Association of age and spherical equivalent with differences in cycloplegic refractive effects between cyclopentolate and atropine

Association of age and spherical equivalent with differences in cycloplegic refractive effects between cyclopentolate and atropine | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Association of age and spherical equivalent with differences in cycloplegic refractive effects between cyclopentolate and atropine Toru Kawanobe, Toshiaki Goseki, Shinya Takahashi, Shingo Noda, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7997186/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: Amblyopia and strabismus are common visual impairments linked to functional and social consequences in children. In this retrospective observational study, we aimed to compare the cycloplegic effects of two cycloplegic eye drops, cyclopentolate hydrochloride (cyclopentolate) and atropine sulfate (atropine), and examine whether age and initial spherical equivalent values influence these effects. Methods: We used the data from patients treated at the Kozawa Eye Hospital and Diabetes Center between 2001 and 2021, excluding cases not initially treated with cyclopentolate or those with an interval of over a month between administrations. The main outcome was the difference in refractive values between cyclopentolate and atropine. Refractive measurements were obtained using an autorefractometer and a handheld refractometer. Statistical analyses included Wilcoxon signed-rank tests and multivariate regression, adjusting for potential confounders such as age and initial spherical values. Results: This study included 188 eyes of 94 patients. Statistical analysis showed a significant difference in the refractive values between cyclopentolate and atropine, with atropine demonstrating a stronger cycloplegic effect. Age at the time of initial examination was markedly linked to the difference in the refractive values between the two agents. In particular, with each additional year of age, the difference in refractive values decreased by 0.04 D. Conclusion: Atropine revealed a consistently stronger refractive effect than cyclopentolate in the pediatric population, and age substantially influenced the cycloplegic effect. These results highlight the requirement for age-specific considerations when selecting cycloplegic agents for pediatric patients, thereby facilitating a more tailored approach to manage refractive errors in children. Clinical trial number : not applicable Amblyopia Strabismus Cyclopentolate hydrochloride Atropine sulfate Refractive value Figures Figure 1 Key Messages Cyclopentolate hydrochloride and atropine sulfate are both used as cycloplegic eye drops in pediatric ophthalmology for accurate diagnosis and treatment of conditions such as amblyopia and strabismus. Atropine has been shown to have a stronger cycloplegic effect compared to cyclopentolate. This study reveals a significant association between age and the difference in refractive values between cyclopentolate and atropine, indicating that the difference in cycloplegic effect decreases by 0.04 D with each additional year of age. This highlights the importance of age-specific considerations when selecting cycloplegic agents for pediatric patients. Unlike previous studies that did not extensively examine the influence of age or initial spherical equivalent values on the difference in cycloplegic effects, this research specifically investigated these factors. The findings provide a basis for tailoring cycloplegic eye drop selection based on patient age, aiming for a more individualized approach to managing refractive errors in children. While previous research has noted differences in cycloplegic effects between the two agents, this study uniquely quantifies the influence of age on this difference, suggesting that the disparity in cycloplegic effect between atropine and cyclopentolate may be smaller in older children. Introduction Amblyopia is a common visual acuity disorder in children, defined as reduced visual acuity due to the abnormal development of the visual cortex during infancy or childhood, in which the visual acuity is below a certain level and cannot be corrected or improved with spectacles [1, 2]. Previous studies have reported a 1.36% global amblyopia prevalence in children [3]. Strabismus in children is linked to decreased functional visual acuity and eye-related quality of life and demonstrates a greater impact on social life, irritability, and distress [4]. An estimated strabismus prevalence of 1.93% has been observed in children worldwide, which is heterogeneously influenced by age, region, and year of publication [5]. In the treatment of amblyopia and strabismus in children, performing refractive testing using cycloplegic eye drops is essential for accurate diagnosis and treatment [6, 7]. Atropine sulfate (atropine), a different type of cycloplegic eye drop, has been shown to demonstrate a stronger cycloplegic effect compared to cyclopentolate hydrochloride (cyclopentolate), which is a cycloplegic eye drop [8, 9]. For instance, Sani et al. investigated the difference in the refractive values between cyclopentolate and atropine in 63 subjects with a mean age of 8.23 years and found higher refractive values for atropine, although no significant difference was observed [8]. Additionally, Fan et al. conducted a similar validation in 25 participants with an average age of 5.7 years and suggested that atropine demonstrated a higher cycloplegic effect by 0.42 D [9]. However, several concerns exist regarding atropine use. First, administering the drops requires time and effort. The effects of atropine, such as cycloplegia and mydriasis, can last for up to 