Preoperative oral thyroid hormones to prevent euthyroid sick syndrome and attenuate myocardial ischemia-reperfusion injury after cardiac surgery with cardiopulmonary bypass in children: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Both euthyroid sick syndrome and myocardial ischemia-reperfusion injury are common and have been significantly associated with morbidity and mortality after pediatric cardiac surgery with cardiopulmonary bypass. This single-center, prospective, double-blind, randomized placebo-controlled clinical pilot trial was designed to assess if preoperative oral thyroid hormone therapy could prevent the occurrence of euthyroid sick syndrome (ESS) and attenuate myocardial ischemia-reperfusion injury (IRI) after cardiac surgery with cardiopulmonary bypass (CPB) in children. METHODS: Forty children aged 3 to 12 year, scheduled for elective congenital heart disease repair surgery with CPB, were randomized into 2 groups of equal size to receive the following treatments in a double-blind manner: placebo (control group) and thyroid tablet 0.4 mg/kg (trial group) taken orally once a day for 4 days before surgery. The perioperative serum thyroid hormone levels and hemodynamic variables were determined. The extubation time, duration of intensive care unit (ICU) stay, and use of inotropic drugs in the ICU were recorded. The myocardial expressions of heat shock protein 70 (HSP70), myosin heavy chain (MHC) mRNA, and thyroid hormone receptor (TR) mRNA were detected. The serum creatine kinase-MB (CK-MB) activity and troponin I (TnI) positive ratio at 24 hour after surgery were assessed. RESULTS: There were no significant differences in hemodynamic variables at all observed points, extubation time, and duration of ICU stay between groups. As compared with baselines on administration, serum triiodothyronine (T3) and free T3 (FT3) levels on the first, second, and fourth postoperative day, and serum thyrotropic-stimulating hormone (TSH), tetraiodothyronine (T4), and free T4 (FT4) levels on the first postoperative day were significantly decreased in the 2 groups. Serum T3, FT3, and T4 levels on the first and second postoperative day, and serum FT4 level on the first postoperative day were significantly higher in the trial group than in control group. As compared with the control group, the number of patients requiring inotropic drugs in the ICU, serum CK-MB activity, serum positive TnI ratio, and myocardial expression of MHCß mRNA were significantly decreased, and myocardial expressions of both HSP70 and MHCα mRNA were significantly increased in the trial group. CONCLUSIONS: In children undergoing cardiac surgery with CPB, preoperative oral small-dose thyroid hormone therapy reduces severity of postoperative ESS and provides a protection against myocardial IRI by increasing HSP70 and MHCα expression.

N-Acetylcysteine Prevents Low T3 Syndrome and Attenuates Cardiac Dysfunction in a Male Rat Model of Myocardial Infarction.

Nonthyroidal illness syndrome (NTIS) affects patients with myocardial infarction (MI). Oxidative stress has been implicated as a causative factor of NTIS, and reversed via N-acetylcysteine (NAC). Male Wistar rats submitted to left anterior coronary artery occlusion received NAC or placebo. Decreases in triiodothyronine (T3) levels were noted in MI-placebo at 10 and 28 days post-MI, but not in MI-NAC. Groups exhibited similar infarct areas whereas MI-NAC exhibited higher ejection fraction than did MI-placebo. Left ventricular systolic and diastolic diameters were also preserved in MI-NAC, but not in MI-placebo. Ejection fraction was positively correlated with T3 levels. Oxidative balance was deranged only in MI-placebo animals. Increased type 3 iodothyronine deiodinase expression was detected in the cardiomyocytes of MI-placebo compared with normal heart tissue. NAC was shown to diminish type 3 iodothyronine deiodinase expression and activity in MI-NAC. These results show that restoring redox balance by NAC treatment prevents NTIS- related thyroid hormone derangement and preserves heart function in rats subjected to MI.

Evaluation of positive inotropic drug effects on thyroid hormone levels after open heart surgery.

