Effects of Calf Blood-Deproteinized Extract Ophthalmic Gel Combined with Sodium Hyaluronate Eye Drops on Conjunctival Hyperemia Score and Tear Film Stability in Patients with Dry Eye.

Objective: The aim of this paper is to research the impact of calf blood-deproteinized extract ophthalmic gel combined with sodium hyaluronate eye drops on conjunctival hyperemia score and tear film stability in patients having dry eye.
Methods: 144 patients having dry eye disease who were hospitalized from July 2018 to July 2021 were chosen as the research targets, which were composed of the control group and research group on the basis of the sequences of hospitalization, and each has 72 cases. The sodium hyaluronate eye drops were gained in the control one. In accordance with the control one, the study ones were given the combined treatment with eye drops of sodium hyaluronate. Treatment of calf blood-deproteinized extract ophthalmic gel, the scores of conjunctival hyperemia, tear film stability, visual function, curative effect, and their adverse reactions were observed and made comparisons among the two groups.
Results: After the treatments of 2 weeks and later 1 month, the numerical values of the conjunctival hyperemia were fewer in the categories which had been mentioned above, and in contrast with the control one (P < 0.05), the numerical values of the conjunctival hyperemia in the study one were distinctly fewer. The data of SIt, BUT, and the heights of the central tear river of the lower eyelid were higher than those before cure. In comparison with the control one, the FL of the study one was distinctly lower, and the heights of SIt, BUT, and the central tear river of the lower eyelid were obviously better than the control one (P < 0.05). After therapy, the visual contrast sensitivity of the patients in two categories at 6.4 c/d and 12c/d increased in comparison with those before treatment, and the visual contrast sensitivity of the study group at 6.4 c/d and 12c/d was apparently higher than the data of control one (P < 0.05); the effective rate of treatment in the study one was 97.22%, which had a higher situation than the control one, 88.89% (P < 0.05); the probability of occurrence of the negative events in the study one after treatment was 4.17%, which was distinctly below the control one, 15.28% (P < 0.05).
Conclusion: In order for the treatments of patients having dry eye disease, the use of calf blood-deproteinized extract ophthalmic gel having the combinations with eye drops of sodium hyaluronate can enhance the extent of visual impairment and conjunctival hyperemia with effect and improve the stability of tear film, with significant safety and high efficiency.

1. Introduction

Dry eye disease, also known as corneal conjunctiva xerosis and dry corneal conjunctiva, is a common chronic disease of the eye and is given rise to the factors of age, sleep, antihypertensive drugs, working environment, and other factors. The exact cause is unknown. It is related to pathological changes of ocular epidermis due to the decrease of stability of tear film and the shortening of tear film rupture time caused by abnormal tear secretion. It is often manifested as dryness, burning sensation, and foreign body sensation in the eyes. The main signs were enlargement, thickening, and edema of bulbar conjunctiva vessels [1-3]. Early dry eye disease has no significant impact on vision and living standards. With the progression of the disease, keratitis, corneal infection, and ulcers occur in the eyes, leading to vision loss or even blindness, which seriously affects daily life and work [4]. The treatment of dry eye disease is mainly conservative treatment, using tear replacement products to maintain the demand of the lacrimal gland and promote tear secretion. However, the effect is slow and the therapeutic effect is poor [5, 6].

Relevant studies have shown [7] that drug therapy can repair damaged cornea and maintain structural and functional stability of the eye. Sodium hyaluronate eye drops are used as an external medicine for eye diseases, mainly composed of sodium hyaluronate; when used as a substitute for artificial tears, it can relieve dry eyes and play a lubricant effect; calf blood-deproteinizing extract eye gel mainly consists of 20% calf blood-deproteinizing extract and part of free amino acids, which can improve eye cell function [8, 9]. The efficacy of these two drugs is slow, and the clinical efficacy of combined therapy is limited for patients with dry eye disease. In this research, 144 patients with dry eye disease, treated in our hospital from July 2018 to July 2021, were enrolled as subjects. Two methods, sodium hyaluronate eye drops monotherapy and calf blood-deproteinized extract eye gel combined therapy, were, respectively, used to study the effects on conjunctival congestion score, tear film stability, visual function, efficacy and adverse reactions, and the report details in the following parts.

