Pharmacologic interventions for mydriasis in cataract surgery

Abstract

Background

Cataract surgery is one of the most common surgical procedures performed worldwide. Achieving appropriate intraoperative mydriasis is one of the critical factors associated with the safety and performance of the surgery. Inadequate pupillary dilation or constriction of the pupil during cataract surgery can impair the surgeon’s field of view and make it difficult to maneuver instruments.

Objectives

To evaluate the relative effectiveness of achieving pupillary dilation during phacoemulsification for cataract extraction using three methods of pupillary dilation: topical mydriatics, intracameral mydriatics, or depot delivery systems. We also planned to document and compare the risk of intraoperative and postoperative complications following phacoemulsification for cataract extraction, as well as the cost‐effectiveness of these methods for pupillary dilation.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register) (2021, Issue 1); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 22 January 2021.

Selection criteria

We included only randomized controlled trial (RCTs) in which participants underwent phacoemulsification for cataract extraction.

Data collection and analysis

We followed standard Cochrane methodology.

Main results

We included a total of 14 RCTs (1670 eyes of 1652 participants) in this review. Of the 14 trials, 7 compared topical versus intracameral mydriatics, 6 compared topical mydriatics versus depot delivery systems, and 1 compared all three methods.

We were unable to calculate overall estimates of comparative effectiveness for most outcomes due to statistical heterogeneity among the estimates from individual studies or because outcome data were available from only a single study. Furthermore, the certainty of evidence for most outcomes was low or very low, due primarily to imprecision and risk of bias.

Comparison 1: topical mydriatics versus intracameral mydriatics

Four RCTs (739 participants, 757 eyes) of the 8 RCTs that had compared these two methods reported mean pupillary diameters at the time surgeons had performed capsulorhexis; all favored topical mydriatics, but heterogeneity was high (I² = 95%). After omitting 1 RCT that used a paired‐eyes design, evidence from three RCTs (721 participants and eyes) suggests that mean pupil diameter at the time of capsulorhexis may be greater with topical mydriatics than with intracameral mydriatics, but the evidence is of low certainty (mean difference 1.06 mm, 95% confidence interval (CI) 0.81 mm to 1.31 mm; I² = 49%).

Four RCTs (224 participants, 242 eyes) reported mean pupillary diameter at the beginning of cataract surgery; the effect estimates from all trials favored topical mydriatics, with very low‐certainty evidence.

Five RCTs (799 participants, 817 eyes) reported mean pupillary diameter at the end of cataract surgery. Data for this outcome from the largest RCT (549 participants and eyes) provided evidence of a small difference in favor of intracameral mydriasis. On the other hand, 2 small RCTs (78 participants, 96 eyes) favored topical mydriatics, and the remaining 2 RCTs (172 participants) found no meaningful difference between the two methods, with very low‐certainty evidence.

Five RCTs (799 participants, 817 eyes) reported total intraoperative surgical time. The largest RCT (549 participants and eyes) reported decreased total intraoperative time with intracameral mydriatics, whereas 1 RCT (18 participants, 36 eyes) favored topical mydriatics, and the remaining 3 RCTs (232 participants) found no difference between the two methods, with very low‐certainty evidence.

Comparison 2: topical mydriatics versus depot delivery systems

Of the 7 RCTs that compared these two methods, none reported mean pupillary diameter at the time surgeons performed capsulorhexis.

Six RCTs (434 participants) reported mean pupillary diameter at the beginning of cataract surgery. After omitting 1 RCT suspected to be responsible for high heterogeneity (I² = 80%), meta‐analysis of the other 5 RCTs (324 participants and eyes) found no evidence of a meaningful difference between the two methods, with very low‐certainty evidence.

Three RCTs (210 participants) reported mean pupillary diameter at the end of cataract surgery, with high heterogeneity among effect estimates for this outcome. Estimates of mean differences and confidence intervals from these three RCTs were consistent with no difference between the two methods. A fourth RCT reported only means for this outcome, with low‐certainty evidence.

Two small RCTs (118 participants) reported total intraoperative time. Surgical times were lower when depot delivery was used, but the confidence interval estimated from one trial was consistent with no difference, and only mean times were reported from the other trial, with very low‐certainty evidence.

Comparison 3: Intracameral mydriatics versus depot delivery systems

Only one RCT (60 participants) compared intracameral mydriatics versus depot delivery system. Mean pupillary diameter at the time the surgeon performed capsulorhexis, phacoemulsification time, and cost outcomes were not reported. Mean pupil diameter at the beginning and end of cataract surgery favored the depot delivery system, with very low‐certainty evidence.

Adverse events

Evidence from one RCT (555 participants and eyes) comparing topical mydriatics versus intracameral mydriatics suggests that ocular discomfort may be greater with topical mydriatics than with intracameral mydriatics at one week (risk ratio (RR) 10.57, 95% CI 1.37 to 81.34) and one month (RR 2.51, 95% CI 1.36 to 4.65) after cataract surgery, with moderate‐certainty evidence at both time points. Another RCT (30 participants) reported iris‐related complications in 11 participants in the intracameral mydriatics group versus no complications in the depot delivery system group, with very low‐certainty evidence. Cardiovascular related adverse events were rarely mentioned.

Authors' conclusions

Data from 14 completed RCTs were inadequate to establish the superiority of any of three methods to achieve mydriasis for cataract surgery, based on pupillary dilation at different times during the surgery or on time required for surgery. Only one trial had a 
sample size adequate to yield a robust effect estimate. Larger, well‐designed trials are needed to provide robust estimates for the comparison of mydriasis approaches for beneficial and adverse effects.

Plain language summary

What is the best way to place medicines directly into the eye to widen the pupil during cataract surgery?

Key messages
We did not find enough good‐quality evidence about the best way to deliver medicines directly to the eye during cataract surgery. We found only one study that had enrolled a large enough number of people to give reliable results.

Larger, well‐designed studies are needed to give better estimates of the benefits and potential harms of the different ways of delivering these medicines.

What are cataracts?
A cataract starts when cloudy patches develop on the lens of the eyes. As the cloudy patches get bigger over time, sight becomes misty and blurred. Untreated cataracts will lead to blindness.

Cataract surgery
Surgery is the only way to improve a person's eyesight if they have cataracts. A tiny cut is made in the eye, and the old, cloudy lens is removed and a plastic lens put in its place.

Before and during surgery, doctors use medicines to widen (dilate) the pupil, the dark part in the center of the eye that lets in light. For surgery, the pupil should be as wide as possible to help doctors see and work inside the eye; wide pupils also reduce the chance of problems during surgery.

Why we did this Cochrane Review
Medicines used to widen the pupil can be:

· dropped onto the surface of the eye, as eye drops;

· injected into the eye; or

· released from a tiny device (depot) placed on the surface of the eye beneath the lower eyelid.

We wanted to find out:

· which way of delivering these medicines worked best to widen the pupil during cataract surgery;

· which was the most cost‐effective (gave benefits, such as savings in surgery time or costs, that might outweigh any additional costs associated with using it); and

· about any unwanted effects the delivery method might cause.

What did we do?
We searched for studies that tested these different ways of delivering medicines to the eye in people having cataract surgery.

Search date: We included evidence published up to 22 January 2021.

What we found
We found 14 studies in 1652 people (aged 57 to 78 years) who had cataract surgery in 1670 eyes. The studies took place at hospitals in Europe, China, India, and Malaysia. One study reported that it had been sponsored by a company that manufactured one of the depot devices used in the study.

The studies compared eye drops against injections (7 studies) or depot devices (6 studies); one study compared all three delivery types. Unfortunately, there were too many differences between the study designs and results reported to allow us to make overall estimates of how well each method worked.

What are the main results of our review?
The results of the 14 studies comparing eye drops against injections or depot devices did not show sufficiently clear differences between different methods. Not all studies reported results for the measures we were interested in.

We do not know whether one method worked better than either of the others to:

· widen the pupil (measured during surgery, and at the beginning and end of surgery);

· reduce how much time the surgery lasted; or

· reduce how much time it took to replace the lens during surgery.

Not all studies reported on unwanted effects. One study showed that eye discomfort was probably greater with eye drops than with an injection, when measured at one week (555 people) and one month (543 people) after surgery. Another study reported problems with the iris (the colored disc that surrounds the pupil) in 11 people who had an injection, compared with none in the group who had a depot device, although our confidence in these results is limited.

No studies reported on cost‐effectiveness of any of the delivery methods.

Our confidence in our results
Our confidence is limited because the results from the studies varied widely, and the studies involved only small numbers of people. Some studies did not clearly report how they were conducted, or whether the people taking part knew who had received which method of delivering the medicine, which could have affected the study's results. Further research is likely to change our results.

Background

Description of the condition

A cataract is defined as any opacity within the naturally clear lens inside the eye. The presence of opacity is associated with increased scattering of light and decreased image contrast sensitivity (Adamsons 1992; Shandiz 2011). Initially, visual acuity is often preserved, but patients commonly complain of glare or difficulty with night driving. Other symptoms include increased light sensitivity, seeing halos around lights, monocular double vision, and perceiving colors to be less bright.

Cataract formation is a multifactorial process. Age is the single biggest risk factor for developing cataracts, with the prevalence increasing from 5% for patients aged 52 to 62 years to 64% for patients aged 70 years and older (Das 1994; Navarro Esteban 2007). Other risk factors reported from multiple studies include smoking, alcohol use, ultraviolet radiation exposure, diabetes, nutritional factors, and certain medications (e.g. steroids) (Prokofyeva 2013). At present, there is no intervention that has been shown to prevent cataract formation, with surgery the only effective treatment.

Cataract is the most common cause of correctable visual impairment. In 2010, an estimated 10.8 million people worldwide were blind and 35.1 million were visually impaired due to cataract (Khairallah 2015). Although 10 million cataract operations are performed each year, the need is estimated to be at least 30 million per year (Foster 2001). It is estimated that over the next 20 years the burden will increase by about one‐third, predominantly in low‐ and middle‐income countries, although the economic impact in high‐income countries is already substantial. In the United States alone, approximately 3 million surgeries are performed annually costing USD 3.4 billion to the Centers for Medicare and Medicaid Services (Congdon 2004; Klein 2013).

Description of the intervention

Cataract surgery is one of the oldest known surgical procedures (Spalton 2000), and has evolved to become one of the safest and most commonly performed surgical procedures worldwide. Initially, the procedure of choice was intracapsular cataract extraction (ICCE), which was later followed by extracapsular cataract extraction (ECCE). However, the most significant development in cataract surgery was the introduction of phacoemulsification in 1967, which is now considered to be the gold standard technique (Kelman 1994; Linebarger 1999).

Achieving appropriate mydriasis intraoperatively is one of the critical factors associated with the ease and safety of performing cataract surgery (Grob 2014; Saenz‐de‐Viteri 2013), because most surgical steps in the procedure (except for the clear corneal incision) are performed at or behind the plane of the iris (Ho 1992). Certain high‐risk groups, such as those with pseudoexfoliation syndrome (Sangal 2014), diabetes mellitus (Smith 1983), posterior synechiae, eye trauma, and those taking alpha‐adrenergic receptor agonists (Manvikar 2006), often show poor pupillary dilation. Inadequate pupillary dilation or constriction of the pupil during cataract surgery reduces the surgeon’s field of view, can make it difficult to maneuver instruments, and is a known risk factor for various intraoperative complications such as iris prolapse/damage, incomplete cortex removal, posterior capsule rupture, dropped nucleus, vitreous loss, cystoid macular edema, and retinal detachment (Chen 2014; Goodman 1989; Hashemi 2013). Adequate pupillary dilation is therefore essential for minimizing complications of cataract surgery.

Mydriatic agents can be administered topically, which is the traditional method, or through alternative methods such as intracamerally and depot delivery systems (Mydriasert/sponge) (EMC 2020).

