This investigation represents one of the largest clinical trials reported in children undergoing cardiopulmonary bypass.7–9
We did not identify a T3 treatment effect on the primary end point, TTE, for the entire study population. Prespecified secondary analyses confirmed the well-known influence of age on TTE and, more importantly, revealed the interaction between age and T3 supplementation effect. Several intraoperative factors, such as cardiopulmonary bypass time, contribute to the impact of age on TTE. Postoperative practice strategies, which execute very early extubation for many older infants and children after surgery for congenital heart disease,19
are used much less frequently in young infants.14
Rapid extubation in the older cohort developed increasing acceptance during the conduct of the study and was not anticipated during the original trial design and power analyses. Thus, the relatively short extubation times in older patients as illustrated in and likely limited our ability to detect a significant treatment effect for the whole study population.
Further secondary analyses indicated that the T3 treatment effect on TTE reversed direction as age increased past 5 months. Accordingly, we believe that the post hoc delineation of the cohorts into 2 age subgroups was justified by the regression analyses (). The separation into these 2 cohorts also corresponds to pediatric cardiology clinical practice in many tertiary centers where most patients younger than 5 months undergo surgery for medical necessity and elective surgeries are delayed until after 5 to 6 months of age.20
We designed the stratification to determine the influence of risk, assessed by Aristotle score, on treatment effect. The results indicate that preoperative risk was not a significant factor. The complex nature of our stratification design in a multicenter trial precluded a priori randomization for additional factors such as graded urgency of surgery. Furthermore, a subjective analysis based on medical necessity could not be performed post hoc without substantial bias, but this dichotomization might be used in design of future studies.
The phenomenon, whereby T3 poses benefit for age younger than 5 months but some detriment for those aged 5 months and older, suggests that the difference in response according to age has a physiological basis. Thyroid hormone elicits multiple affects on the cardiovascular system and other organ systems. Therefore, we can only speculate on the mechanisms responsible for these developmental differences. Our data indicate that T3 levels in the Triostat group return to levels near those in the placebo group by 24 hours. One might question how the temporary elevation impacts clinical parameters several hours or days after declination. T3 exerts action through both nongenomic and genomic mechanisms.21,22
The nongenomic mechanisms likely occur at the cell membrane and are immediate. These actions include rapid T3-mediated stimulation of Na+
influx, which indirectly increases intracellular Ca2+
exchange, leading to positive inotropic effects.23
However, the genomic mechanisms involve T3 transport across membranes, binding to thyroid nuclear receptors and modulation of transcription and protein translation. Although our previous study showed that T3 rapidly initiates transcription of some genes in infants,24
the ultimate result of this transactivation may not be apparent for several hours or days.21
Delay in some T3-mediated actions may explain, in part, the lack of treatment benefit in the patients older than 5 months, particularly because most are extubated by 24 hours. Conceivably, the relatively minor but highly significant prolongation of TTE in this age group with T3 supplementation reflects the dominance of nongenomic action relative to the genomic soon after receiving the loading doses. The significant decrease in inotropic agent use in the treated patients younger than 5 months old not only supports the validity of our TTE results but also suggests that T3 alters adrenoreceptor sensitivity in an age-dependent manner. The existence of an interaction between T3 and the inotropic agents, particularly the β-adrenergic agonists, is plausible and has been suggested by studies in cells or hearts ex vivo.25
However, evidence from most studies performed in vivo does not support a role for T3 enhancement in myocardial adrenoreceptor sensitivity.26,27
More likely, the reduction in inotropic support represents the treating physician response to improved hemodynamics such as improved cardiac function and lower systemic vascular resistance, which are well-documented effects of thyroid hormone therapy28
and implicated by echocardiographic data in our study.
Importantly, T3 repletion appears safe, and this study should obviate the perception of risk generated by symptoms in patients with hyperthyroid states. Previous studies included either scattered reports of various adverse events, often not assigned to a specific treatment group, or no safety assessment at all.6,8,9
Isolated cases of tachyarrhythmia were reported in patients receiving T3.6,9
Our current study corroborated data from large studies in adults showing no increased risk of postoperative rhythm disorders.3,4
In summary, this controlled randomized study showed that time to extubation among children younger than 5 months of age recovering from cardiac surgery was reduced by T3 supplementation during and after cardiopulmonary bypass. The clinical response was accompanied by an improvement in cardiac function and a decrease in inotropic support. Placebo-controlled trials in infants undergoing cardiac procedures are rare, and conduct of these trials encounters multiple challenges. The results of this study emphasize the importance importance of appropriate age or diagnostic stratification in this population. The data in our study are somewhat limited by lack of previous specification in age stratification. However, the data strongly support performance of another trial in the patients younger than 5 months of age.