The Effectiveness of a Balanced Salt Solution on Dry Eyes in Comatose Patients: A Randomized Trial

Objective: Dry eye is one of the complications of hospitalization in ICUs. This study was conducted to assess the effectiveness of a Balanced Salt Solution (BSS) on dry eyes in comatose patients. This clinical trial was conducted in 2019 on 34 patients admitted to the ICUs. The control group received sterile eye ointment with articial tears (2 drops every 6 hours) and a tape over the eye. The trial group also received BSS (2 drops every 6 hours) in the opposite eye over ve days. The patients' dry eye was examined on rst day and sixth day of the study using Schirmer’s Test (ST) and the Tear Breakup Time Test (TBUT). The data were analyzed in SPSS-21. Results: The results of the paired T-test based on ST and TBUT showed no signicant change from rst day one to sixth day in the BSS-receiving group (P>0.999 and P=0.187, respectively). Furthermore, no signicant difference was observed between the two groups in the mean score of dry eye after eliminating the effect of the demographic and clinical variables (P=0.947). The administration of this solution by nurses seems to be an effective method for preventing the progression of dry eye in ICU patients.


Introduction
Intensive Care Units (ICUs) provide the most critically-ill patients with care and treatment using advanced equipment [1]. The Patients admitted to ICUs are exposed to a condition called the dry eye [2,3]. Mercieca et al. found that 75% of patients in ICUs develop lagophthalmos and are exposed to dryness of the cornea [4]. The results of a study conducted by Masoudi-Alavi et al. on patients admitted to ICUs in Kashan showed that 33.2% of these patients suffered from dry eye on their fth day of admission [5]. The method currently used in Iran for patients with closed eyes is to wash the hands before applying eye care and using arti cial tear drops [6]. Many studies have shown that arti cial tear improves visual acuity [7,8] and contrast sensitivity [7] in patients with dry eyes. One of the rinsing solutions used is the Balanced Salt Solution (BSS), which is a sterile isotonic physiological solution containing the electrolytes needed for the cells' normal metabolic activities. The results of a study on patients who had underwent phacoemulsi cation showed that BSS has more advantages than Ringer's lactate solution, such as corneal thickness and spark in the BSS group [9]. Thus, given the high prevalence of dry eyes in ICU patients and the importance of maintaining corneal health in the ICU and the lack of studies on the effectiveness of other eye care methods, including the use of BSS, the present study was conducted to assess the effectiveness of BSS on dry eyes in comatose patients.

Methods
This study adheres to CONSORT guidelines. The present triple-blind, controlled, clinical trial was conducted on 34 patients gradually admitted to the ICU, from 2019 to 2020. The study inclusion criteria were: Hospitalization in the ICU, mechanical ventilation support in the rst 24 hours of admission, the consent of the patient's legal guardian to take part in the study, age 18-75 years, no known history of eye disease, liver disease, and eye surgery in the last six months, GCS score ≤ 8. The study exclusion criteria were: Less than ve days of hospitalization, GCS exceeding 8 in the rst three days of hospitalization, spontaneous blinking due to changes in the consciousness level, getting extubated, and the lack of consent on the part of the patient's legal guardian to continue the treatment. Based on β = 0.2, α = 0.05, S1 = 1.5, S2 = 1.5 and the below equation, the sample size was determined as 36.
Ongoing sampling was carried out and each eye was then assigned to one of the treatment protocols by the toss of a coin (simple random allocation) perfarmed by nurses.

Study condition
The patients who met the inclusion criteria entered the study based on the ophthalmologist's opinion and after obtaining written consent from their legal guardian.
Before beginning the intervention, the researcher and ophthalmologist trained the collaborating nurses on how to provide eye care in a uniform manner, and their performance was tested on the patients to ensure consistency. After receiving this practical training on how to provide eye care consistently, these ICU nurses were assigned the duty of providing eye care to the patients as per the given protocols. The eligible patients were then selected for the study. At the outset, ST (to assess their dry eye) and TBUT were carried out by the optometrist. Schirmer Tear Test Strips (made by ERC in Turkey) were used for the ST. Then, each eye was administered one of the eye solutions (either BSS or arti cial tear drops) for ve days. The eye care protocol in the control group included using two drops of arti cial tears every six hours alongside sterile Vitamin A eye ointment applied at the same intervals and the eyes were then covered with tape. In addition to the routine care protocol, the trial group also received BSS (2 drops every 6 hours) for the opposite eye. This solution was prepared and encoded by the Drug Company in the same form as the arti cial tear drops. On sixth day, TBUT and ST were performed for both eyes. The required information was collected and entered into the demographic and medical history form by the nurses who had received the initial training. The nurses, the optometrist, and the statistician had no knowledge of the type of eye care solution used until the data analysis was over.

Measurement of the outcomes
In the present study, no complication was observed after using arti cial tears and the BSS. The main outcome of this study was changes in dry eyes, which were assessed through the ST and TBUT on sixth day of the intervention, as follows: In ST, the eye was carefully dried, and then Whatman lter paper strips were bent by 5 mm from one end and placed in the lateral third of the lower fornix, and after 5 minutes, the length of strip wetted by tears was read in millimeters. A wetted area of 15 mm or more was considered normal and less than 15 mm abnormal (1-5 severe, 5-10 moderate, and 10-15) [5]. To measure TBUT, a drop of sodium uorescein was rst poured onto the lower part of the bulbar conjunctiva, and the patient's eyes were opened and closed several times by the examiner so as to spread uorescein thoroughly in the eye and cover the cornea. Then, a broad ray of blue light was emitted from the ophthalmoscope, and the tear lm was assessed without the patient blinking. Black spots or lines indicated dry areas. The time of appearance of the rst dry spots was measured in seconds.