14 days, whereas cyclopentolate has a duration of action of 24 h [10]. Adverse reactions such as flushing and fever have also been reported [11–15]. As mentioned above, differences have been found between the refractive values of cyclopentolate and atropine. However, to the best of our knowledge, no studies have examined whether differences in the cycloplegic effects of cyclopentolate and atropine depend on age or the initially measured spherical equivalent values. Therefore, this study aimed to examine whether the difference in refractive values between cyclopentolate and atropine depends on the age and initial spherical equivalent values. The findings of this study may assist in establishing a theory for selecting the most appropriate cycloplegic eye drops based on the purpose and patient background. Methods Study design and population In this study retrospective observational study, we collected data from the electronic medical records of patients who visited Kozawa Eye Hospital and Diabetes Center between January 2001 and December 2021. The study population included patients who underwent refractive examinations with cyclopentolate and atropine eye drops. However, this study excluded cases in which the first cycloplegic eye drops administered were other than cyclopentolate and those with an interval between cyclopentolate and atropine administration exceeding one month. Collected variables The outcome variable was the difference between the refractive values of cyclopentolate and atropine in each study population. In particular, cyclopentolate was administered as eye drops twice every 5 minutes after the patient arrived at the hospital at a concentration of 1% in all cases. The refractive index was measured after 60 min. Furthermore, atropine was administered as an eye drop twice daily for seven days. Children aged < 6 years received 0.5% atropine, and children aged ≥ 6 years received 1.0% atropine. Refraction values were measured using an autorefractometer (Tomey, Aichi, Japan) or a handheld refractometer (Right, Tokyo, Japan). The difference in the refraction values was defined as the refraction value of atropine minus that of cyclopentolate. In addition, data on sex, age at the time of cyclopentolate administration, ocular position, and hyperopia or hyperopic changes were collected from the electronic medical records. Statistical analysis Descriptive statistics were utilized to summarize the patient demographics and baseline characteristics. In particular, the median and first and third quartiles were used as the summary statistics for continuous variables, and categorical variables included frequency and percentage. The Mann–Whitney U-test was performed to assess whether a difference existed between the refractive values of cyclopentolate and atropine. Finally, multivariate analyses were conducted to evaluate whether the differences in refractive values between cyclopentolate and atropine varied according to age and first spherical equivalent values. Specifically, the difference in the refractive values between cyclopentolate and atropine was utilized as the dependent variable. A Yeo-John transformation was performed to approximate a normal distribution, as described previously [16], given that the difference in the refractive values may contain negative numbers and may not still fit a normal distribution. Age and initial spherical values were used as independent variables. Adjustments were made for potential confounders. All the above computations were two-tailed, and a p-value of < 0.05 was considered statistically significant. Data analysis was performed using R (version 4.3.2, R Foundation for Statistical Computing, Vienna, Austria). Ethics The Institutional Review Board (IRB) of Kozawa Eye Hospital and Diabetes Center reviewed and approved the study protocol (approval number: KG 2024-5). The IRB exempted the study population from obtaining individual consent, given the retrospective nature of this study. However, information on the nature of the study, intended use of the data, and protection of privacy were included on the webpage, and it was clearly stated that participants could only choose to request exclusion from the study if they did not want their data to be utilized in the study. Data were anonymized and securely handled to maintain confidentiality, in accordance with the ethical standards of the Declaration of Helsinki (2024). Results Table 1 shows the characteristics of the study population. This constituted 188 eyes in 94 individuals, 105 with a refractive difference of < 0.5 D, 69 with a refractive difference of ≥ 0.5 D and < 1.0 D, and 14 with a refractive difference of ≥ 1.0 D. The median refractive values of cyclopentolate and atropine were 2.50 and 2.75, respectively. Furthermore, the median age at first examination of the study population was 6.0 years, and 31 (16%) patients exhibited myopic changes. Figure 1 shows the differences between the mean refractive indices of cyclopentolate and atropine. A Mann–Whitney U-test was conducted, and a statistically significant difference was found between the two eye drops (p = 0.024). Fig. 1 Distribution of spherical equivalent values for cyclopentolate and atropine The equivalent sphere value for cyclopentolate was 2.84 ± 2.14 D and that for atropine was 3.25 ± 2.09 D. Mann–Whitney U-test indicated a significant difference between the groups (p = 0.024). Tables 2 and 3 present the findings of the multivariate analysis. The difference in refractive values between cyclopentolate and atropine was significantly associated with age at the first examination even after adjusting for sex and the eye in which the eye received the eye drops (β = −0.04; 95% confidence interval (CI): −0.07, −0.01). In other words, the difference in refractive values decreased by 0.04 D with an additional year of age. However, no significant association was observed between the first spherical equivalent values and the difference in the refraction values (β = 0.09; 95% CI: −0.22, 0.03). Discussions This study assessed whether differences existed in the cycloplegic effects of the cyclopentolate hydrochloride and atropine sulfate eye drops and whether these differences varied according to age and initial spherical equivalent value. The cycloplegic effect of atropine was markedly stronger than that of cyclopentolate, and the difference in the cycloplegic effect of atropine and cyclopentolate was substantially linked to age. The finding that the modulatory cycloplegic effect of atropine was stronger than that of cyclopentolate in the present study is consistent with previous reports. However, the refractive values differed from those in previous studies [8, 9]. For instance, the difference in the cycloplegic effect was 0.2 D in the study by Sani et al. and 0.42 D in the study by Fan DS et al., as compared to 0.41 D in the present study. We speculated that this was largely because of the differences in the mean age of the study population. The present study suggested that the difference in the cycloplegic effect of atropine and cyclopentolate may be smaller with increasing age, with the mean age of the study population being 8.23 years in the study by Sani et al, 5.7 years in the study by Fan DS et al., and 5.89 years in the present study, which is consistent with the above inference. The clinical implication of this study is that it provides a basis for decision-making when considering the clinical use of cyclopentolate versus atropine. Additionally, an association between age and differences in the cycloplegic effects of the two drops has been suggested, emphasizing that age should also be considered. The difference in refractive values between cyclopentolate and atropine narrows by 0.04 D over the course of one year. We estimated that the difference between the refractive values of cyclopentolate and atropine was almost non-existent, with a value of 14.5 years (95% CI: 9.82, 19.93). However, collecting samples from a wide range of age groups and performing analyses to derive a more valid estimation formula in the future are necessary, given that this estimation formula was derived based on sample data from ages 3 to 11. In addition to age, several other factors were considered when comparing the use of cyclopentolate versus atropine. For instance, Singh et al. stated that atropine use is appropriate for children with hyperopia > 5.0 D [17]. Additionally, atropine has been suggested for patients with esotropia [16]. Moreover, the use of cyclopentolate in patients with neurological disease is linked to a risk of adverse reactions such as speech disorders, visual and tactile hallucinations, as well as ataxia [6, 10]. This study had some limitations. First is the possibility of bias in selecting cyclopentolate eye drops, as the first choice was made for a few patients with esotropia or high hyperopia. Second, the measurement instrument was changed during the data collection period, and the data measured with stationary and handheld autorefractometers were mixed, which compromised the data integrity. However, individual patients were measured using the same instrument. We believe that the errors between instruments were negligible, consistent with a study by Karabulut et al. who reported a strong correlation between the spherical equivalent frequencies of both instruments [18]. Conclusion Significant differences were found between the cycloplegic effects of cyclopentolate hydrochloride and atropine sulfate eye drops, with atropine exhibiting a stronger refractive effect. Age was substantially linked to these differences, suggesting that age-related factors should be considered when selecting adjunctive paralyzing eye drops in pediatric ophthalmology. These results support an individualized approach to managing pediatric refractive errors and advocate further research to optimize treatment strategies according to age. Declarations Author contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Toru Kawanobe, Toshiaki Goseki, and Shinya Takahashi. The first draft of the manuscript was written by Toru Kawanobe and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Disclosure of potential conflicts of interest None declared. Funding No funding was received. Ethics approval The Institutional Review Board (IRB) of Kozawa Eye Hospital and Diabetes Center reviewed and approved the study protocol (approval number: KG 2024-5). Data were anonymized and securely handled to maintain confidentiality, in accordance with the ethical standards of the Declaration of Helsinki (2024). Informed consent The Institutional Review Board exempted the study population from obtaining individual consent, given the retrospective nature of this study. Consent to participate Information on the nature of the study, intended use of the data, and protection of privacy were included on the webpage, and it was clearly stated that participants could only choose to request exclusion from the study if they did not want their data to be utilized in the study. Consent to publish Not applicable. Data availability statement The data presented in this study is contained within the article. Acknowledgements We thank Mr. Motoi Miura for their guidance in manuscript preparation. Additionally, we would like to thank Editage (www.editage.jp) for the English language editing. References Gunton KB. Advances in amblyopia: what have we learned from PEDIG trials? Pediatrics. 