Evaluation of serum levels of thyroid hormones in myocardial revascularization

Abstracts

JUSTIFICATIVAS E OBJETIVOS: Os hormônios tireóideos tiroxina (T4) e triiodotironina (T3) regulam o anabolismo de proteínas, lipídios e carboidratos e aumentam o consumo de oxigênio. Estresse cirúrgico e circulação extracorpórea (CEC) podem alterar os níveis hormonais ativos por meio de interferência na conversão periférica e diminuição do nível sérico de T3 sem alterações da tirotrofina (TSH), caracterizando a síndrome eutireóidea. Objetivou-se comparar os níveis séricos de T3, T4 e TSH em pacientes submetidos à revascularização miocárdica (RM) com ou sem utilização de CEC. MÉTODO: Foram estudados 18 pacientes com programação para cirurgia eletiva de RM, sendo: Grupo CEC (n = 9): pacientes submetidos à CEC e Grupo sem CEC (n = 9): pacientes não submetidos à CEC. Realizou-se dosagem de T3, T4 e TSH séricos antes da indução anestésica (início SO), ao término da cirurgia (final SO), no primeiro dia (1º PO) e no segundo dia de pós-operatório (2º PO). Na análise estatística (Análise de Variância de medidas repetidas, teste de Mann-Whitney e prova de Friedman) considerou-se significativo p < 0,05. RESULTADOS: Ocorreu diminuição do nível sérico de T3 nos dois grupos. Os níveis séricos de T4 mostraram diferença entre os momentos final SO e 1º PO, quando o grupo não-submetido à CEC mostrou níveis mais elevados de T4. Os níveis séricos de TSH permaneceram dentro dos limites da normalidade. CONCLUSÕES: Ocorre diminuição dos níveis séricos de T3 após revascularização miocárdica com e sem a utilização de CEC e com maior diminuição de T4 no grupo submetido à CEC. A ausência de resposta hipofisária às alterações dos níveis séricos de T3 e T4 caracteriza a síndrome eutireóidea nos dois grupos.

CIRURGIA, Cardíaca; HORMÔNIOS

SCIENTIFIC ARTICLE

Evaluation of serum levels of thyroid hormones in myocardial revascularization^*

Evaluación de los niveles séricos de hormonas tireoideas en revascularización miocárdica

Elaine Rahal Rodas Messias^I; José Otávio Costa Auler Jr, TSA^II; Maria José Carvalho Carmona, TSA^III

^IAnestesiologista. Mestre em Ciências pelo Programa de Pós-Graduação em Anestesiologia da Faculdade de Medicina da Universidade de São Paulo

^IIProfessor Titular da Disciplina de Anestesiologia da Faculdade de Medicina da Universidade de São Paulo; Diretor do Serviço de Anestesia do Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

^IIIProfessora-Associada da Disciplina de Anestesiologia da Faculdade de Medicina da Universidade de São Paulo; Diretora da Divisão de Anestesia do Instituto Central do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

^{Correspondence to}

SUMMARY

BACKGROUND AND OBJECTIVES: Thyroid hormones, thyroxine (T₄) and triiodothyronine (T₃), regulate anabolism of proteins, lipids, and carbohydrates, and increase oxygen consumption. Surgical stress and cardiopulmonary bypass (CPB) can change active hormone levels by interfering with the peripheral conversion and reducing serum levels of T₃, without changing the levels of thyrotropin (TSH), which are the characteristics of the euthyroid syndrome. The objective of this work was to compare serum levels of T₃, T₄ and TSH in patients undergoing myocardial revascularization (MR) with or without ECC.

METHODS: Eighteen patients scheduled for elective MR divided as follows: CPB Group (n = 9): patients undergoing CPB, and the Group without CPB (n = 9): patients that did not undergo CPB. The serum levels of T₃, T₄ and TSH were determined before anesthetic induction (initial OR), at the end of the surgery (final OR), in the first (1^st PO) and in the second (2^nd PO) postoperative days. Statistical analysis (Analysis of Variance for repeated measures, Mann-Whitney test, and Friedman test) considered significant a p < 0.05.

