

Table 5 shows the comparison of vasoactive inotropic score (VIS) between the two groups. There were no significant differences in VIS at any of the measured time points, including baseline, 6, 24, 48, and 72 hours postoperatively (all p > 0.05). Despite hormonal elevation in the intervention group, this did not translate into reduced inotropic support needs, indicating limited clinical impact on inotrope requirement.

Table 6 shows the clinical recovery markers: time to extubation and length of ICU stay. Both parameters were statistically comparable between groups. The mean time to extubation was 11.48 ± 8.86 hours in the thyronorm group and 12 ± 9.43 hours in the placebo group (p = 0.5477). Length of ICU stay was nearly identical between groups at 2.79 ± 0.81 days for the thyronorm group and 2.76 ± 0.77 days for the placebo group (p = 0.8223), suggesting no significant improvement in these outcome measures with thyronorm administration.

The cardiac function between the two groups showed no significant difference, with a preoperative p-value of 0.616 and a postoperative p-value of 0.728.. (Table 7)

Table 1: Demographic Data (Age, Weight, Gender)

Table 2: Serum T3 and T4 Values at Different Time Points

Table 3: Preoperative and postoperative lactate values at 6 hrs, 24hrs, 48hrs, 72 hrs

Table 4: Preoperative and postoperative mixed venous oxygen saturation values at 6 hrs, 24hrs, 48hrs, 72hrs are comparable

Table 5 : Vasoactive Inotropic Score (VIS)

Table 6: Time to Extubation and Length of ICU Stay

Table 7: preoperative and postoperative cardiac function between two groups

In this prospective randomized controlled study, we evaluated the effect of perioperative oral thyronorm supplementation on thyroid hormone levels and clinical outcomes in infants undergoing congenital heart surgery under cardiopulmonary bypass (CPB). The results revealed a significant increase in serum T3 and T4 levels in the thyronorm group compared to the placebo group postoperatively, while TSH levels remained comparable. Despite the hormonal elevation, no statistically significant differences were noted between the groups in terms of vasoactive inotropic score (VIS), time to extubation, length of ICU stay, or cardiac function.

The findings align with those of Talwar et al. [1] and Karri et al. [4], who also observed elevated thyroid hormone levels following thyronorm supplementation but minimal effect on hemodynamic or clinical recovery outcomes in routine cases. Alok Kumar et al. [2] similarly reported an improvement in thyroid hormone profiles without significant impact on extubation times or inotrope requirement, suggesting that thyroid hormone normalization does not always translate to improved perioperative recovery in infants.

While thyroid hormones are known to enhance cardiac contractility, heart rate, and systemic vascular resistance modulation [11], the magnitude of change necessary to produce clinically relevant benefits may vary across age groups, cardiac lesion complexity, and surgical durations.

Alok kumar et al [2] showed no significant difference in heart rate, mean arterial pressure between two groups, Sachin Talwar et al [1] study showed no difference in serum lactate levels between two groups and this is comparable to our study. Mackie et al [10] showed no difference heart rate and diastolic blood pressure after thyronorm administration.

Our findings are consistent with the meta-analysis by Flores et al. [15], which concluded that although T3 therapy reduced inotrope scores slightly, there was no substantial effect on mechanical ventilation duration or ICU length of stay.

Interestingly, studies like those by Martinez et al. and Zou et al. have demonstrated that low postoperative free T3 levels may predict adverse outcomes such as prolonged CPB, arrhythmias, and extended ventilation [12,13]. However, in our study, the supplementation did not result in improved outcomes, perhaps due to early enteral administration, the form of hormone used (oral vs. intravenous), or the patient selection criteria.

Furthermore, the potential benefits of thyroid supplementation may be more evident in high-risk patients or neonates with RACHS-1 score ≥4, where the suppression of the hypothalamic-pituitary-thyroid axis is more profound [14, 15]. Our study included infants ≤1 year undergoing RACHS category 2–5 surgeries, possibly reducing the contrast in outcomes between groups.

Additionally, timing and dosage of supplementation may influence outcomes. Hauss et al. [11] emphasized the importance of individualized dosing and suggested further trials focusing on free hormone levels and cardiac output indices.

Overall, while thyroid hormone supplementation clearly restores hormonal balance, the lack of impact on postoperative clinical recovery metrics in this cohort suggests limited routine utility unless targeted to specific high-risk subgroups.

Present study showed no much difference in cardiac function between two groups. Cardiac index is measured through impedence cardiometry with an icon monitor. but present study measured cardiac function by transthoracic echocardiography. Talwar et al¹ showed significant improvement in cardiac index values in group (T) compared to group(P).

This study demonstrated that oral thyronorm supplementation in infants undergoing congenital heart surgery under CPB effectively elevated serum T3 and T4 levels without significantly altering TSH levels. However, no statistically significant differences were observed in clinical outcomes such as VIS, cardiac function, extubation time, or ICU stay. Therefore, routine administration of oral thyroid hormone may not be necessary in all infants but may hold promise in more complex or high-risk surgical populations. Larger multicenter trials are warranted to further delineate subgroups that might benefit from such intervention.

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