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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.57 no.5 Campinas Sept./Oct. 2007
Evaluation of serum levels of thyroid hormones in myocardial revascularization*
Evaluación de los niveles séricos de hormonas tireoideas en revascularización miocárdica
Elaine Rahal Rodas MessiasI; José Otávio Costa Auler Jr, TSAII; Maria José Carvalho Carmona, TSAIII
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
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 (1st PO) and in the second (2nd 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 1st 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.
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.
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 metabolyte3-6. 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.
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.
1st PO in the first postoperative day.
2nd 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.
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.
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 2nd 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 2nd and 4th 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, 1st PO, and 2nd 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.
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Dra. Maria José Carvalho Carmona
Divisão de Anestesia do ICHC
Av. Enéas Carvalho de Aguiar, 255/8° andar Cerqueira César
05403-900 São Paulo, SP
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)