2013;131:540–7. doi:10.1542/peds.2012-1622. Meyniel C, Bodaghi B, Robert PY. Revisiting vision rehabilitation. Front Syst Neurosci. 2017;11:82. doi:10.3389/fnsys.2017.00082. Hu B, Liu Z, Zhao J, Zeng L, Hao G, Shui D, et al. The global prevalence of amblyopia in children: A systematic review and meta-analysis. Front Pediatr. 2022;10:819998. doi:10.3389/fped.2022.819998. Hatt SR, Leske DA, Castañeda YS, Wernimont SM, Liebermann L, Cheng-Patel CS, et al. Association of strabismus with functional vision and eye-related quality of life in children. JAMA Ophthalmol. 2020;138:528–35. doi:10.1001/jamaophthalmol.2020.0539. 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A randomized trial of atropine regimens for treatment of moderate amblyopia in children. Ophthalmology. 2004;111:2076–85. doi:10.1016/j.ophtha.2004.04.032. Chia A, Chua WH, Cheung YB, Wong WL, Lingham A, Fong A, et al. Atropine for the treatment of childhood myopia: safety and efficacy of 0.5%, 0.1%, and 0.01% doses (atropine for the Treatment of Myopia 2). Ophthalmology. 2012;119:347–54. doi:10.1016/j.ophtha.2011.07.031. Chen DX, He XG, Xu X. [The safety of atropine for myopia prevention and control]. Zhonghua Yan Ke Za Zhi. 2021;57:299–304. doi:10.3760/cma.j.cn112142-20200622-00413. Veiz E, Kieslich SK, Czesnik D, Herrmann-Lingen C, Meyer T, Staab J. Increased Concentrations of Circulating Interleukins following Non-Invasive vagus nerve Stimulation: results from a Randomized, Sham-Controlled, Crossover Study in Healthy Subjects. Neuroimmunomodulation. 2022;29:450–9. doi:10.1159/000524646. Singh RP, Amitava AK, Sharma N, Gupta Y, Raza SA, Bose A, et al. Comparison of cycloplegia with atropine 1% versus cyclopentolate 1. Indian J Ophthalmol. 2023;71:3633–6. doi:10.4103/IJO.IJO_1159_23. Karabulut M, Karabulut S, Karalezli A. Refractive outcomes of table-mounted and hand-held auto-refractometers in children: an observational cross-sectional study. BMC Ophthalmol. 2021;21:424. doi:10.1186/s12886-021-02199-5. Tables Table 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Table2.docx Table3.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7997186","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":546370793,"identity":"6ce2a238-eeb4-4a36-b0fa-5bf9d74c72dd","order_by":0,"name":"Toru Kawanobe","email":"","orcid":"","institution":"Kozawa Eye Hospital and Diabetes Center","correspondingAuthor":false,"prefix":"","firstName":"Toru","middleName":"","lastName":"Kawanobe","suffix":""},{"id":546370794,"identity":"3b61a378-b7b1-4bf7-8cd7-72aaaef3c3d7","order_by":1,"name":"Toshiaki 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16:39:14","extension":"html","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":56794,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7997186/v1/5ed79bd0976e658b75855449.html"},{"id":96202128,"identity":"04cdefff-18e5-4cf3-b713-098a1bec1a3a","added_by":"auto","created_at":"2025-11-18 16:39:13","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":34280,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of spherical equivalent values for cyclopentolate and atropine\u003c/p\u003e\n\u003cp\u003eThe equivalent sphere value for cyclopentolate was 2.84 ± 2.14 D and that for atropine was 3.25 ± 2.09 D. Mann–Whitney U-test indicated a significant difference between the groups (p = 0.024).\u003c/p\u003e","description":"","filename":"floatimage127.png","url":"https://assets-eu.researchsquare.com/files/rs-7997186/v1/8795878451b2f43d94e610a3.png"},{"id":101206994,"identity":"c2f4b607-92a4-4a23-84f6-0c2baa8ca1e0","added_by":"auto","created_at":"2026-01-27 09:57:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":504236,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7997186/v1/de225b8d-d8c1-49f5-b744-4586b3b1d864.pdf"},{"id":96202150,"identity":"4c3152d1-d3e5-47b5-91b6-9c05993ef2a2","added_by":"auto","created_at":"2025-11-18 16:39:16","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":17946,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7997186/v1/eb5b408a2efdf11d172312b0.docx"},{"id":96202148,"identity":"fcad0702-0608-4a01-a209-54ae16971fda","added_by":"auto","created_at":"2025-11-18 16:39:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16549,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7997186/v1/d94609172e90fde86aeffb43.docx"},{"id":96202154,"identity":"ae411955-a43c-4eae-a599-2a8df8aab249","added_by":"auto","created_at":"2025-11-18 16:39:17","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":15758,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-7997186/v1/f016be6092945a5c43f0d0e7.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association of age and spherical equivalent with differences in cycloplegic refractive effects between cyclopentolate and atropine","fulltext":[{"header":"Key Messages","content":"\u003cp\u003eCyclopentolate hydrochloride and atropine sulfate are both used as cycloplegic eye drops in pediatric ophthalmology for accurate diagnosis and treatment of conditions such as amblyopia and strabismus. Atropine has been shown to have a stronger cycloplegic effect compared to cyclopentolate.\u003c/p\u003e\n\u003cp\u003eThis study reveals a significant association between age and the difference in refractive values between cyclopentolate and atropine, indicating that the difference in cycloplegic effect decreases by 0.04 D with each additional year of age. This highlights the importance of age-specific considerations when selecting cycloplegic agents for pediatric patients.\u003c/p\u003e\n\u003cp\u003eUnlike previous studies that did not extensively examine the influence of age or initial spherical equivalent values on the difference in cycloplegic effects, this research specifically investigated these factors. The findings provide a basis for tailoring cycloplegic eye drop selection based on patient age, aiming for a more individualized approach to managing refractive errors in children.