Abstract
Objective: In this study, we compared the systemic stress response induced by microwave ablation with that induced by conventional open surgery for treatment of benign thyroid nodules.
Methods: A total of 108 patients with benign thyroid nodules were randomly assigned to receive ultrasound-guided thyroid microwave ablation (microwave group, n = 57) and conventional open thyroid surgery (open group, n = 51). Body temperature, white blood cell (WBC) counts, visual analogue scale (VAS) scores for pain, and serum levels of high sensitive C-reactive protein (hs-CRP), interleukin 6 (IL-6) and cortisol were measured at 24 h before operation and at 8 h, 24 h and 48 h after operation.
Results: No significant between-group differences were observed with respect to preoperative body temperature, VAS scores, WBC counts, serum hs-CRP, IL-6 and cortisol levels. Patients in the open group exhibited higher body temperature at 24 h after operation and higher WBC counts at both 24 h and 48 h after operation, as compared to those in the microwave group. As compared with microwave ablation, open surgery was associated with significantly higher VAS scores, and significantly higher serum levels of hs-CRP, IL-6 and cortisol at all postoperative time-points (8 h, 24 h and 48 h).
Conclusion: Microwave ablation induces a lower systemic stress response than open surgery for treatment of benign thyroid nodules.
Introduction
Thyroid nodules are common, and are detected in 3–7% of general population by palpation and in 20–50% of general population by high-frequency ultrasonography [Citation1]. A benign, asymptomatic nodule can be managed by watchful waiting; however, some patients require treatment because of cosmetic concerns, subjective symptoms or to allay fears of malignant transformation [Citation2]. Surgery is the conventional approach for treatment of thyroid nodules. However, it has some disadvantages, including scar formation, long duration of hospitalisation, requirement for general anaesthesia and risk of complications such as hypothyroidism, bleeding, infection and hoarseness of voice due to recurrent laryngeal nerve injury [Citation3,Citation4]. In order to reduce these complications, various ablation methods as minimally invasive nonsurgical techniques have been widely used to treat benign and malignant thyroid tumours, which include radiofrequency, laser, microwave, thermal ablation and high-intensity-focus ultrasound ablation [Citation5–10]; these techniques have been shown to be effective in decreasing the volume of thyroid nodules and are associated with minimal complications [Citation2,Citation11,Citation12].
Microwave ablation has been successfully used for minimally-invasive treatment of benign and malignant tumours of liver, kidney and lung. Of late, microwave ablation has been increasingly used for treatment of benign thyroid nodules with satisfactory outcomes [Citation13,Citation14]. Microwave ablation has its own advantages especially with respect to simplified operation and cosmetic benefits; however, it is not suitable for treatment of larger nodules (diameter >30–40 mm) [Citation15,Citation16].
Both conventional open surgery or microwave ablation are liable to induce a systemic stress response owing to the associated trauma and/or thermal reaction [Citation17]. Although several studies have shown a beneficial effect of microwave ablation therapy in the context of benign thyroid nodules [Citation18–20], its influence on systemic stress response is not clear. In this study, we compared the systemic stress response induced by microwave ablation with that induced by conventional open surgery for treatment of benign thyroid nodules. The study seeks to provide a reference to guide the selection of surgical method for treatment of certain patients with thyroid nodules.
Materials and methods
Subjects and grouping
Patients with biopsy-proven benign thyroid nodules in the period between February 2016 and September 2016 at our hospital were screened. The inclusion criteria were as follows: (1) Fine needle aspiration biopsy (FNAB)-proven benign thyroid nodules; and (2) any of the following conditions: hyperfunctional nodules; thyroid nodule-related symptoms (pain, foreign body sensation, neck discomfort; protruding nodules affecting appearance). The exclusion criteria included: (1) substernal goitre; (2) malignant thyroid lesions; (3) severe blood coagulation disorders or severe cardio-pulmonary diseases; (4) Graves disease, nodular goitre with hyperthyroidism, hypothyroidism, Hashimoto’s disease with subclinical hypothyroidism; and (5) inability to tolerate surgery, or refusal for surgical treatment or clinical observation.
