Patients and methods: Between April 2008 and December 2010, a total of 37 patients (20 females, 17 males; mean age 54.9±10.2 years; range, 26 to 76 years) with thyroid dysfunctions who underwent CABG and 11 patients (2 females, 9 males; mean age 46.9±15.5 years; range, 26 to 65 years) without thyroid dysfunction who underwent on-pump CABG as the control group were included in the study. Patients were divided into groups as overt and subclinical hypothyroidism, overt hyperthyroidism, and subclinical hyperthyroidism according to the thyroid function test results. The European System for Cardiac Operative Risk Evaluation (EuroSCORE) scores were evaluated and the Gensini severity scores were calculated according to coronary angiographies. All patients were followed for seven days after surgery. The duration of endotracheal intubation, inotropic support, cardiac complications, duration of stay in the intensive care unit (ICU) and hospital were recorded.

Results: There were no statistically significant differences between the groups in terms of the duration of intubation, need of inotropic support, and duration of stay in the ICU and hospital. Arrhythmia was more frequent in the overt hyperthyroid group than in the overt hypothyroid group postoperatively. Thyroid-stimulating hormone (TSH) levels remained unchanged after surgery, whereas free T3 decreased and free T4 increased, which was compatible with postoperative euthyroid sick syndrome. The EuroSCORE scores were positively correlated with pre- and postoperative TSH levels, duration of intubation, and duration of ICU and hospital stay, but was negatively correlated with free T3.

Conclusion: Subclinical or overt thyroid dysfunctions do not seem to affect early mortality after CABG. However, overt hyperthyroidism is associated with postoperative arrhythmia complications. Euthyroid sick syndrome may also occur after surgery in certain cases. Pre- and postoperative TSH and free T3 levels may be useful to identify mortality and morbidity risk in patients undergoing CABG.

Subclinical thyroid dysfunctions have not been widely studied in cardiac surgery patients. In accordance with the current consensus, authors have advocated that subclinical thyroid dysfunction is not a causative factor of surgical complications or mortality. However, no case-controlled study has been reported on the effects of overt or subclinical thyroid dysfunctions on mortality and morbidity after cardiac surgery.

In the present study, we aimed to evaluate early mortality and morbidity in patients with overt and subclinical thyroid dysfunction undergoing CABG.

Thyroid status was established by history and clinical examination and confirmed by preoperative thyroid function tests including free T3 (fT3), free T4 (fT4), and thyroid-stimulating hormone (TSH). The patients were divided into groups as overt hypothyroidism (n=8), overt hyperthyroidism (n=8), subclinical hypothyroidism (n=11), and subclinical hyperthyroidism (n=10) according to their thyroid function test results. The European System for Cardiac Operative Risk Evaluation (EuroSCORE) scores were evaluated and the Gensini severity scores were calculated according to coronary angiographies. Adequate premedication was applied to the patients with overt thyroid dysfunction. The patients with subclinical thyroid dysfunction were followed without any medication for the thyroid status. All patients were followed for the first seven days after surgery in the intensive care unit (ICU) and ward. Duration of endotracheal intubation, need for inotropic support longer than six hour after surgery, cardiac complications such as arrhythmia or infection, duration of stay in the ICU and hospital were recorded. Postoperative thyroid function tests were performed in the first week after surgery.

Assessment of thyroid function
Serum TSH, fT₃, fT₄, T₃, and T₄ concentrations were measured by immunochemiluminometric assay using the Siemens ADVIA Centaur analyzer (Siemens Ltd., Bayswater, Victoria, Australia and Penrose, Auckland, New Zealand-Diagnostics Division, Tarrytown, NY, USA). The percentage coefficient of variation (CV%) was 1.7% at TSH concentrations of 0.1-0.5 mIU/L and 2.1% at 5-10 mIU/L. Normal ranges were between 0.55-4.78 mIU/L for TSH; 2.3-4.2 pg/mL for fT3, and 0.59-1.3 ng/dL for fT₄.

Calculation of EuroSCORE and Gensini scores
EuroSCORE
EuroSCORE is a simple, objective, and up-to-date scoring system to predict early mortality based on the objective risk factors in cardiac surgery patients in Europe.[5] The EuroSCORE risk was calculated based on the study of Nashef et al.[6] in all patients. Pointing chart of the scoring system was done according to the risk factors related to the patients and cardiovascular system (CVS) (Table 1). The scoring system was, then, applied to three risk groups. The low-risk group has a score of EuroSCORE 1-2, intermediate-risk group has a score of EuroSCORE 3-5, and the high-risk group has a score of EuroSCORE 6 plus.

