DOI: https://doi.org/10.21203/rs.3.rs-2480181/v1
This study comprised 80 patients with dry eye whose tear osmolarity measurement using the TearLab® os molarity system was 300 mOsm/L or greater. Patients who had external ocular disease, glaucoma, or other concomitant ocular pathology were excluded. After being randomly divided into four groups, the participants received different kinds of SH eye drops as follows: Groups 1–3 were given one of three concentrations (0.1%, 0.15%, and 0.3%) of isotonic drops, while Group 4 received 0.18% hypotonic SH eye drops. The tear osmolarity concentrations were evaluated at baseline and again at 1-, 5-, and 10-minutes after instillation of each eye drop.
Tear osmolarity showed a significant decrease after instillation of four types of SH eye drops after up to 10 minutes compared to baseline. Patients who received hypotonic SH eye drops showed an enhanced decrease in tear osmolarity compared with the isotonic SH eye drops after 1 minute (p < 0.001) and 5 minutes (p = 0.006), but the difference was not significant at 10 minutes (p = 0.836).
The enhanced immediate effect of hypotonic SH eye drops at lowering tear osmolarity in patients with dry eye seems to be limited unless these drops were used frequently.
Dry eye syndrome is a multifactorial disease in which loss of tear film homeostasis plays a central role in pathophysiology[1]. Increased osmolarity of the tear film and inflammation of the ocular surface are also involved[2, 3], and increasing evidence suggests that tear hyperosmolarity plays a pivotal role in pathogenesis of dry eye[4, 5, 6]. Tear hyperosmolarity increases the levels of proinflammatory cytokines and chemokines that stimulate a series of inflammatory events in the corneal epithelium[7]. These inflammatory events lead to apoptosis of the epithelial cells, including goblet cells, and eventually to worsening of the vicious cycle[8].
Several hypotonic tear substitutes have been developed that focus on the central role of tear hyperosmolarity in the pathogenesis of dry eye syndrome and are expected to reduce tear osmolarity and restore osmotic balance. A few studies have investigated hypotonic tear substitutes[4, 7, 9, 10] and reported enhanced effects on the tear film stability and ocular surface integrity.
However, those studies indirectly evaluated the effect of hypotonic tear substitutes using other clinical assessments instead of direct changes in tear osmolarity. Despite the technical challenges of measuring osmolarity, the TearLab® osmolarity system (OcuSense, Inc., San Diego, CA, US), a point-of-care device[1, 11], allows assessment of tear osmolarity in a quick and simple way.
The purpose of this study was to investigate short-term changes in tear osmolarity of dry eye patients after using artificial tears containing sodium hyaluronate (SH) at different osmolarities.
Eighty patients with dry eye were included in this study. The mean age of the participants was 51.4 ± 14.2 years, and 70 (87.5%) were female. Table 1 summarizes the demographics and characteristics of the four groups at baseline. There were no statistically significant differences in age, TBUT, corneal staining score, or tear osmolarity between groups before the treatment.
|
Group 1 (0.1% isotonic) |
Group 2 (0.15% isotonic) |
Group 3 (0.3% isotonic) |
Group 4 (0.18% hypotonic) |
P-value |
|
|---|---|---|---|---|---|
|
Age, years |
52.1 ± 16.7 |
52.9 ± 12.3 |
51.6 ± 11.9 |
49.0 ± 16.2 |
0.828 |
|
TBUT, sec |
3.03 ± 0.96 |
2.72 ± 0.69 |
3.00 ± 0.64 |
3.35 ± 2.33 |
0.448 |
|
NEI score |
3.40 ± 3.92 |
3.60 ± 2.76 |
2.60 ± 2.47 |
3.35 ± 2.33 |
0.560 |
|
TOSM, Osm/L |
311.60 ± 14.98 |
309.75 ± 10.78 |
311.70 ± 16.86 |
310.50 ± 11.97 |
0.700 |
| TBUT = Tear break up time; NEI = National Eye Institute grading system; TOSM = Tear osmolarity; Groups 1–4: isotonic 0.1%, isotonic 0.15%, isotonic 0.3%, and hypotonic 0.18% sodium hyaluronate eyedrops, respectively. | |||||
| * Statistically significant differences (p < 0.05) according to a Kruskal-Wallis test. | |||||
Changes in tear osmolarity over time after the treatment.