RESULTS: There was a reduction in serum levels of T₃ in both groups. Serum levels of T₄ showed differences in final OR and 1^st PO, which were elevated in the group that did not undergo CPB. Serum levels of TSH remained within normal limits.

CONCLUSIONS: Serum levels of T₃ are reduced after myocardial revascularization with and without CPB, with greater reduction in T₄ in the group that underwent CPB. The absence of pituitary response to changes in serum levels of T₃ and T₄ characterized the euthyroid syndrome in both groups.

Key Words: HORMONES: thyroid; SURGERY, Cardiac: myocardial revascularization, cardiopulmonary bypass.

RESUMEN

JUSTIFICATIVAS Y OBJETIVOS: Las hormonas tireoideas tiroxina (T₄) y triiodotironina (T₃) regulan el anabolismo de proteínas, lipídeos y carbohidratos y aumentan el consumo de oxígeno. Estrés quirúrgico y circulación extracorpórea (CEC) pueden alterar los niveles hormonales activos por medio de interferencia en la conversión periférica y en la disminución del nivel sérico de T₃ sin alteraciones de la tirotrofina (TSH), caracterizando el síndrome eutireóideo. Se pensó comparar los niveles séricos de T₃, T₄ y TSH en pacientes sometidos a la revascularización miocárdica (RM) con o sin utilización de CEC.

MÉTODO: Fueron estudiados 18 pacientes con programación para cirugía electiva de RM, siendo: Grupo CEC (n = 9): pacientes sometidos a la CEC y Grupo sin CEC (n = 9): pacientes no sometidos a la CEC. Se realizó la dosificación de T₃, T₄ y TSH séricos antes de la inducción anestésica (Inicio SO), al término de la cirugía (Final SO), al primer día (1° PO) y en el segundo día del postoperatorio (2°PO). En el análisis estadístico (Análisis de Variancia de medidas repetidas, test de Mann-Whitney y prueba de Friedman) se consideró el significativo p < 0,05.

RESULTADOS: Ocurrió una disminución del nivel sérico de T₃ en los dos grupos. Los niveles séricos de T₄ mostraron diferencia entre los momentos Final SO y 1° PO, cuando el grupo no sometido a la CEC mostró niveles más elevados de T₄. Los niveles séricos de TSH permanecieron dentro de los límites de la normalidad.

CONCLUSIONES: Ocurre una disminución de los niveles séricos de T₃ después de la revascularización miocárdica con y sin la utilización de CEC y con más disminución de T₄ en el grupo sometido a la CEC. La falta de respuesta hipofisaria a las alteraciones de los niveles séricos de T₃ y T₄ caracteriza el síndrome eutireóideo en los dos grupos.

INTRODUCTION

Maintenance of normal levels of triiodothyronine (T₃) is essential for homeostasis of several systems, especially the cardiovascular system. Triiodothyronine increases cardiac contractility and output by changing the speed of shortening of the myofibril associated with a reduction in systemic vascular resistance. The reduction in serum levels of T₃ has opposing effects, such as reduction in myocardial contractility and heart rate, increased systemic vascular resistance, and atrioventricular blockade. Diastolic dysfunction is also present, since a reduction in the period of isovolumetric relaxation has been described. Replacement of thyroid hormone increases some of the determinants of regional myocardial oxygen consumption, such as heart rate and myocardial contractility; however, this increase is compensated by a reduction in end-diastolic volume and wall tension (preload), with a reduction in final systolic pressure in the ventricular wall (postload) ¹.

