Efficacy of tetracaine eye drops in strabismus surgery: a systematic review and meta-analysis of randomized controlled trials

ABSTRACT Aim To comprehensively evaluate the efficacy and safety profile of tetracaine eye drops as a local anesthetic agent among pediatric patients undergoing for strabismus surgery. Methods We systemically searched four electronic databases (PubMed, Scopus, Web of Science, and Cochrane Library) from inception until April 2023. We included randomized controlled trials (RCTs) comparing tetracaine and placebo or no intervention for intraoperative and postoperative outcomes in strabismus surgery patients. We used the Cochrane risk of bias-2 tool for the risk of bias assessment. Continuous variables were pooled as mean difference (MD) or standardized mean difference (SMD), and categorical variables were pooled as risk ratio (RR) with a 95% confidence interval (CI). Results Six RCTs were included in the meta-analysis, with a total of 326 patients. There was no significant difference between the tetracaine and the control groups regarding the mean operative time (MD = −0.10 minutes, 95% CI [−3.79, 3.59], p = .96), the mean time to first analgesia (MD = −0.87 minutes, 95% CI [−11.15, 9.40], P = .87), the mean behavior score (SMD = −S0.48, 95% CI [−1.24, 0.28], p = .22), the rate of postoperative vomiting (RR = 1.27, 95% CI [0.62, 2.61], p = .52), or the number of additional analgesia (RR = 0.55, 95% CI [0.27, 1.13], p = .10). Conclusion Our systematic review and meta-analysis found no significant differences in the safety and efficacy of tetracaine eye drops for strabismus surgery when compared to placebo or no intervention. Further investigation is needed to establish the best local anesthetic for strabismus surgery.


Introduction
Strabismus is a disorder in which the eyes are misaligned and do not point in the same direction. 1f left untreated, this can lead to difficulties with depth perception, eye strain, and possibly vision loss. 2 Strabismus can result from several factors, including genetics, trauma, or neurological diseases. 3Strabismus surgery is a common therapeutic option for patients suffering from moderate to severe strabismus. 4The operation is intended to correct eye misalignment by modifying the position of the eye muscles. 4While strabismus surgery is typically regarded as safe and successful, 5 it can be accompanied by pain, discomfort, and other consequences. 6,7One of the difficulties of this surgery is dealing with pain and discomfort both during and after the procedure. 8 topical anesthetic is routinely utilized to anesthetize the eye and surrounding tissues, while additional drugs are used to control pain and reduce inflammation. 9However, the best anesthesia strategy for strabismus surgery is still being debated, and there is minimal evidence on the efficacy and safety of various anesthetic regimens. 8,9etracaine is a topical anesthetic drug used in ophthalmology to anesthetize the eye and surrounding areas during operations such as strabismus surgery. 9Tetracaine is an ester-type local anesthetic that blocks nerve impulse transmission in the area where it is applied. 10,11Tetracaine eye drops are often used for strabismus surgery and other ocular treatments because they are simple to administer and give anesthetic quickly. 8,12While tetracaine generally appears to be safe and well-tolerated, it can induce stinging, burning, or itching at the site of administration. 13,14Tetracaine can induce serious allergic reactions or systemic toxicity in rare cases, particularly when large doses are taken when the medicine is accidentally injected into the eye. 14he efficiency and safety of tetracaine eye drops for strabismus surgery, however, have not been thoroughly demonstrated.Therefore, this systematic review and meta-analysis aimed to evaluate the safety and efficacy of tetracaine eye drops as an anesthetic agent for strabismus surgery.

Methods
We followed the PRISMA statement guidelines when reporting this systematic review and metaanalysis. 15All steps were done in strict accordance with the Cochrane Handbook of Systematic Reviews and Meta-analysis of Interventions. 16To avoid reporting bias, this meta-analysis was registered in PROSPERO database [ID: CRD42023415611].