All four SH eye drops showed a significant decrease in tear osmolarity at all time points (Fig. 1). This decrease was maximized at 1 minute after instillation except for Group 2, the 0.15% isotonic group. When comparing patients from the 0.18% hypotonic group to those in the 0.15% isotonic group, the former showed an enhanced decrease in tear osmolarity at 1 minute (p < 0.001) and 5 minutes (p = 0.006) post instillation, but this difference diminished at 10 minutes (p = 0.836; Fig. 2). In addition, among the isotonic SH groups at different concentrations, Group 3, the 0.3% isotonic group, showed an enhanced decrease in tear osmolarity after 5 minutes (p = 0.009; Fig. 3).
Average tear osmolarity at 5 and 10 minutes.
At the 5-minute time point, the average tear osmolarity of all patients was 302 mOsm/L. This value was used to divide the patients into two groups of higher than vs. lower than 302 mOsm/L regardless of the type of eye drops used. Table 2 summarizes the subgroup analysis. The baseline TBUT was significantly longer in the low tear osmolarity group (mean TBUT: 3.08 ± 0.84 sec) compared to the high tear osmolarity group (mean TBUT: 2.72 ± 0.71 sec; p = 0.042). The baseline NEI score was also lower in the low tear osmolarity group (mean NEI score: 2.36 ± 3.14) compared to the high tear osmolarity group (mean NEI score: 3.95 ± 2.51; p = 0.014) (Table 2). Table 3 summarizes a similar subgroup analysis based on the average value of tear osmolarity at 10 minutes, which was 306 mOsm/L. The low tear osmolarity group showed significantly lower baseline NEI scores compared to the high tear osmolarity group (p = 0.043).
|
TOSM, mOsm/L ≥ 302 |
TOSM, mOsm/L < 302 |
P-value |
|
|---|---|---|---|
|
(n = 44) |
(n = 36) |
||
|
Age, years |
53.8 ± 12.4 |
48.4 ± 15.9 |
0.10 |
|
TBUT, sec |
2.72 ± 0.71 |
3.08 ± 0.84 |
0.042* |
|
NEI score |
3.95 ± 2.51 |
2.36 ± 3.14 |
0.014* |
|
VAS |
1.03 ± 0.90 |
1.12 ± 0.99 |
0.669 |
| TBUT = Tear break up time; NEI = National Eye Institute grading system; VAS = Visual analogue scale; TOSM = Tear osmolarity. | |||
| * Statistically significant differences (p < 0.05) according to a T-test. | |||
|
TOSM, mOsm/L ≥ 306 |
TOSM, mOsm/L < 306 |
P-value |
|
|---|---|---|---|
|
(n = 41) |
(n = 39) |
||
|
Age, years |
53.4 ± 13.1 |
49.3 ± 15.2 |
0.196 |
|
TBUT, sec |
2.76 ± 0.73 |
3.02 ± 0.83 |
0.13 |
|
NEI score |
3.88 ± 3.03 |
2.56 ± 2.65 |
0.043* |
|
VAS |
1.08 ± 0.99 |
1.06 ± 0.88 |
0.920 |
| TBUT = Tear break up time; NEI = National Eye Institute grading system; VAS = Visual analogue scale; TOSM = Tear osmolarity. | |||
| * Statistically significant differences (p < 0.05) according to a T-test. | |||
Subjective discomfort.
When comparing the subjective discomfort experienced during eye drop instillation, the 0.3% isotonic group showed a higher discomfort score than the 0.1% (p < 0.038) and the 0.15% isotonic (p < 0.028) groups, while the other groups reported no differences. Age, TBUT, corneal staining score, and tear osmolarity were not associated with subjective discomfort score (all, p > 0.05).
In 2017, the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS) II reported that a tear osmolarity value > 308 mOsm/L in either eye or a ≥ 8 mOsm/L difference between eyes was a good indicator of tear film homeostasis and a diseased ocular surface[16]. Several hypotonic eye drops have been commercialized to decrease elevated tear osmolarity, which is believed to be the primary pathogenic factor in dry eye syndrome. In several studies, the effects of hypotonic eye drops have been investigated[4, 7, 17], and superior effects on symptoms and corneo-conjunctival conditions have been reported over isotonic eye drops. However, since there are no data on the changes that take place in tear osmolarity, we investigated how isotonic and hypotonic eye drops affect tear osmolarity and the duration of the effect.
In our previous study, the osmolarity values of three isotonic and one hypotonic SH eye drop concentrations were evaluated. The osmolarity was 287 ± 2.08 mOsm/L for 0.1% isotonic SH eye drops, 301.00 ± 2.64 mOsm/L for 0.15% isotonic SH eye drops, and 284.67 ± 1.53 mOsm/L for 0.3% isotonic eye drops. In addition, the osmolarity of the 0.18% hypotonic eye drops was 141.00 ± 1.00 mOsm/L, about half those of the isotonic eye drops[18].