\u003c/p\u003e\n\u003cp\u003eWhile previous research has noted differences in cycloplegic effects between the two agents, this study uniquely quantifies the influence of age on this difference, suggesting that the disparity in cycloplegic effect between atropine and cyclopentolate may be smaller in older children.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eAmblyopia is a common visual acuity disorder in children, defined as reduced visual acuity due to the abnormal development of the visual cortex during infancy or childhood, in which the visual acuity is below a certain level and cannot be corrected or improved with spectacles [1, 2]. Previous studies have reported a 1.36% global amblyopia prevalence in children [3]. Strabismus in children is linked to decreased functional visual acuity and eye-related quality of life and demonstrates a greater impact on social life, irritability, and distress [4]. An estimated strabismus prevalence of 1.93% has been observed in children worldwide, which is heterogeneously influenced by age, region, and year of publication [5].\u003c/p\u003e\u003cp\u003eIn the treatment of amblyopia and strabismus in children, performing refractive testing using cycloplegic eye drops is essential for accurate diagnosis and treatment [6, 7]. Atropine sulfate (atropine), a different type of cycloplegic eye drop, has been shown to demonstrate a stronger cycloplegic effect compared to cyclopentolate hydrochloride (cyclopentolate), which is a cycloplegic eye drop [8, 9]. For instance, Sani et al. investigated the difference in the refractive values between cyclopentolate and atropine in 63 subjects with a mean age of 8.23 years and found higher refractive values for atropine, although no significant difference was observed [8]. Additionally, Fan et al. conducted a similar validation in 25 participants with an average age of 5.7 years and suggested that atropine demonstrated a higher cycloplegic effect by 0.42 D [9]. However, several concerns exist regarding atropine use. First, administering the drops requires time and effort. The effects of atropine, such as cycloplegia and mydriasis, can last for up to 14 days, whereas cyclopentolate has a duration of action of 24 h [10]. Adverse reactions such as flushing and fever have also been reported [11\u0026ndash;15]. As mentioned above, differences have been found between the refractive values of cyclopentolate and atropine. However, to the best of our knowledge, no studies have examined whether differences in the cycloplegic effects of cyclopentolate and atropine depend on age or the initially measured spherical equivalent values.\u003c/p\u003e\u003cp\u003eTherefore, this study aimed to examine whether the difference in refractive values between cyclopentolate and atropine depends on the age and initial spherical equivalent values. The findings of this study may assist in establishing a theory for selecting the most appropriate cycloplegic eye drops based on the purpose and patient background.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design and population\u003c/h2\u003e\u003cp\u003eIn this study retrospective observational study, we collected data from the electronic medical records of patients who visited Kozawa Eye Hospital and Diabetes Center between January 2001 and December 2021. The study population included patients who underwent refractive examinations with cyclopentolate and atropine eye drops. However, this study excluded cases in which the first cycloplegic eye drops administered were other than cyclopentolate and those with an interval between cyclopentolate and atropine administration exceeding one month.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eCollected variables\u003c/h3\u003e\n\u003cp\u003eThe outcome variable was the difference between the refractive values of cyclopentolate and atropine in each study population. In particular, cyclopentolate was administered as eye drops twice every 5 minutes after the patient arrived at the hospital at a concentration of 1% in all cases. The refractive index was measured after 60 min. Furthermore, atropine was administered as an eye drop twice daily for seven days. Children aged\u0026thinsp;\u0026lt;\u0026thinsp;6 years received 0.5% atropine, and children aged\u0026thinsp;\u0026ge;\u0026thinsp;6 years received 1.0% atropine. Refraction values were measured using an autorefractometer (Tomey, Aichi, Japan) or a handheld refractometer (Right, Tokyo, Japan). The difference in the refraction values was defined as the refraction value of atropine minus that of cyclopentolate. In addition, data on sex, age at the time of cyclopentolate administration, ocular position, and hyperopia or hyperopic changes were collected from the electronic medical records.\u003c/p\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eDescriptive statistics were utilized to summarize the patient demographics and baseline characteristics. In particular, the median and first and third quartiles were used as the summary statistics for continuous variables, and categorical variables included frequency and percentage. The Mann\u0026ndash;Whitney U-test was performed to assess whether a difference existed between the refractive values of cyclopentolate and atropine. Finally, multivariate analyses were conducted to evaluate whether the differences in refractive values between cyclopentolate and atropine varied according to age and first spherical equivalent values. Specifically, the difference in the refractive values between cyclopentolate and atropine was utilized as the dependent variable. A Yeo-John transformation was performed to approximate a normal distribution, as described previously [16], given that the difference in the refractive values may contain negative numbers and may not still fit a normal distribution. Age and initial spherical values were used as independent variables. Adjustments were made for potential confounders. All the above computations were two-tailed, and a p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant. Data analysis was performed using R (version 4.3.2, R Foundation for Statistical Computing, Vienna, Austria).