How the intervention might work

Topical mydriatic agents (phenylephrine, cyclopentolate, and/or tropicamide) typically have sympathomimetic or anticholinergic properties (or both) and are frequently administered before and during cataract surgery to maintain adequate pupillary dilation. However, this regimen has significant limitations. These topical agents have low penetration into the eye (2% to 10%), with most of the drug being absorbed systemically (Salminen 1990). Frequent administration of topical drops is required, typically at 5‐ to 10‐minute intervals, to achieve adequate pupil dilation before surgery. Due to the slow penetration, the maximum onset of dilation takes at least 30 minutes after instillation of drops, which can be longer than the time required for cataract surgery. Moreover, the dilation can wear off during the surgery (Liou 2009; Lundberg 2003). In addition, there is a risk of cardiovascular complications (i.e. increase in blood pressure and heart rate) associated with their use, especially in people who have a history of hypertension or underlying cardiac disease (Diamond 1997; Hakim 1990). Furthermore, frequent spillage of the drop from the palpebral fissure makes successful administration of topical mydriatics difficult in some patients.

Intracameral mydriasis involves the injection of a mydriatic agent directly into the anterior chamber after the initial incision into the eye (Lundberg 2008; Lundberg 2009). This method usually requires lesser concentrations of mydriatics as compared with standard topical doses (Lundberg 2003), and has been shown to decrease the risk of systemic adrenergic side effects, including cardiovascular complications (Fraunfelder 1985; Morgado 2010).

Depot delivery methods include Mydriasert, a long‐acting drug insert (0.28 mg tropicamide and 5.4 mg phenylephrine hydrochloride) with greater bioavailability, increased local efficacy, and decreased systemic absorption than topical mydriatic agents (Saenz‐de‐Viteri 2013). The risk of systemic complications is therefore less with Mydriasert, which can serve as a safe and effective alternative to topical mydriatics. Mydriasert is usually applied to the inferior fornix 60 minutes before surgery. Hence, it may be a simple and effective alternative. However, despite these advantages, the use of this insert is limited due to doubts regarding the best time for its insertion and its ability to maintain mydriasis long enough during cataract surgery (Saenz‐de‐Viteri 2013).

Why it is important to do this review

Traditionally, topical mydriatic drops have been used to achieve pupillary dilation during cataract surgery. Intracameral mydriatics and depot mydriatic delivery systems are reasonable alternatives but have not been well studied. We have attempted in this review to identify the most effective intervention to achieve adequate intraoperative mydriasis during cataract surgery.

Objectives

To evaluate the relative effectiveness of achieving pupillary dilation during phacoemulsification for cataract extraction using various methods of pupillary dilation: topical mydriatics, intracameral mydriatics, or depot delivery systems. We also planned to document and to compare the risk of intraoperative and postoperative complications following phacoemulsification for cataract extraction as well as the cost‐effectiveness of these methods for pupillary dilation.

Methods

Criteria for considering studies for this review

Types of studies

We included only randomized controlled trials (RCTs).

Types of participants

We included trials in which participants underwent phacoemulsification for cataract extraction; we excluded studies of Femtosecond laser‐assisted cataract surgery. We did not apply any age or gender restrictions.

Types of interventions

We included trials that compared the effectiveness and safety of the following pairs of interventions:

1. topical mydriatics versus intracameral mydriatics;

2. topical mydriatics versus depot delivery systems;

3. intracameral mydriatics versus depot delivery systems.

We did not include dosing studies in which no active comparison group was included. We did not include studies that compared only one type of mydriatic agent with placebo.

Types of outcome measures

Primary outcomes

The primary outcome for this review was mean pupillary diameter (millimeters) at the time surgeons had performed capsulorhexis, measured using a pupillometer, surgical caliper, or comparable device or measurements registered from digital video recordings of cataract surgery. We also assessed and compared the mean pupillary diameter at the beginning of the cataract surgery and at the end of the surgery when data were available.

Secondary outcomes

1. Total intraoperative surgical time, from when the initial incision was made to the end of the procedure when the surgery was complete and the eye patched.

2. Total time the surgeon took to perform phacoemulsification.

3. Participant‐reported ocular discomfort at any time during or after the surgery.

Adverse events

We compared the risk of intraoperative complications including iris prolapse or damage, incomplete cortex removal, posterior capsule rupture, dropped nucleus, vitreous loss, cystoid macular edema, and retinal detachment when data were available.

We also investigated the risk of cardiovascular complications (other than transient increases in blood pressure and heart rate) pre‐, intra‐, and postoperatively when relevant data were reported.

Economic outcomes

We planned to compare the cost of procedures assessed in the included trials in order to determine whether the use of one mydriatic delivery method had a significant cost‐effectiveness benefit over the others that would warrant its use in clinical practice.

Search methods for identification of studies

Electronic searches

The Cochrane Eyes and Vision Information Specialist searched the following electronic databases for RCTs and controlled clinical trials. There were no restrictions on language or year of publication. We last searched the electronic databases on 22 January 2021.

1. Cochrane Central Register of Controlled Trials (CENTRAL, 2021, Issue 1) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (searched 22 January 2021) (Appendix 1).

2. MEDLINE Ovid (1946 to 22 January 2021) (Appendix 2).

3. Embase.com (1947 to 22 January 2021) (Appendix 3).

4. PubMed (1946 to 22 January 2021) (Appendix 4).

5. Latin American and Caribbean Health Science Information Database (LILACS) (1982 to 22 January 2021) (Appendix 5).

6. US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 22 January 2021) (Appendix 6).

7. World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp; searched 22 January 2021) (Appendix 7).

Searching other resources

We searched the reference lists of reports from identified trials to look for additional trials. We did not conduct manual searches of conference proceedings or abstracts specifically for this review because conference proceedings from relevant ophthalmology meetings are searched annually by Cochrane Eyes and Vision, and abstracts are included in the CENTRAL database.

Data collection and analysis

Selection of studies

Although the search results included both RCTs and CCTs (i.e., in case few RCTs were identified), only RCTs were selected for inclusion in the review. Two review authors independently classified each record identified by the searches as relevant, potentially relevant, or definitely not relevant. We retrieved the full‐text reports of records assessed as relevant or potentially relevant by either review author. Two review authors also independently screened each full‐text report to determine eligibility of the reported study for inclusion in the review, classifying each study as eligible for inclusion, to be excluded, or uncertain. We documented studies excluded at this stage and reported the reasons for exclusion. We allowed the authors of study reports classified as uncertain two weeks to respond to our request for information required to determine eligibility for our review. We included or excluded such studies based on the information available at the end of the two‐week period.

Disagreements between the pairs of review authors who screened records and reports were resolved by discussion or by arbitration from a third review author as needed. We did not mask the names of the authors, institutions, or journals when reviewing study reports.

Data extraction and management

Two review authors independently extracted data from the included trials using a standard data extraction form. We extracted data related to study and participant characteristics, study methods, and outcomes. Any discrepancies or disagreements were resolved through discussion or by arbitration from a third review author as needed. One review author entered the data into Review Manager 5 (Review Manager 2020), and a second review author checked the data for accuracy.

Assessment of risk of bias in included studies

Two review authors independently assessed the included trials for risk of bias. We assessed the following domains for each included trial as described in Chapter 8 of the Cochrane Handbookfor Systematic Reviews of Interventions (Higgins 2017).

1. Selection bias: random sequence generation and allocation concealment before randomization

2. Performance bias: masking of participants and personnel

3. Detection bias: masking of outcome assessment

4. Attrition bias: completeness of outcome data

5. Reporting bias: reporting of all planned study outcomes. When the protocol or clinical trial registry record for the included trial was available, we evaluated the study for evidence of systematic differences between reported and unreported findings.

We assessed each 'Risk of bias' domain for each included study as low, high, or unclear (indeterminate) and provided descriptions of reasons for our assessments. Any disagreements between review authors were resolved by discussion or by consulting a third review author when necessary. No other specific source of bias was evaluated.

Measures of treatment effect

We calculated mean differences with 95% confidence intervals for outcome measures reported as continuous data (pupillary diameter at various times during surgery, total intraoperative surgical time, total time to perform phacoemulsification). We calculated risk ratios with 95% confidence intervals for outcome measures reported as dichotomous data (the proportion of participants with adverse events and participant‐reported ocular discomfort).

Unit of analysis issues

The unit of analysis was the participant in 13 of 14 included studies, in which only one eye of each participant was of interest. The exception was Yu 2016, which had a paired‐eyes design in which opposite interventions were assigned to the two eyes of each participant. We had planned to extract data that accounted for the correlation and referred to Chapter 23 of the Cochrane Handbook for Systematic Reviews of Interventions for guidelines (Higgins 2021). However, in the report from that trial, data from both eyes of each participant were analyzed with the eye as the unit of analysis without adjustment for intraocular correlation of outcomes. We therefore included data from this study in our review and assessed its impact on the effect estimates in sensitivity analyses restricted to studies for which the participant was the unit of randomization and analysis.

Dealing with missing data

We performed our analyses using the available data. We did not impute data for the purposes of this review.

Assessment of heterogeneity

We assessed clinical, methodological, and statistical heterogeneity among included studies. When no substantial clinical or methodological heterogeneity was identified, we combined studies in meta‐analysis to estimate overall relative effects across studies. We judged the consistency of effect estimates across studies by examining the value of the I² statistic, consistency in the direction of effect estimates, and the overlap of confidence intervals in the forest plots. We considered I² values greater than 60% to represent substantial statistical heterogeneity. Differences in the direction of effects and poor overlap of confidence intervals among studies also suggested heterogeneity among studies.

Assessment of reporting biases

We did not assess publication bias with the funnel plot and Egger’s regression intercept because no meta‐analysis included a sufficient number (10 or more) studies for such an assessment to be informative. We assessed potential selective outcome reporting by study as part of the 'Risk of bias' assessment.

Data synthesis

When data were sufficient and no substantial clinical, methodological, or statistical heterogeneity was identified, we conducted meta‐analysis using a random‐effects model. We used a fixed‐effect model when fewer than three studies were included in a meta‐analysis. Whenever we determined that conducting a meta‐analysis was inappropriate due to the presence of heterogeneity, we have provided a narrative or tabulated summary. We used a 95% confidence interval throughout.

Subgroup analysis and investigation of heterogeneity

We did not undertake any subgroup analysis due to lack of sufficient data regarding baseline characteristics of participants in the included trials. When sufficient data are available in a future update of this review, we will compare effect estimates between pairs of subgroups defined a priori:

1. participants using alpha‐adrenergic agonists versus not using alpha‐adrenergic agonists;

2. participants with pseudoexfoliation syndrome versus without pseudoexfoliation syndrome;

3. participants with diabetes mellitus versus non‐diabetics;

4. participants with pre‐existing cardiac conditions versus those without; and

5. participants receiving preoperative and intraoperative non‐steroidal anti‐inflammatory drugs versus those not given such drugs.

We will determine whether the treatment effect differs between pairs of subgroups and assess the overlap in confidence intervals.

Sensitivity analysis

We did not conduct any of the following planned sensitivity analyses because sufficient data were not available:

1. excluding trials assessed as being at high risk of bias for allocation concealment or masking domains;

2. excluding studies that were industry funded; and

3. excluding completed studies with findings that have not been published in a full‐length report.

Summary of findings and assessment of the certainty of the evidence

We prepared a 'Summary of findings' table for the main outcomes for each comparison (topical mydriatics versus intracameral mydriatics, topical mydriatics versus depot delivery systems, and intracameral mydriatics versus depot delivery systems). The seven main outcomes for this review were as follows.