Table 1: Baseline demographic and clinical characteristics of patients

Gensini severity scores
Gensini Severity Index was used to evaluate the severity of atherosclerosis according to coronary angiography (CAG) imaging. In the Gensini?s coronary artery scoring method,[7] the geometrically increasing severity of lesions, the cumulative effects of multiple obstructions, the significance of their locations, the modifying influence of the collaterals, and the size and quality of the distal vessels are considered. According to the severity of angiographic stenosis, ratings are as follows: 0-25% (1), 25-50% (2), 50-75% (4), 75-90% (8), 90-99% (16), and 100% (32). All these points are multiplied with coefficient factor for each main vessels and segment. The result is calculated by adding all values.

Statistical analysis
Statistical analysis was performed using the InStat-GraphPad version 3.10 (GraphPad Software, Inc., San Diego, CA., USA). Descriptive data were expressed in mean ± standard deviation (SD). Numeric variations were compared using the Student's t-test for independent samples or by the Mann-Whitney test. The chi-square test or Fisher?s exact test, if applicable, were used to compare the groups. The Pearson?s correlation analysis was used for the comparison of variables. A p value of <0.05 was considered statistically significant.

Table 2: Pre- and postoperative thyroid function test results

When pre- and postoperative thyroid function tests were compared between the groups (Table 3), TSH was not found to change significantly after surgery. However, in patients with subclinical thyroid dysfunctions, fT₃ decreased and fT₄ increased significantly, whereas only fT₃ decreased in the overt hypothyroidism group and only fT₄ increased in the overt hyperthyroid and control groups, suggesting postoperative euthyroid sick syndrome.

Table 3: Correlation of EuroSCORE scores with thyroid function test results (n=48)

The EuroSCORE and Gensini severity scores were evaluated for all study groups. The mean EuroSCORE score was 2.25 for overt hyperthyroidism, 5.75 for overt hypothyroidism, 3.6 for subclinical hyperthyroidism, 3.81 for subclinical hypothyroidism, and 2.18 for the control group. There was no statistically significant difference between the groups. However, we found a positive and significant correlation of EuroSCORE with preoperative TSH levels (p=0.004; r=0.42), postoperative TSH levels (p=0.05; r=0.30), duration of intubation (p=0.04; r=0.31), ICU stay (p<0.005; r=0.49), and hospital stay (p=0.01; r=0.37), but negatively and significantly correlated with the preoperative fT₃ levels (p=0.01; r= -0.38) and postoperative fT₃ levels (p=0.006; r= -0.42) (Table 4) (Figure 1). Pre- and postoperative fT4 levels were negatively correlated with the EuroSCORE, but were not statistically significant (p=0.06; r= -0.28 and p=0.08; r= -0.26, respectively). The Gensini severity scores were 106.6 for overt hyperthyroidism, 69.5 for overt hypothyroidism, 81.8 for subclinical hyperthyroidism, 62 for subclinical hypothyroidism, and 74 for the control group. However, there was no significant difference between the groups and no correlation between the Gensini scores and thyroid function test results or other follow-up parameters.

Figure 1: Correlation of EuroSCORE with pre- and postoperative fT3 and TSH levels. TSH: Thyroid-stimulating hormone; fT₃: Free T₃.

There are some reported cases with hyperthyroidism undergoing open heart surgery with or without premedication. Onoe et al.[13] reported that, in two patients with known thyrotoxicosis, open heart surgery was successfully performed by preoperative and early postoperative anti-thyroid agents. However, in a recent article, Bish et al.[14] found thyroid storm developing in a patient after urgent CABG caused by Graves? disease which was unknown before surgery and controlled by immediate potassium iodide and thionamides through nasogastric tube, as well as high-dose intravenous hydrocortisone. In our study, we found no increase in the mortality rate in overt hyperthyroid patients, although we observed increased arrhythmia in this patient group after surgery, compared to the hypothyroid group, which was not statistically significant.