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEthics\u003c/h3\u003e\n\u003cp\u003e The Institutional Review Board (IRB) of Kozawa Eye Hospital and Diabetes Center reviewed and approved the study protocol (approval number: KG 2024-5). The IRB exempted the study population from obtaining individual consent, given the retrospective nature of this study. However, information on the nature of the study, intended use of the data, and protection of privacy were included on the webpage, and it was clearly stated that participants could only choose to request exclusion from the study if they did not want their data to be utilized in the study. Data were anonymized and securely handled to maintain confidentiality, in accordance with the ethical standards of the Declaration of Helsinki (2024).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eTable 1 shows the characteristics of the study population. This constituted 188 eyes in 94 individuals, 105 with a refractive difference of \u0026lt; 0.5 D, 69 with a refractive difference of \u0026ge; 0.5 D and \u0026lt; 1.0 D, and 14 with a refractive difference of \u0026ge; 1.0 D. The median refractive values of cyclopentolate and atropine were 2.50 and 2.75, respectively. Furthermore, the median age at first examination of the study population was 6.0 years, and 31 (16%) patients exhibited myopic changes.\u003c/p\u003e\n\u003cp\u003eFigure 1 shows the differences between the mean refractive indices of cyclopentolate and atropine. A Mann\u0026ndash;Whitney U-test was conducted, and a statistically significant difference was found between the two eye drops (p = 0.024).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e1\u003c/strong\u003e Distribution of spherical equivalent values for cyclopentolate and atropine\u003c/p\u003e\n\u003cp\u003eThe equivalent sphere value for cyclopentolate was 2.84 \u0026plusmn; 2.14 D and that for atropine was 3.25 \u0026plusmn; 2.09 D. Mann\u0026ndash;Whitney U-test indicated a significant difference between the groups (p = 0.024).\u003c/p\u003e\n\u003cp\u003eTables 2 and 3 present the findings of the multivariate analysis. The difference in refractive values between cyclopentolate and atropine was significantly associated with age at the first examination even after adjusting for sex and the eye in which the eye received the eye drops (\u0026beta; = \u0026minus;0.04; 95% confidence interval (CI): \u0026minus;0.07, \u0026minus;0.01). In other words, the difference in refractive values decreased by 0.04 D with an additional year of age.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHowever, no significant association was observed between the first spherical equivalent values and the difference in the refraction values (\u0026beta; = 0.09; 95% CI: \u0026minus;0.22, 0.03).\u003c/p\u003e"},{"header":"Discussions","content":"\u003cp\u003eThis study assessed whether differences existed in the cycloplegic effects of the cyclopentolate hydrochloride and atropine sulfate eye drops and whether these differences varied according to age and initial spherical equivalent value. The cycloplegic effect of atropine was markedly stronger than that of cyclopentolate, and the difference in the cycloplegic effect of atropine and cyclopentolate was substantially linked to age.\u003c/p\u003e\u003cp\u003eThe finding that the modulatory cycloplegic effect of atropine was stronger than that of cyclopentolate in the present study is consistent with previous reports. However, the refractive values differed from those in previous studies [8, 9]. For instance, the difference in the cycloplegic effect was 0.2 D in the study by Sani et al. and 0.42 D in the study by Fan DS et al., as compared to 0.41 D in the present study. We speculated that this was largely because of the differences in the mean age of the study population. The present study suggested that the difference in the cycloplegic effect of atropine and cyclopentolate may be smaller with increasing age, with the mean age of the study population being 8.23 years in the study by Sani et al, 5.7 years in the study by Fan DS et al., and 5.89 years in the present study, which is consistent with the above inference.\u003c/p\u003e\u003cp\u003eThe clinical implication of this study is that it provides a basis for decision-making when considering the clinical use of cyclopentolate versus atropine. Additionally, an association between age and differences in the cycloplegic effects of the two drops has been suggested, emphasizing that age should also be considered. The difference in refractive values between cyclopentolate and atropine narrows by 0.04 D over the course of one year. We estimated that the difference between the refractive values of cyclopentolate and atropine was almost non-existent, with a value of 14.5 years (95% CI: 9.82, 19.93). However, collecting samples from a wide range of age groups and performing analyses to derive a more valid estimation formula in the future are necessary, given that this estimation formula was derived based on sample data from ages 3 to 11. In addition to age, several other factors were considered when comparing the use of cyclopentolate versus atropine. For instance, Singh et al. stated that atropine use is appropriate for children with hyperopia\u0026thinsp;\u0026gt;\u0026thinsp;5.0 D [17]. Additionally, atropine has been suggested for patients with esotropia [16]. Moreover, the use of cyclopentolate in patients with neurological disease is linked to a risk of adverse reactions such as speech disorders, visual and tactile hallucinations, as well as ataxia [6, 10].