Eligibility criteria
Studies were included in our review if they satisfied the following criteria: Population: studies on patients who have undergone strabismus surgery.Intervention: studies where the experimental group received tetracaine eye drops treatment.Comparator: studies where the control group received a placebo or nothing.Outcome: studies reporting at least one of the following outcomes: the mean operative time, the mean time to first analgesia, the mean behavior score, postoperative vomiting, and the number of additional analgesia.Study design: We included only randomized controlled trials (RCTs).We considered both blind and open-label studies.We excluded studies whose data were unreliable for extraction and analysis, clinical trials with historical control groups, observational studies, case reports, case series, studies reported as abstracts only or thesis, and studies whose complete full-texts were not available.

Information sources and search strategy
We performed a comprehensive search of four electronic databases (PubMed, Scopus, Web of Science, and Cochrane Library) from inception until April 2023 using the following query: (strabismus OR "strabismus surgery" OR squint OR exotropia OR esotropia OR hypertropia OR hypotropia OR Phoria OR Hypertropia OR Heterotropia OR Heterophoria OR convergent OR divergent OR "eye deviation") AND (tetracaine OR amethocaine OR dicaine OR ametop OR pentocaine OR pantocaine)."Further, the references of the included studies were manually searched for any potentially eligible studies.The detailed search strategy for each database is presented in Table S1.

Selection process
Duplicates were removed using Endnote (Clarivate Analytics, PA, USA), and the retrieved references were screened in two steps: the first step was to screen titles/abstracts of all identified articles independently by all authors to assess relevance to this meta-analysis, and the second step was to screen the full-text articles of the identified abstracts for final eligibility to meta-analysis.

Data collection process and data items
Data was extracted onto a standardized data extraction sheet.The extracted information encompassed the following: (1) Characteristics of the studies encompassing study ID, design, country, total sample size, trial arms, American Society of Anesthesiology (ASA) physical status class, patient age group, and time of administration; (2) Population characteristics from the included studies such as age, sex, weight, laterality, and type of anesthesia; (3) Evaluation of bias risk domains; and (4) Outcome measures, including the mean operative time, mean time to first analgesia, mean behavior score, postoperative vomiting, and the count of additional analgesia.For the assessment of behavior scores, various tools were employed.The Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) was used in two RCTs, 17,18 the Modified Behavioral Pain Scale (MBPS) in another RCT, 19 and a four-point scale [1, sleeping; 2, awake and quiet; 3, agitated; 4, crying] in one RCT.It's important to note that all these tools have established validity and reliability.

Assessing the risk of bias
Utilizing the Cochrane tool for the assessment of the Risk of Bias-2 (RoB2), two independent reviewers will evaluate the quality of the studies included. 20The evaluation of risk of bias will encompass the subsequent domains: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in the measurement of the outcome, bias in the selection of the reported result, and other potential biases.The judgments of the authors will be classified as "low risk," "high risk," or "some concerns" regarding bias.Any discrepancies were resolved through discussion until a consensus is achieved.In cases where agreement cannot be reached among the authors, a senior author will be consulted.

Synthesis methods
The analysis was done using Review Manager Software (RevMan 5.4.1)under the inverse variance method.The continuous outcomes were pooled as mean difference (MD) or standardized mean difference (SMD), and the categorical outcomes were pooled as risk ratio (RR) in a random effect model with a relative 95% CI. p-value <.05 was considered statistically significant.
We calculated the pooled effect size for all outcomes according to the DerSimonian Liard metaanalysis model.This random effect model assumes the included studies represent a random sample from the population and assigns a slightly higher weight to small studies on the expenses of larger studies.We chose this model because, unlike the fixed-effects model, it accommodates a larger standard error in the pooled estimate, which makes it suitable in case of inconsistent or controversial estimates.Thus, the calculated effects in our metaanalysis are conservative estimates that take into consideration the possible inconsistencies.
Statistical heterogeneity among studies was evaluated by the Chi-square test (Cochrane Q test).Then, the chi-square statistic, Cochrane Q, was used to calculate the I-squared according to the equation: A chi-square p value less than .1 was considered significant heterogeneity.I-square values ≥ 50% were indicative of high heterogeneity.
In the present study, we could not assess the existence of publication bias by Egger's test for funnel plot asymmetry, as according to Egger and colleagues, 21 publication bias assessment is unreliable for less than 10 pooled studies.To test the robustness of the evidence, we conducted a certainty assessment through sensitivity analysis (also called a leave-one-out meta-analysis).For every outcome in the meta-analysis, we ran sensitivity analysis in multiple scenarios, excluding one study in each scenario to make sure the overall effect size was not dependent on any single study.