Renal and liver diseases or myocardial infarction besides surgical stress, especially that related with cardiac surgery with cardiopulmonary bypass (CPB), have been associated with the euthoyroid syndrome ², characterized by a reduction in serum levels of T₃, normal or reduced serum levels of thyroxine (T₄), without the concomitant increase in TSH levels. Peripheral conversion of T₄ to T₃ is inhibited, with low levels of free T₃ and T₄, and concomitant increase in T₃r, the inactive metabolyte^3-6. This syndrome seems to be caused by the excess of endogenous circulating catecholamines, which, in several tissues, activate the enzyme 5 deiodinase, which converts T₄ in T₃r, or inhibit the enzyme 5' deiodinase that converts T₄ in active T₃^7,8.

Different studies have demonstrated that CPB causes a reduction in the levels of T₃, which return to normal only after 48 to 72 hours. There is a close temporal relationship between the reduction in hormone levels and the hemodynamic instability caused by low cardiac output, and evidence indicating that hormonal replacement can improve cardiovascular performance and survival when compared with patients that were not treated ^7,9. Minimally invasive myocardial revascularization can be performed with or without median sternotomy and does not use CPB. In theory, patients undergoing this surgical approach would not be exposed to the hormonal changes of the euthoyroid syndrome. The results of different studies are controversial; the type of replacement and the doses for the treatment of this syndrome are undetermined, and it is necessary to investigate which patients could benefit from triiodothyronine replacement.

The objective of this study was to evaluate the changes in serum levels of the hormones of the pituitary-thyroid axis (triiodothyronine – T₃, thyroxine – T₄, and thyrotropin – TSH), caused by myocardial revascularization, comparing patients with CPB to those without it.

METHODS

After approval by the Scientific Committee of the Instituto do Coração (InCor) and by the Medical Ethics Committee of the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo and after they signed the informed consent, 18 patients with a left ventricular ejection fraction of 40% undergoing elective myocardial revascularization were divided into two groups: Group CPB (n = 9): patients undergoing myocardial revascularization with cardiopulmonary bypass(CPB); Group without CPB (n = 9); patients undergoing myocardial revascularization by the minimally invasive technique without CPB.

Patients with a history of thyroid disease and those taking amiodarone were excluded. The upper age limit for inclusion in the study was 75 years.

Patients received oral midazolam (0.1 to 0.2 mg.kg^-1) 30 minutes before surgery, up to a maximum of 15 mg. Monitoring with a 5 lead electrocardiogram, on derivations DII and V5, and pulse oximetry were instituted upon admission to the operating room. For invasive blood pressure monitoring, the right radial artery was punctured with a 20G catheter. After the initial oxygenation, fentanyl (20 to 30 µg.kg^-1) and midazolam (0.3 to 0.5 mg.kg^-1) were used for induction, followed by neuromuscular blockade with pancuronium bromide (0.1 to 0.2 mg.kg^-1). Manual ventilation with a mask was done just before tracheal intubation with a tracheal tube of the proper size, and controlled mechanical ventilation was initiated, monitoring of expired CO₂, nasopharyngeal temperature, and urine output. Maintenance of anesthesia consisted of fractionated doses of fentanyl, midazolam, and pancuronium bromide, associated with variable concentrations of inhalational isoflurane.

Hemodynamic monitoring also included a 7.0F Swan-Ganz catheter (Pulmonary Artery Catheter, Baxter Critical Care, California, USA) inserted in the right internal jugular vein, monitoring mean pulmonary arterial pressure (MPAP), systolic and diastolic pulmonary arterial pressures; right atrial pressure (RAP); pulmonary wedge pressure (PCWP); and cardiac output (CO) determined by thermodilution, using the mean value of 3 measurements. The cardiac index (CI) was obtained by the ratio between CO and body surface area of the patient. Systemic and pulmonary vascular resistance were determined by indirect calculations.

In the group of patients with cardiopulmonary bypass (CPB), a membrane oxygenator (Braile, Brazil) with non-pulsatile flow was used, associated with moderate hypothermia, with a minimal temperature of 32°C. Before removing the extracorporeal circulation, variable doses of vasodilators (sodium nitroprusside and/or nitroglycerin) were administered. To implement cardiopulmonary bypass, heparin (400 UI.kg^-1), followed by fractionated doses of 5,000 UI, to keep the PTT grater than 600 seconds, was used to anticoagulate the patient. Anticoagulation was reversed using protamine sulfate (4 mg.kg^-1).