The eligible patients were randomly assigned to receive ultrasound-guided thyroid microwave ablation (microwave group) or conventional open thyroid surgery (open group). Randomization was performed with the envelope method using random numbers generated by software. The odd array of patients was assigned as the microwave group, and the even array of patients was assigned as the open group. The randomisation procedure was conducted by clinicians who did not participate in the other parts of the study.
Patients were counselled about the study objectives and operation procedures in detail. Ethical approval was obtained from the ethics committee at the Panzhihua Central Hospital, China. Written informed consent was obtained from all patients prior to their enrolment.
Microwave ablation technique
Microwave ablation was performed on an inpatient basis. The patient was placed in the supine position with neck hyperextended. Ultrasound examination was performed to examine the position, distribution and blood supply of each thyroid nodule before operation. With ultrasound guidance, the optimal puncture point and path were determined. Local anaesthesia with 1% lidocaine was applied in the region of the puncture site and along the puncture path and around the thyroid. If the nodule was located close to the dorsal aspect of the thyroid gland, a mixture of 1% lidocaine and physiological saline was infused into the surrounding thyroid capsule to form a liquid-isolating region, protecting the vital structures of the neck (trachea, oesophagus and recurrent laryngeal nerve). The antenna was inserted from the isthmus to the lateral part of a targeted nodule and microwave ablation (power: 25 W–35 W) was performed with “moving shot” technique [Citation21,Citation22]. A heat-generated hyperechoic zone of ablation that encompassed the entire nodule was created. The whole procedure was monitored by real-time ultrasound till the blood flow signal around the nodules completely vanished. The neck was compressed for 30 min after operation to prevent haematoma formation.
Conventional open thyroid surgery
A 6–8 cm transverse arc incision was made 2 cm above the sternal notch, and then the skin flap was dissected between platysma muscle and deep cervical fascia with an electrotome. Thereafter, the deep cervical fascia was cut open longitudinally, and the jugular anterior fascicles were dissected to expose the thyroid. Finally, subtotal thyroidectomy or thyroid nodule resection was performed with meticulous capsular dissection technique [Citation23]. A drainage tube was retained as per convention, and the incision was intradermally sutured.
Clinical and laboratory indicators
Demographic and clinical data of patients, including age, gender, the number and diameter of thyroid nodules were recorded. The pathological type of thyroid nodule was also recorded according to the results of biopsy.
The body temperature and postoperative pain scores were determined at 24 h before operation and at 8 h, 24 h and 48 h after operation. At each time point, the body temperature of patients was measured for three times and the average value recorded. The pain intensity of patients was evaluated using a visual analogue scale (VAS) (score range: 0 to 10; 0, no pain; 10, most severe pain).
At 24 h before operation and at 8 h, 24 h and 48 h after operation, peripheral venous blood samples were collected from all patients. White blood cell (WBC) counts (reference range 4–10 × 109/L), serum high sensitive C-reactive protein (hs-CRP, reference range 0–5 mg/L), cortisol (reference range 66–286 ng/ml) and interleukin 6 (IL-6, reference range 2.5–5.8 ng/L) were measured, separately. hs-CRP was measured using an OLYMPUS-AU5400 automatic biochemical analyzer (Olympus, Tokyo, Japan) with the supplied reagents. Serum IL-6 was measured by enzyme linked immunosorbent assay (Shanghai Jianglai Biotech, catalogue number JL14113–48 T). Cortisol level was measured by radioimmunoassay.
Statistical analysis
All statistical analyses were performed using SPSS 20.0 software (SPSS Inc., Chicago, IL). Data pertaining to quantitative variables are presented as mean ± standard deviation (SD) and between-group differences assessed with t test. Frequencies and percentages were analysed with chi-square test. p < 0.05 represented a statistically significant difference.
