Effect of 0.01% atropine eyedrops on intraocular pressure in schoolchildren: a randomized clinical trial

INTRODUCTION

Myopia has become a severe worldwide public health issue

. It is predicted globally that the occurrence of myopia and high myopia is projected to a greater extent,affecting almost 5 billion and 1 billion people respectively by 2050

. Among urban Chinese children, the prevalence of myopia was 3.9% in grade 1 children, with 67.3% in grade 7 children

. Wei

conducted a cross-sectional universitybased study in central China and found the prevalence of myopia was 83.2%, and 11.1% for high myopia among university students. It has been reported that high or pathologic myopia can lead to irreversible blinding conditions, such as myopic retinopathy, retinal detachment, and choroidal neovascularization

.

In summary, it is concluded that 0.01% of atropine eye drops did not induce a rise in IOP in our study, and 0.01% of atropine eye drops are relatively safe to use in myopic children. In the future, further studies can conduct more details with a larger sample size and more years of follow-up to authenticate our study findings.

Except for the confirmed eye complications, the potential complications were that atropine leads to elevated intraocular pressure (IOP), owing to pupil dilation. Greenstein

showed that IOP tends to rise by more than 6 mm Hg due to topical administration of anticholinergics about in 8% of normal adults. However, Mughannam

identified that no significant IOP changes by using 1% atropine in horse eye. Wu

have conducted a retrospective study on a larger scale of 621 myopic children to evaluate the effect of dosage ranging from 0.1% to 1% atropine eye drops on IOP. They found no relationship between the treatment period and increasing dose of atropine with IOP elevation. Yu

conducted a study to determine whether long-term topical atropine therapy at various concentrations induces IOP elevation and subsequent development of glaucoma. This study revealed that topical atropine eye drops do not induce ocular hypertension and effectively slow the progression of myopia. Chan

enrolled 67 eyes of 35 myopic children receiving 0.25%atropine treatment. They found no significant change in IOP,optic nerve parameters, or retinal nerve fiber layer thickness over a mean of 15.2±2.4mo of treatment.

Many studies have evaluated the effect of atropine eye drops on IOP in myopic children. At present, 0.01% atropine is increasingly used to treat myopic children

. However,the effect of 0.01% atropine eye drops on IOP has not been extensively evaluated in myopic children. All above studies do not include the most frequently used 0.01% atropine eye drops in clinical practice.

In this placebo-controlled, double-masked, randomized trial of one year study, we represent the findings of IOP at baseline, 6 and 12mo of school children during administration of 0.01%atropine eye drops. The main objective of this research is to assess the effect of 0.01% atropine on IOP.

SUBJECTS AND METHODS

Written informed consent was obtained from at least one parent and verbal assent from all children.This clinical trial adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Beijing Tongren Hospital, Capital Medical University.Trial registration http://www.chictr.org.cn identifier: ChiCTRIOR-17013898.

制造企業(yè)作為當前市場經(jīng)濟體系中不可或缺的一部分，對社會經(jīng)濟發(fā)展發(fā)揮著一定效力。制造型企業(yè)全面開展動態(tài)成本管理工作，對促進自身管理水平，減少成本投放起到了重要作用。因此，在制造型企業(yè)運營發(fā)展過程中，應該給予動態(tài)成本管理工作高度注重，結(jié)合實際實際情況，充分落實到成本管理工作，各個部門各司其職，充分協(xié)調(diào)和配合，在增強企業(yè)綜合競爭實力的基礎(chǔ)上，實現(xiàn)企業(yè)良好發(fā)展。

This is a placebo-controlled, double-masked,randomized study conducted from April 2018 to July 2019.Children aged 6-12y were recruited to receive either 0.01%atropine eye drops or a placebo in a 1:1 ratio once nightly for one year. Details of the methodology have been provided elsewhere

.

