Originally, Lugol’s solution was used as a treatment for tuberculosis, disinfectants and test kits for starch. Until the 1920s, Lugol’s solution was formally given to Graves’ disease patients as a standard preoperative preparation (13). Through the Na+/I symporter, excess iodine is transported to the thyroid, inhibiting TPO and decreasing the synthesis of thyroid hormones (14).

Even though iodine is used singly, the dosage and usage are also different; the common duration is approximately 10 days for the escape phenomenon (14) from Wolff-Chaikoff is expected to probably appear 10 days later. Using Lugol’s solution preoperatively resulted in a 7.4x reduction in the rate of intraoperative blood loss (15) compared with the control group. A randomized controlled trial (RCT) showed that the mean blood loss was significantly different between the experience group, which was given 8 drops of saturated potassium iodide solution (SSKI) for 7 days, and the control group (p=0.036) (16). Taking 1 drop containing 0.05 g potassium chloride (KI) ter in die (tid) orally for 10 days prior to operation, the incidence of transient hypoparathyroidism (P = 0.018) and transient hoarseness (P = 0.009) were decreased with the matched group (17). GD patients who accepted potassium iodide solution of three drops bis in die (bid) for 13 days of treatment (18) had an obviously longer operation time (p<0.001) and heavier weight of the thyroid gland (p<0.001), which indicates that this group probably has a higher degree of difficulty, while the occurrence of postoperative vocal cord paresis (temporary vocal cord paralysis, p=0.082) was significantly decreased.

In the past 30 years, iodine interventions have varied from 0.3 ml tid for 9 days, 20 drops quaque die (qd) for 10-14 days, 10 drops qd for 10 days, 0.8 mg/kg qd for 10 days, to 8 drops qd for 7days,1 drop tid for 10 days and 7 drops qd for 10 days (19, 20). However, in GD patients, the application of iodine before surgery is still the subject of big debate. Iodine solution indeed decreases the vascularity of the thyroid and ultimately reduces intraoperative blood loss, but it is not equivalent to decreasing postoperative complications; in other words, its advantages sometimes cannot be reflected in clinical perioperative results. Research has confirmed that regarding the main postoperative complications, there were no significant differences between the SSKI group and the group without SSKI: the incidence of transient hypoparathyroidism was 40.9% versus 50%, while the incidence rate of permanent hypoparathyroidism was 6.8% versus 13%,which may attribute to the adhesion of surrounding tissues, that of transient recurrent laryngeal nerve (RLN) palsy was 2.3% versus 8.7%,and that of definitive RLN palsy was 2.3% versus 2.2% (21, 22). Furthermore, iodine causes adhesion to the surrounding tissue through fibrotic reactions, which makes it harder to position and protect the parathyroid gland during thyroidectomy, which increases the incidence of hypoparathyroidism (20). Other reasons for refusing to use iodine before surgery are mainly due to anxiety about side effects, including intolerance, digestive tract reaction, allergy, rash, neck indisposition or painless thyroiditis caused by iodine (23). These controversies could be understood, for negative results may be attributed to the thyroid volume of GD enrolled patients in research, or the hyperthyroidism severity of those patients is mild to moderate. For such patients, euthyroidism is not required preoperatively, and the operation can be carried out safely in hyperthyroidism.

Effective preoperative preparation still consists of iodine solution considering its advantages. Examples and effects of different applications of iodide as preoperative preparations are summarized in Table 1 . More prospective research on GD patients with severe, under-controlled hyperthyroidism is needed to confirm the target GD patients who are suitable to accept iodine preoperatively and elaborate the necessity of iodine preparation before surgery.

In addition to the previous experience of using a certain kind of drug mentioned above singly, surgeons made some exploration of combined regimens of medicine, some of which obtained satisfactory results.

ATDs are empirically considered basic medicine for the long-term control of hyperthyroidism. However, sometimes ATDs used singly are not enough for those patients with moderate to severe hyperthyroidism. Additional iodine solution treatment for ten days is beneficial to preoperative preparation by decreasing thyroid vascularity and minimizing surgical blood loss (28). When a patient develops side effects of ATDs or who relapses and is still thyrotoxic, iodine is an excellent means of rendering the toxic patient’s euthyroid for its Wolff-Chaikoff effect (29).