OBJECTIVE: The aim of this study was to examine the effects of positive inotropic drugs, including adrenaline, dopamine, and dobutamine on thyroid hormone levels following open heart surgery. METHODS: We analyzed free thyroid hormones (FT3 and FT4) and thyroid-stimulating hormones (TSH) in 200 consecutive patients undergoing open heart surgery. Patients were divided into 5 groups according to the inotropic drug administration as follows: Group A (n = 46) received dopamine alone; Group B (n = 40), dopamine and dobutamine; Group C (n = 36), dopamine, dobutamine, and adrenaline; Group D (n = 32), adrenaline alone; and Group E (n = 46), placebo. Procedural factors affecting thyroid hormones were recorded and included cardiopulmonary bypass (CPB) time, cross-clamping time, degree of hypothermia, and the duration and doses of positive inotropic drugs. Blood samples for hormone assays were collected before initiation of inotropic drug therapy (baseline) and postoperatively at 24, 72, and 120 hours after drug therapy. RESULTS: FT3, FT4, and TSH levels at baseline were similar in all groups. Although there was a trend showing very slight increases in thyroid hormone levels from baseline to the 24th, 72nd, and 120th postoperative hours after drug therapy, these changes were not significant, and there were also no significant differences between the groups. There was also no significant statistical difference in CPB time, cross-clamping time, degree of hypothermia, and duration and doses of positive inotropic drugs between groups. CONCLUSION: Although thyroid hormone levels were affected by positive inotropic drug usage after open heart surgery, this effect was not significant and thyroid hormone levels remained within normal ranges.

Peri-operative oral triiodothyronine replacement therapy to prevent postoperative low triiodothyronine state following valvular heart surgery.

This study evaluated the effect of oral triiodothyronine (T(3)) replacement therapy, starting on the day of the surgery, on thyroid hormone concentrations and clinical outcome in high-risk patients undergoing valvular heart surgery. Fifty patients were randomly allocated to either T(3) or placebo. In the treatment (T(3)) group patients received 20 microg of oral or nasogastric T(3) every 12 h starting just before induction of anaesthesia and until the first day after surgery. T(3) concentrations were significantly higher in the T(3) group than the placebo group from 1 to 36 h after removal of the aortic cross clamp. The number of patients requiring vasopressin after discontinuing cardiopulmonary bypass was significantly greater in the placebo group than the T(3) group. Significantly fewer patients required vasopressors in the T(3) group on the first day after surgery.

Effects of rehabilitation treatment on thyroid function.

OBJECTIVE: The aim of the study was to evaluate the effects of an intensive rehabilitation programme on thyroid metabolism, the relationship between disability and thyroid hormone level, and the occurrence of nonthyroidal illness syndrome (NTIS) before and after rehabilitation. DESIGN, SUBJECTS AND MEASUREMENTS: This was a clinical prospective study. Orthopaedic surgery patients (n = 82) were classified into two groups: patients in whom early active mobilization and walking were possible (walking group, WG, n = 45), and patients in whom these were not recommended (nonwalking group, NWG, n = 37). Levels of free T3 (fT3), fT4, TSH and rT3 were measured before and after surgery, and then at 1, 3, 7, 14 and 30 days from the beginning of rehabilitation. Personal, nutritional and clinical data were acquired for all patients. The Barthel Index (BI) was used to assess disability before and after rehabilitation. RESULTS: Immediately after surgery, both groups of patients showed a significant decrease in mean fT3 concentrations and a significant increase in rT3; mean fT4 values decreased significantly only in NWG patients. Once rehabilitation had been completed, fT3 and rT3 levels returned to baseline values in WG patients. In NWG patients mean fT3 and fT4 levels continued to decrease significantly and rT3 values remained significantly high until the end of rehabilitation. NTIS occurred in 38% of the NWG patients. No significant changes in TSH levels were observed in either group. Finally, we observed a direct correlation between fT3 levels and the BI in WG patients. CONCLUSIONS: Our data suggest that early patient mobilization and physical activity during an active and intensive rehabilitation programme induce recovery of thyroid function and avoid occurrence of NTIS.

Oral triiodothyronine for the prevention of thyroid hormone reduction in adult valvular cardiac surgery.

Treatment of non-thyroidal illness by intravenous triiodothyronine (T3) after cardiac surgery causes a disproportional elevation of hormone levels. The administration of oral T3, which has never been studied in this context, could cause physiological hormone levels. The aim of this study was to test oral T3 for the prevention of T3 reduction during the postoperative period of valvular cardiac surgery in adults. Eighteen patients who underwent cardiac surgery for valvular disease with invasive hemodynamic monitoring were randomly assigned to 2 groups: the T group received oral T3 (N = 8), 25 microg three times/day, initiated 24 h before surgery and maintained for 48 h and the NT group (N = 10) received placebo. Serum T3, thyroxine and thyrotropin were determined at baseline, 1 h before surgery, within 30 min of cardiopulmonary bypass and 6, 12, 24, and 48 h after removal of the aortic cross-clamp. Baseline T3 was similar in both groups (T: 119 +/- 13; NT: 131 +/- 9 ng/dL). Serum T3 increased during the first 24 h in the T group compared to the NT group (232 +/- 18 vs 151 +/- 13 ng/dL; P < 0.001). In the NT group, T3 was reduced by 24% (P = 0.007) 6 h after removal of the aortic cross-clamp, confirming the non-thyroidal illness syndrome. There were no differences in clinical or hemodynamic parameters between groups. Administration of oral T3 prevented its serum reduction after valvular cardiac surgery in adults, with normal serum levels for 48 h without disproportional elevations.