1. Mean pupillary diameter (mm) at the beginning of cataract surgery

2. Mean pupillary diameter (mm) before capsulorhexis

3. Mean pupillary diameter (mm) at the end of cataract surgery

4. Total intraoperative surgical time

5. Total time to perform phacoemulsification

6. Participant‐reported ocular discomfort after each intervention at any time point during or after the surgery

7. Proportion of participants with adverse events during or after surgery.

We assessed the certainty of the evidence using the GRADE approach (GRADEpro GDT), grading the evidence for each outcome as high, moderate, low, or very low with penalties for specific deficiencies according to the criteria described in Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2021). Initially, we judged the evidence from each included study as high due to the randomized design, which provided direct evidence. We reduced the certainty of evidence by:

1. high risk of bias among included studies;

2. indirectness of evidence;

3. unexplained heterogeneity or inconsistency of results;

4. imprecision of results (i.e. wide confidence intervals); and

5. high probability of publication bias

We downgraded the certainty of evidence by one point for each of the above deficiencies, and presented a 'Summary of findings' table (Table 1; Table 2; Table 3) for each comparison of interest when data were available. The following comparisons were included:

Summary of findings 1. Topical mydriatics compared to intracameral mydriatics for mydriasis in cataract surgery.

Topical mydriatics compared to intracameral mydriatics for mydriasis in cataract surgery
Patient or population: patients undergoing cataract surgery Setting: hospital Intervention: topical mydriatics Comparison: intracameral mydriatics
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with intracameral mydriatics	Risk with topical mydriatics
Mean pupillary diameter—at the time the surgeon performs capsulorhexis (mm)	We noted that the design of Yu 2016 (paired‐eyes) differed from that of the other 3 studies. The overall effect estimate after omitting Yu 2016 was MD 1.06, 95% CI 0.81 to 1.31; I2 = 49%; 3 RCTs, 721 eyes.		‐	757 (4 RCTs)	⊕⊕⊝⊝ LOW 1 3	‐
Mean pupillary diameter—at the beginning of cataract surgery (mm)	Data from Labetoulle 2016 showed no difference of effect for pupil dilation, whereas the other 3 RCTs favored the use of topical mydriatics.		‐	242 (4 RCTs)	⊕⊕⊝⊝ LOW 1 2	We omitted Yu 2016, which had a large effect estimate (RR 2.89, 95% CI 2.40 to 3.38), and this had little effect on statistical heterogeneity (I2 = 80% after omission).
Mean pupillary diameter—at the end of cataract surgery (mm)	Data for this outcome from 1 RCT favored intracameral mydriasis; 2 RCTs found no difference between interventions, and 2 RCTs favored topical mydriatics.		‐	799 (5 RCTs)	⊕⊕⊝⊝ LOW 1 2	There was high heterogeneity (I2 = 93%), and therefore did not combine estimates from the 5 RCTs for this outcome. Omitting Yu 2016 which had a large point estimate (RR 1.96, 95% CI 1.35 to 2.57), did not reduce heterogeneity substantially (I2 = 81%).
Total intraoperative surgical time (min)	3 RCTs favored topical mydriatic use for decreased total intraoperative time; 1 RCT found increased in total intraoperative time with intracameral mydriatics; and 1 RCT found no difference between the 2 approaches to mydriasis.		‐	817 (5 RCTs)	⊕⊕⊝⊝ LOW 1 3	We omitted Yu 2016 and Labetoulle 2016 that accounted for high heterogeneity, and combined the remaining 3 RCTs (RR ‐0.24; 95% CI: ‐1.08 to 0.60, I2 = 0%; 232 participants)
Total time it took for the surgeon to perform phacoemulsification (seconds)	Bäckström 2013 reported less time with intracameral mydriatics, whereas Yu 2016 reported less time with the use of topical mydriatics.		‐	48 (2 RCTs)	⊕⊝⊝⊝ VERY LOW 1 2 3	‐
AE: participant‐reported ocular discomfort—week 1	4 per 1000	39 per 1000 (5 to 299)	RR 10.57 (1.37 to 81.34)	555 (1 RCT)	⊕⊝⊝⊝ VERY LOW 1 3	‐
AE: participant‐reported ocular discomfort—month 1	49 per 1000	123 per 1000 (66 to 227)	RR 2.51 (1.36 to 4.65)	543 (1 RCT)	⊕⊕⊕⊝ MODERATE 1	‐
AE: posterior capsule rupture	4 per 1000	1 per 1000 (0 to 29)	RR 0.32 (0.01 to 7.83)	555 (1 RCT)	⊕⊕⊝⊝ LOW 1 3	‐
AE: posterior capsule rupture—any time point during or after surgery	4 per 1000	1 per 1000 (0 to 29)	RR 0.32 (0.01 to 7.83)	555 (1 RCT)	⊕⊕⊝⊝ LOW 1 3	‐
AE: cystoid macular edema	4 per 1000	1 per 1000 (0 to 29)	RR 0.32 (0.01 to 7.83)	555 (1 RCT)	⊕⊕⊝⊝ LOW 1 3	‐
AE: cystoid macular edema ‐ any time point during or after surgery	4 per 1000	1 per 1000 (0 to 29)	RR 0.32 (0.01 to 7.83)	555 (1 RCT)	⊕⊕⊝⊝ LOW 1 3	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AE: adverse event; CI: confidence interval; MD: mean difference; RCT: randomized controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹Downgraded one level for risk of bias (most 'Risk of bias' domains were either unclear or high risk).
²Downgraded one level for inconsistency due to high statistical heterogeneity or poor overlap of confidence intervals, or both.
³Downgraded one level for imprecision due to wide confidence intervals.

Summary of findings 2. Topical mydriatics compared to depot delivery systems for mydriasis in cataract surgery.

Topical mydriatics compared to depot delivery systems for mydriasis in cataract surgery
Patient or population: patients undergoing cataract surgery Setting: hospital Intervention: topical mydriatics Comparison: depot delivery systems
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with depot delivery systems	Risk with topical mydriatics
Mean pupillary diameter—at the time the surgeon performs capsulorhexis (mm)	‐	‐	‐	‐	‐	Data were not reported.
Mean pupillary diameter—at the beginning of cataract surgery (mm)	The mean pupillary diameter at the beginning of cataract surgery was 5.09.	MD 0.02 lower (0.22 lower to 0.19 higher)	‐	324 (5 RCTs)	⊕⊕⊝⊝ LOW 1 2	We omitted Dubois 2006 from calculation of the overall effect estimate because it contributed to high heterogeneity (I2 = 80%).
Mean pupillary diameter—at the end of cataract surgery (mm)	The mean pupillary diameter at the end of cataract surgery was 5.8.	MD 0.09 lower (0.71 lower to 0.54 higher)	‐	210 (3 RCTs)	⊕⊕⊝⊝ VERY LOW 1 2	‐
Intraoperative surgical time—total intraoperative time (min)	The mean intraoperative surgical time—total intraoperative time was 15.87.	MD 0.88 higher (0.64 lower to 2.4 higher)	‐	58 (1 RCT)	⊕⊝⊝⊝ VERY LOW 1 2 3	‐
AE: participant‐reported ocular discomfort—week 1	‐	‐	‐	‐	‐	Data were not reported.
AE: participant‐reported ocular discomfort—month 1	‐	‐	‐	‐	‐	Data were not reported.
AE: vitreous loss—any time point during or after surgery	‐	‐	‐	‐	‐	Data were not reported.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AE: adverse event; CI: confidence interval; MD: mean difference; RCT: randomized controlled trial
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹Downgraded one level for risk of bias (most 'Risk of bias' domains were either unclear or high risk).
²Downgraded one level for inconsistency due to high statistical heterogeneity or poor overlap of confidence intervals, or both.
³Downgraded one level for imprecision due to wide confidence intervals.

Summary of findings 3. Intracameral mydriatics compared to depot delivery systems for mydriasis in cataract surgery.

Intracameral mydriatics compared to depot delivery systems for mydriasis in cataract surgery
Patient or population: patients undergoing cataract surgery Setting: hospital Intervention: intracameral mydriatics Comparison: depot delivery systems
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
	Risk with depot delivery systems	Risk with intracameral mydriatics
Mean pupillary diameter—at the time the surgeon performs capsulorhexis (mm)	‐	‐	‐	‐	Data were not reported.
Mean pupillary diameter—at the beginning of cataract surgery (mm)	The mean pupillary diameter at the beginning of cataract surgery was 0.	MD 1.9 lower (2.45 lower to 1.35 lower)	‐	60 (1 RCT)	⊕⊕⊝⊝ VERY LOW 1 2
Mean pupillary diameter—at the end of cataract surgery (mm)	The mean pupillary diameter at the end of cataract surgery was 8.2.	MD 1.6 lower (2.13 lower to 1.07 lower)	‐	60 (1 RCT)	⊕⊕⊝⊝ VERY LOW 1 2
Intraoperative surgical time—total intraoperative time (min)	The mean intraoperative surgical time—total intraoperative time was 7.7.	The mean difference in intraoperative surgical times reportedly favored depot delivery (MD 4.2 min, P < 0.05, ANOVA)	‐	60 (1 RCT)	⊕⊕⊝⊝ VERY LOW 1 2
AE: participant‐reported ocular discomfort—week 1	‐	‐	‐	‐	Data were not reported.
AE: participant‐reported ocular discomfort—month 1	‐	‐	‐	‐	Data were not reported.
Adverse events	Posterior capsule rupture occurred at the irrigation/aspiration phase in 1 participant (3.3%), and iris‐related complications, including flaccid iris, iris herniation, and iris capture by the handpiece, were observed in 11 participants (36.6%), all in the intracameral mydriatics group. No complication was reported for the depot delivery system group.		‐	60 (1 RCT)	⊕⊕⊝⊝ VERY LOW 1 2
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AE: adverse event; ANOVA: analysis of variance; CI: confidence interval; MD: mean difference; RCT: randomized controlled trial
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹Downgraded one level for risk of bias (most 'Risk of bias' domains were either unclear or high risk).
²Downgraded two levels for imprecision due to small sample size and wide confidence intervals.

• topical mydriatics versus intracameral mydriatics

• topical mydriatics versus depot delivery systems

• intracameral mydriatics versus depot delivery systems

Results

Description of studies

Results of the search

The searches of the electronic databases on 12 September 2019 yielded 2149 records (2139 after duplicates were removed). After screening titles and abstracts, we identified 27 relevant reports for full‐text review. Of these, we excluded the studies in 11 reports and documented our reasons for exclusion. We assessed studies in two reports as awaiting classification, one of which was a report from an ongoing trial. We included 14 RCTs identified from 14 reports in the review. In a top‐up search conducted on 22 January 2021, we identified 183 records; screened 181 records after removal of duplicates; retrieved 11 full‐text reports and further excluded 10 reports with reasons; and classified one record as an ongoing trial (Figure 1). Overall, we included 14 RCTs; excluded 21 studies (21 records); assessed two studies (two records) as ongoing trials; and categorized two studies (two records) as awaiting classification.

1.

Study flow diagram.

Included studies

The characteristics of each of the 14 included RCTs are described in the Characteristics of included studies table.

Type of studies

Thirteen of the 14 RCTs had a parallel‐group design in which one eye of each participant was randomized to a mydriatic delivery method. Yu 2016 had a paired‐eyes study design: one eye of each participant was randomly selected to be in one treatment group, and the other eye was assigned to the other group. Thirteen of the included studies were single‐center trials conducted in China (2 RCTs), Spain (2 RCTs), Sweden (3 RCTs), the United Kingdom (2 RCTs), and 1 RCT each in Denmark, Malaysia, Portugal, and India. Labetoulle 2016 was the only multicenter study; participants in that trial enrolled from nine countries (France, Germany, Belgium, Portugal, Italy, Spain, Algeria, Austria, Sweden).

Type of participants

Overall, 1670 eyes of 1652 participants were included in the 14 RCTs. The numbers of participants in individual studies ranged from 18 to 591 (median = 65). The mean age of the participants was 69 years (range 57 to 78 years). Typically, more than half the participants in each trial were women; however, one trial enrolled only men (Hargitai 2013), all of whom were being treated for benign prostatic hyperplasia. Four of the trials were conducted in Asian countries and presumably enrolled only or primarily Asian participants; the remaining trials did not report the race or ethnicity of participants.

