Pharmacokinetic Evaluation of Triiodothyronine Supplementation in Children After Modified Fontan Procedure
Background—Triiodothyronine (T3) supplementation may be a useful adjunct in the management of patients after cardiopulmonary bypass. Limited data are available regarding the use and pharmacokinetics of T3 in children. The present study was performed to evaluate T3 pharmacokinetics in a cohort of children undergoing the modified Fontan procedure.
Methods and Results—A total of 28 patients were enrolled in this randomized, prospective study. The patients were divided into 4 groups: 1 group received a placebo and 3 groups received intravenous T3 at dosages of 0.4, 0.6, and 0.8 μg/kg, respectively. All 28 patients survived their operative procedures. Two patients developed low cardiac output, and 3 patients had pleural effusions. The median length of hospital stay was 7 days. The mean free T3 level was 316±67 pg/dL after then administration of a placebo. Patients who received T3 had mean peak free T3 levels of 972±88, 1351±299, and 1869±281 pg/dL for the dosages of 0.4, 0.6, and 0.8 μg/kg, respectively. The calculated half-life of T3 was 7 hours.
Conclusions—The half-life of intravenous T3 in children is approximately one-third of that reported for adults. These results provide a framework for studying the efficacy of T3 supplementation in children undergoing open-heart surgery.
Cardiopulmonary bypass is associated with altered endocrine responses, including a marked reduction in thyroid hormone levels.1 2 Adult patients undergoing cardiopulmonary bypass demonstrate a 30% to 40% decrease in serum levels of free triiodothyronine (T3), the form of thyroid hormone that has the greatest biological activity at the cellular level. Thyroid hormone has important effects on cardiovascular performance; these include increasing heart rate and contractility, improving diastolic function, and decreasing systemic vascular resistance.3 4 Changes in serum free T3 levels correlate with changes in cardiac output through these mechanisms. The magnitude of reduced T3 availability demonstrated in adult patients undergoing cardiopulmonary bypass may be sufficient to adversely affect cardiovascular performance postoperatively.
The recognition that cardiopulmonary bypass in adult patients results in significant reductions in free T3 availability has led to an interest in providing supplemental T3 to cardiotomy patients postoperatively as a means to improve myocardial performance.5 Adult patients undergoing open-heart surgery who receive T3 supplementation demonstrate a dose-dependent increase in cardiac output.6 This increase in cardiac output not only lessens the need for other inotropic or mechanical circulatory support,7 but is associated with improved outcome.8 These clinical results have prompted animal investigations that have confirmed that T3 has a benefit on both contractility9 and ventriculoarterial coupling.10 These results support the use of T3 supplementation as a valuable adjunct in the management of adult patients undergoing cardiopulmonary bypass.
Children who are born with congenital heart disease may also have a need for open-heart surgery. Some of these procedures are complex and may be associated with a significant risk due to poor cardiac performance after the procedure. Preliminary studies indicate that children undergoing cardiopulmonary bypass experience reductions in serum free T3 levels that are more profound than their adult counterparts.11 12 These observations suggest that T3 supplementation could potentially be beneficial in pediatric patients undergoing open-heart surgery.
The clinical experience in adult patients and the research data in adult animals supporting the efficacy of T3 supplementation may not be applicable to children undergoing cardiopulmonary bypass because of differences in the surgical procedures, postoperative hemodynamics, and the intrinsic metabolic rate. We previously evaluated the changes in thyroid hormone levels in children undergoing the modified Fontan procedure, which is an open-heart operation used for the treatment of patients born with a functional single ventricle.13 This study indicated that patients undergoing the Fontan procedure demonstrated a 75% decrease in serum T3 levels postoperatively. We also had preliminary experience with T3 supplementation in this population that indicated the safety of T3 supplementation at a relatively low dose.14 However, before a study can be performed to assess the efficacy of T3 treatment in children undergoing cardiopulmonary bypass, it is important to assess the pharmacokinetics of T3 to determine an appropriate dosing regimen. The purpose of the present study was to evaluate the pharmacokinetics of T3 supplementation in children undergoing the modified Fontan procedure.