2. Data and Methods

2.1. General Information

From July 2018 to July 2021, 144 hospitalized patients in all with dry eye disease were chosen as the research targets and consisted of the control group and study group in the light of the sequence of hospitalization, with 72 patients being in each. In the control one, 31 men and 41 women were included aged from 39 to 65 years, with an average year of 45.32 ± 3.18 and a disease course of 4.02 ± 1.53 years. In terms of the severity of the disease, 24 cases were mild, 38 were moderate, and 10 were severe. There were 32 men and 40 women in the study one, aged from 38 to 64 years, with an average year of 45.83 ± 3.20. The process of disease was 4.05 ± 1.51 years. As far as the severity of disease was considered, 25 cases were mild, 40 were moderate, and 7 were severe. Statistically, there were no significant discrepancies in the parts of age, gender, disease process, and other relevant factors among the two categories (P > 0.05), implying similarity. The patients in the control one were given the treatment with eye drops of sodium hyaluronate, while the ones in research group were treated with calf blood-deproteinized eye gel combined treatment on the basis of the control one. This study was in favor of by the medical ethics committee of the hospital.

2.2. Inclusion and Exclusion Criteria

Inclusion criteria: (1) the standards of the disease of dry eye were met in the Third edition of Ophthalmic Disease Diagnosis and Treatment Guide [10]; (2) dry eye disease was diagnosed by pathological biopsy and western blot cytology; (3) tear secretion test < 5 mm, tear film rupture time <10 s, tear lysozyme content <1200 μg/mL, etc.; (4) the clinical manifestations are dry eyes, itching, fatigue, sensitivity to wind, light, and so on; (5) those who have not received other drugs recently or have stopped taking drugs for more than 1 month; and (6) complete clinical data, clear consciousness, complete questionnaire survey. The subjects and their families signed informed consent.

Exclusion criteria: (1) patients having the problem of the functional impairment of heart, liver, lung, and other important organs; (2) patients having chronic diseases such as hypertension, diabetes, and hyperlipidemia; (3) with glaucoma, cataract, conjunctivitis, congenital no tears, and other eye diseases; (4) surgical history of ophthalmic diseases, laser treatment, and myopia correction; (5) with autoimmune diseases, allergic to the study drugs; and (6) poor compliance and withdrawal from the study.

2.3. Research Methods

After admission, patients in both groups filled in basic information and examinations, including age, gender, history of allergy, history of disease, and history of medication, and were given health education, diet control, eye hot compress, and massage. The control group was cured with sodium hyaluronate eye drops (Guangdong Hongying Technology Co., LTD., National drug approval H20183330, specification 5 ml:5 mg (0.1%)), dropped into the conjunctival sac, 1 drop per time, about 5 to 6 times per day, relying on the severity of symptoms. According to the control one, the study group was given combined treatment with calf blood protein removing extract eye gel (Shenyang Xingqi Pharmaceutical Co., Ltd., State Drug Approval H20070295, specification 5G (20%)), dropping on the surface of the eyeball, about 1 to 2 drops per time, 3 to 4 times per day, which could be increased or decreased according to the severity of symptoms. Both groups were treated for 2 weeks.

2.4. Observation Indicators

2.4.1. Conjunctiva Congestion Score

The conjunctiva congestion situation before and after the treatment of 2 weeks and later 1 month was analyzed according to Cornea and Contact Lens Research Unit (CCLRU) grading standard [11], which was divided into 4 grades. Grade 1 (0 points): no conjunctiva congestion. Grade 2 (1 point): mild conjunctiva hyperemia, confined to the fornix, with bright red blood vessels, clearly visible blood vessels. and normal blepharon texture; Grade 3 (2 points): moderate conjunctiva hyperemia, from the hyperemia site to the eyelid fissure, with deep red blood vessels, and unclear vascular sites; Grade 4 (3 points): diffuse hyperemia of the conjunctiva, purplish red hyperemia of the blood vessels, and indistinct texture of the normal meibomian glands.

2.4.2. Determination of Tear Film Stability

Corneal fluorescent staining (FL), tear secretion test, Schirmer I test (SIt), tear film rupture time (BUT), and the height of the central lacrimal river of the lower eyelid were measured before treatment and 1 month after treatment, respectively. FL test was performed by dipping 1.00% of 20 g/L sterile fluorescein into the conjunctival sac of the patient with a sterilized glass stick. The cornea of the patient was divided into four quadrants by irradiating cobalt blue light with a slit lamp. Fluorescein staining was evaluated by 0∼3 points, which consist of no, mild, moderate, and severe staining, and the score in all was 0∼12 points. The score was positively correlated with corneal staining. Sit test operation: filter paper with high absorption capacity (5 mm × 35 mm) was used in patients without anesthesia and without eye examination and medication. One end is folded back and placed in the conjunctiva sac (about 1/3 of the lateral lower eyelid), and the other end is protruded out of the eye to ensure natural droop. The filter paper was taken out after 5 minutes of eye closure, and the total infiltration length of the filter paper was measured. BUT determination: after staining the conjunctival sac with 1.00% sterile fluorescein, eyes were slowly opened after scanning cobalt blue light with a slit lamp. The periods from eye opening to the appearance of the first ruptured spot were recorded, and 3 measurements were taken in a continuous way, and the average value was taken. The height of the central lacrimal river of the lower eyelid was measured by 0∼10 cm ruler under slit lamp irradiation.