\u003c/p\u003e\u003cp\u003eThis study had some limitations. First is the possibility of bias in selecting cyclopentolate eye drops, as the first choice was made for a few patients with esotropia or high hyperopia. Second, the measurement instrument was changed during the data collection period, and the data measured with stationary and handheld autorefractometers were mixed, which compromised the data integrity. However, individual patients were measured using the same instrument. We believe that the errors between instruments were negligible, consistent with a study by Karabulut et al. who reported a strong correlation between the spherical equivalent frequencies of both instruments [18].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSignificant differences were found between the cycloplegic effects of cyclopentolate hydrochloride and atropine sulfate eye drops, with atropine exhibiting a stronger refractive effect. Age was substantially linked to these differences, suggesting that age-related factors should be considered when selecting adjunctive paralyzing eye drops in pediatric ophthalmology. These results support an individualized approach to managing pediatric refractive errors and advocate further research to optimize treatment strategies according to age.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Toru Kawanobe, Toshiaki Goseki, and Shinya Takahashi. The first draft of the manuscript was written by Toru Kawanobe and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of potential conflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone declared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Institutional Review Board (IRB) of Kozawa Eye Hospital and Diabetes Center reviewed and approved the study protocol (approval number: KG 2024-5). Data were anonymized and securely handled to maintain confidentiality, in accordance with the ethical standards of the Declaration of Helsinki (2024).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Institutional Review Board exempted the study population from obtaining individual consent, given the retrospective nature of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformation on the nature of the study, intended use of the data, and protection of privacy were included on the webpage, and it was clearly stated that participants could only choose to request exclusion from the study if they did not want their data to be utilized in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data presented in this study is contained within the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Mr. Motoi Miura for their guidance in manuscript preparation. Additionally, we would like to thank Editage (www.editage.jp) for the English language editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGunton KB. Advances in amblyopia: what have we learned from PEDIG trials? Pediatrics. 2013;131:540\u0026ndash;7. doi:10.1542/peds.2012-1622.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMeyniel C, Bodaghi B, Robert PY. Revisiting vision rehabilitation. Front Syst Neurosci. 2017;11:82. doi:10.3389/fnsys.2017.00082.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHu B, Liu Z, Zhao J, Zeng L, Hao G, Shui D, et al. The global prevalence of amblyopia in children: A systematic review and meta-analysis. Front Pediatr. 2022;10:819998. doi:10.3389/fped.2022.819998.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHatt SR, Leske DA, Casta\u0026ntilde;eda YS, Wernimont SM, Liebermann L, Cheng-Patel CS, et al. Association of strabismus with functional vision and eye-related quality of life in children. JAMA Ophthalmol. 2020;138:528\u0026ndash;35. doi:10.1001/jamaophthalmol.2020.0539.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHashemi H, Pakzad R, Heydarian S, Yekta A, Aghamirsalim M, Shokrollahzadeh F, et al. Global and regional prevalence of strabismus: a comprehensive systematic review and meta-analysis. Strabismus. 2019;27:54\u0026ndash;65. doi:10.1080/09273972.2019.1604773.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eContreras-Salinas H, Orozco-Ceja V, Romero-L\u0026oacute;pez MS, Barajas-Virgen MY, Baiza-Dur\u0026aacute;n LM, Rodr\u0026iacute;guez-Herrera LY. Ocular cyclopentolate: A mini review concerning its benefits and risks. Clin Ophthalmol. 2022;16:3753\u0026ndash;62. doi:10.2147/OPTH.S388982.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSun YY, Wei SF, Li SM, Hu JP, Yang XH, Cao K, et al. Cycloplegic refraction by 1% cyclopentolate in young adults: is it the gold standard? The Anyang University Students Eye Study (AUSES). Br J Ophthalmol. 2018:bjophthalmol-2018-312199. doi:10.1136/bjophthalmol-2018-312199.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSani RY, Hassan S, Habib SG, Ifeanyichukwu EP. Cycloplegic effect of atropine compared with cyclopentolate-tropicamide combination in children with hypermetropia. Niger Med J. 2016;57:173\u0026ndash;7. doi:10.4103/0300-1652.184065.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFan DS, Rao SK, Ng JS, Yu CB, Lam DS. Comparative study on the safety and efficacy of different cycloplegic agents in children with darkly pigmented irides. Clin Exp Ophthalmol. 2004;32:462\u0026ndash;7. doi:10.1111/j.1442-9071.2004.00863.x.