In the group of myocardial revascularization without cardiopulmonary bypass, heparin (1500 UI.kg^-1) was administered, followed by protamine sulfate (1 mg.kg^-1).

When needed, inotropic support was provided by the continuous administration of dobutamine, and the doses were adjusted to maintain a CI equal or greater than 2.2 L.min^-1.m^-2.

A continuous infusion of nitroglycerin (0.25 to 0.5 µg.kg^-1.min^-1) was initiated when the pulmonary artery catheter introduced, but it was discontinued during cardiopulmonary bypass in the CPB group.

Blood was drawn for determination of the hematocrit, serum levels of total triiodothyronine (T₃), total thyroxin (T₄), and thyrotropin (TSH), in a dry tube with a separator gel, and sent to the laboratory for centrifugation and separation of the serum. The material was stored at -20°C until it was analyzed. Laboratorial analysis was done by the radioimmunometric method (Coat-a Count; Diagnostic Products Corporation – Los Angeles, CA) at the Research Laboratory of the Instituto do Coração.

The moments of the study for determination of T₃, T₄, TSH, and hematocrit were:

• Initial OR – before anesthetic induction.

• Final OR – at the end of the surgery.

• 1^st PO – in the first postoperative day.

• 2^nd PO – in the second postoperative day.

Since the variability of the data indicated that the normalcy hypothesis is valid, parametric tests were used. When the standard deviation was greater than 25%, non-parametric tests were used. Age, height, weight, and body surface area of both groups were compared by the Student t test. Triiodothyronine levels were analyzed by ANOVA for repeated measurements with two factors (factor group x factor time), and application of independent tests to test the factors time and group. Thyroxin was also analyzed by ANOVA for repeated measures with two factors (time and group), followed by the Student t test for each time factor separately, besides the application of the ANOVA for repeated tests to evaluate the groups separately. For the parameter thyrotropin, the Mann-Whitney test for different moments was used, associated with the Friedman test for each group. A significance level of 0.05 (a = 5%) was used.

RESULTS

The results are showed on tables with the mean and standard deviation.

Table I shows the demographic data of both groups, while Table II presents the perioperative hematocrit and its variation. Data regarding T₃, T₄, and TSH for patients undergoing myocardial revascularization with and without cardiopulmonary bypass can be found in Tables III, ^IV, and ^V, respectively, followed by the results of the statistical analysis.

DISCUSSION

This study allowed us to observe that there is a reduction in serum levels of triiodothyronine (T₃) after myocardial revascularization, with and without cardiopulmonary bypass (CPB), but the group that underwent myocardial revascularization with CPB had a greater reduction in serum levels of thyroxin (T₄). The absence of pituitary response to the changes in serum levels of T₃ and T₄, characterizes the euthyroid syndrome in both groups.

Statistical analysis regarding age, height, and surface body area showed no significant difference. Comparison of the weight in both groups showed a significant result (p = 0.029), probably reflecting the strict criteria for myocardial revascularization by the minimally invasive technique, due to its greater difficulty ¹⁰.

The choice of the study groups was based on the idea that CPB could not be the only cause responsible for the development of the euthyroid syndrome, but also the surgical stress of the group undergoing the minimally invasive technique. The incidence of myocardial ischemia in patients with coronary artery disease undergoing cardiac or non-cardiac surgeries is associated with elevated postoperative morbidity and mortality. Initial studies on the subject evaluated only the strategy of limiting intraoperative myocardial oxygen demand, by decreasing the reduction of heart rate and preventing hypotension. Afterwards, the incidence of ischemia not related to hemodynamic conditions was detected, and the treatment strategy was changed in order to prevent intraoperative reduction in the delivery of myocardial oxygen. Since myocardial ischemia is associated with anesthesia and surgical interventions free of adverse events, treatment strategies to reduce postoperative morbidity related to the patient with coronary artery disease are the focus, among them the use of T₃, are being sought ¹¹.