2.4.3. Visual Function Measurement

The visual contrast sensitivity of the two categories was evaluated before and after treatment for 1 month. Multifunctional visual sensitivity instrument (Wenzhou Raymond Photoelectric Technology Co., LTD., model RM800) was used to detect the contrast sensitivity. Different sine grating was used to measure the contrast sensitivity beyond 6 m. The duration was 5 min, and the spatial frequency was set to 6.4 C/d and 12 C/d.

2.4.4. Evaluation of Clinical Treatment Effect

The therapeutic effect of dry eye was evaluated according to clinical symptoms, and cured: clinical symptoms and signs disappeared completely, Schirmer range ≥10 mm, FL score (-), BUT≥10 s; the Schirmer range was 5–9 mm, FL score was (-), BUT range was 5–9 s. Effective: slight improvement in clinical symptoms and signs, Schirmer range <5 mm, FL score (+), BUT < 5 s; ineffective: no improvement or deterioration of clinical symptoms, signs, Schirmer, FL, BUT, etc. Total effective rate = cure rate + obvious efficiency + effective rate. (5) Incidence of clinical adverse reactions: the probability of occurrence of adverse events, including blepharitis, pruritus, congestion, and diffuse surface keratitis, was observed and recorded during the period of treatment and 3 months after treatment in both groups.

2.5. Statistical Treatment

The relevant data were processed by SPSS 24.00 statistical software. The evaluations were in the expression of ± S, and t-test was applied for the contrast among the two types of categories. The statistical data were composed of the number of cases (n) and percentage (%), and the contrast between the categories was employed by the χ2 test, and P < 0.05 revealed the manifested discrepancy in terms of statistics.

3. Results

3.1. Comparison of Conjunctival Congestion Scores

The results revealed that no significant difference was available in conjunctiva congestion score between the following type before treatment (P > 0.05). Statistically, after the treatment of 2 weeks and 1 month, the scores of conjunctival congestion in the 2 groups were lower than before (P < 0.05). After treatment, numerical values of conjunctival congestion in the study one were evidently less than the control one (P < 0.05) as shown in Table 1.

Table 1

Comparison of scores of conjunctival congestion .

Time	Control group (n = 72)	Study group (n = 72)
Before the treatment	2.86 ± 0.63	2.85 ± 0.65
After 2 weeks of treatment	2.14 ± 0.49	1.68 ± 0.31∗
After 1 month of treatment	1.52 ± 0.29∗	0.45 ± 0.07∗#

Note. Comparison of data before treatment and of control group, #P < 0.05.

3.2. Comparison of Tear Film Stability

The results suggested that there was no statistically obvious discrepancy in tear film stability between the 2 categories before treatment (P > 0.05). After treatment, FL was lower than data before treatment, and SIt, BUT, and the heights of the central lacrimal river of the lower eyelid were higher, and the distinct discrepancy was not present (P < 0.05). After treatment, FL in the study group significantly presented a decline when compared with control one, while SIt, BUT, and the height of the central lacrimal river of the lower eyelid had a better situation when compared with the control group (P < 0.05) as shown in Table 2 and Figure 1.

Table 2

Comparison of tear film stability (x ± s).

Group	Time	Control group (n = 72)	Study group (n = 72)
FL (points)	Before the treatment	7.05 ± 1.48	7.06 ± 1.47
	After the treatment	2.97 ± 0.96	1.45 ± 0.45∗#
Sit (mm/5 min)	Before the treatment	3.73 ± 1.27	3.73 ± 1.25
	After the treatment	5.95 ± 1.42	8.68 ± 1.50∗#
BUT (s)	Before the treatment	4.80 ± 0.84	4.81 ± 0.83
	After the treatment	6.91 ± 0.97∗	8.24 ± 1.15∗#
Lower eyelid central lacrimal river height (mm)	Before the treatment	0.28 ± 0.07	0.27 ± 0.09
	After the treatment	0.32 ± 0.11∗	0.43 ± 0.13∗#

Note. Comparison of the data before treatment and of the control group, #P < 0.05.