At baseline, the mean IOP was 15.74 mm Hg (95%CI, 15.13 to 16.34 mm Hg) for the 0.01% atropine group and 15.59 mm Hg(95%CI, 15.00 to 16.19 mm Hg) for placebo group (analysis of covariance, mean difference, 0.14 mm Hg;

=0.743)after adjusting for central corneal thickness at baseline. The respective mean IOP values for the 0.01% atropine eye drops and placebo groups at baseline, 6 and 12mo were shown in Figure 1. At 6mo of follow-up, the IOP ranged from 11.3 to 22.7 mm Hg in the 0.01% atropine group, and five children had increased IOP by more than 21 mm Hg. The IOP ranged from 11.1 mm Hg to 22.6 mm Hg in the placebo group, and two children had increased IOP by more than 21 mm Hg. At one year of follow-up, the IOP ranged from 11.0 to 22.0 mm Hg in the 0.01% atropine group, and one child had increased IOP by more than 21 mm Hg. The IOP ranged from 10.7 to 22.1 mm Hg in the placebo group, and two children had increased IOP by more than 21 mm Hg.

科學技術(shù)作為人類生存發(fā)展不可或缺的重要組成部分，尤其在世界人口不斷增加，人類發(fā)展對各方面需求也與日俱增的嚴峻形勢下，技術(shù)就成了解決諸多問題的重要途徑。目前，我國正處于加快社會主義現(xiàn)代化建設(shè)的關(guān)鍵時期，但科技總體水平和科技哲學的發(fā)展同世界先進水平相比仍有較大差距，想要跟上國際社會發(fā)展的步伐，我們就必須針對上述問題進行認真思考，筆者希望通過學習芬伯格技術(shù)批判理論從中得到啟示。

All children experienced identical standardized investigation strategies at the baseline, 6-month,and 12-month visits. Cycloplegic refraction was measured by an autorefractor (HRK7000 A, Huvitz, South Korea) at each visit after a cycloplegic procedure with 3 drops of 1%cyclopentolate at 5-minute intervals. The measurement was performed after 30min of installation of the third drop. Another drop of the same cycloplegic eye drops would be administered after the third drop if full cycloplegia had not been achieved after 30min, and the examination was performed 15min later. All 3 readings should be at most 0.25 D apart in both the spherical and cylinder components. Before cycloplegic refraction, three readings of IOP measurements were taken by a non-contact tonometer (HNT-7000, Huvitz, South Korea).

The relationship between IOP and myopia continues to receive attention from researchers

. It has also been reported that moderate myopic children have significantly higher IOP than emmetropic children (

=0.022)

. Studies have suggested that the extension of the AL and thinning of the sclera caused by the development of myopia may lead to a decrease in eyeball compliance and an increase in IOP, thereby increasing IOP

.Therefore, myopic subjects with higher IOP levels may have a higher risk of glaucoma. It is shown that 0.01% of atropine eye drops did not increase IOP in myopic school-aged children.

RESULTS

At six months follow-up, the mean change of IOP was 0.66 mm Hg(95%CI, 0.13 to 1.18 mm Hg) for the 0.01% atropine group and 0.33 mm Hg (95%CI, -0.20 to 0.85 mm Hg) for placebo group (analysis of covariance, mean difference, 0.33 mm Hg;

=0.378) after adjusting for central corneal thickness (Table 2). At one year follow-up, the mean change of IOP was 0.16 mm Hg(95%CI, -0.43 to 0.76 mm Hg) for the 0.01% atropine group and -0.11 mm Hg (95%CI, -0.71 to 0.50 mm Hg) for placebo group (analysis of covariance, mean difference, 0.27 mm Hg;

=0.525) after adjusting for central corneal thickness (Table 2).There were no significant differences in the mean change of IOP between the two groups at 6 and 12mo.

This study was conducted at Beijing Tongren Hospital, Beijing, China. All children are 6-12y with spherical equivalent (SE) ranging from -1.00 to -6.00 D in the right and left eyes, astigmatism of less than 1.50 D in both eyes, IOP of less than 21 mm Hg. Exclusion criteria were those with combined ocular diseases, such as strabismus, cataract,amblyopia, glaucoma, corneal scar, and ocular tumor, allergy to atropine, cyclopentolate, or excipients, current or previous use of atropine, bifocals, contact lenses, or other methods for myopia control. Poor general health children with history of cardiac or significant respiratory diseases, and long-term systemic medication use were also excluded.