Type of interventions

Seven RCTs compared only topical mydriatics and intracameral mydriatics (Bäckström 2013; Johansson 2007; Labetoulle 2016; Lay Suan 2017; Li 2006; Lundberg 2003; Yu 2016); six other RCTs compared only topical mydriatics and depot delivery systems (Dubois 2006; Hargitai 2013; McCormick 2006; Saenz‐de‐Viteri 2013; Sengupta 2010; Torrón 2013); and one RCT compared all three methods of administration, that is topical mydriatics, intracameral mydriatics, and depot delivery systems (Morgado 2010). Consequently, there were data for comparisons of topical mydriatics versus intracameral mydriatics (8 trials), topical versus depot delivery of mydriatics (7 trials), and intracameral versus depot delivery (1 trial).

Type of outcomes

Investigators of only six RCTs reported preoperative pupil diameter (range 1.96 to 9.2 mm); Labetoulle 2016 reported only that all pupils were at least 7.0 mm or larger 30 minutes after dilation at the "selection visit." Four RCTs, all of which compared topical mydriatics with intracameral mydriatics, reported our primary outcome of pupil diameter (mm) at the time the surgeon performed capsulorhexis (Labetoulle 2016; Lay Suan 2017; Li 2006; Yu 2016).

Nine RCTs reported on the pupil diameter at the beginning of the cataract surgery (Bäckström 2013; Dubois 2006; Hargitai 2013; Li 2006; McCormick 2006; Morgado 2010; Saenz‐de‐Viteri 2013; Torrón 2013; Yu 2016), of which three compared topical mydriatics with intracameral mydriatics (Bäckström 2013; Li 2006; Yu 2016), five topical mydriatics versus depot delivery systems (Dubois 2006; Hargitai 2013; McCormick 2006; Saenz‐de‐Viteri 2013; Torrón 2013), and one that compared all three methods of administration (Morgado 2010). Eight RCTs reported the pupil diameter at the end of the cataract surgery (Bäckström 2013; Labetoulle 2016; Lay Suan 2017; Morgado 2010; Saenz‐de‐Viteri 2013; Sengupta 2010; Torrón 2013; Yu 2016), of which four compared topical mydriatics with intracameral mydriatics (Bäckström 2013; Labetoulle 2016; Lay Suan 2017; Yu 2016), three topical versus depot delivery systems (Saenz‐de‐Viteri 2013; Sengupta 2010; Torrón 2013), and one that compared all three methods of administration (Morgado 2010).

Seven RCTs reported on our secondary outcome of total intraoperative surgical time (Bäckström 2013; Hargitai 2013; Labetoulle 2016; Lay Suan 2017; Lundberg 2003; Morgado 2010; Yu 2016); only two of these RCTs included comparisons with depot delivery systems (Hargitai 2013; Morgado 2010). One RCT reported phacoemulsification time and mydriatic response, but did not specify the time during surgery at which these outcomes were assessed (Johansson 2007).

Two RCTs reported the total time the surgeon had taken for phacoemulsification when comparing topical versus intracameral mydriatics (Bäckström 2013; Yu 2016). No included RCT reported costs for any of the comparisons of methods of mydriasis.

Adverse events

Three studies reported adverse events (Labetoulle 2016; Hargitai 2013; Morgado 2010).

Excluded studies

We excluded 21 reports after full‐text screening. The reasons for exclusion are summarized in the Characteristics of excluded studies table. Briefly, 11 studies were not RCTs; two were not conducted in the population of interest; one evaluated an intervention of interest but only after cataract surgery; and seven did not evaluate either the interventions (3 RCTs) or the comparator (4 RCTs) of interest.

Ongoing studies and studies awaiting classification

We identified one ongoing trial; two trials are awaiting classification when more information about the trials becomes available.

Risk of bias in included studies

We have provided our judgements regarding the risk of bias in the individual included trials in Figure 2. We did not classify any included study as having been at low risk of bias in all domains assessed. The overall risk of bias in the 14 RCTs is summarized in Figure 3.

2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Random sequence generation

Only four of the 14 RCTs reported the method of random sequence generation (Bäckström 2013; McCormick 2006; Sengupta 2010; Yu 2016); we judged these three studies to be at low risk of bias for random sequence generation.

Allocation concealment before assignment

Three RCTs reported that allocation was concealed prior to random assignment (Hargitai 2013; McCormick 2006; Sengupta 2010); we judged these studies to be at low risk of bias for treatment allocation concealment. Two of these three RCTs used draws of cards marked with the assignment, but the details of the method, such as number of cards in the batch and whether draws were with replacement, were not reported; therefore it is unclear whether treatment allocation concealment was achieved (McCormick 2006; Sengupta 2010). The remaining eleven RCTs did not describe how treatment allocation was concealed. We judged these 11 studies to be at unclear (indeterminate) risk of bias for this domain. We judged only two RCTs to be at low risk of selection bias when both random sequence generation and allocation concealment were considered (McCormick 2006; Sengupta 2010).

Masking (performance bias and detection bias)

Reports from four RCTs stated that both participants and surgeons were masked to the assigned intervention (Bäckström 2013; Johansson 2007; Lundberg 2003; Torrón 2013), therefore we judged these studies to be at low risk of performance bias. We judged another four RCTs to be at high risk for performance bias: reports from three of these RCTs stated that the surgeons were masked, but masking of participants was either not described or was not possible due to the nature of the intervention (Hargitai 2013; McCormick 2006; Sengupta 2010), and in one RCT, investigators reported that participants but not surgeons were masked (Yu 2016). We judged the remaining six RCTs to be at unclear risk of performance bias because investigators did not report whether or how participants and surgeons were masked.

Seven RCTs stated that outcome assessors (i.e. the person who measured the pupil diameters) were masked (Dubois 2006; Johansson 2007; Labetoulle 2016; McCormick 2006; Sengupta 2010; Torrón 2013; Yu 2016); we judged these studies to be at low risk of detection bias. Masking was not mentioned in reports from the remaining seven RCTs (Bäckström 2013; Hargitai 2013; Lay Suan 2017; Li 2006; Lundberg 2003; Morgado 2010; Saenz‐de‐Viteri 2013), therefore we judged these studies as having had unclear (indeterminate) risk of detection bias.

Incomplete outcome data

We considered 10 RCTs to be at low risk of attrition bias because there were no missing data on outcomes included in our review (Bäckström 2013; Hargitai 2013; Johansson 2007; Labetoulle 2016; McCormick 2006; Morgado 2010; Saenz‐de‐Viteri 2013; Sengupta 2010; Torrón 2013; Yu 2016). We judged one RCT to be at high risk of attrition bias because 15%  of participants  were excluded from analysis (Dubois 2006). We assessed the remaining three RCTs to be at unclear risk of attrition bias.

Selective reporting

We considered three RCTs to be at low risk of bias for selective reporting because the prespecified outcomes in trial registry records had been reported (Hargitai 2013; McCormick 2006; Yu 2016). Another RCT did not report all adverse events posted in the trial registry (Labetoulle 2016); we judged this study as at high risk of bias for this domain. The remaining 10 RCTs did not provide sufficient information in protocols or registry records to judge risk of reporting bias.

Other potential sources of bias

None.

Effects of interventions

See: Table 1; Table 2; Table 3

Eight RCTs compared topical mydriatics to intracameral mydriatics (Bäckström 2013; Johansson 2007; Labetoulle 2016; Lay Suan 2017; Li 2006; Lundberg 2003; Morgado 2010; Yu 2016); seven RCTs compared topical mydriatics to depot delivery systems for pupil dilation at the time of cataract surgery (Dubois 2006; Hargitai 2013; McCormick 2006; Morgado 2010; Saenz‐de‐Viteri 2013; Sengupta 2010; Torrón 2013); and Morgado 2010 also compared intracameral mydriatics to depot delivery systems.

Comparison 1: topical mydriatics versus intracameral mydriatics (8 RCTs)

Of the eight RCTs from which data for this comparison were reported, seven had evaluated one eye per participant; numbers of participants ranged from 60 (Bäckström 2013; Lundberg 2003; Morgado 2010) to 591 (Labetoulle 2016). Yu 2016 had a paired‐eyes design; data for 36 eyes of 18 participants were reported from this trial.

Pupil diameter at the time surgeons performed capsulorhexis

Four RCTs (Labetoulle 2016; Lay Suan 2017; Lundberg 2003; Yu 2016), which together randomized 739 participants (757 eyes), reported pupil diameter at the time the surgeons had performed capsulorhexis. Mean pupil diameter was greater with topical mydriatics in all studies, with the mean difference (MD) ranging from 0.83 mm to 1.77 mm; however, we did not calculate a summary effect estimate from the four studies due to very high heterogeneity (I² = 72%) (Analysis 1.1.1; Figure 4). We noted that the design of Yu 2016 (paired eyes), with a large point estimate of risk ratio (RR) 1.77, 95% confidence interval (CI) 1.31 to 2.23 differed from that of the other three studies. The overall effect estimate after omitting Yu 2016 was MD 1.06, 95% CI 0.81 to 1.31; I² = 49%; 3 RCTs, 721 eyes. We assessed the certainty of evidence from the three RCTs as low after downgrading for risk of bias and imprecision.

1.1. Analysis.

Comparison 1: Topical mydriatics versus intracameral mydriatics, Outcome 1: Mean pupillary diameter

4.

Forest plot of comparison: 1 Topical mydriatics vs intracameral mydriatics, outcome: 1.1 Mean pupillary diameter.

Pupil diameter at the beginning of cataract surgery

Four RCTs (Bäckström 2013; Li 2006; Morgado 2010; Yu 2016), with a combined enrollment of 224 participants (242 eyes), compared pupil diameter at the beginning of cataract surgery. Effect estimates from all four trials favored topical mydriatics. We detected considerable heterogeneity (I² = 92%) (Analysis 1.1.2; Figure 4), and therefore did not combine estimates from the studies for this outcome. Omitting Yu 2016, which had a large effect estimate (RR 2.89, 95% CI 2.40 to 3.38), had little effect on statistical heterogeneity (I² = 80% after omission). We assessed the certainty of evidence as low after downgrading for risk of bias and inconsistency.

Pupil diameter at the end of cataract surgery

Five RCTs (Bäckström 2013; Labetoulle 2016; Lay Suan 2017; Morgado 2010; Yu 2016), with 799 participants (817 eyes) total, compared pupil diameter at the end of cataract surgery. Effect estimates from individual trials ranged from 0.24 mm in favor of intracameral mydriatics, to 1.96 mm in favor of topical mydriatics. Data for this outcome from three RCTs showed no difference between interventions; point estimates from two RCTs favored topical mydriatics, and from one RCT favored intracameral mydriasis (Analysis 1.1.3, Figure 4). We detected high heterogeneity (I² = 93%), and therefore did not combine estimates from the five studies for this outcome. Again, omitting Yu 2016, which had a large point estimate (RR 1.96, 95% CI 1.35 to 2.57), did not reduce heterogeneity substantially (I² = 81%). We assessed the certainty of evidence as low after downgrading for risk of bias and inconsistency.

