Effects on Thyroid Function of Topical Liposomal Hydrogel with 3% Povidone-Iodine Dressing
Article information
Abstract
Background
Povidone-iodine (PVP-I) is an antiseptic that is commonly used as an alternative to alcohol in clinical settings, including for perioperative skin disinfection. However, the presence of iodine in PVP-I can result it adverse effects on thyroid function. This study explored the effect of PVP-I on thyroid function and assessed its safety profile.
Methods
We assessed thyroid function in patients before and after treatment with Repigel (topical liposomal hydrogel with 3% PVP-I) between January 2017 and January 2023, for a period of at least 2 weeks. Patients were stratified by age, sex, and previous history.
Results
No significant changes in thyroid function were observed in the 61 patients enrolled until 2 weeks after application of Repigel. Significant increases in T3, T4, and free T4 levels were detected 4 weeks after Repigel application. A comparison of the initial thyroid function test (TFT) and TFT 4 weeks post-application found that the mean T3 levels were 71.12 ± 17.55 ng/dL and 59.84 ± 18.60 ng/dL and mean T4 levels were 6.48 ± 1.49 µg/dL and 5.50 ± 1.36 µg/dL, respectively. The mean free T4 levels were 1.08 ± 0.39 ng/dL and 0.90 ± 0.19 ng/dL, respectively.
Conclusion
Changes in thyroid function during the application of Repigel were observed. We conclude that thyroid function should be examined at regular intervals before and after topical application of Repigel. Additionally, clinicians should exercise caution when administering iodine-containing substances such as Repigel to patients with abnormal thyroid function, and schedule follow-up TFTs at 4 weeks.
Introduction
In recent years, numerous products have been developed and used for wound healing. Many of them contain povidone-iodine (PVP-I), a broad-spectrum microbicide that is widely used against Gram-positive and Gram-negative bacteria, molds, and even viruses [1-3] and has shown clinical benefits in cases where inflammation and reactive oxygen species interfere with wound healing (e.g., burns, chronic wounds, and in smokers). Iodine is the best-known antiseptic and has been used for centuries [2,4]. Among one of these PVP-I containing products is Repigel, a liposomal hydrogel with PVP-I (3%) that combines the broad-spectrum antimicrobial activity of PVP-I and moisturizing properties of liposomes in a hydrogel formulation [5].
Unlike other antiseptic substances such as chlorhexidine, the development of resistance to PVP-I has not been observed, and PVP-I causes less bleeding than other antiseptics [6,7]. However, PVP-I has adverse effects on thyroid function due to its iodine content. Studies have shown that because iodine in PVP-I is composed of effective iodine and iodine ions (I-) [8], plasma iodine levels increase even after a single topical application on the umbilical cord and the surrounding intact skin of newborns, and remain at a significantly higher level following multiple applications [9].
Although iodine itself has no microbicidal activity, free iodine released from the PVP-I complex in an aqueous medium has microbicidal activity that increases with continued PVP-I application [4]. Particularly, unlike PVP-I, which dries quickly within conventional PVP-I dressings, the liposomal hydrogel in Repigel allows free iodine in PVP-I to remain active on the wound for an extended period, prolonging the contact time between the wound and free iodine [4]. The advantages of topical liposomal hydrogel with PVP-I maintaining both antimicrobial activity and tissue tolerability makes it specifically useful for moist wound healing [10,11].
Thyroid hormones are essential for maintaining homeostasis and are regulated through feedback based on circulating thyroid hormone levels, which can be affected by thyroid toxicants [12]. Even if thyroid dysfunction may be asymptomatic, measuring serum thyroid-stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3) provides a clear method for detecting thyroid dysfunction and is crucial for diagnosing subclinical thyroid dysfunction [13].
Most patients with chronic wounds require long-term treatment, and closely monitoring patients who had topical PVP-I treatment for an extended period would be prudent. This study explored the influence of topical liposomal hydrogel with PVP-I dressing on thyroid function and assessed its safety profile.