Results
Characteristics of patients
A total of 140 patients with biopsy-proven benign thyroid nodules were screened during the study reference period. In the open group (n = 70), 19 patients were excluded because of substernal goitre (n = 2), malignant thyroid lesions (n = 7), nodular goitre with hyperthyroidism (n = 1), Hashimoto’s disease with subclinical hypothyroidism (n = 3) or owing to refusal for surgical treatment (n = 6). In the microwave group (n = 70), 13 patients were excluded because of substernal goitre (n = 1), malignant thyroid lesions (n = 8), Hashimoto’s disease with subclinical hypothyroidism (n = 2) or owing to refusal for treatment (n = 2). Finally, a total of 108 patients were included in the study (microwave group, n = 57; open group, n = 51). None of the subjects were lost to follow-up. The study population included 19 male and 89 female patients; the mean age of patient was 46.1 ± 11.7 years. In the microwave group, the mean number of thyroid nodules per patient was 3.4 ± 0.8 (mean diameter: 2.55 ± 1.13 cm); in the open group, the mean number of thyroid nodules per patient was 3.2 ± 0.5 (mean diameter: 2.34 ± 1.05 cm). The mean duration of hospitalisation in the microwave group and open group was 4.6 ± 0.4 days and 6.9 ± 0.7 days, respectively. The clinical and pathological characteristics of patients are shown in . No significant between-group differences were observed with respect to age (p = 0.849), gender (p = 0.304), number of thyroid nodules (p = 0.118), diameter of nodules (p = 0.425) and the pathological type (p = 0.425).
Table 1. Comparison of clinical data between the two groups before operation.
Postoperative complications
Postoperative recovery was uneventful in the entire study population. In the open group, one patient experienced hypocalcaemia and tetania postoperatively, which were resolved soon after calcium supplementation; none of the patients developed cervical haematoma or showed signs of recurrent laryngeal nerve injury. In the microwave group, none of the patients underwent a secondary open surgery.
Comparison of body temperature, VAS scores and WBC count between the two groups before and after operation
There was no significant difference between the two groups with respect to body temperature at 24 h before operation (p = 0.386; ). In the microwave group, the body temperature was maintained at a relatively stable level, both before and after operation. In contrast, the body temperature in the open group was elevated at 24 h after operation, which was significantly higher than that in the microwave group (p = 0.025).
Table 2. Comparison of systemic stress response indicators between the two groups before and after operation.
Postoperative VAS scores in the open group were found to be significantly higher than those in the microwave group at all time points (p < 0.05). No significant between-group difference was observed with respect to the WBC counts at 24 h before operation (p = 0.386). Patients in both groups experienced postoperative increase in WBC counts with peak values observed at 24 h after operation, followed by a gradual decline. However, the WBC counts in the open group were significantly higher than those in the microwave group, both at 24 h (p = 0.031) and 48 h after operation (p = 0.004).
Comparison of hs-CRP, IL-6 and cortisol between the two groups before and after operation
No significant between-group difference was observed with respect to serum hs-CRP levels at 24 h before operation (p = 0.480). However, postoperative serum hs-CRP levels at 8 h, 24 h and 48 h after operation in the open group were significantly higher than those in the microwave group (p < 0.05).
Similar to serum hs-CRP, serum IL-6 levels in the open group were significantly increased at 8 h, 24 h and 48 h after operation, as compared to those at baseline (p < 0.05). On the contrary, patients in the microwave group did not exhibit such dramatic changes in serum IL-6 levels (p < 0.05 vs. open group at all time-points).
A similar trend was observed with respect to cortisol levels. The patients in the open group exhibited dramatic increase in cortisol levels after operation, which were significantly higher than those in the microwave group (p < 0.05, ).
Intra-group comparison of WBC count, hs-CRP, IL-6 and cortisol levels
Intra-group comparison of various indices (WBC, hs-CRP, IL-6 and cortisol) was performed between three time-points: 24 h before the operation, and 24 h and 48 h after the operation. All four indices were increased to different extent in patients of both groups at 24 h and 48 h after operation, as compared with those at 24 h before the operation (p < 0.05, Supplementary Table 1). However, the indices in the open group showed a more obvious increasing trend.