Similarly, overt hypothyroidism may cause many of the signs and symptoms associated with heart failure including dyspnea, edema, cardiomegaly, and effusions and increase the risk of coronary artery disease.[3] However, these patients have a lower incidence of angina and myocardial infection, perhaps secondary to the reduction in cardiac metabolic demands. The patients usually have hypertension due to alterations in the peripheral vascular resistance and an increased risk of ventricular arrhythmias.[4] In untreated overt hypothyroidism patients, acute thyroid hormone replacement therapy may worsen myocardial ischemia due to increased myocardial oxygen consumption.[15] There are still conflicting data regarding the safety of CABG in untreated patients. Some authors have reported no adverse effects in patients with untreated mild-to-moderate hypothyroidism undergoing cardiac surgery,[16-18] whereas some others have suggested adverse effects such as severe myxedema after cardiac surgery, leading to significant hemodynamic compromise.[19] Some reports have also shown that percutaneous transluminal coronary angioplasty (PTCA) can be a better choice before CABG in hypothyroid patients who have a higher incidence of complications, if there is no time to render them euthyroid.[20,21] In our study, one patient with overt hypothyroidism who was operated emergently died due to critical coronary obstruction and aortic valve failure. However, the incidence of other complications was not higher in the overt hypothyroid patients, compared to the control group.

Subclinical thyroid diseases continue to be an issue in the preoperative evaluation of patients and are more common than overt thyroid disorders. The prevalence ranges between 2 and 8% in the general population and higher in women over the age of 60.[22] Subclinical thyroid dysfunctions may develop after a contrast agent administration during PTCA or CAG.[23] In a recent study Marraccini et al.[24] reported that thyroid dysfunction was frequent in patients who underwent CAG, and low T3 syndrome was the predominant feature in these patients. Furthermore, in patients with valvular heart diseases, euthyroid sick syndrome (low T3 syndrome) is a common problem, particularly who have heart failure and affects mortality.[25,26] Thus, patients with subclinical thyroid dysfunction should be investigated in detail about exposure of the contrast agents, family history of thyroid disea§ses, diseases affecting blood circulation, and the use of inotropic drugs which leads to decreased TSH.

In the literature, there are few studies and case reports which are controversial regarding the safety of cardiac surgery in subclinical thyroid diseases. Mantzoros et al.[27] revealed that subclinical hypothyroidism did not appear to be a risk factor for significant morbidity or increased mortality following PTCA. Ripoli et al.[28] examined the effects of subclinical hypothyroidism on the cardiac pump performance and found that subclinical hypothyroidism decreased the end-diastolic volume and increased systemic vascular resistance, leading to impairment of the cardiac pump performance, compared to healthy subjects. More importantly, the incidence of transient atrial fibrillation after CABG was found to be slightly higher in patients with subclinical hypothyroidism.[29] This finding suggests that the detection of preoperative thyroid dysfunction or the routine assessment of thyroid function may be useful for patients undergoing CABG. In our study, there was no significant difference between the subclinical hypothyroid or hyperthyroid patients and control group in terms of the morbidity and surgery complication rates.

The EuroSCORE is a simple and common risk scoring system for predicting operative mortality.[6,30] Gensini severity scoring system is also commonly used to identify the severity of coronary artery stenosis according to CAG.[7] To the best of our knowledge, correlation of these risk scores and thyroid function test results has not been studied in the literature, yet. In this study, we were unable to find a significant correlation between the Gensini scores and any of the thyroid function test results. However, the EuroSCORE scores were positively correlated with the pre- and postoperative TSH levels and negatively correlated with the pre- and postoperative fT₃ levels and slightly correlated with fT₄ levels. The correlations were more evident for fT₃ and TSH, followed by fT₄, suggesting that mortality increases with high TSH and low fT₃ levels. That is why preoperative thyroid function test should be routinely performed and may be useful postoperatively in predicting mortality, in particular in patients with a known thyroid disease.