Methods
We conducted a retrospective review of the records of 137 patients, both inpatients and outpatients, who received topical application of Repigel on their wounds from a plastic surgeon at our hospital between January 2017 and January 2023. All investigations were performed in accordance with the principles of the World Medical Association Declaration of Helsinki (June 1964) and its subsequent amendments. This study was approved by the Institutional Review Board of Wonkwang University Hospital (IRB No. WKUH 2022-12-034-001). The informed consent was waived because this design is a retrospective study.
Patients
A total of 137 patients who received topical Repigel treatment between January 2017 and January 2023 were retrospectively analyzed via a chart review. The history of the patients was diverse and included diabetes mellitus and hypertension. However, judging from the normal value derived in chemiluminescence immunoassays of the thyroid [14], initially all patients had normal thyroid function, and were found without any thyroid-related diseases.
Before applying Repigel on patients’ wounds, we evaluated the wounds and selected only cases of inflammation with minimal discharge. Next, we performed debridement to remove unhealthy or necrotic tissue and calluses. Administration of Repigel was limited to patients with shallow, small (8×8 cm or less) wounds without any exposed subcutaneous fat. Additionally, Repigel was only applied topically in patients whose thyroid function test (TFT) results did not deviate from the normal range in at least two tests during our study.
To prevent skin maceration around the wound, precautions were taken to ensure that only an appropriate amount of Repigel was used, so that it would not extend beyond the wound area when covered afterwards with a foam dressing.
Seventy-six patients refused to take additional laboratory thyroid tests after the initial TFT (e.g., TSH, T3, T4, and free T4) or were lost to follow-up. The remaining 61 patients applied Repigel topically at least once every 2 days until the wound healed and underwent TFTs before starting topical applications of Repigel and every 2 weeks thereafter. If there were no significant changes in TFT results until 1 month after the initiation of Repigel treatment, follow-up TFTs were performed once monthly for up to 3 months.
To determine any residual effects of Repigel on thyroid function, follow-up TFTs were recommended even to patients whose wounds healed within approximately 2 weeks with no need for more Repigel administration, however, the majority of these patients refused to visit the outpatient clinic for a follow-up TFT at 4 weeks after starting the use of Repigel. Thus, the patients were divided into two groups: 30 patients who were followed up for up to 2 weeks (the short-term group), and 31 patients who were followed up for more than 4 weeks (the long-term group).
Thyroid assessments: chemiluminescence immunoassays
Normal values of thyroid function parameters were [14]: TSH, normal range: 0.25–5.25 µIU/mL; T3, normal range: 60–165 ng/dL; T4, normal range: 4.40–11.00 g/dL; and free T4, normal range: 0.70–1.70 ng/dL.
Statistical analysis
Statistical results are expressed as mean±standard deviation. Using data from laboratory tests, we compared differences between the groups considering variable parameters via one-way analysis of variance (ANOVA); multiple data comparisons between time points and between the groups were performed using the chi-square test, repeated measures ANOVA and Tukey method using SPSS Statistics v.27 (IBM Corp.). The level of significance was set at P<0.05.
Results
Study population
Demographic data and patient characteristics are presented in Table 1. The mean age of patients in the short-term and long-term groups was 68.97±13.22 years and 65.26±15.49 years, respectively; the male to female ratio was 24:6 and 22:9, respectively. Patients with a history of angina, myocardial infarction, or stent insertion were classified as having cardiac disease, and those with a history of tuberculosis were classified as having pulmonary disease. The medical histories of the patients in the two groups were compared. No significant differences were observed excluding durations of dressing application (Table 1). By diagnoses, the largest group was diabetic foot patients, followed by pressure injury patients. Other patients included ingrown nails or scalp wounds.
Demographic characteristics of the patients in this study
Thyroid function test
Before applying Repigel, the mean T3 levels were 70.84±11.46 ng/dL in the short-term group and 71.12±17.55 ng/dL in the long-term group, while the mean T4 levels were 7.09±1.07 µg/dL and 6.48±1.49 µg/dL, respectively. The mean TSH levels in the two groups were 1.67±1.22 µIU/mL and 3.43±5.70 µIU/mL, and the mean free T4 levels were 1.06±0.13 ng/dL and 1.08±0.39 ng/dL, with no significant differences between the groups (Table 2).