Total intraoperative time

Five RCTs (Bäckström 2013; Labetoulle 2016; Lay Suan 2017; Lundberg 2003; Yu 2016), with a combined enrollment of 799 participants (817 eyes), reported total intraoperative time. Three of these trials found no difference between the two methods. Point estimates from one small trial (Yu 2016) (18 participants) favored topical mydriatics, and from the largest trial (Labetoulle 2016) (296 participants) favored intracameral mydriatics in terms of decreased total intraoperative time. Because of the high heterogeneity (I² = 100%) (Analysis 1.2.1, Figure 5), we re‐examined the reports from the two RCTs that produced the two outlier estimates. Yu 2016 had a paired‐eyes design with surgery in the second eye performed two days after surgery in the first eye. Labetoulle 2016 reported the combined preoperative and surgery times for the two interventions rather than merely intraoperative surgery times; the investigators of this study also reported that the time to perform the technical part of the cataract extraction and lens implantation (i.e. between capsulorhexis and end of surgery) was similar between groups (P = 0.840). We repeated the analysis without Yu 2016 and Labetoulle 2016; while we observed a substantial reduction in the statistical heterogeneity from (I² = 100%) to (I² = 0%), after combining the remaining three trials in a meta‐analysis,there was no evidence of adifference in the effect estimate before and after their omission from analysis (RR ‐0.24; 95% CI: ‐1.08 to 0.60, I² = 0%; 3 RCT, 232 participants). We assessed the certainty of evidence as low, downgrading for risk of biasand imprecision. Morgado 2010 also reported means for this outcome (8.3 min for topical mydriatics and 12.3 min for intracameral mydriatics), reportedly yielding a statistically significant difference between methods of mydriasis, but did not report standard deviations that would have permitted estimation of a confidence interval on the mean difference and inclusion of data from this trial in the forest plot.

1.2. Analysis.

Comparison 1: Topical mydriatics versus intracameral mydriatics, Outcome 2: Intraoperative surgical time

5.

Forest plot of comparison: 1 Topical mydriatics vs intracameral mydriatics, outcome: 1.2 Intraoperative surgical time.

Phacoemulsification time

Two RCTs that together enrolled 78 participants (98 eyes) evaluated time required for the surgeon to perform phacoemulsification. Bäckström 2013 reported a mean of 5.4 s less time with intracameral mydriatics, whereas Yu 2016 reported a mean of 2.45 s less time with the use of topical mydriatics. We detected heterogeneity (I² = 89%; difference in direction of effect; non‐overlapping confidence intervals), and therefore did not combine estimates from the two studies for this outcome (Analysis 1.3, Figure 6). We assessed the certainty of evidence as very low, downgrading for risk of bias, inconsistency, and imprecision.

1.3. Analysis.

Comparison 1: Topical mydriatics versus intracameral mydriatics, Outcome 3: Total time it took for the surgeon to perform phacoemulsification (seconds)

6.

Forest plot of comparison: 1 Topical mydriatics vs intracameral mydriatics, outcome: 1.3 Total time it took for the surgeon to perform phacoemulsification (seconds).

Participant‐reported ocular discomfort at any time during or after the surgery

One RCT with 555 participants reported adverse events (Labetoulle 2016): 11 (3.8%) participants at week 1 and 34 (12.2%) participants at month 1 in the topical mydriatics group experienced ocular discomfort, whereas 1 (0.3%) participant at week 1 and 13 (4.8%) participants at month 1 experienced ocular discomfort in the intracameral mydriatics group. Point estimates indicate that compared with participants in the intracameral mydriatics group, those in the topical mydriatics group were more likely to experience adverse events at one week (RR 10.57, 95% CI 1.37 to 81.34; 1 RCT, 555 participants) and at one month (RR 2.51, 95% CI 1.36 to 4.65; 1 RCT, 543 participants) (low‐certainty evidence after downgrading for risk of bias and imprecision (−1) for the one‐week outcome, and moderate‐certainty evidence for the one‐month outcome after downgrading for risk of bias) (Analysis 1.4).

1.4. Analysis.

Comparison 1: Topical mydriatics versus intracameral mydriatics, Outcome 4: AE: participant‐reported ocular discomfort

Adverse events reported

Posterior capsule rupture and cystoid macular edema were reported in one participant in the intracameral mydriatics group. Posterior capsule rupture and cystoid macular edema were rare in both groups, 0/283 and 1/272 events for both posterior capsule rupture and cystoid macular edema in the topical and intracameral groups, respectively. Point estimates were the same for these events and indicated no difference between the two groups in terms of posterior capsule rupture or cystoid macular edema (RR 0.32, 95% CI 0.01 to 7.83). We assessed the certainty of evidence for both outcomes as low after downgrading for risk of bias and imprecision. Cardiovascular related adverse events were never mentioned.

Cost outcomes

No study compared costs between topical and intracameral methods of mydriasis.

Comparison 2: topical mydriatics versus depot delivery systems (7 RCTs)

Seven RCTs reported data for this comparison. The numbers of participants enrolled and randomized in each study ranged from 56 (McCormick 2006) to 225 (Sengupta 2010). Only one eye per participant was assessed in each trial.

Pupil diameter at the time surgeons performed capsulorhexis

No RCT that compared topical mydriatics with a depot delivery system reported pupil dilation achieved at the time the surgeon performed capsulorhexis using the two methods.

Pupil diameter at the beginning of cataract surgery

Six RCTs reported the pupil diameter at the beginning of cataract surgery for a combined total of 434 participants (Dubois 2006; Hargitai 2013; McCormick 2006; Morgado 2010; Saenz‐de‐Viteri 2013; Torrón 2013). Owing to substantial statistical heterogeneity (I² = 80%), we did not calculate an overall effect estimate for the six studies (Analysis 2.1, Figure 7). Heterogeneity was reduced after omitting Dubois 2006, which excluded a large proportion of participants (15%) from analysis; the overall effect estimate without that study showed no evidence of a difference between the two groups (MD −0.02, 95% CI −0.22 to 0.19; I² = 0%; 5 RCTs, 324 participants). We assessed the certainty of evidence as low, downgrading for risk of bias and imprecision.

2.1. Analysis.

Comparison 2: Topical mydriatics versus depot delivery systems, Outcome 1: Mean pupillary diameter

7.

Forest plot of comparison: 2 Topical mydriatics vs depot delivery systems, outcome: 2.1 Mean pupillary diameter.

Pupil diameter at the end of cataract surgery

Three RCTs with 210 participants reported the pupil diameter at the end of cataract surgery (Morgado 2010; Saenz‐de‐Viteri 2013; Torrón 2013). Point estimates of effect ranged from 0.70 mm in favor of the depot delivery system to 0.36 in favor of topical mydriatics. We detected substantial statistical heterogeneity (I² = 0.78%), and therefore did not calculate an overall mean difference (Analysis 2.1, Figure 7). Sengupta 2010 also reported means that yielded a larger difference in favor of depot delivery than any of the other estimates (4.4 mm for topical drops and 5.8 for depot delivery), reportedly yielding a statistically significant difference, but these investigators did not report standard deviations or a P value from a statistical test that would have permitted estimation of the confidence interval on the mean difference and inclusion of the study data in the forest plot in Figure 7. We assessed the certainty of evidence as very low, downgrading for risk of bias, inconsistency, and imprecision.

Total intraoperative time

Only one RCT (58 participants) reported intraoperative surgical time for this comparison in a manner that permitted an estimate of the mean difference and its confidence interval (Hargitai 2013). Surgical times were lower when depot delivery was used (MD 0.88 min, 95% CI −0.64 to 2.40) (Analysis 2.2), but the confidence interval was consistent with no difference. Morgado 2010 (60 participants) reported mean intraoperative surgery times for the two delivery methods suggestive of no meaningful difference (8.3 min for topical mydriatics and 8.1 min for depot delivery), but did not report standard deviations that would have permitted estimation of the confidence interval on the mean difference and inclusion in the forest plot. We assessed the certainty of evidence as very low, downgrading for risk of bias and imprecision (−2).

2.2. Analysis.

Comparison 2: Topical mydriatics versus depot delivery systems, Outcome 2: Intraoperative surgical time

Phacoemulsification time

No study reported phacoemulsification time for the comparison topical versus depot delivery of mydriatics.

Participant‐reported ocular discomfort at any time during or after the surgery

No study reported ocular discomfort at anytime during or after the surgery between topical and depot delivery of mydriatics or reported the cost of either method.

Adverse events

One RCT (58 participants) reported no major adverse events related to the use of topical mydriatics or depot delivery systems (very low‐certainty evidence) (Hargitai 2013). Cardiovascular related adverse events were never mentioned.

Cost outcomes

No study compared costs between topical and depot delivery of mydriatics or reported the cost of either method.

Comparison 3: intracameral mydriatics versus depot delivery systems (1 RCT)

Morgado 2010 (30 participants in each arm) was the only RCT that compared intracameral mydriatics versus depot delivery system.

Pupil diameter at the time surgeons performed capsulorhexis

Morgado 2010 did not report this outcome.

Pupil diameter at the beginning of cataract surgery

Morgado 2010 reported a statistically significant difference in mean pupil diameter (mm) in favor of depot delivery systems at the beginning of cataract surgery (MD −1.90 mm, 95% CI −2.45 to −1.35) (Analysis 3.1.1). We assessed the certainty of evidence as very low, downgrading for risk of bias and imprecision (−2).

3.1. Analysis.

Comparison 3: Intracameral mydriatics versus depot delivery systems, Outcome 1: Mean pupillary diameter

Pupil diameter at the end of cataract surgery

Morgado 2010 also reported a statistically significant difference in mean pupil diameter at the end of cataract surgery in favor of depot delivery system (MD −1.60 mm, 95% CI −2.13 to −1.07) (Analysis 3.1.2). We assessed the certainty of evidence as very low, again downgrading for risk of bias and imprecision (−2).

Intraoperative surgical time (minutes)

Morgado 2010 reported mean surgical times of 8.1 min and 12.3 min for the depot delivery system and intracameral mydriatics, respectively. The estimated mean difference favored depot delivery (MD 4.2 min, P < 0.05, analysis of variance), but standard deviations for the mean surgical times for the intervention groups that were required to permit the computation of 95% CIs were not reported (very low‐certainty evidence).

Phacoemulsification time

Morgado 2010 did not report this outcome.

Participant‐reported ocular discomfort at any time during or after the surgery

Morgado 2010 did not report ocular discomfort at anytime during or after the surgery for either method of delivery of mydriatics.

Adverse events

Posterior capsule rupture occurred during the irrigation/aspiration phase in one participant (3.3%) in Morgado 2010; iris‐related complications, including flaccid iris, iris herniation, and iris capture by the handpiece, were observed in 11 participants (36.6%), all in the intracameral mydriatics group. No complication was reported for the depot delivery system group. Cardiovascular related adverse events were never mentioned.

Cost outcomes

Morgado 2010 did not report the cost of either method of delivery of mydriatics.

Discussion

Summary of main results

We identified 14 RCTs for inclusion in the review which compared key outcomes between different drug delivery routes for mydriatics in cataract surgery. We were unable to calculate overall effect estimates for most outcomes due to statistical heterogeneity among effect estimates of outcomes from individual studies or because data were available from a single study. As a result, most of the evidence provided in this review is of low or very low certainty. We presented our findings from analyses of the available evidence for the outcomes in the Table 1, Table 2, and Table 3 for the main comparisons.

Overall, most of the eight RCTs that had compared topical mydriatics versus intracameral mydriatics favored topical mydriatics in terms of achieving greater pupillary dilation at the time of capsulorhexis and at the beginning and end of surgery. There was no difference in intraoperative time required in three of the five trials that reported this outcome, possibly due to the ease and familiarity associated with topical mydriatics. Only two RCTs provided data regarding the time taken to perform phacoemulsification, with conflicting results. Only one RCT provided data on adverse events, with participants given topical mydriatics having more ocular (19.1% versus 17.7%) and systemic (6.0% versus 4.8%) adverse events.

Comparison of topical mydriatics with depot delivery systems in seven RCTs did not favor either method regarding pupillary dilation at the beginning or end of surgery. The only trial that had reported total intraoperative time did not find either a clinically or statistically meaningful difference between methods for this outcome. The investigators of the same RCT reported that there were no major adverse events related to the use of depot delivery system.