Statistical analysis
Mean and standard deviation were used to analyze the study data for quantitative variables. Paired t-test was used for in-group comparison in each group and for comparing the mean changes of dry eye between the two groups, a marginal model with GEE estimation method was used through SPSS21 statistical software. A value of P < 0.05 was considered statistically signi cant.

Participant characteristics
Thirty-four subjects entered the stage of nal analysis (A owchart of the participants can be found in Additional le 1). The majority of the participating patients were male (67.65%), had multiple traumas (29.41%), and were under Assisted mode ventilation (79.41%). Table 1 presents the other clinical details of the patients. The results of the paired t-test based on ST and TBUT showed no signi cant change from rst day to sixth day in the BSS group (P > 0.999 and P = 0.187, respectively). The results of the paired t-test based on ST and TBUT also showed no signi cant change from rst day to sixth day in the arti cial tear group (P = 0.818 and P = 0.535, respectively). Moreover, no signi cant difference was observed between the two groups in terms of the mean dry eye score after eliminating the effect of the demographic and clinical variables (P = 0.947; Tables 2 and 3).

Discussion And Conclusion
The results showed no signi cant differences between the arti cial tear and BSS groups in terms of the mean scores of ST and TBUT after eliminating the effect of the demographic and clinical variables. The researchers' review of literature showed no studies comparing the effects of BSS and arti cial tear drops on dry eyes in comatose patients admitted to ICUs. Vasavada et al. (2009) showed that using BSS had more advantages than Ringer's lactate in terms of corneal thickness and post-operative in ammation in the rst day after operation [9]. In agreement with these ndings, in another study on intraocular and extraocular tissues, conjunctival and iris tissue samples from patients undergoing cataract surgery and samples from laboratory rabbits, Merrill et al. (1960) found that using BSS for both human and laboratory samples causes no damage to the intraocular tissues compared to sodium chloride [11]. In a clinical trial on patients with dry eyes, Qui et al. (2012) found that the patients' symptoms were relieved after using each of the two care protocols (using punctual plugs vs. arti cial tears) and no signi cant difference was observed between the two groups. In ST, no signi cant change was observed in the arti cial tear group, but the punctual plug group showed signi cant changes [12]. It can be inferred from the results of the cited studies that other treatment methods are preferable over arti cial tears in preventing dry eyes in patients admitted to ICUs. On the one hand, arti cial tears normally contain chemical preservatives for preventing bacterial infections and buffers (such as bicarbonate and phosphate) for maintaining the pH within the normal range (7.4) [13]. On the other hand, the frequent use of eye drops containing preservatives, especially benzalkonium chloride (such as gel tears), is associated with ocular allergies and toxicity [14]. Therefore, BSS can be used as an alternative to arti cial tears in patients with dry eyes or those exposed to its risk.
The results of the paired t-test based on ST and TBUT showed no signi cant differences between rst days and sixth day in the BSS and arti cial tear groups; however, ve days after admission, the severity of dry eyes did not worsen compared to rst day of admission and it remained within the moderate range.
BSS contains electrolytes needed for the long-term maintenance of endothelial cells, including Sodium Chloride, Potassium Chloride, Calcium Chloride Dihydrate, Magnesium Chloride Hexahydrate, Sodium Acetate Trihydrate, Sodium Citrate Dihydrate, and Sodium Hydroxide [9,15]. BSS also appears to act as a nutritional supplement. Compared to other solutions, BSS has isotonic osmolality and is neutral (Osm = 302 mMol, pH = 7.4), which is similar to the osmolality of the eye (Osm = 302 mMol, pH = 7.4). Moreover, BSS contains a citrate acetate and magnesium buffer system that is essential for Mg-ATPase endothelial pump [9].
As a result, despite the high effectiveness of the noted treatment options, since one of the items determining the ease of use of a drug is its cost-effectiveness, BSS appears to be superior. The results of many studies have shown that using arti cial tear improves visual acuity [7,8], and wavefront aberrations [16] in patients with dry eyes. Wei et al. (2020) found that the standard deviation of the objective scatter index (SD-OSI) and the objective scatter index decreased signi cantly ve minutes after the administration of arti cial tears in the intervention group of patients with severe dry eyes, while a signi cant increase was observed in the control group. Nonetheless, 30 minutes after the intervention, no signi cant difference was observed between two groups in the visual quality parameters. Overall, arti cial tears were found to have different effects on the visual quality of patients with dry eyes depending on the severity of their condition [17]. In another systematic study, Ribeiro et al. (2019) found that arti cial tears are more effective than ocular lubricants [18]. However, Ishioka et al. (2009) found no signi cant change in visual acuity in patients with mild dry eyes ve minutes after the administration of different concentrations of arti cial tears [19].
Based on our ndings, BSS can prevent the progression of dry eyes as well as arti cial tears. Thus, given the high prevalence of dry eyes among ICU patients and considering the lower costs and good effectiveness of the BSS and its simple formulation, which enables its easier manufacturing, and also the fairly high costs of arti cial tear drops, BSS is recommended to be administered by nurses as a useful and effective method for preventing dry eyes in ICU patients.

Limitations
Given the small sample size of this study and the impossibility of assessing the effects of each of these methods on different severities of dry eyes, further studies with larger sample sizes and on patients with different degrees of dry eyes are required to ensure the generalizability of these ndings.
The present study was conducted in accordance with the Helsinki Declaration guidelines. Approval was obtained from the ethics committee of Lorestan University of Medical Sciences (Code: IR.LUMS.REC.1398.025) and the study was registered at the Iranian Registry of Clinical Trials (Code: IRCT20200113046121N1). Informed written consent was obtained from the guardians of all the patients before beginning sampling.

Consent to publish
Not applicable.