Even though this combination mainly concluded from practice lacks adequate statistical data, the three-step regimen was commonly acknowledged as effective, including giving ATDs to establish a euthyroid state first, and then deciding whether to use beta-blockers and the dosage according to the severity of individual hyperthyroidism. Iodine therapy is not a routine treatment for most patients, but it is also an important means for some patients with poor preoperative preparation for ATD. For these patients, once the operation time is determined, iodine can be applied 7-8 days before the operation date (30).

In addition to the regimen of ATD combined with iodine, Chinese scholars have also proposed other schemes. ATDs can control hyperthyroidism but increase TSH, which promotes the generation of goiters to a certain extent and increases the difficulty of surgery. Levothyroxine sodium is often utilized as replacement therapy for hypothyroidism, which can also decrease TSH via negative feedback of the pituitary thyroid axis. These two drugs may complement each other to maintain stable thyroid function. Based on this, Zhu Jing-qiang et al. (12) designed a study in which patients were divided into different groups on the basis of the dosage and duration of drugs prepared before operation in a double-blind design. Furthermore, the treatment group was divided into 4 subgroups: A (60 cases), B (61 cases), C (64 cases) and D (59 cases). Phase I: Patients were given propylthiouracil 450-900mg/d or methimazole 45-90mg/d. Phase II: continue to take antithyroid drugs plus levothyroxine(L-T4) 1.6 μg/kg or thyroxine tablets 20-60mg/d. For group A, the time of phase II was 2-4 months, and group B halved. The dosage of ATDs was reduced to propylthiouracil 150-300mg/d or methimazole 15-30mg/d in group C. In contrast, group D adjusted the time of phase II to 1-2 months, maintaining the same dosage of ATDs as group C. The results showed no significant difference in blood loss between group D and the control group, which was more significant than that in the other treatment groups (control group (324.76 ± 163.26) ml, group A (195.74 ± 57.07) ml, group B (230.00 ± 70.81) ml, group C (240.47 ± 80.29) ml, group D (314.75 ± 96.46) ml, P<0.05).They also drew a similar conclusion to predecessors that group A (sufficient ATDs and L-T4) is closer to the histologically positive pathological changes of normal thyroid tissue. They named this preoperative treatment the “preoperative preparation method of sequential thyroid defunctionalization”.

In another clinical study, 272 GD patients were enrolled to receive different preoperative treatments (ATDs and thyroxine, ATDs and iodine, iodine, no preparation), 74% of whom accepted ATDs and thyroxine (31). Starting with carbimazole (or methimazole), 10 mg quarter in die (q.i.d.) or propylthiouracil 100 mg q.i.d. to block the synthesis of thyroid hormone, and then maintain an adequate drug dosage. Then, reducing the doses of ATDs by half and providing patients with thyroxine 0.20 mg qd continued this regimen for at least 4 weeks. The thyroid is close to the normal state after adequate pretreatment, which is beneficial to risk reduction of intraoperative blood loss. Moreover, no thyroid storm postoperatively occurred in the GD patients prepared preoperatively with ATDs, and the hospitalization time was shorter than that in patients who took ATDs and iodine preoperatively (6.5 days versus 18 days), for the latter have more severe hyperthyroidism and need to be hospitalized for observation during preoperative preparation.

For GD patients who decide to choose thyroidectomy, remaining euthyroid and continuously inhibiting TSH secretion are of critical importance. Combining a medium dose of methimazole and L-T4 is also called the “block-and-replace” (BR) method in internal medicine treatment, which can not only maintain euthyroid status but also postpone surgery to a suitable age for pediatric GD patients. In the comparison of practical application before surgery, the incidence of euthyroid was present in 87.4 ± 18.6% of patients with the BR approach, which was better than that of methimazole alone (47.1 ± 30.9%) (32) by one ATD treatment period. Even though the ultimate goals were different from the discipline perspective, the essence of the effect on the thyroid is the same: blocking endogenous thyroid hormone synthesis and inhibiting TSH to maintain the morphology of the thyroid by providing exogenous hormones. This regimen offers GD patients a worth deserving method to achieve a euthyroid state before the surgery safely and quickly, reducing the incidence of complications in the perioperative period and providing a choice for GD patients who are allergic to iodine.