Only one small trial compared intracameral mydriatics with depot delivery. The available data favored depot delivery of mydriatics with respect to pupil dilation at the beginning and end of surgery and to adverse events.

No RCT had reported the overall cost of any of the three methods or the relative cost of any pair of methods.

Overall completeness and applicability of evidence

The 13 single‐center trials included in the review were conducted in eight different countries: China, Denmark, India, Malaysia, Portugal, Spain, Sweden, and the United Kingdom. The only multicenter trial enrolled participants in countries in Europe and North Africa. Consequently, the race and ethnicity of participants in the included trials was quite diverse. Individuals at risk of poor pupillary dilation were excluded from most studies, thereby decreasing the generalizability of findings.

Interpretation of the evidence and assessment of the outcomes mentioned in the studies may help decipher their applicability. Pupillary diameter and surgery times can be measured objectively in different populations. We found few clinically or statistically meaningful differences in outcomes between methods of delivering mydriatics. Due to the paucity of reports regarding adverse effects and the absence of any cost data or comparisons, it was not possible to determine whether any of the three methods of delivery of mydriatics considered in this review is superior to another in terms of practical applicability.

Quality of the evidence

The quality of evidence generated in this review is low due to both failure of study investigators to report key methodological information regarding randomization and masking of participants, trial personnel, and outcome assessors, and the few outcomes reported from most studies. In addition, most of the included studies failed to comply with CONSORT guidelines (Altman 2012); the quality of reporting on methods used in individual studies was poor. We also noted that the published reports from the 13 single‐center studies were fairly short; the numbers of participants tended to be small, with fewer than 50 participants per method of mydriatic delivery. When provided, sample size estimates had been based on assumptions of much larger differences between methods than were observed, and perhaps larger than could have been expected in the setting of cataract surgery and current knowledge. A longer report with more methodological details had been published from the multicenter international trial by Labetoulle 2016, in which two to three times as many participants had enrolled as in any single‐center trial.

Another issue was the difference in reported outcomes, particularly intraoperative time. Few reports clearly specified the time intervals for which data were given. Thirteen of the 14 RCTs evaluated mydriatic effects of interventions in one eligible eye of each participant; the remaining trial used a paired‐eyes design. In the latter trial, surgery was performed on the second eye two days after the first eye. Outcomes from both eyes were reported without adjustment for correlations of outcomes between pairs of eyes. We also concluded that values reported as standard deviations for means of many values in fact were standard errors. We contacted the investigators of this study for confirmation. Effect estimates from the paired‐eyes study were often outliers when we examined forest plots, and thus accounted for some of the statistical heterogeneity among studies. However, as that study was small (18 participants, 36 eyes), omission of it from meta‐analyses affected estimates of the relative effects of interventions very little.

Although the reports from most trials specified that participants were analyzed within the intervention group to which they had been randomly assigned, it was not always clear from the study reports that an outcome had been measured for all enrolled participants, the second requirement of an intention‐to‐treat analysis. Furthermore, despite the time interval during which most of the study reports were published, few included studies reported registration; searches of registries such as WHO International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for these RCTs were unproductive. In some cases it was thus not possible to assess whether all prespecified outcomes had been reported and whether there was any bias in terms of selective reporting. Finally, with respect to other potential risk of bias, although several studies of depot delivery used a commercial device, only the multicenter trial reported the role of the sponsor in the design or conduct of the trial or mentioned possible investigator financial interests in the device.

Potential biases in the review process

The Cochrane Eyes and Vision Information Specialist searched databases for studies using prespecified criteria; references lists in the reports from relevant studies were also screened for any further trials. Two review authors independently screened the titles and abstracts of pertinent studies identified by the searches and extracted the data. One review author entered the data into Review Manager 5 (Review Manager 2020), while another review author checked the data for inaccuracies and anomalies. To reduce potential biases in our review and judgements, multiple review authors independently evaluated the included trials for accurate data extraction and risk of bias. Wherever possible, we estimated missing standard deviations from available data using methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021).

Agreements and disagreements with other studies or reviews

Adequate mydriasis during cataract surgery is a key outcome determinant. While topical mydriatics have traditionally been used, their limitations have prompted ophthalmologists to research alternative methods (Grob 2014). Unfortunately, while intracameral agents and depot delivery systems have been available for many years, there have not been enough studies that have evaluated their safety and efficacy in prospective, randomized trials to provide reliable estimates of comparative effectiveness. The authors of earlier reviews have acknowledged this deficiency, even those who included in their reviews case‐control and cohort studies in addition to clinical trials (Behndig 2015; Vazquez‐Ferreiro 2017), or included other surgeries in addition to phacoemulsification (Behndig 2015). Nevertheless, both intracameral mydriatics and depot delivery systems are regarded as viable alternatives to topical mydriatics, with distinct advantages which merit further research.

Several clinical studies (including RCTs, case‐control, and cohort studies) that compared mydriatic ophthalmic inserts or intracameral mydriatics with mydriatic eyedrops for different surgeries and diagnostic/therapeutic procedures were reviewed by Behndig 2015. The authors of this review concluded that mydriatic ophthalmic inserts are a viable alternative to topical mydriatics with comparable efficacy.

Vazquez‐Ferreiro 2017 was a systematic review conducted to compare the effectiveness of intracameral phenylephrine and topical mydriatics in achieving mydriasis and their complication rates. That review included cohort and case‐control studies in addition to clinical trials (four of which are included in this review). The authors concluded that there was no evidence of a difference between intracameral phenylephrine and topical mydriatics in terms of mydriatic effect.

Consequently, the findings of our review are similar to those of other reviews that included some of the same studies and other studies of more varied designs to compare the effects of different methods to deliver mydriatics for cataract surgery.

Authors' conclusions

Implications for practice.

In the absence of high‐quality evidence, we cannot recommend the use of either depot delivery systems or intracameral mydriatics over traditional topical mydriatics. While some studies have found intracameral mydriatics to be a safe and effective alternative to topical mydriatics, most of them favor topical mydriatics in terms of objective surgical parameters such as pupillary dilation and intraoperative time. Similarly, while most studies have found depot delivery systems to be comparable to topical mydriatics, there is insufficient evidence to justify a change in standard practice. This conclusion is supported by the fact that none of the studies in this review included any comparisons of cost‐effectiveness, an important measure of real‐world applicability. Furthermore, only a handful of studies had reported data regarding adverse events, further limiting the practical use of alternative methods. Although we did not seek to compare patient‐reported outcomes in this review, we found only occasional mention of participant discomfort with one of the methods of mydriatic delivery in the reports from the 14 trials included in the review.

Implications for research.

Even though topical mydriatics have long been the mainstay of achieving pupillary dilation during cataract surgery, they present several disadvantages which can be improved upon. Given the fact that cataract surgery is one of the most common surgical procedures worldwide, there is a clear impetus to evaluate alternative methods of mydriasis. It is therefore important to develop well‐designed randomized controlled trials that can provide high‐quality evidence regarding the different drug delivery routes for mydriatics. Sample size estimates should be based on defensible assumptions. If investigators wish to conduct trials with paired‐eyes designs in the interest of efficiency, they should be aware that effective sample sizes of trials with this design are smaller than the number of eyes because of correlation of outcomes within the same participant. Other logistical issues apply that are beyond the scope of this discussion but that cannot be ignored. Methods for randomization should be reproducible and reported clearly. With the number of clinical trials registers now available, all future trials should be registered near the time of initiation. Consideration should be given to publishing the trial protocol or making it available to interested individuals in some other way, for example posting it on a website.

We recommend that designers of future trials consider stratifying participants at time of randomization by baseline pupil size and risk factors for poor pupillary dilation such as diabetes, pseudoexfoliation syndrome, and alpha‐adrenergic agonist use. If stratified randomization is deemed not feasible or desirable, then outcomes should be reported within subgroups defined by these baseline characteristics of participants and eyes in addition to overall findings. Furthermore, objective parameters such as pupillary dilation and intraoperative time should be standardized. Pupil size should be measured before mydriatic administration, corneal incision, capsulorhexis, phacoemulsification, and intraocular lens implantation. Similarly, time should be recorded at the beginning of each step in order to provide clear information regarding pre‐ and intraoperative timing of measurements. Most importantly, future trials should include comprehensive safety and cost‐effectiveness assessments. Safety assessment should include all intraoperative and postoperative adverse events, including those that the investigators do not believe were attributable to the delivery method. Cost‐effectiveness assessment should include not only the cost of the intervention itself but also the indirect costs associated with changes in pre‐ and postoperative protocols such as nursing time and patient turnover. Patient‐reported outcomes should be assessed in trials in which only one eye of each participant has surgery to generate information useful for patient counseling regarding expectations before cataract surgery.