In the current study, the four SH eye drops all produced a significant decrease in tear osmolarity at all time points up to 10 minutes after instillation. The hypotonic SH solution showed a stronger effect than the isotonic SH drops at lowering the tear osmolarity up to 5 minutes, but this difference diminished at 10 minutes. In addition, the 0.3% isotonic SH drops showed an enhanced reduction in tear osmolarity at 5 minutes compared to the other concentrations of isotonic SH eye drops. The longer retention time tendency of 0.3% for SH eye drops may explain this difference[19].
At the 5- and 10-minute time points, the patients were divided into two groups based on mean tear osmolarity. Patients with a higher-than-average tear osmolarity showed worse clinical findings, a shorter TBUT, and greater corneal erosion. The results were consistent with the findings of other studies, which have reported that tear osmolarity has a good correlation with severity of dry eye[1, 20]. In patients with severe dry eye syndrome, tear osmolarity may have a higher value at baseline and may return to baseline level quickly after instillation of appropriate eye drops.
Our study had a few limitations. As commercially available SH eye drops were used, the concentrations of the 0.15% isotonic and 0.18% hypotonic solutions were slightly different. In addition, patients were not classified according to subtype of dry eye.
In conclusion, instillation of all types of SH eye drops lowered the tear osmolarity, and the hypotonic SH drops produced an immediate improvement compared to the isotonic SH drops. This difference was observed for 5 minutes after the instillation, but it diminished after 10 minutes. Therefore, unless used frequently, any additional lowering effect of hypotonic SH eye drops on tear osmolarity may be limited.
This study followed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Korea University Hospital. All patients provided written informed consent prior to beginning the study.
Subjects and study design.
This was a prospective and randomized study conducted from June 2017 to February 2018 that included participants who met the Korean guidelines for dry eye syndrome[12] and whose tear osmolarity as assessed using TearLab®[11] was 300 mOsm/L or greater. Patients with external ocular disease, glaucoma or other concomitant ocular pathology, a history of ocular surgery, viral or bacterial infection of the cornea and conjunctiva, who regularly wore contact lenses within the past three months, or who reported any current systemic disease that might affect tear film stability were excluded. Only one eye per patient with higher osmolarity was included in this study.
A total of 80 patients was recruited, and they were randomly divided into four groups of 20 patients: Group 1 (isotonic 0.1% SH; Hyalein ophthalmic solution 0.1%®, Taejoon, Seoul, Korea), Group 2 (isotonic 0.15% SH; New Hyaluni ophthalmic solution 0.15%®, Taejoon, Seoul, Korea), Group 3 (isotonic 0.3% SH; Hyaluni ophthalmic solution 0.3%®; Taejoon, Seoul, Korea), and Group 4 (hypotonic 0.18% SH; Kynex2 ophthalmic solution 0.18%®, Alcon, Seoul, Korea).
Clinical evaluation included slit-lamp examination, tear film break up time (TBUT), corneal staining score, and tear osmolarity. Ocular surface examinations were performed on both eyes by the same physician (IHW). The TBUT was evaluated as follows; after instillation of fluorescein, the participants were asked to blink several times. The time between the last complete blink and the appearance of the first corneal black spot in seconds was measured three times, and the mean value was recorded[13]. The corneal staining score was evaluated using the National Eye Institute scoring method (NEI score) between 0 and 15[14]. The tear osmolarity was assessed using the TearLab® system immediately after blinking; the osmometer required a tiny tear sample obtained directly from the inferior tear meniscus using lab-on-chip technology[15]. All tests were performed in the same space using the same devices. The subjective discomfort when the drops were instilled was assessed using the visual analogue scale (VAS) from 0–10 where 0 means no pain and 10 indicates severe pain or discomfort.
Tear osmolarity was evaluated four times for each participant: at baseline and at 1, 5, and 10 minutes after instillation of the eye drop.
Statistical analysis.
All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 21.0 (IBM Corp., Armonk, NY, USA). The Kruskal-Wallis test, Mann-Whitney U test, T-test, and one-way analysis of variance (ANOVA) were used to compare the measurements between groups. Repeated measures ANOVA was used to compare points within a group. P-values < 0.05 were considered statistically significant.
Data availability
The raw data for this study are available upon reasonable request from the corresponding author.
Author contributions
JSS was involved in the conception and design of the study. WJK, IHW, and YSE were involved in data collection and literature research. WJK was involved in the data analysis and drafting of the manuscript. WJK, IHW, YSE and JSS were involved in final approval of the article.
Additional Information
Competing interests
This study was supported by an unrestricted educational grant from Taejoon Pharm (Seoul, Korea). The sponsor or funding organization had no role in the design or conduct of this research.