Literature search results
Our literature search process retrieved 114 records.Following the title and abstract screening, nine articles were eligible for full-text screening.Of them, six studies [17][18][19][22][23][24] were included in the meta-analysis. The reerences of the included studies were manually searched, and no further articles were included.The PRISMA flow diagram of the study selection process is shown in Figure 1.

Characteristics of the included studies
Six studies [17][18][19][22][23][24] were included in the metaanalysis, with a total of 326 patients who underwent strabismus surgery. In fie studies, patients were assigned to receive either tetracaine eye drops or a placebo, and in one study, patients were assigned to receive tetracaine eye drops or nothing.All the included RCTs incorporated the use of tetracaine drops in conjunction with general anesthesia.In general, the types of drops followed the induction of anesthesia.However, the eye drops were administered at different points in time among the included RCTs.While some RCTs applied the drops just before the surgery, others did so at the end of surgery.A summary and baseline characteristics of the included studies are provided in Tables 1 and 2. Regarding the risk of bias, according to Cochrane ROB-2, three studies 19,23,24 had a low risk of bias, two studies 17,22 had some concerns risk of bias, and one study 18 had a high risk of bias, Figure 2.

The mean operative time
The overall MD between the tetracaine and control groups did not favor either of the two groups   regarding the mean operative time (MD =-0.10 minutes, 95% CI [−3.79, 3.59], p = .96),and the pooled studies were homogeneous (p = .47;I 2 = 0%) (Figure 3a).

The mean time to the first analgesia
The overall MD between the tetracaine and control groups did not favor either of the two groups regarding the mean time to first analgesia (MD =  −0.87minutes, 95% CI [−11.15,9.40], p = .87),and the pooled studies were homogeneous (p = .33;I 2 = 0%) (Figure 3b).

Significance of the study
To the best of our knowledge, this is the first systematic review and meta-analysis evaluating the safety and efficacy of tetracaine eye drops as an anesthetic agent for strabismus surgery.This study helps in building the current evidence about the exact effectiveness of anesthetic agents on intraand postoperative outcomes of ophthalmological procedures.

Summary of findings
The current meta-analysis includes six studies with a total of 326 strabismus surgery participants.Our meta-analysis found no statistically significant difference between the tetracaine and control groups in mean operative time, mean time to first analgesia, mean behavior score, postoperative vomiting, or the number of additional analgesics.