History

Protocol first published: Issue 10, 2017

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Cataract] explode all trees
#2 MeSH descriptor: [Cataract Extraction] explode all trees
#3 (extract* or aspirat* or operat* or remov* or surg* or excis* or implant*) near/4 (cataract*)
#4 (extract* or aspirat* or operat* or remov* or surg* or excis* or implant* or emulsif*) near/4 (lens*)
#5 phakectom* or lensectom* or zonulolys* or catarectom*
#6 pha?oemulsif* or (pha?o next/1 emulsif*) or facoemulsif* or (faco next/1 emulsif*)
#7 Capsulorhexis or Capsulorrhexis
#8 {or #1‐#7}
#9 MeSH descriptor: [Mydriasis] explode all trees
#10 MeSH descriptor: [Miotics] explode all trees
#11 MeSH descriptor: [Miosis] explode all trees
#12 Miotic* or Miosis or myosis or mydriasis or Mydriasert or (pupil* near/3 dilat*)
#13 MeSH descriptor: [Mydriatics] explode all trees
#14 mydriatic*
#15 cycloplegic*
#16 MeSH descriptor: [Atropine] explode all trees
#17 Atropine or atrinal or "atro‐polygyl" or atrop or atropen or atropin or atropina or "atropini sulfas" or atropinol or atropisol or atropt or atroptol or atrospan or "atrosulf‐1" or "bar bropin" or "bellpino‐artin" or "cendo tropine" or "dextro levo hyosciamine" or "ichtho bellol" or "isopto" or isoptoAtropine or "ocu‐tropine" or "sal‐tropine" or skiatropine or "tropine dextro levo tropate" or ximex or "51‐55‐8" or "55‐48‐1"
#18 berefrine or POPD or "105567‐83‐7"
#19 MeSH descriptor: [Cyclopentolate] explode all trees
#20 Cyclopentolate or "ak‐pentolate" or akpentolate or "bell pentolate" or ciclolux or cyclogyl or cyclomydri or cyclopentol or cyclopentolat or cylate or cyplegin or diopentolate or midriodavi or mydrilate or "ocu‐pentolate" or ocucyclo or "oftan‐syklo" or pentolair or "refractyl ofeno" or skiacol or zyklolat or "512‐15‐2" or "5870‐29‐1"
#21 MeSH descriptor: [Epinephrine] explode all trees
#22 Epinephrine or Adrenaline or adrenalin or Epitrate or Lyophrin or Epifrin or adnephrin or adnephrine or adrenaclick or "adrenal hydrochloride" or adrenalina or adrenamine or adrenapax or adrenazin or adrenine or adrin or adrine or advaradin or balmadren or biorenine or bosmin or chelafrin or dylephrin or epiglaufrin or epimephrine or epinefrina or epinephran or epinephrin or epirenamine or epirenan or exadrin or glaucon or glaucosan or glaufrin or "glin epin" or glycirenan or haemostatin or hemisine or hemostasin or hemostatin or hypernephrin or "isopto epinal" or levoadrenalin or levoadrenaline or levoepinephrine or levorenin or levorenine or methylaminoethanolcatechol or methylarterenol or mucidrina or myosthenine or "n methylnoradrenalin" or nephridine or nieraline or paranephrin or posumin or renaglandin or renaglandulin or renaleptine or renalina or renaline or renoform or renostypticin or renostyptin or scurenaline or simplene or soladren or sphygmogenin or styptirenal or supracapsulin or supranephrane or supranephrin or supranol or suprarenaline or suprarenin or suprarenine or suprel or surenine or surrenine or "sus‐phrine sulfite‐free" or susphrine or "sympathin I" or takamina or tonogen or vasoconstrictine or vasodrine or vasotonin or weradren or "51‐43‐4" or "55‐31‐2" or "6912‐68‐1"
#23 MeSH descriptor: [Ethylmorphine] explode all trees
#24 Ethylmorphine or Ethomorphine or Trachyl or codethyline or diolan or dionine or "ethyl morphine" or ethylmorfine or ethylmorphin or "morphine ethyl ether" or "125‐30‐4" or "76‐58‐4"
#25 Eucatropine or euphthalmine or "100‐91‐4" or "536‐93‐6"
#26 Homatropine or homatro or homatrocil or homatropaire or homatropin or homatropina or isoptoHomatropine or "I Homatrine" or "mandelyl tropeine" or mandelyltropeine or "mydryn eye" or "omatropina lux" or "tropine mandelate" or "51‐56‐9" or "87‐00‐3"
#27 MeSH descriptor: [Hyoscyamine] explode all trees
#28 Hyoscyamine or anaspaz or cystospaz or cytospaz or daturine or donnamar or duboisine or egacen or hyoscamine or hyosciamine or hyoscyanin or hyosyne or "ib‐stat" or levbid or levsin or "levsinex sr" or neosol or nulev or spasdel or "symax sl" or "symax sr" or "tropine l tropate" or "101‐31‐5" or "306‐03‐6"
#29 Ibopamine or "N‐methyldopamine diisobutyrate" or "SB 7505" or "SB7505" or Escandine or Inopamil or "diisobutyric n methyldopamine ester" or scandine or "skf 100168" or "skf 100168 a" or "66195‐31‐1" or "75011‐65‐3"
#30 Methylatropine or "8‐methylatropinium nitrate" or "31610‐87‐4"
#31 MeSH descriptor: [Naphazoline] explode all trees
#32 Naphazoline or "Afazol Grin" or "AK Con" or AKCon or Albalon or albasol or "All Clear" or allersol or antan or benil or cefasan or "Clear Eyes" or coldan or "Colirio Alfa" or "comfort eye drops" or dazolin or "degest 2" or derinox or Idril or imidin or minha or Miraclar or mirafrin or Nafazair or nafazoline or naftazolina or "naphacel ofteno" or naphasal or naphazolin or Naphcon or "naphozoline hydrochloride" or naphtears or naphthazoline or naphthizine or naphthyzin or nastizol or "nazil ofteno" or niazol or "ocu‐zoline" or opcon or Optazine or Privin or privina or Privine or privine or Proculin or rhinantin or rhinazin or rhinoperd or rimidol or sanorin or sanotin or Siozwo or strictylon or "Tele Stulln" or TeleStulln or Vasoclear or Vasocon or "Vasoconstrictor Pensa" or VasoNit or vistalbalon or vistobalon or "5144‐52‐5" or "550‐99‐2" or "835‐31‐4"
#33 Oxedrine or Synephrine or Sympaethamin or Synephrin or aetaphen or pentedrine or vasoton or "94‐07‐5"
#34 MeSH descriptor: [Synephrine] explode all trees
#35 MeSH descriptor: [Oxyphenonium] explode all trees
#36 Oxyphenonium or Methacin or Oxyphenon or Atrenyl or Spastrex or antrenyl or "ba 5473" or ba5473 or "c 5473" or c5473 or helkamon or metacin or metacinum or oxyphenium or "oxyphenomium bromide" or spasmofen or spasmophen or "14214‐84‐7" or "50‐10‐2"
#37 MeSH descriptor: [Phenylephrine] explode all trees
#38 Phenylephrine or adrianol or "af‐taf" or "ak‐dilate" or "albalon relief" or alconefrin or almefrin or altafrin or biomidrin or biomydrin or derizene or "despec‐sf" or "disneumon pernasal" or drosin or "efrin‐10" or efrisel or fenylephrine or idrianol or isonefrine or isophrin or isophrine or "isopto frin" or isoptofrin or lexatol or "m synephrine" or mesaton or "meta sympathol" or "meta synephrine" or Metaoxedrin or metaoxedrine or Metasympatol or metasynephrine or Mezaton or "murucoll 2" or mydfrin or "n 105 to" or "nefrin‐ofteno" or "Neo Synephrine" or neofrin or neooxedrine or neophryn or neosynephrin or Neosynephrine or "neosynephrin‐pos" or neosynesin or neosynesine or "ocu‐phrin" or "oftan‐metaoksedrin" or optistin or phenoptic or phenylefrine or phenylephedrine or prefrin or "pupiletto forte" or rectasol or "rhinall 10" or "slv 325" or slv325 or sucraphen or vazculep or visadron or vistafrin or vistosan or "532‐38‐7" or "59‐42‐7" or "61‐76‐7"
#39 Pholedrine or "4 hydroxy n methylamphetamine" or "4 hydroxymethamphetamine" or adyston or "para hydroxymethamphetamine" or "p‐hydroxymethamphetamine" or paredrinol or "Pholedrin liquidum" or "Pholedrin‐longo‐Isis" or pulsotyl or venosan or veritol or "370‐14‐9"
#40 MeSH descriptor: [p‐Hydroxyamphetamine] explode all trees
#41 p‐Hydroxyamphetamine or "1 para hydroxyphenyl 2 propylamine" or "alpha methyl para tyramine" or "alpha methyl tyramine" or "dl 1 p hydroxyphenyl 2 propylamine" or "dl 1 para hydroxyphenyl 2 propylamine" or "dl p hydroxy alpha methylphenethylamine" or "dl para hydroxy alpha methylphenethylamine" or "h 66 37" or "para hydroxy alpha methylphenethylamine" or Hydroxyamfetamine or Hydroxyamphetamin or Hydroxyamphetamine or Hydroxyphenylisopropylamine or Methyltyramine or Norpholedrin or norpholedrine or oxamphetamine or Oxyamphetamine or paradrine or parahydroxyamphetamine or Paredrine or paredrinea or paredrinex or pedrolone or pulsoton or "103‐86‐6" or "1518‐86‐1" or "306‐21‐8"
#42 MeSH descriptor: [Racepinephrine] explode all trees
#43 Racepinephrine or asthmanefrin or Micronefrin or micronefrine or Micronephrine or mikronephrin or racadrenalin or "Racepinefrine Hydrochloride" or racinephrine or Vaponefrin or vaponefrine or vaponephrin or "329‐65‐7"
#44 MeSH descriptor: [Scopolamine Hydrobromide] explode all trees
#45 Scopolamine or "Boro Scopol" or BoroScopol or Hyoscine or Kwells or "levo hyoscinehydrobromide" or Scoburen or Scopace or scopos or "Travacalm HO" or Vorigeno or "114‐49‐8" or atrochin or atroquin or atroscine or hyosceine or hysco or "kimite‐patch" or "l epoxytropine tropate" or "n methylhyoscine" or oscine or scopalamine or "scopine tropate" or scopoderm or scopolamin or transcop or "transderm scop" or "transderm v" or "tropic acid ester with scopine" or "138‐12‐5" or "51‐34‐3" or "55‐16‐3"
#46 MeSH descriptor: [Tropicamide] explode all trees
#47 Tropicamide or "alcon‐mydril" or bistropamide or "cendo mydriatyl" or "Colircusi Tropicamida" or midriaticum or mydiacyl or mydral or mydramide or mydriacyl or Mydriafair or Mydriaticum or "mydrin m" or "mydrin p" or Mydrum or "n ethyl 2 phenyl n pyrid 4 ylmethylhydracrylamide" or "n ethyl n 4 picolyltropamide" or "n ethyl n gamma picolyltropamide" or "n ethyl n pyrid 4 ylmethyltropamide" or "Ocu‐Tropic" or OcuTropic or opticyl or sandol or sintropic or "tropamid forte" or "tropic acid n ethyl n gamma picolyl amide" or Tropicacyl or tropicamid or "tropico eye" or tropicol or tropikamid or tropimil or visumidriatic or "1508‐75‐4"
#48 MeSH descriptor: [Tyramine] explode all trees
#49 Tyramine or "4 hydroxyphenethylamine" or lyramine or mydrial or "para hydroxyphenethylamine" or paratyramine or systogene or tiramine or tocosine or tyramin or tyrosamine or uteramine or "51‐67‐2" or "60‐19‐5"
#50 Vibrocil or "8059‐14‐1"
#51 MeSH descriptor: [Yohimbine] explode all trees
#52 Yohimbine or actibine or aphrodine or aphrodyne or Corynanthine or "corynine hydrochloride" or "dayto‐himbin" or "methyl yohimbine 16alpha carboxylate" or "methylyohimbane 16alpha carboxylate" or Pluriviron or quebrachin or "quebrachine hydrochloride" or Rauhimbine or Rauwolscine or urobine or yobin or yobinol or yocan or yocaral or Yocon or yocon or yohimbe or "yohimbic acid methyl ester" or yohimbin or Yohimex or yohimex or yohimibin or yovital or "146‐48‐5" or "65‐19‐0"
#53 {or #9‐#52}
#54 #8 and #53