All 28 children survived the Fontan procedure (no operative mortality). For the entire group of patients, the median length of mechanical ventilation was 8 hours, the median length of time in the pediatric intensive care unit (PICU) was 72 hours, and the median length of hospital stay was 7 days. Patients 5 and 15 developed a low cardiac output that resolved with supportive care. Patient 5 had junctional tachycardia that contributed to her low cardiac output state. The 2 patients who had low cardiac outputs had the longest durations of mechanical ventilation and PICU stay, and both had hospital lengths of stay >10 days. Patients 21, 22, and 23 developed pleural effusions, and these 3 patients accounted for the 3 longest lengths of hospital stay. No patient who received T3 supplementation exhibited signs of hyperthyroidism, such as ventricular irritability, persistently elevated temperature, or unusual vasodilatation. Data for individual patients are shown in Table 1⇓.
The randomization process resulted in 7 patients who received the placebo. In the groups that received T3, 7 patients received a dose of 0.4 μg/kg, 8 patients received a dose of 0.6 μg/kg, and 6 patients received a dose of 0.8 μg/kg. The 4 groups were similar in age, weight, age at bidirectional Glenn procedure, interval between bidirectional Glenn and Fontan procedures, cross-clamp time, and cardiopulmonary bypass time (Table 2⇓). Both patients who developed low cardiac output were in the group that received a dose of 0.6 μg/kg T3. Of the 3 patients who developed pleural effusions, 1 received 0.6 μg/kg T3, and 2 received 0.8 μg/kg T3. Statistical analysis revealed that the length of PICU stay was longer in the group that received 0.6 μg/kg because 3 patients in this group had complications of low cardiac output or pleural effusion.
Serum free T3 levels for the 4 groups are shown in Figure 1⇓. Baseline values were similar in all groups. Peak free T3 serum levels measured 10 minutes after the administration of T3 were 972±88, 1351±313, and 1869±281 pg/dL, respectively, for groups 2 through 4, and 313±60 pg/dL in the placebo group (group 1). Serum free T3 levels were again similar in all groups 12 and 24 hours after T3 administration. The calculated half-lives of T3 were 7.0±1.0, 7.3±1.1, and 7.0±0.9 hours, respectively, in groups 2 through 4. The areas under the curve attributable to T3 administration for serum free T3 were 2160±729, 3446±1120, and 5085±1673 pg · hr/dL, respectively, for groups 2 through 4.
Serum total T3 levels for the 4 groups are shown in Figure 2⇓. Baseline total T3 levels were similar in the 4 groups, but they increased to peak levels of 314±28, 383±81, and 494±105 ng/dL, respectively, for the 3 doses of T3, compared with 105±23 ng/dL for the placebo group. Total T3 levels were similar in all groups at 6, 12, 24, 48, and 72 hours postoperatively. The areas under the curves attributable to T3 administration for serum total T3 were 707±203, 1207±428, and 1564±591 ng · hr/dL, respectively, for groups 2 through 4. The volume of distribution of the central compartment was 0.17±0.05 L/kg, and the volume of distribution at a steady state was 0.31±0.09 L/kg.
Data for reverse T3 levels are summarized in Figure 3⇓. Reverse T3 levels were similar in all groups at baseline, but they increased significantly at 24 hours postoperatively. Reverse T3 levels then began to return to baseline values, with the greatest fall in reverse T3 levels seen in the groups that received 0.6 and 0.8 μg/kg T3 supplementation.
The thyroid stimulating hormone (TSH) and thyroglobulin data are summarized in Table 3⇓. Although baseline TSH levels were somewhat disparate among the 4 groups, a significant increase in TSH levels existed in each group at 5 days when compared with the baseline levels for that group. Similarly, thyroglobulin levels increased significantly at 5 days when compared with the baseline values for each group.
Free and total T3 data are shown in Figure 4⇓ for the 5 patients who developed postoperative complications (2 patients with low cardiac output and 3 with pleural effusions). Children who experienced low cardiac output had persistently low T3 levels at 72 and 120 hours, whereas children with pleural effusions demonstrated some recovery of T3 levels at 120 hours.
Figure 5⇓ demonstrates the free and total T3 levels from 24 to 120 hours postoperatively for the 19 patients who did not experience complications and for the 5 who did experience a complication. At 120 hours, patients who received supplemental T3 had higher serum T3 levels than those who received placebo. However, the placebo group had higher serum free and total T3 levels than patients who developed low cardiac output or pleural effusions.
