Triiodothyronine Supplementation in Infants and Children Undergoing Cardiopulmonary Bypass (TRICC): a multicenter placebo-controlled randomized trial: age analysis

Abstract

Background: Triiodothyronine levels decrease in infants and children after cardiopulmonary bypass. We tested the primary hypothesis that triiodothyronine (T3) repletion is safe in this population and produces improvements in postoperative clinical outcome.

Methods and results: The TRICC study was a prospective, multicenter, double-blind, randomized, placebo-controlled trial in children younger than 2 years old undergoing heart surgery with cardiopulmonary bypass. Enrollment was stratified by surgical diagnosis. Time to extubation (TTE) was the primary outcome. Patients received intravenous T3 as Triostat (n=98) or placebo (n=95), and data were analyzed using Cox proportional hazards. Overall, TTE was similar between groups. There were no differences in adverse event rates, including arrhythmia. Prespecified analyses showed a significant interaction between age and treatment (P=0.0012). For patients younger than 5 months, the hazard ratio (chance of extubation) for Triostat was 1.72. (P=0.0216). Placebo median TTE was 98 hours with 95% confidence interval (CI) of 71 to 142 compared to Triostat TTE at 55 hours with CI of 44 to 92. TTE shortening corresponded to a reduction in inotropic agent use and improvement in cardiac function. For children 5 months of age, or older, Triostat produced a significant delay in median TTE: 16 hours (CI, 7-22) for placebo and 20 hours (CI, 16-45) for Triostat and (hazard ratio, 0.60; P=0.0220).

Conclusions: T3 supplementation is safe. Analyses using age stratification indicate that T3 supplementation provides clinical advantages in patients younger than 5 months and no benefit for those older than 5 months. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00027417.

Figure 1

Flow diagram for patient enrollment and protocol completion.

Figure 2

Inotropic score and cardiac function parameters for the study population (see Table 2 for analysis of variance results). Data shown as mean±standard error of the mean. Scale does not start at 0. Results for statistical analyses are shown in Table 3.

Figure 3

Relationship between time to extubation and age in months (top). Smoothed regression lines for placebo and Triostat groups converge just after 5 months of age. Median time to extubation with confidence intervals is shown by age groups (bottom).

Figure 4

Subject numbers for each surgical diagnostic category. Abbreviations are listed in Table 1.

Figure 5

Kaplan–Meier curves for subjects younger than 5 months age and subjects aged 5 months and older. Statistics by Cox proportional hazards: hazard ratio for the Triostat group among patients younger than 5 months was 1.72 (P=0.0216), and for those older than 5 months hazard ratio was 0.60 (P=0.0220). Below the graph are number at risk and number of extubations (% intubated).

Figure 6

Inotropic score and cardiac function data. Statistics from analysis of variance are shown in Table 2. Data shown as mean±standard error of the mean. Scale does not start at 0. Results for statistical analyses are shown in Table 3.

Figure 7

Total serum triiodothyronine levels in ng/dL showing median and intraquartile range. The median (50^th percentile) and the intraquartile range (25^th–75^th percentile) are displayed. Probability values are from the Wilcoxon test. Normal values are 95 to 220 ng/dL (see text for reference). *P<0.001 compared to placebo for individual time point.