Figure 1

Comparison of tear film stability. (a) FL; (b) Sit; (c) BUT; (d) central tear river height of lower eyelid, compared with before treatment and control group, #P < 0.05.

3.3. Comparison of Visual Functions

The results implied that significant difference was not present in visual function level between the 2 types before treatment (P > 0.05). After therapy, the visual contrast sensitivity at 6.4 c/d and 12c/d in 2 groups increased in comparison with the period before treatment with no significance in statistics (P < 0.05). The visual contrast sensitivity of the study group at 6.4 c/d and 12c/d had an increasing situation compared with the control one, and from the perspective of the statistics, the discrepancies were not distinct (P < 0.05), which was shown in Table 3 and Figure 2.

Table 3

Comparison of visual function .

Group	Time	Control group (n = 72)	Study group (n = 72)
Visual contrast sensitivity (6.4 c/d)	Before the treatment	46.95±10.25	46.93±10.37
	After the treatment	53.68±11.98∗	60.87±14.64∗#
Visual contrast sensitivity (12c/d)	Before the treatment	29.14±8.67	29.15±8.65
	After the treatment	37.50±9.31∗	43.26±10.19∗#

Note. Comparison of data before treatment and of the control group, #P < 0.05.

Figure 2

Visual function comparison. (a) Visual contrast sensitivity (6.4 c/d); (b) visual contrast sensitivity (12c/d), compared with before treatment and control group, #P < 0.05.

3.4. Comparison of Therapeutic Effects

As the results showed, the effective rate of 97.22% in the study group had a high situation contrast with the control one, which was 88.89, in terms of the statistics, (P < 0.05), which was shown in Table 4.

Table 4

Comparison of therapeutic effects (cases, %).

Group	Control group (n = 72)	Study group (n = 72)	x 2	P
Cured	29 (40.28)	41 (56.94)
Efficient	22 (30.55)	23 (31.94)
Effective	13 (18.06)	6 (8.33)
Invalid	8 (11.11)	2 (2.78)
Therapeutic
Response rate	88.89%	97.22%	3.004	0.025

3.5. Comparison of Incidence of Adverse Reactions

The information manifested that after the stage of treatment, the possibility of occurrence of negative events in the study group (4.17%) had a vivid decline compared with the control one (15.28%), with statistical significance in difference (P < 0.05), which was shown in Table 5.

Table 5

Comparison of incidence of adverse events (cases, %).

Group	Control group(n = 72)	Study group (n = 72)	x 2	P
Blepharitis	5 (6.94)	1 (1.39)
Blepharodermatitis	2 (2.78)	0 (0.00)
Itching	1 (1.39)	1 (1.39)
Congestion	1 (1.39)	0 (0.00)
Diffuse superficialKeratitis	2 (2.78)	1 (1.39)
Incidence adverse events	15.28%	4.17%	6.240	0.001

4. Discussion

As an important part of the eye, the corneal conjunctiva controls eye wettability and maintains normal vision by regulating tear secretion and evaporation [12, 13]. The incidence of dry eye disease in China accounts for 2.7% of the total population, and about 30 million people suffer from dry eye disease of varying degrees.

Ninety percent of people who spend more than three hours a day in front of a computer have dry eyes. Due to the lack of eye cognition and nursing knowledge, the incidence rate is increasing year by year, significantly threatening patients' vision and quality of life [14]. Therefore, the adoption of active and effective drug treatment is a widespread concern. Sodium hyaluronate eye drops as a first-line medicine for the treatment of dry eye can effectively relieve visual fatigue. However, most clinical emphasis is laid on the treatment effect of the two, and the influence of the combined treatment on conjunctival congestion score and on the stability of the tear film of patients having dry eye is limited [15, 16]. The treatment of calf blood-deproteinized eye gel combined with sodium hyaluronate eye drops is beneficial to relieve symptoms of conjunctival congestion, improve the sense of dryness and discomfort, and improve the therapeutic effect.