All the patients enrolled in this study are alive. The mean duration of follow-up is 24±5 months. Two patients in this cohort have undergone subsequent procedures: one had plication of a hemidiaphragm, and the other had closure of a “baffle leak.”
The modified Fontan procedure is used to separate the systemic and pulmonary circulations in children born with a functional single ventricle. Although the results of this procedure have improved dramatically over the past 15 years,15 16 the Fontan operation is still associated with a significant mortality rate. Low cardiac output remains the most common cause of mortality. The causes of low cardiac output after the Fontan procedure are multifactorial, and they include increased pulmonary vascular resistance, mechanical obstruction, inadequate myocardial protection, and diastolic dysfunction.
Previous studies have shown that patients undergoing the Fontan procedure have marked reductions in their serum free T3 levels,13 and this may contribute to the incidence of low cardiac output after this procedure. The present study was performed to evaluate the pharmacokinetics of T3 supplementation after the modified Fontan procedure. The results of this study demonstrate a dose-dependent increase in peak serum free T3 levels, with free T3 levels returning to baseline within 12 hours. The calculated half-life of free T3 was 7 hours. The study also confirmed the safety of T3 supplementation in children in a dose ranging from 0.4 to 0.8 μg/kg, because no complications occurred that were perceived to be attributable to T3 supplementation.
The children who received placebo demonstrated decreases in free and total T3 levels that reached a nadir at 48 hours postoperatively. These results are quantitatively and qualitatively similar to those previously reported.13 The cause of this decline in T3 levels is probably multifactorial but may include factors such as fasting, anesthetic agents, and surgical stress, as well as the administration of dopamine17 and steroids.18 The present study also demonstrated an increase in reverse T3 levels at 24 hours postoperatively, a finding that is consistent with the euthyroid sick syndrome.19 The exact cause of euthyroid sick syndrome is unknown; however, experimentally, it has been related to the generation of cytokines, tumor necrosis factor,20 and interleukin-1β.21
T3 supplementation at doses between 0.4 and 0.8 μg/kg resulted in a dose-dependent increase in both free and total serum T3 levels. This increase in serum T3 levels in response to T3 supplementation was short-lived, because the calculated half-life for free T3 was 7 hours. The half-life of supplemental T3 in adult patients undergoing cardiopulmonary bypass was previously reported as 24 hours,22 or ≈3-fold longer than that observed in the present study. These results suggest that children undergoing cardiopulmonary bypass who receive T3 supplementation may require higher or more frequent dosing to demonstrate its efficacy in this population.
Patients who received T3 supplementation demonstrated significant differences in the late phase of their endocrinologic response when compared with patients who received placebo. Patients who received T3 supplementation had higher serum free and total T3 levels, higher TSH levels, and lower reverse T3 levels at 120 hours when compared with the placebo group. These findings are similar to our previous observations14 and indicate that T3 supplementation results in enhanced recovery of the pituitary-thyroid axis. Although a more rapid recovery of the pituitary-thyroid axis may correlate with the improved recovery of the individual, this association has not been proven.
In summary, the administration of exogenous T3 to children undergoing the modified Fontan procedure results in a dose-dependent increase in serum peak free T3 levels. The serum half-life of T3 in this patient population was approximately one-third of that previously reported in adults. The administration of supplemental T3 was associated with a more rapid endocrinologic recovery. T3 supplementation was not associated with adverse reactions, suggesting that this is a safe drug in the dose range of 0.4 to 0.8 μg/kg. Future studies evaluating the efficacy of T3 supplementation in children undergoing open-heart surgery can now be undertaken using this study of pharmacokinetics.
This randomized, prospective, double-blinded study began in January 1996 and concluded in November 1997. During this interval, 31 children underwent Fontan completion at our institution. The families of the children were presented with a description of the research protocol and a request for permission to enroll their child in the study, which the Institutional Review Board approved in August 1995. A total of 28 of the 31 families agreed to participate in the study and signed the consent form. All of the patients enrolled in the study completed the protocol.