Oral triiodothyronine for the prevention of thyroid hormone reduction in adult valvular cardiac surgery

Treatment of non-thyroidal illness by intravenous triiodothyronine (T3) after cardiac surgery causes a disproportional elevation of hormone levels. The administration of oral T3, which has never been studied in this context, could cause physiological hormone levels. The aim of this study was to test oral T3 for the prevention of T3 reduction during the postoperative period of valvular cardiac surgery in adults. Eighteen patients who underwent cardiac surgery for valvular disease with invasive hemodynamic monitoring were randomly assigned to 2 groups: the T group received oral T3 (N = 8), 25 æg three times/day, initiated 24 h before surgery and maintained for 48 h and the NT group (N = 10) received placebo. Serum T3, thyroxine and thyrotropin were determined at baseline, 1 h before surgery, within 30 min of cardiopulmonary bypass and 6, 12, 24, and 48 h after removal of the aortic cross-clamp. Baseline T3 was similar in both groups (T: 119 ± 13; NT: 131 ± 9 ng/dL). Serum T3 increased during the first 24 h in the T group compared to the NT group (232 ± 18 vs 151 ± 13 ng/dL; P < 0.001). In the NT group, T3 was reduced by 24 percent (P = 0.007) 6 h after removal of the aortic cross-clamp, confirming the non-thyroidal illness syndrome. There were no differences in clinical or hemodynamic parameters between groups. Administration of oral T3 prevented its serum reduction after valvular cardiac surgery in adults, with normal serum levels for 48 h without disproportional elevations.

Induction of type 1 iodothyronine deiodinase to prevent the nonthyroidal illness syndrome in mice.

Essentially all serious illness is associated with a decrease in circulating T(3), a condition known as the nonthyroidal illness syndrome. Substantial evidence suggests that a contributing factor to this syndrome is a cytokine-induced decrease in hepatic type 1 iodothyronine deiodinase (D1), an enzyme that converts T(4) to T(3). The type 1 deiodinase is induced at the transcriptional level by T(3), but illness-associated cytokines block this induction, resulting in decreased T(3) and hence a further decline in D1 expression. We demonstrated that IL-1 blocks the ability of T(3) to induce D1 in rat hepatocyte primary cultures and that forced expression of steroid receptor co- activator 1 (SRC-1) prevents this cytokine effect. This led us to test whether forced hepatic expression of SRC-1 can prevent the nonthyroidal illness syndrome in vivo. Pretreatment of endotoxin-treated mice with an adenovirus that expresses SRC-1, compared with a control adenovirus, prevented the endotoxin-induced decreases in hepatic D1 and plasma T(3). The data suggest that a cytokine-induced defect in T(3) receptor coactivators is an important component of this animal model of nonthyroidal illness and that the syndrome can be overcome by forced expression of the coactivator.

Influence of selenium supplements on the post-traumatic alterations of the thyroid axis: a placebo-controlled trial.

OBJECTIVE: To investigate whether early selenium (Se) supplementation can modify the post-traumatic alterations of thyroid hormone metabolism, since the first week after trauma is characterised by low plasma Se and negative Se balances. DESIGN: Prospective, placebo-controlled randomised supplementation trial. SETTING: Surgical ICU in a tertiary university hospital. PATIENTS: Thirty-one critically ill trauma patients aged 42 +/- 16 years (mean +/- SD), with severe multiple injury (Injury Severity Score 30 +/- 7). INTERVENTION: Supplementation during the first 5 days after injury with either Se or placebo. The selenium group was further randomised to receive daily 500 microg Se, with or without 150 mg alpha-tocopherol (AT) and 13 mg zinc supplements. The placebo group received the vehicle. Circulating Se, AT, zinc, and thyroid hormones were determined on D0 (= day 0, admission), D1, D2, D5, D10, and D20. RESULTS: Plasma Se, low on D0, normalised from D1 in the selenium group; total T4 and T3 increased more and faster after D2 (P = 0.04 and 0.08), reverse T3 rising less between D0 and D2 (P = 0.05). CONCLUSIONS: Selenium supplements increased the circulating Se levels. Supplementation was associated with modest changes in thyroid hormones, with an earlier normalisation of T4 and reverse T3 plasma levels. The addition of AT and zinc did not produce any additional change.

Selective macrophage depletion in the liver does not prevent the development of the sick euthyroid syndrome in the mouse.