Dry eye patients due to low lipid secretion, resulting in reduced tear film stability. In addition, lipid deposition can induce bacterial breeding, enhance the stability of tear film destruction but also cause conjunctiva damage. At the same time, it induces histopathological changes around the eyeball, resulting in conjunctival congestion, dry eye pain, etc. Clinical symptoms, FL, SIt, BUT, and the height of the central lacrimal river of the lower eyelid can be measured to accurately evaluate the severity and therapeutic effect of dry eye [17]. Yang et al. [18] treated patients having dry eye disease with sodium hyaluronate eye drops combined with pranoprofen, which can effectively improve tear secretion, maintain eyeball moisture, and promote tear film stability. Wu et al. [19] used sodium hyaluronate eye drops and calf blood proteinless extract eye gel to treat patients with dry eye, which can effectively reduce SIt and BUT levels, improve FL score, and relieve eye pain and light sensitivity. The results showed that after the process of cure of 2 weeks and 1 month, the numerical values of conjunctival congestion in the two categories had a decline compared with data before treatment; and the one in the study group presented a decline. After therapy, FL in 2 groups decreased, while SIt, BUT, and the height of the central lacrimal river of the lower eyelid came into increase. In the study group, the number of FL was significantly below than that in the control one, while SIt, BUT, and the height of the central lacrimal river of the lower eyelid had a significantly better situation in contrast with the control one, which had a basic agreement with the results of Yang and Wu. This indicates that sodium hyaluronate eye drops combined with calf blood-deproteinized extract eye gel can effectively protect tear film and improve conjunctival congestion and other symptoms. Sodium hyaluronate eye fluid as artificial tear lubrication conjunctiva, tear film, etc. can repair the function of the tissue around the eye and maintain the stability of the environment around the eye; calf blood-deproteinized extract eye gel contains a variety of free amino acids and can maintain the normal function of eye cell tissue, repair damaged corneal tissue and cells, and enhance the relief of conjunctival congestion. In addition, as a gel preparation, it can also maintain the sense of eye moisture, relieve the friction of the eyelid on the eye tissue, and then improve the eye comfort and the stability of tear film.

Visual contrast sensitivity reflects the improvement of eye function by comparing the discrimination ability of the visual system to the grating under different spatial frequencies [20]. Chen et al. [21] applied sodium hyaluronate eye drops of different concentrations to patients with dry eye cataracts. Among them, the percentage of the sodium hyaluronate eye drops being 0.1, and this could effectively maintain the regularity and function of the corneal surface, increase the tear film stability, and improve the effect significantly. Nam et al. [22] treated corneal epithelial cells with deproteinized extract of calf blood, which can promote the secretion of mucin and increase the protective function of the human eye surface. The results showed that the visual contrast sensitivity at 6.4 c/d and 12c/d in both categories increased after treatment when compared with the process before treatment. The visual contrast sensitivity of the study group at 6.4 c/d and 12c/d was, to some extent, obviously higher. The effective rate of the study group manifested a significant below situation. Compared with the control one, the possibility of occurrence of negative events in the study group was significant in a lower situation. This is similar to the data of Chen and Nam, suggesting that the therapy of patients having dry eye disease with sodium hyaluronate eye drops combined with calf blood proteolytic extract ocular gel can improve the function and structure of the eye and improve the clinical efficacy.

Sodium hyaluronate eye fluid is mainly a linear polysaccharide. Through the interaction of sodium hyaluronate and fibrin, it enhances the tissue repair ability of epithelial cells and then ensures the reasonable secretion and volatilization of tear film water. At the same time, sodium hyaluronate can effectively have a promotion in the connection and extension of corneal tissue, promote the healing of injured cornea, and maintain the structure and function of the tear film; calf blood-deproteinized eye gel contains more organic components and peptides, which can participate in the oxidation of cells and tissues, energy circulation, and so on and enhance the nutrition and growth of eye tissues. It can repair corneal epithelial tissues and fibers, increase the secretion of mucin, maintain the stability of tear film, and increase eye comfort. The combined application of the two can significantly maintain the tear film and ocular structure and improve ocular visual symptoms [23].

The limitation of this study is that the sample size is limited, and there may be some difference between clinical results and actual data. In addition, the follow-up period of this project was short, and the long-term effects, drug resistance, and prognosis were not further explored. Therefore, it is necessary to have a further study to expand the score of samples and to make full use of the subsequent time to explore the general adaptability and long-term safety.

In conclusion, for patients having dry eye disease, sodium hyaluronate eye drops combined with calf blood-deproteinizing extract eye gel treatment can significantly improve the symptoms of ocular discomfort and conjunctival congestion and maintain the structural and functional stability of tear film. At the same time, it can also protect the normal tissues of the eyes and improve the comfort of the eyes, which is worth promoting.