The patient characteristics of the 28 children in the study are shown in Table 4⇓. There were 14 male and 14 female children. The average age at surgery was 27±15 months (median, 23 months; range, 15 to 78 months), and the average weight at surgery was 11.5±2.8 kg (median, 11.1 kg; range, 8.5 to 22.1 kg). All 28 children had undergone a previous bidirectional Glenn procedure. The average age at the time of bidirectional Glenn procedure was 10.0±5.2 months (median, 8.5 months; range, 2.5 to 28 months). The average interval between bidirectional Glenn and Fontan procedure was 17.2±11.4 months (median, 12.5 months; range, 8.5 to 60 months).
A total of 22 of the 28 children underwent the Fontan procedure using the lateral baffle technique; 21 of the lateral baffles were fenestrated. Six of the 28 children had heterotaxy, and in these 6 patients, an extracardiac conduit Fontan was performed.23 Median cross-clamp and cardiopulmonary bypass times were 48 and 131 minutes, respectively. Cardiopulmonary bypass data for individual patients are summarized in Table 5⇓.
After the surgical procedure, the children were transported to the pediatric intensive care unit (PICU) for monitoring and care. All patients received intravenous infusions of dopamine at 2 μg · kg−1 · min−1 and epinephrine at 0.01 to 0.05 μg · kg−1 · min−1.Extubation was performed as early as was deemed feasible. All 6 patients who underwent extracardiac conduit Fontan procedures were given heparin within 24 hours postoperatively. These patients were maintained on heparin until adequate anticoagulation had been achieved with oral Coumadin (warfarin). This subset of patients was observed in the PICU for the duration of heparin therapy.
Cardiac output was assessed on the basis of blood pressure, filling pressures, urine output, and physical examination. Low cardiac output was diagnosed when the patient continued to have cool extremities and decreased urine output, despite low- or medium-dose inotropic support. All patients had mediastinal and right pleural chest tube drains placed at the time of surgery. The chest tubes were discontinued when drainage was <3 to 4 cc · kg−1 · day−1. The diagnosis of pleural effusion was defined by this amount of pleural chest tube drainage for >7 days.
Patients were randomized into 4 groups on the basis of T3 dosage. Group 1 received a placebo, and groups 2 through 4 received a single intravenous dose of 0.4, 0.6, or 0.8 μg/kg T3, respectively. Randomization was performed in the hospital pharmacy. Prepared syringes were delivered unlabeled to the PICU to maintain the double-blinded protocol. Contents of the syringes were administered over 20 minutes beginning 1 hour after arrival in the PICU. Venous blood samples (8 mL) were obtained before the administration of the T3 or placebo and then at 10 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, and 120 hours after the administration of the T3 or placebo. The blood samples were placed in red-topped tubes, and the serum fraction was separated and stored at −70°C for subsequent quantitative analysis.
Serum samples were analyzed at the Quest Diagnostics Nichols Institute reference laboratories (San Juan Capistrano, Calif); measurements of total T3, free T3, reverse T3, thyroid stimulating hormone, and thyroglobulin were determined. Details of the quantitative analysis can be found in our previous publications.11 13 14
Pharmacokinetic analysis was performed to determine the serum half-life of T3 for each of the 3 groups that received T3 supplementation. The radioimmunoassays do not distinguish between endogenous and exogenous free T3, so free T3 levels for the groups that received T3 supplementation were corrected by subtracting the free T3 values for the placebo group at each temporal point. The result was an adjusted free T3 level that reflected only the influence of exogenously administered free T3 on serum free T3 levels. A 2-compartment model was assumed.
Statistical analyses were performed separately for the 4 groups of patients. For each group, the patient serum values before the administration of the T3 or placebo (eg, immediate postoperative) were compared with the serum values after the administration of T3 or placebo using a Wilcoxon signed rank test. A comparison of the groups receiving T3 supplementation with the group that did not receive supplementation was performed using repeated measures for ANOVA. Results are expressed as mean±SEM. P<0.05 was considered significant.
The authors thank Ms Jill Keezer for her assistance as the research coordinator of this project. This study was supported by grant FD-R-01195 (Orphan Products Development) from the Department of Health and Human Services, Food and Drug Administration.
The Methods section of this article can be found at http://www.circulationaha.org
- Received April 30, 1999.
- Revision received October 7, 1999.
- Accepted October 20, 1999.
- Copyright © 2000 by American Heart Association
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