A decreased serum triiodothyronine (T3) level is one of the main characteristics of the sick euthyroid syndrome, caused mainly by a decreased 5'-deiodination of thyroxine (T4) in the liver. Cytokines have been implicated in the pathogenesis of the changes in thyroid hormone metabolism during illness. We therefore investigated the role of cytokines produced by the liver macrophages (Kupffer cells) in the development of the sick euthyroid syndrome, which was induced in mice by a single injection of bacterial endotoxin (lipopolysaccharide) or by 24-h starvation. Experiments were carried out with or without previous selective depletion of liver macrophages by intravenous administration of liposome-encapsulated dichloromethylene diphosphonate. Relative to saline-injected pair-fed controls, the administration of lipopolysaccharide caused a decrease of serum T3 and T4 and liver 5'-deiodinase mRNA. Selective depletion of liver macrophages, did not affect these changes. Starvation for 24h decreased serum T3 and T4, associated with a slight decrease of liver 5'-deiodinase mRNA. There were no differences between macrophage-depleted and non-depleted animals in this respect. In summary, selective depletion of liver macrophages did not affect the decrease in serum T3, T4 or liver 5'-deiodinase mRNA induced by lipopolysaccharide or 24-h starvation in mice. We conclude that cytokines produced by Kupffer cells are not involved in the pathogenesis of the sick euthyroid syndrome in this experimental model.

Cardiopulmonary bypass temperature does not affect postoperative euthyroid sick syndrome?

STUDY OBJECTIVE: To determine if temperature during cardiopulmonary bypass (CPB) has an effect on perioperative and postoperative thyroid function. DESIGN: Prospective study comparing thyroid function during and after hypothermic and normothermic CPB. SETTING: Cardiac surgical unit at a university-affiliated hospital. PATIENTS: Twelve patients scheduled to undergo cardiac operations with normothermic (n = 6) or hypothermic (n = 6) CPB. INTERVENTIONS: Blood was analyzed for serum concentration of total thyroxine (TT4), total triiodothyronine (TT3), free T3 (fT3), reverse T3 (rT3), and thyroid stimulating hormone (TSH) preoperatively, 60 min after CPB was initiated, 30 min after discontinuing CPB, and on postoperative days (POD) 1, 3, and 5. MEASUREMENTS AND RESULTS: Patients who underwent either cold (26 degrees +/- 5 degrees C) or warm (35 degrees +/- 1 degree C) CPB were comparable with regard to age, body weight, duration of CPB, cross-clamp time, use of inotropes, total heparin dose, and length of hospital stay. Incidence of postoperative myocardial infarction, congestive heart failure, and death were similar. In both groups, TT4 and TT3 were reduced below baseline values beginning with CPB and persisting for up to 5 days after CPB (p < 0.05), free T3 was reduced for up to 3 days after CPB (p < 0.05), mean serum rT3 was elevated on POD 1 and POD 3 (p < 0.05), and TSH remained unchanged. CONCLUSION: The results of this study suggest that normothermic CPB does not prevent the development of the "euthyroid sick syndrome" during and after CPB. Despite these changes in thyroid function, most patients in both groups had a normal postoperative recovery.

Thyroid hormone loss and replacement during resuscitation from cardiac arrest in dogs.

Circulating concentrations of thyroxine (T4), triiodothyronine (T3), and reverse triiodothyronine (rT3) were followed in dogs subjected to 9 min of normothermic ventricular fibrillation. Significant decreases were detected 12 h post-arrest when compared to pre-arrest levels in total T4 (P < 0.0005), free T4 (P < 0.0005), total T3 (P < 0.003), and free T3 (P < 0.003), and levels of reverse T3 were significantly elevated (P = 0.0001). Similar changes occurred with only 30 s of arrest. Post-arrest replacement therapy with 7.5 micrograms/kg per h (Rx-7.5) and 15 micrograms/kg per h (Rx-15) levothyroxine sodium (L-T4) increased total T4, free T4, and total T3 (P < 0.01). Free T3 decreased in the Rx-7.5 group (P < 0.01) and did not fall in the Rx-15 group (P = 0.16). Reverse T3 increased with either treatment (P < 0.005). Both treatment groups had higher levels of all five hormones than non-treated animals (P < 0.001). Neurologic function, assessed with a standardized scoring system, showed significant improvement in the treated groups by 6 h (P < 0.05, compared to non-treated group) and remained significant through 24 h post-arrest (P < 0.05). The documentation of rapid and dramatic changes in thyroid hormones immediately following cardiac arrest and resuscitation indicates a significant acute hypothyroid state that may potentially benefit from replacement therapy.