A total of 220 children were recruited into the study, with equal randomization to the 0.01% atropine and the placebo groups.Of 220 children, 103 were girls (46.8%). No significant differences were found between the 0.01% atropine and the placebo groups in the baseline characteristics, including age,gender, initial AL, initial SE, parental myopia, age at myopia onset, time outdoors, and near work. A total of 159 (72.3%)participants completed the follow-up during the 1-year study,with 76 and 83 children allocated into the 0.01% atropine and placebo groups (Table 1). No significant differences were found in initial IOP between discontinued and completed subjects in the 0.01% atropine eye drops and placebo groups(

＞0.05).

The 0.01% atropine and placebo eye drops were prepackaged in identical bottles with only the subject number and expiration date. The investigators and subjects were masked to identify the contents to make the entire process more accurate. A statistician operated the randomization independently with the schedule generated by the SAS program (SAS Institute, Cary, NC, USA). Every four children were arbitrarily randomized into the intervention or control group among eligible children.

Figure 2 shows the distribution of IOP change for the 0.01%atropine and placebo groups at 6 and 12mo. At 6mo, 65.3%of children had increased IOP in the 0.01% atropine group,compared with 42.3% in the placebo group (

=0.004). At 12mo, 51.4% of children had increased IOP in the 0.01%atropine group, compared with 45.9% in the placebo group(

=0.511). In our multiple logistic regression analysis, among subjects whose IOP was increased in the 0.01% atropine group at 12mo, the increased IOP was not significantly associated with age (

=0.205), gender (

=0.407), SE (

=0.933), and AL(

=0.184).

不要你舉雙手，舉一只手就有了個八成。我放心了。牛皮糖還想說什么，那個記者要走，過來打招呼。村長見狀就匆匆離開了。

DISCUSSION

In this randomized trial, our study showed that 0.01% atropine eye drops have no significantly elevated IOP during one year.At one year follow-up, the mean change of IOP in the 0.01%atropine group was 0.16 mm Hg (95%CI, -0.43 to 0.76 mm Hg)compared with -0.11 mm Hg (95%CI, -0.71 to 0.50 mm Hg) in the placebo group (

=0.525) after adjusting for central corneal thickness. The 51.4% of children have increased IOP in the 0.01% atropine group, compared with 45.9% in the placebo group (

=0.511). To our knowledge, the present trial was the first randomized, placebo-controlled study to present 0.01%atropine eye drops on the effect of IOP in mainland China.Some studies had evaluated the effect of atropine eye drops on IOP in myopic children. In a retrospective study of 621 myopic children aged 10.5±2.3y to evaluate IOP for dosages ranging from 0.1% to 1% atropine eye drops, Wu

found that the cumulative dose and duration of atropine treatment are not associated with the potential risk of increased IOP. However,the change concentrations of 1%, 0.5%, 0.25%, and 0.1%atropine eye drops were used according to clinicians prescribed based on the severity of myopia for children on each visit in their study. Therefore, it is difficult to estimate the degree of influence of each concentration of atropine eye drops on IOP. Consistently, Lee

found that the respective mean changes of IOP for the 0.25% atropine, 0.125% atropine, and control groups were -1.28, 0.54, and -0.33 mm Hg at one year,showing no significant differences for three groups. However,in the study, only 32 children, 12 children, and 12 children were recruited in the 0.125 % atropine group, 0.25% atropine eye drop, and control group, respectively. In addition, both above two studies did not include the most frequently used 0.01% atropine eye drops in clinical practice. Our study found that the mean change of IOP in the 0.01% atropine group was 0.16 mm Hg (95%CI, -0.43 to 0.76 mm Hg) compared with-0.11 mm Hg (95%CI, -0.71 to 0.50 mm Hg) in the placebo group at one-year follow-up after adjusting for central corneal thickness, and no significant difference in the mean change of IOP between 0.01% atropine group and placebo group at 12mo.In our study, we further analyzed the changes in the IOP of each subject during regular administration of 0.01% atropine eye drops. The IOP for the 0.01% atropine and placebo groups ranged from 11.0 to 22.0 and 10.7 mm Hg to 22.1 mm Hg at one-year follow-up. Only one child has increased IOP by more than 21 mm Hg in the 0.01% atropine group, and two children have increased IOP by more than 21mm Hg in the placebo group. The 51.4% of children have increased IOP in the 0.01%atropine group, compared with 45.9% in the placebo group(

=0.511) at 12mo. The present study demonstrated that a once-nightly dose of 0.01% atropine eye drops does not induce a rise in IOP in myopic children during one year.