Explanation of the finding
Based on the results of this meta-analysis, it seems that tetracaine eye drops do not provide significant benefits for several outcomes related to strabismus surgery.There are multiple factors that may account for tetracaine lack of efficacy.First, the small number of included studies with a limited sample size may not be sufficient to show a significant difference between the two groups.
Second, the variability between the included studies regarding the dose of tetracaine and the number of drops as two studies 19,24 used tetracaine 1% and four 17,18,22,23 used 0.5%.When we evaluated each study's results individually, we saw that Anninger et al. 19 and Watson 24 used tetracaine 1% and found a significant difference favoring the tetracaine group over the control group in terms of the postoperative analgesia and the need for additional analgesics.Controversially, the other studies that used tetracaine 0.5% 17,18,22,23 found no significant difference.So, the dose of tetracaine may be a key factor for its efficacy and needs further investigation.In addition, the patients' mean age was less than six years in all studies except one, 23 which was 17.2 years.
Regarding postoperative behavioral changes, several variables have been identified as potential causes of elevated levels of postoperative agitation.Child age, past operations, use of inhaled anesthetics such as isoflurane or sevoflurane, and prior eye or ENT procedures, among other things, might all contribute to postoperative agitation. 25,26reoperative fear promotes the development of emerging delirium, increased postoperative anxiety, and postoperative sleep issues. 25,279][30] As these study findings consist with our results.
A double-blind randomized trial was conducted to evaluate the efficacy of lidocaine gel versus tetracaine drops in one-stage adjustable suture strabismus surgery. 31The study revealed that lidocaine proved to be more effective than tetracaine in terms of pain control.Additionally, Habib et al. 32 performed a randomized trial that compared the efficacy of subconjunctival bupivacaine with topical tetracaine to reduce pain after strabismus surgery.Their findings indicated that both subconjunctival bupivacaine or topical tetracaine could be used routinely in strabismus surgery, although topical amethocaine is easier to administer.

Implications of these findings in practice
The findings of this meta-analysis have important implications for clinical practice as there is a trend to use anesthetic agents during strabismus surgery. 12,33Firstly, tetracaine may not be the best local anesthetic for strabismus surgery.Secondly, our findings emphasize the significance of tailoring the right local anesthetic for strabismus surgery to the individual patient and surgical circumstances.When choosing a local anesthetic, surgeons should consider the length of the surgery, the patient's medical history, and personal choice.While tetracaine may not be appropriate for strabismus surgery, it may be useful in other ocular operations or conditions requiring a short-duration anesthetic effect.

Strength points and limitations
Our study is the first systematic review and meta-analysis investigating the safety and efficacy of tetracaine eye drops as an anesthetic agent for strabismus surgery.One of the strengths of this meta-analysis is the comprehensive search strategy and the inclusion of high-quality studies.Additionally, a sensitivity analysis was conducted to assess the robustness of the findings.However, some limitations should be considered, including the small number of studies included in the metaanalysis and the heterogeneity in the mean behavior score across studies.Furthermore, some important outcomes like time to first analgesia and additional analgesia were not defined properly by the included studies, which may affect the strengths of the reported outcomes.

Recommendations for future research and clinical practice
Future research should consider conducting largescale randomized controlled trials to evaluate the safety and efficacy of tetracaine eye drops as an anesthetic agent for strabismus surgery.Additionally, studies should investigate the optimal concentration and dosage of tetracaine eye drops for achieving adequate anesthesia.For clinical practice, we do not recommend the use of tetracaine eye drops as an anesthetic agent for strabismus surgery except after developing further research to prove its efficacy.

Conclusion
Our systematic review and meta-analysis found no significant differences in the safety and efficacy of tetracaine eye drops for strabismus surgery when compared to placebo or no intervention.Tetracaine eye drops had no effect on the mean operative time, time to first analgesia, behavior score, postoperative vomiting, or the number of additional analgesics needed.According to our findings, tetracaine usage in strabismus surgery may not provide any further advantage.Further investigation is needed to establish the best local anesthetic for strabismus surgery, taking patient safety and comfort into mind, as well as the surgeon's technical requirements.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
The author(s) reported there is no funding associated with the work featured in this article.

Figure 1 .
Figure 1.PRISMA flow graph for the systematic search and record selection.

Figure 2 .
Figure 2. Risk of bias graph and summary.

Figure 3 .
Figure 3. Meta-analysis of [a] the mean operative time (min), and [b] the mean time to first analgesia (min).

Figure 4 .
Figure 4. Meta-analysis of [a] the mean behavior score, and [b] the mean behavior score after sensitivity analysis.

Figure 5 .
Figure 5. Meta-analysis of [a] the rate of postoperative vomiting, [b] the number of additional analgesia, and [C] the number of additional analgesia after sensitivity analysis.

Table 1 .
Summary of the included trials.

Table 2 .
Baseline characteristics of the included patients.