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMajor E, Dutson T, Moshirfar M. Cycloplegia in children: an optometrist\u0026rsquo;s perspective. Clin Optom (Auckl). 2020;12:129\u0026ndash;33. doi:10.2147/OPTO.S217645.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWakayama A, Nishina S, Miki A, Utsumi T, Sugasawa J, Hayashi T, et al. Incidence of side effects of topical atropine sulfate and cyclopentolate hydrochloride for cycloplegia in Japanese children: a multicenter study. Jpn J Ophthalmol. 2018;62:531\u0026ndash;6. doi:10.1007/s10384-018-0612-7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePediatric Eye Disease Investigator Group. A randomized trial of atropine vs. patching for treatment of moderate amblyopia in children. Arch Ophthalmol. 2002;120:268\u0026ndash;78. doi:10.1001/archopht.120.3.268.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRepka MX, Cotter SA, Beck RW, Kraker RT, Birch EE, Everett DF, et al. A randomized trial of atropine regimens for treatment of moderate amblyopia in children. Ophthalmology. 2004;111:2076\u0026ndash;85. doi:10.1016/j.ophtha.2004.04.032.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChia A, Chua WH, Cheung YB, Wong WL, Lingham A, Fong A, et al. Atropine for the treatment of childhood myopia: safety and efficacy of 0.5%, 0.1%, and 0.01% doses (atropine for the Treatment of Myopia 2). Ophthalmology. 2012;119:347\u0026ndash;54. doi:10.1016/j.ophtha.2011.07.031.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen DX, He XG, Xu X. [The safety of atropine for myopia prevention and control]. Zhonghua Yan Ke Za Zhi. 2021;57:299\u0026ndash;304. doi:10.3760/cma.j.cn112142-20200622-00413.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVeiz E, Kieslich SK, Czesnik D, Herrmann-Lingen C, Meyer T, Staab J. Increased Concentrations of Circulating Interleukins following Non-Invasive vagus nerve Stimulation: results from a Randomized, Sham-Controlled, Crossover Study in Healthy Subjects. Neuroimmunomodulation. 2022;29:450\u0026ndash;9. doi:10.1159/000524646.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSingh RP, Amitava AK, Sharma N, Gupta Y, Raza SA, Bose A, et al. Comparison of cycloplegia with atropine 1% versus cyclopentolate 1. Indian J Ophthalmol. 2023;71:3633\u0026ndash;6. doi:10.4103/IJO.IJO_1159_23.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKarabulut M, Karabulut S, Karalezli A. Refractive outcomes of table-mounted and hand-held auto-refractometers in children: an observational cross-sectional study. BMC Ophthalmol. 2021;21:424. doi:10.1186/s12886-021-02199-5.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Amblyopia, Strabismus, Cyclopentolate hydrochloride, Atropine sulfate, Refractive value","lastPublishedDoi":"10.21203/rs.3.rs-7997186/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7997186/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003e\u003c/em\u003eAmblyopia and strabismus are common visual impairments linked to functional and social consequences in children. In this retrospective observational study, we aimed to compare the cycloplegic effects of two cycloplegic eye drops, cyclopentolate hydrochloride (cyclopentolate) and atropine sulfate (atropine), and examine whether age and initial spherical equivalent values influence these effects.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/em\u003e We used the data from patients treated at the Kozawa Eye Hospital and Diabetes Center between 2001 and 2021, excluding cases not initially treated with cyclopentolate or those with an interval of over a month between administrations. The main outcome was the difference in refractive values between cyclopentolate and atropine. Refractive measurements were obtained using an autorefractometer and a handheld refractometer. Statistical analyses included Wilcoxon signed-rank tests and multivariate regression, adjusting for potential confounders such as age and initial spherical values.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eResults: \u003c/strong\u003e\u003c/em\u003eThis study included 188 eyes of 94 patients. Statistical analysis showed a significant difference in the refractive values between cyclopentolate and atropine, with atropine demonstrating a stronger cycloplegic effect. Age at the time of initial examination was markedly linked to the difference in the refractive values between the two agents. In particular, with each additional year of age, the difference in refractive values decreased by 0.04 D.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/em\u003e Atropine revealed a consistently stronger refractive effect than cyclopentolate in the pediatric population, and age substantially influenced the cycloplegic effect. These results highlight the requirement for age-specific considerations when selecting cycloplegic agents for pediatric patients, thereby facilitating a more tailored approach to manage refractive errors in children.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e: not applicable\u003c/p\u003e","manuscriptTitle":"Association of age and spherical equivalent with differences in cycloplegic refractive effects between cyclopentolate and atropine","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-18 16:38:52","doi":"10.21203/rs.3.rs-7997186/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b03730e4-d23f-4755-af9b-64caf268d4f4","owner":[],"postedDate":"November 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-27T02:40:00+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-18 16:38:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7997186","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7997186","identity":"rs-7997186","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}