2.日本血吸蟲毛蚴 （Schistosoma japonicum miracidium）：是日本血吸蟲幼蟲發(fā)育中的最早階段，呈梨形或長橢圓形，左右對稱，銀灰色。 大小為（78～120） μm×（30～40） μm，前端有錐形突起，體表具有纖毛。

The SE was calculated as the spherical D and half of the cylinder (sphere+0.5×cylinder). All statistical analysis was performed using SPSS V.15.0 (SPSS, Chicago,Illinois, USA) software. There was a high correlation between the right and left eyes, so the statistical analysis was performed using the right eye data. Two independent sample

-tests and an analysis of covariance were used to compare the IOP between 0.01% atropine and placebo groups. We used Chi-square tests to compare the proportion of subjects with increased IOP and categorical variables between the two groups. Age, sex, SE,axial length (AL), and IOP were calculated and analyzed. The 2-sided

-value was considered statistically significant when the values were less than 0.05.

The strength of our trial was that the first placebo-controlled,randomized study to present 0.01% atropine eye drops on the effect of IOP. It provided affirmative findings of the association between IOP and 0.01% atropine eye drops. However, there are some restrictions in our study. First, we used a non-contact tonometer instead of a Goldmann applanation tonometer as the gold standard to evaluate IOP, potentially leading to a higher reading of IOP in our study than if the IOP had been measured by Goldmann applanation tonometry

. However, a noncontact tonometer is clinically more tolerable for children

.In addition, an analysis of covariance was used to control for potential differences concerning central corneal thickness.Second, this study only evaluated the efficacy of 0.01%atropine eye drops on IOP for 1y. Thus, more years of followup studies should be performed.

Many experiments were carried out to explore the interventions of reducing myopia progression in children

. Atropine, a competitive antagonist of muscarinic cholinergic receptors,showed a remarkable part in the control of the progression of myopia

. In the atropine for the treatment of myopia 2(ATOM 2) study in Singapore, Chia

reported the mean myopia progression over 2y was -0.30±0.60, -0.38±0.63, and-0.49±0.63 diopters (D) in the atropine 0.5%, 0.1%, and 0.01%groups, respectively. In a randomized, placebo-controlled study, Wei

showed that 0.01% atropine eye drops could reduce axial elongation and myopia progression in children without serious adverse reaction. Apart from its fruitful results, atropine was thought to have some eye complications.Previous studies have reported that myopia progression can be stopped or reversed due to installing 1% atropine eye drops but causes the risk of pupillary dilation, stinging sensation, eye pain, photophobia, and blurring.

式中，En—林木資源資產(chǎn)經(jīng)濟價值量；W—銷售總收入；C—林木資源資產(chǎn)的各項經(jīng)營成本；F—林木資源資產(chǎn)經(jīng)營期間的合理利潤。

The authors thank all staff who contributed to this study.

Supported by the National Natural Science Foundation of China (No.82071000); the Beijing Science Foundation for Distinguished Yong Scholars (No.JQ20029);the Capital Health Research and Development of Special(No.2020-2-1081); Supported by the Beijing Municipal Administration of Hospitals Incubating Program (No.

港珠澳大橋總長約55 km，是目前世界最長的跨海大橋，并擁有世界最長的沉管海底隧道。大橋建造包含了基建、防銹、防腐、防水、抗臺風等多方面內(nèi)容，瀝青、涂料、防水材料等石化產(chǎn)品在其中發(fā)揮了巨大作用。

PX2022007); the Primary Scientific Research Foundation for the Junior Researcher in Beijing Tongren Hospital, Capital Medical University (No.2020-YJJ-ZZL-011).

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是一檔叫做“古今圍城”的節(jié)目，每周五期，每期兩個小時。思蓉會在節(jié)目里與聽眾分享與探討有關(guān)愛情和婚姻的任何話題，比如古今中外的愛情故事，古今中外的愛情名言，古今中外的婚姻觀點，古今中外的婚姻形式，等等。當然，這檔節(jié)目最主要的任務是接聽聽眾電話，為他們所遇到的愛情和婚姻問題出謀劃策。電話內(nèi)容千奇百怪，比如今天，電話里的男人傷心欲絕。

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