The hematocrit was used as perioperative control, because levels of hematocrit below 21% (hemoglobin around 7.9 g.dL^-1) in patients with adequate ventricular filling pressures, contribute to the development of postoperative low cardiac output syndrome. Patients did not present low hematocrit levels during the study.

In the present study, a reduction in serum levels of T₃ from inicial OR to the 2^nd postoperative day was observed. In both groups, serum levels of T₃ were similar after anesthetic induction and other moments of the study and they did not show statistically significant differences by the Analysis of Variance for repeated measures with two factors (group ´ time) and when the factor group was analyzed isolatedly. The behavior of the group that did not undergo CPB was similar to the CPB group. It is possible that the organic responses to the anesthetic-surgical procedure and myocardial ischemia, caused by the period of closure of the coronary arteries, contributed to the development of the euthyroid syndrome in the group without CPB.

Initial serum levels of T₃ were close to the lower normal limit in both groups. Hypothyroidism is under-diagnosed; its symptoms are not always evident, and can go unnoticed in it initial phase, especially in elderly patients, and the most important repercussions affect lipid metabolism and blood pressure, with increased predisposition of vasculopathy and coronary disease, in general.

The euthyroid syndrome, with decreased serum levels of T₃, and low cardiac output after the use of CPB has been widely reported in the literature ^7,9,12, and T₃ levels of those studies are similar to the one found in this study.

The development of left ventricular dysfunction after cardiopulmonary bypass is well known, even in patients with good preoperative ventricular function. The interest on triiodothyronine as a potential inotropic agent in cardiac surgery developed after the determination that serum levels of T₃ showed an important reduction after CPB, although there are controversies regarding the magnitude and clinical consequences of hormonal variations ^4-7,9,12.

The effects of T₃ after myocardial ischemia include synthesis of proteins and increase in ion transport in myocardial cells⁴. The effects of T₃ replacement were demonstrated in pigs undergoing CPB ⁸, and left ventricular contractility returned to normal in animals that received T₃ supplementation 90 minutes after the end of CPB. The structure of the endoplasmic reticulum and mitochondria in the animals that received T₃ supplementation was better preserved when compared with the placebo group. However, the level of high energy phosphates was similar in both groups of animals, decreasing approximately to 50% of basal levels, suggesting that improvement in contractility was not secondary to an increase in the availability of high energy phosphates.

In human beings, it has not been fully established when the reduction in serum levels of T₃ contributes for ventricular dysfunction after cardiac surgery, as well as the vantages and disadvantages postoperative hormonal replacement ¹³. Studies that investigated the effects of T₃ administration in patients undergoing cardiac surgery showed contradictory results ^7,14. Klemperer et al. ¹⁵ were not capable of demonstrating the advantages of the treatment with T₃ in patients operated with CPB regarding the need of vasoactive drugs. Although the authors did not recommend the routine administration of T₃ in patients undergoing cardiac surgeries, the study demonstrated that T₃ supplementation is safe, without side effects, but it does not identify the groups of patients that could benefit from the treatment. Bennett-Guerrero et al.¹⁴, studying patients with poor ventricular function, demonstrated that the administration of T₃ after CPB did not have important effects on hemodynamic variables when compared with the placebo group. It did not decrease the use of inotropic drugs, and the need for mechanical support with intra-aortic balloon counterpulsation was the same in both groups. The length of stay in the Intensive Care Unit and in the hospital was similar in both groups. Clinical results contrast with the excellent response obtained in animal studies.