Comparison of initial and 2 weeks TFT levels between groups
Two weeks after beginning to apply Repigel, the mean T3 values increased to 76.29±11.51 ng/dL and 76.84±16.12 ng/dL in the short- and long-term groups, respectively. The mean T4 levels were 7.31±1.13 µg/dL and 6.91±1.26 µg/dL, while the mean TSH levels were 1.87±1.41 µIU/mL and 5.85±11.55 µIU/mL. The mean free T4 levels were 1.00±0.13 ng/dL and 0.93±0.28 ng/dL. Again, no significant differences were found between the short- and long-term groups until 2 weeks after treatment (Table 3, Fig. 1).
Comparison of initial, 2nd week, and 4th week TFT levels
Graph comparing thyroid function test (TFT) levels in the long-term group. a)P<0.05.
For TFT values 4 weeks after initiation of Repigel treatment in the long-term group, the mean TSH value was 5.29±12.14 µIU/mL; no significant differences were observed between the groups at any time point (Table 3, Fig. 1). However, the mean T3 was 59.84±18.60 ng/dL, the mean T4 was 5.50±1.36 µg/dL, and the mean free T4 level was 0.90±0.19 ng/dL, which were significantly different from the previous values (Table 3, Fig. 1).
Based on these results, TFT values 4 weeks after Repigel treatment were compared with the values pre-treatment and after 2 weeks of treatment. The mean T3 and T4 values at 4 weeks showed significant differences compared with the pretreatment values and values at 2 weeks of treatment in the long-term group (Table 4). As for the mean free T4, no significant differences were observed at 4 weeks compared with 2 weeks of treatment. However, significant differences were found between the initial mean free T4 levels and at 4 weeks of treatment. There were no differences in the mean TSH levels at any time point (Table 4).
Comparison of initial and 2 weeks TFT results with 4 weeks TFT results
Discussion
Several studies have shown that short-term PVP-I use could affect thyroid function [15]. However, most studies evaluated only blood or urinary iodine levels, while none have unveiled specifically how PVP-I affected TFT levels. Furthermore, these studies were limited to investigations of mucous membranes, such as mouthwash and douching, or were conducted over a short period. The present report is a valuable retrospective study including patients who continuously applied PVP-I to chronic wounds that had progressed for more than 4 weeks [8,16-18]. This study specifically showed that PVP-I had an effect on TFT not only when applied to mucous membranes but also when applied to wounds.
In a study by Nobukuni et al. in 1997 [19], where PVP-I was applied in 27 of 40 patients, correlation with thyroid dysfunction was observed. In some patients who used PVP-I for a prolonged period (>40 months), free T4 levels increased beyond the normal range. In our study, we included a larger number of patients in each group; patients wherein PVP-I was topically applied for a short period of time, instead of patients who had not been administered PVP-I, were grouped separately to address the shortcoming of the study design of the previous literature.
Next, PVP-I treatment was administered to patients whose initial TSH levels were at the upper limit of the normal range (0.35–4.94 µIU/mL) on their TFT. As TSH exceeding the range of 0.2–1.9 µIU/mL is associated with an increase in anti-TPO antibodies (anti-TPO Ab), further studies are needed to exclude patients with abnormal pathology [20,21]. Based on the results of this study, as TSH levels in the patients did not significantly increase or decrease, the possibility of euthyroid hyperthyroxinemia cannot be ruled out. However, in this study, the increases and decreases in T3, T4, and free T4 were all within the normal range. Therefore, additional studies on euthyroid Graves’ disease are advisable; further information on medication history such as amiodarone is needed [20,22]. In addition, since free T4 elevation with normal TSH levels is correlated with cardiovascular diseases such as atrial fibrillation [23], further evaluation is needed.
The effect of the wound size and depth on differences in the use of Repigel must also be considered. Most of the wounds among the patients in this study had an area of less than 5×5 cm, making it unlikely that differences in wound size significantly affected the results. Similarly, since Repigel was applied only when subcutaneous fat was not visible, ensuring that bones or tendons were not exposed, it is difficult to gauge the effect of wound depth on the results. Prospective research that investigates all conditions including the effect of different sizes and depth of wounds should be conducted in the future.