Discussion
Inflammation is a non-specific systemic response of the body to various stressful factors such as surgical trauma, general anaesthesia and thermal stimulation [Citation24,Citation25]. Surgery-induced systemic stress response is characterised by endocrine-metabolic changes which are proportional to the severity and duration of postoperative stress response [Citation26]. The direction of modern surgery is to minimise the postoperative systemic stress response. In this study, microwave ablation was found to be superior to conventional open thyroid surgery with respect to postoperative systemic stress response, as evidenced by relatively stable body temperature, lower serum levels of hs-CRP, IL-6 and cortisol as well as lower VAS scores in the microwave ablation group.
Surgical trauma induces inflammatory response. It stimulates increased cytokine secretion by macrophages as well as affects the hypothalamus, which serves as the control centre for thermoregulation. The resultant neuroendocrinal changes induce pyrogenetic reaction [Citation27]. On the other hand, surgical trauma to tissues stimulates the mononuclear phagocyte system, and induces hyperplasia of endothelial cells and neutrophils and increase in peripheral WBCs. Thus, the elevation of body temperature and increase in peripheral WBC counts has a certain reference value for evaluating the systematic stress response. In this study, patients in the microwave group exhibited lower body temperature at 24 h after operation as well as lower WBC counts at 24 h and 48 h after operation, as compared to that in the open surgery group; these findings indicates a milder level of systemic stress response in the microwave group. In addition, severe postoperative pain also reflects the stress response, and is associated with the severity of trauma [Citation28,Citation29]. VAS scoring is a simple and commonly used method for the evaluation of variations in pain intensity. In our study, VAS scores in the microwave group were lower than those in the open group at all time points (8 h, 24 h and 48 h) after operation. It further reinforces that microwave ablation exerts less systemic stress than open surgery for the treatment of benign thyroid nodules.
Cortisol is an important glucocorticoid secreted by the adrenal cortex. In addition to its basic metabolic function, it is also considered to be a sensitive indicator of the systemic stress response [Citation25]. Surgical injury induces activation of sympathetic nervous system and pituitary gland-adrenal gland axis, which triggers a series of neuroendocrinal reactions and upregulates the release of cortisol from the adrenal gland. Serum levels of cortisol were shown to be increased in postoperative patients and to directly correlate with the extent of surgical trauma [Citation26]. Maas et al. [Citation30] also found that cortisol levels were increased at 2–3 h after surgery and reached its peak at 24 h; the amplitude of change was directly proportional to the severity of surgical trauma. Thus, the extent or degree of surgery stress may be evaluated by measuring perioperative cortisol levels. In this study, serum cortisol levels in the open group were higher than those in the microwave group at all postoperative time-points (8 h, 24 h and 48 h), which indicates that the systemic stress response to conventional open surgery was more severe than that induced by microwave ablation.
Surgical stress is a consequence of a variety of events including psychological regulation, modulation of stress hormones and tissue injury-induced alterations, accompanied by elevation of acute-phase reactive proteins and cytokines, particularly CRP and IL-6 [Citation20,Citation26]. CRP is synthesised by the liver. CRP levels were shown to be markedly increased in stress states, for instance following surgery, and its level was shown to be associated with the degree of surgery trauma [Citation19]. IL-6 is a multi-functional cytokine, which maintains a low level in the plasma under normal conditions. However, stress response to surgical trauma triggers the synthesis and release of proinflammatory cytokines (such as IL-6 and IL-8) by macrophages and monocytes [Citation31]. IL-6 is believed to be a sensitive inflammatory marker which reflects tissue injury [Citation32]. In the present study, both IL-6 and CRP levels in the open group were greater than those in the microwave group at 8 h, 24 h and 48 h after operation, which suggests that microwave ablation of thyroid nodules induced lesser degree of surgical stress as compared to open surgery.
This study has several limitations. First, it was a single-centre study. Second, some unmeasured confounding factors that could have possibly influenced the observed association cannot be entirely ruled out. Third, the indicators were measured within 48 h perioperation, and long-term follow up was not performed.
Conclusion
Microwave ablation exerts less systemic stress on patients than open surgery for treatment of benign thyroid nodules, which demonstrates the superiority of microwave ablation.
Disclosure statement
The authors have no financial interests or any conflicts of interest to disclose.
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