The postoperative administration of T₃ after CPB in patients with poor ventricular function prevents the development of postoperative atrial tachyarrhythmias, especially between the 2^nd and 4^th days. Due to the association of those arrhythmias with increased morbidity and, maybe, mortality, and also with increasing hospital costs, hormonal treatment could be recommended in those cases, although more studies on the use of T₃ are necessary. Regarding thyroxine (T₄), in this study both groups presented similar levels upon admission to the operating room, but with a distinct behavior during the evaluation. We observed a difference between groups in final OR, 1^st PO, and 2^nd PO, when the group that did not undergo CPB presented more elevated levels of T₄. This result could just reflect the dilution of serum levels of T₄ in the group that underwent CPB, because in the other group, higher levels of T₄ did not result in significant increase in serum T₃. Considering that the main characteristic of the euthyroid syndrome is a decrease in the peripheral conversion of T₄ in T₃, the presence of this syndrome could explain those results.

Serum levels of thyrotropin (TSH) remained within normal limits, except for the initial elevated levels of two patients in the group without CPB that remained so during the entire study, although both groups had been statistically similar. In those two cases, it is possible that they presented subclinical hypothyroidism, since it is known that this entity affects 3 to 4% of the population, is more frequent after the age of 40 and has subtle symptoms. Any functional abnormality of the thyroid is initially detected by increased levels of TSH, which, in the majority of cases, is above 10 µUI/mL, and this is the exam of choice to detect hypothyroidism ^17,18. Every patient in this study was included in the statistical analysis of TSH and, consequently, there was a large standard deviation, forcing the use of non-parametric tests for the analysis of this parameter. Friedman test showed differences between both groups, corroborating the data in the literature that demonstrate reduced hypophysial response to the low levels of circulating T₃ in the euthyroid syndrome ^5,19.

Serum levels of TSH increase with the reduction of the serum levels of thyroid hormones due to the absence of the mechanism of negative feedback, and extremely high levels of TSH can be found in primary hypothyroidism. In patients without thyroid disease and low levels of T₃ and T₄, high levels of TSH in the serum are expected, and the demonstration of normal levels led to denomination of euthyroid syndrome. Control of TSH secretion in those circumstances could be influenced by opposing forces, since stress is inhibitory, while low levels of T₃ and T₄ are stimulating ²⁰. This opposition of forces would result in fundamental normal levels of TSH, and patients would remain in a state of physiological hypothyroidism.

A comparison of patients who underwent cardiac surgery with CPB, large size non-cardiac surgeries, or clinical treatment of pulmonary embolus, demonstrated reduced levels of T₃ without the concomitant increase in TSH ⁹, and the response to the stimulus with TRH was not favorable, because TSH levels did not increase, as it would be expected, in patients without abnormalities of the thyroid gland. It is believed that the levels of T₄ in those patients could have caused the inhibition of the pituitary gland, although it is known that pituitary receptors are more sensitive to T₃ than to T₄. Other authors ⁶ also observed the lack of response of the pituitary gland to low levels of T₃ and T₄ in patients undergoing CPB, without adequate response to the stimulation with TRH. Evaluation of thyroid function in newborns undergoing cardiac surgery with CPB demonstrated a reduction in the levels of T₃ and T₄, with an increase of TSH between the beginning and the end of the surgery ²¹. The surgical stress associated with cardiac surgeries stimulates the secretion of cortisol by the adrenal gland, and it could be one of the factors responsible for the inhibition of the pituitary gland. In this study, the group undergoing the minimally invasive technique also demonstrated a lack of pituitary response to the levels of T₃ and T₄, corroborating that hypothesis.

Considering the objectives of this study, we concluded that, although the group undergoing myocardial revascularization with CPB had a greater reduction in serum levels of thyroxine (T₄), there was a reduction in serum levels of triiodothyronine (T₃) after myocardial revascularization with and without cardiopulmonary bypass (CPB), and the lack of pituitary response to altered serum levels of T₃ and T₄ characterizes the euthyroid syndrome in both groups.

REFERENCES

Submitted em 06 de setembro de 2006

Accepted para publicação em 22 de junho de 2007

* Received from Instituto Central do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFM/USP)

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Publication Dates

• Publication in this collection
  14 Sept 2007
• Date of issue
  Oct 2007

History

• Accepted
  22 June 2007
• Received
  06 Sept 2006