Several studies have identified changes in season and circadian rhythm, among others, as factors that affect thyroid function. For example, it has been reported that TSH increases after midnight, maintains an elevated level during the night, and then maintains a low level during the day [13]. Given this circadian variation, patients who had their TFT samples taken at the outpatient clinic, even if they visited early in the morning, may have demonstrated lower TSH values than those who had regular laboratory tests taken before 6 AM during hospitalization. In this study, because TFT evaluation after 4 weeks was often performed after discharge for previously hospitalized patients, TSH levels may have been measured to be lower than during hospitalization. Also, as TFT levels at 4 weeks were determined within the 4th week rather than precisely at the 4th-week point, some changes might have gone undetected.
This study has a number of limitations. Serum T3 tends to be higher in winter than T4 and TSH; hence, the T3 levels of patients who visited hospitals with lower indoor temperatures during the seasonal transition just before summer may have been elevated before declining after discharge [13]. Conversely, in patients hospitalized in winter, T3 levels may have increased when they were discharged after 2 weeks. Further research is required to study patients of a similar age group or include hospitalized patients who have not been exposed to significant temperature changes.
Since a prolonged wound increases the likelihood of delayed or incomplete healing [24], it is important to explain to patients prior to Repigel treatment that, even if TFT values are normal, there is a higher chance that the wound may take a long time to heal, and that continued use of Repigel may cause changes in thyroid function.
Although changes in thyroid function were observed following PVP-I treatment, whether TSH, T3, T4, and free T4 levels increased or decreased was confirmed to be patient-dependent, and the degree of increase also differed by patient. There was also a significant difference in the mean TSH levels from the initial TFT results and that at 2 weeks of applying PVP-I in both the short- and long-term groups. However, the mean was distorted due to two patients whose initial TFT was significantly higher than the mean (30.18 µIU/mL and 14.58 µIU/mL, respectively). Furthermore, when the two patients were excluded, the mean decreased to 2.11 µIU/mL. Of the two patients, the TSH level of the patient with an initial TSH of 30.18 µIU/mL increased to 67.67 µIU/mL at the 4-week follow-up. However, the TSH level in the patient with an initial TSH of 14.58 µIU/mL decreased to 7.49 µIU/mL at the 2-week follow-up; at the 4-week follow-up, this patient’s TSH levels gradually stabilized at 5.85 µIU/mL without significant changes in other thyroid hormone levels. In short, data distortion may have occurred because of two patients with high initial TSH levels. As these incidents demonstrate, additional studies with larger numbers of patients are needed to determine differences caused by patient history, conditions of use, or anti-TPO Ab levels. Since the patient’s varied diet and application of dressings may have impacted the results, additional studies under more controlled conditions are needed.
In addition, though this study aimed to observe the patients for up to 6 months, the application of Repigel ended in approximately a month in most patients, making follow-up observation impossible. This made it more difficult to determine whether thyroid function could change reversibly or irreversibly after long-term use of Repigel. For example, in the patient wherein TSH was measured at 67.67 µIU/mL at the 4-week follow-up, TSH decreased to 6.41 µIU/mL at the 3-month follow-up. During the same period, the patient’s free T4 level increased from 0.8 ng/dL to 1.29 ng/dL, and other thyroid function parameters remained within the normal range. Further research including an extended follow-up observation is required to evaluate patients in a group in which Repigel was applied.
In conclusion, this study demonstrated that thyroid function was significantly reduced in patients who topically applied Repigel, since the mean T3, T4, and free T4 levels tended to decline at the 4th week. Therefore, it is recommended that patients using PVP-I such as Repigel undergo follow-up TFT at the 4th week. Additionally, patients with abnormal thyroid function should avoid using iodine-containing substances, including PVP-I, unless absolutely necessary, and should undergo follow-up TFT testing in the 4th week.
Notes
This work was supported by Wonkwang University in 2023. Young Cheon Na is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.