Euthyroid sick syndrome and low T₃ syndrome are also well-described after cardiac surgery. In severe stress or major surgery, circulating levels of T3 decrease within two hours which is thought to reflect a reduction in the peripheral conversion of T₄ to T₃.[31,32] The majority of studies investigating thyroid hormone levels in patients undergoing cardiac surgery have demonstrated a well-established reduction in the fT3 levels, particularly under cardiopulmonary bypass.[33-35] Murzi et al.[35] showed a significant reduction in the fT₃ levels with a nadir at 48 h postoperatively and that the levels were still below baseline values at up to six days following surgery. The degree of the decline in the fT₃ levels was higher than the fT4 levels. Similarly, in our study, we found a decline in the fT₃ levels on postoperative Days 5-7 and reduction of fT₃ levels were more prominent than the fT₄ levels. Postoperative low T₃ syndrome decreases cardiac output as in chronic hypothyroidism and systemic vascular resistance increases.[36] Recent studies have mostly addressed into the effects of postoperative T₃ replacement therapy. Previous studies performed in small study groups have shown that T₃ replacement therapy increases cardiac output, decreases the need for inotropic agents and incidence of atrial fibrillation after cardiac surgery.[34,37,38] Although it has been shown that T₃ replacement therapy decreases the incidence of arrhythmia by improving hemodynamic performance, its association with mortality has not been established in large-scale, randomized-controlled studies, yet.[39-41] In a clinical review, Kaptein et al.[41] analyzed 14 randomized-controlled studies involving patients undergoing cardiac surgery and reported that, although cardiac index increased and the need for inotropic agents decreased, particularly in elderly patients with low ejection fraction values with T3 replacement therapy, there was no significant difference in the mortality rates. On the other hand, there is a limited number of data regarding the duration of stay in the ICU and hospital. In our study, the complication risk did not significantly decrease in the patients, even if the fT₃ levels decreased. The strong association between the EuroSCORE scores and fT₃ and TSH levels suggests that T₃ replacement therapy may have positive effects on mortality. Based on these findings, we suggest that certain patients with low T₃ and high TSH levels in the postoperative period may benefit from T₃ replacement therapy. However, further studies including the mortality endpoint is required to investigate the possible benefits of thyroid hormone replacement.

Most reviewers and authors recommend premedication for overt hyperthyroidism to prevent thyroid storm or other complications during the perioperative period.[42-44] For patients with uncontrolled hyperthyroidism who are candidates for an elective surgery, surgical procedure should be postponed, until they become stable on antithyroid therapy. For patients presenting urgent or emergent surgery, the anesthesiologist should be informed about the patent?s status to have drugs which block the systematic effects of thyroid hormones such as beta-blockers, iodide, and thionamides ready. Although premedication for hyperthyroidism is clear in general, there is still controversy for hypothyroid patients with known ischemic heart diseases or those who are candidates for coronary revascularization. Rapid treatment of thyroid dysfunction may increase myocardial oxygen demand, leading to ischemia. Currently, the consensus is that, if a patient needs urgent cardiac revascularization, they should undergo the procedure before replacement therapy;[44,46] however, many endocrinologists prefer starting lowdose T₄ treatment in hospitalized patients. In our overt hyperthyroid patients, we started oral thionamides before surgery, although overt hypothyroid patients underwent surgery, particularly those who had critical coronary stenosis. Our common idea was that revascularization is more important than hypothyroidism, as at least four weeks are needed to render those patients in the euthyroid state. Unfortunately, one of our overt hypothyroid patients with severe coronary artery stenosis and aortic valve stenosis who underwent emergent surgery died.

The main limitation of our study is its small sample size. In addition, total thyroid function test was not performed in this study, as free thyroid hormone levels are more reliable in this study population. In our study, for the first time, thyroid function tests were correlated with coronary artery stenosis risk scores and surgical mortality scores such as Gensini and EuroSCORE. Also, subclinical thyroid disorders were evaluated in patients undergoing CABG for the first time in a controlled study. Nonetheless, further largescale, prospective, randomized-controlled studies are needed to confirm these findings.

In conclusion, CABG seems to be safe in patients with thyroid dysfunction. Overt hyperthyroidism increases the risk of arrhythmia and other potential complications due to hyperthyroidism. Conversely, subclinical thyroid disorders are not associated with any complications and there is no need for premedication before and after CABG. The EuroSCORE scores also increase with low fT₃ and high TSH levels in the perioperative period, suggesting that thyroid hormones may affect open heart surgery-related mortality or morbidity rates and should be, therefore, evaluated before and after surgery. Based on our study findings, T₃ replacement therapy may be useful in patients with low fT₃ and high TSH levels who have a higher mortality risk score, according to the EuroSCORE.

Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding
The authors received no financial support for the research and/or authorship of this article.

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