Appendix 2. MEDLINE Ovid search strategy

1. Randomized Controlled Trial.pt.
2. Controlled Clinical Trial.pt.
3. (randomized or randomised).ab,ti.
4. placebo.ab,ti.
5. drug therapy.fs.
6. randomly.ab,ti.
7. trial.ab,ti.
8. groups.ab,ti.
9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8
10. exp animals/ not humans.sh.
11. 9 not 10
12. exp Cataract/
13. exp cataract extraction/
14. (Cataract* adj4 (extract* or aspirat* or operat* or remov* or surg* or excis* or implant*)).tw.
15. (lens* adj4 (extract* or aspirat* or operat* or remov* or surg* or excis* or implant* or emulsif*)).tw.
16. (phakectom* or lensectom* or zonulolys* or catarectom*).tw.
17. (pha*oemulsif* or pha*o emulsif* or facoemulsif* or faco emulsif*).tw.
18. (Capsulorhexis or Capsulorrhexis).tw.
19. or/12‐18
20. exp Mydriasis/
21. exp Miotics/
22. exp Miosis/
23. (Miotic* or Miosis or myosis or mydriasis or Mydriasert or (pupil* adj3 dilat*)).tw.
24. exp Mydriatics/
25. mydriatic*.tw.
26. cycloplegic*.tw.
27. exp Atropine/
28. (Atropine or atrinal or "atro‐polygyl" or atrop or atropen or atropin or atropina or "atropini sulfas" or atropinol or atropisol or atropt or atroptol or atrospan or "atrosulf‐1" or "bar bropin" or "bellpino‐artin" or "cendo tropine" or "dextro levo hyosciamine" or "ichtho bellol" or "isopto" or isoptoAtropine or "ocu‐tropine" or "sal‐tropine" or skiatropine or "tropine dextro levo tropate" or ximex or "51‐55‐8" or "55‐48‐1").tw.
29. ("51‐55‐8" or "55‐48‐1").rn.
30. (berefrine or POPD or "105567‐83‐7").tw.
31. "105567‐83‐7".rn.
32. exp Cyclopentolate/
33. (Cyclopentolate or "ak‐pentolate" or akpentolate or "bell pentolate" or ciclolux or cyclogyl or cyclomydri or cyclopentol or cyclopentolat or cylate or cyplegin or diopentolate or midriodavi or mydrilate or "ocu‐pentolate" or ocucyclo or "oftan‐syklo" or pentolair or "refractyl ofeno" or skiacol or zyklolat or "512‐15‐2" or "5870‐29‐1").tw.
34. ("512‐15‐2" or "5870‐29‐1").rn.
35. exp Epinephrine/
36. (Epinephrine or Adrenaline or adrenalin or Epitrate or Lyophrin or Epifrin or adnephrin or adnephrine or adrenaclick or "adrenal hydrochloride" or adrenalina or adrenamine or adrenapax or adrenazin or adrenine or adrin or adrine or advaradin or balmadren or biorenine or bosmin or chelafrin or dylephrin or epiglaufrin or epimephrine or epinefrina or epinephran or epinephrin or epirenamine or epirenan or exadrin or glaucon or glaucosan or glaufrin or "glin epin" or glycirenan or haemostatin or hemisine or hemostasin or hemostatin or hypernephrin or "isopto epinal" or levoadrenalin or levoadrenaline or levoepinephrine or levorenin or levorenine or methylaminoethanolcatechol or methylarterenol or mucidrina or myosthenine or "n methylnoradrenalin" or nephridine or nieraline or paranephrin or posumin or renaglandin or renaglandulin or renaleptine or renalina or renaline or renoform or renostypticin or renostyptin or scurenaline or simplene or soladren or sphygmogenin or styptirenal or supracapsulin or supranephrane or supranephrin or supranol or suprarenaline or suprarenin or suprarenine or suprel or surenine or surrenine or "sus‐phrine sulfite‐free" or susphrine or "sympathin I" or takamina or tonogen or vasoconstrictine or vasodrine or vasotonin or weradren or "51‐43‐4" or "55‐31‐2" or "6912‐68‐1").tw.
37. ("51‐43‐4" or "55‐31‐2" or "6912‐68‐1").rn.
38. exp Ethylmorphine/
39. (Ethylmorphine or Ethomorphine or Trachyl or codethyline or diolan or dionine or "ethyl morphine" or ethylmorfine or ethylmorphin or "morphine ethyl ether" or "125‐30‐4" or "76‐58‐4").tw.
40. ("125‐30‐4" or "76‐58‐4").rn.
41. (Eucatropine or euphthalmine or "100‐91‐4" or "536‐93‐6").tw.
42. ("100‐91‐4" or "536‐93‐6").rn.
43. (Homatropine or homatro or homatrocil or homatropaire or homatropin or homatropina or isoptoHomatropine or "I Homatrine" or "mandelyl tropeine" or mandelyltropeine or "mydryn eye" or "omatropina lux" or "tropine mandelate" or "51‐56‐9" or "87‐00‐3").tw.
44. ("51‐56‐9" or "87‐00‐3").rn.
45. exp Hyoscyamine/
46. (Hyoscyamine or anaspaz or cystospaz or cytospaz or daturine or donnamar or duboisine or egacen or hyoscamine or hyosciamine or hyoscyanin or hyosyne or "ib‐stat" or levbid or levsin or "levsinex sr" or neosol or nulev or spasdel or "symax sl" or "symax sr" or "tropine l tropate" or "101‐31‐5" or "306‐03‐6").tw.
47. ("101‐31‐5" or "306‐03‐6").rn.
48. (Ibopamine or "N‐methyldopamine diisobutyrate" or "SB 7505" or "SB7505" or Escandine or Inopamil or "diisobutyric n methyldopamine ester" or scandine or "skf 100168" or "skf 100168 a" or "66195‐31‐1" or "75011‐65‐3").tw.
49. ("66195‐31‐1" or "75011‐65‐3").rn.
50. (Methylatropine or "8‐methylatropinium nitrate" or "31610‐87‐4").tw.
51. "31610‐87‐4".rn.
52. exp Naphazoline/
53. (Naphazoline or "Afazol Grin" or "AK Con" or AKCon or Albalon or albasol or "All Clear" or allersol or antan or benil or cefasan or "Clear Eyes" or coldan or "Colirio Alfa" or "comfort eye drops" or dazolin or "degest 2" or derinox or Idril or imidin or minha or Miraclar or mirafrin or Nafazair or nafazoline or naftazolina or "naphacel ofteno" or naphasal or naphazolin or Naphcon or "naphozoline hydrochloride" or naphtears or naphthazoline or naphthizine or naphthyzin or nastizol or "nazil ofteno" or niazol or "ocu‐zoline" or opcon or Optazine or Privin or privina or Privine or privine or Proculin or rhinantin or rhinazin or rhinoperd or rimidol or sanorin or sanotin or Siozwo or strictylon or "Tele Stulln" or TeleStulln or Vasoclear or Vasocon or "Vasoconstrictor Pensa" or VasoNit or vistalbalon or vistobalon or "5144‐52‐5" or "550‐99‐2" or "835‐31‐4").tw.
54. ("5144‐52‐5" or "550‐99‐2" or "835‐31‐4").rn.
55. (Oxedrine or Synephrine or Sympaethamin or Synephrin or aetaphen or pentedrine or vasoton or "94‐07‐5").tw.
56. "94‐07‐5".rn.
57. exp Synephrine/
58. exp Oxyphenonium/
59. (Oxyphenonium or Methacin or Oxyphenon or Atrenyl or Spastrex or antrenyl or "ba 5473" or ba5473 or "c 5473" or c5473 or helkamon or metacin or metacinum or oxyphenium or "oxyphenomium bromide" or spasmofen or spasmophen or "14214‐84‐7" or "50‐10‐2").tw.
60. ("14214‐84‐7" or "50‐10‐2").rn.
61. exp Phenylephrine/
62. (Phenylephrine or adrianol or "af‐taf" or "ak‐dilate" or "albalon relief" or alconefrin or almefrin or altafrin or biomidrin or biomydrin or derizene or "despec‐sf" or "disneumon pernasal" or drosin or "efrin‐10" or efrisel or fenylephrine or idrianol or isonefrine or isophrin or isophrine or "isopto frin" or isoptofrin or lexatol or "m synephrine" or mesaton or "meta sympathol" or "meta synephrine" or Metaoxedrin or metaoxedrine or Metasympatol or metasynephrine or Mezaton or "murucoll 2" or mydfrin or "n 105 to" or "nefrin‐ofteno" or "Neo Synephrine" or neofrin or neooxedrine or neophryn or neosynephrin or Neosynephrine or "neosynephrin‐pos" or neosynesin or neosynesine or "ocu‐phrin" or "oftan‐metaoksedrin" or optistin or phenoptic or phenylefrine or phenylephedrine or prefrin or "pupiletto forte" or rectasol or "rhinall 10" or "slv 325" or slv325 or sucraphen or vazculep or visadron or vistafrin or vistosan or "532‐38‐7" or "59‐42‐7" or "61‐76‐7").tw.
63. ("532‐38‐7" or "59‐42‐7" or "61‐76‐7").rn.
64. (Pholedrine or "4 hydroxy n methylamphetamine" or "4 hydroxymethamphetamine" or adyston or "para hydroxymethamphetamine" or "p‐hydroxymethamphetamine" or paredrinol or "Pholedrin liquidum" or "Pholedrin‐longo‐Isis" or pulsotyl or venosan or veritol or "370‐14‐9").tw.
65. "370‐14‐9".rn.
66. exp p‐Hydroxyamphetamine/
67. (p‐Hydroxyamphetamine or "1 para hydroxyphenyl 2 propylamine" or "alpha methyl para tyramine" or "alpha methyl tyramine" or "dl 1 p hydroxyphenyl 2 propylamine" or "dl 1 para hydroxyphenyl 2 propylamine" or "dl p hydroxy alpha methylphenethylamine" or "dl para hydroxy alpha methylphenethylamine" or "h 66 37" or "para hydroxy alpha methylphenethylamine" or Hydroxyamfetamine or Hydroxyamphetamin or Hydroxyamphetamine or Hydroxyphenylisopropylamine or Methyltyramine or Norpholedrin or norpholedrine or oxamphetamine or Oxyamphetamine or paradrine or parahydroxyamphetamine or Paredrine or paredrinea or paredrinex or pedrolone or pulsoton or "103‐86‐6" or "1518‐86‐1" or "306‐21‐8").tw.
68. ("103‐86‐6" or "1518‐86‐1" or "306‐21‐8").rn.
69. exp Racepinephrine/
70. (Racepinephrine or asthmanefrin or Micronefrin or micronefrine or Micronephrine or mikronephrin or racadrenalin or "Racepinefrine Hydrochloride" or racinephrine or Vaponefrin or vaponefrine or vaponephrin or "329‐65‐7").tw.
71. "329‐65‐7".rn.
72. exp Scopolamine Hydrobromide/
73. (Scopolamine or "Boro Scopol" or BoroScopol or Hyoscine or Kwells or "levo hyoscinehydrobromide" or Scoburen or Scopace or scopos or "Travacalm HO" or Vorigeno or "114‐49‐8" or atrochin or atroquin or atroscine or hyosceine or hysco or "kimite‐patch" or "l epoxytropine tropate" or "n methylhyoscine" or oscine or scopalamine or "scopine tropate" or scopoderm or scopolamin or transcop or "transderm scop" or "transderm v" or "tropic acid ester with scopine" or "138‐12‐5" or "51‐34‐3" or "55‐16‐3").tw.
74. ("114‐49‐8" or "138‐12‐5" or "51‐34‐3" or "55‐16‐3").rn.
75. exp Tropicamide/
76. (Tropicamide or "alcon‐mydril" or bistropamide or "cendo mydriatyl" or "Colircusi Tropicamida" or midriaticum or mydiacyl or mydral or mydramide or mydriacyl or Mydriafair or Mydriaticum or "mydrin m" or "mydrin p" or Mydrum or "n ethyl 2 phenyl n pyrid 4 ylmethylhydracrylamide" or "n ethyl n 4 picolyltropamide" or "n ethyl n gamma picolyltropamide" or "n ethyl n pyrid 4 ylmethyltropamide" or "Ocu‐Tropic" or OcuTropic or opticyl or sandol or sintropic or "tropamid forte" or "tropic acid n ethyl n gamma picolyl amide" or Tropicacyl or tropicamid or "tropico eye" or tropicol or tropikamid or tropimil or visumidriatic or "1508‐75‐4").tw.
77. "1508‐75‐4".rn.
78. exp Tyramine/
79. (Tyramine or "4 hydroxyphenethylamine" or lyramine or mydrial or "para hydroxyphenethylamine" or paratyramine or systogene or tiramine or tocosine or tyramin or tyrosamine or uteramine or "51‐67‐2" or "60‐19‐5").tw.
80. ("51‐67‐2" or "60‐19‐5").rn.
81. (Vibrocil or "8059‐14‐1").tw.
82. "8059‐14‐1".rn.
83. exp Yohimbine/
84. (Yohimbine or actibine or aphrodine or aphrodyne or Corynanthine or "corynine hydrochloride" or "dayto‐himbin" or "methyl yohimbine 16alpha carboxylate" or "methylyohimbane 16alpha carboxylate" or Pluriviron or quebrachin or "quebrachine hydrochloride" or Rauhimbine or Rauwolscine or urobine or yobin or yobinol or yocan or yocaral or Yocon or yocon or yohimbe or "yohimbic acid methyl ester" or yohimbin or Yohimex or yohimex or yohimibin or yovital or "146‐48‐5" or "65‐19‐0").tw.
85. ("146‐48‐5" or "65‐19‐0").rn.
86. or/20‐85
87. 19 and 86
88. 11 and 87

The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville 2006.

Appendix 3. Embase.com search strategy

#1 'randomized controlled trial'/exp
#2 'randomization'/exp
#3 'double blind procedure'/exp
#4 'single blind procedure'/exp
#5 random*:ab,ti
#6 #1 OR #2 OR #3 OR #4 OR #5
#7 'animal'/exp OR 'animal experiment'/exp
#8 'human'/exp
#9 #7 AND #8
#10 #7 NOT #9
#11 #6 NOT #10
#12 'clinical trial'/exp
#13 (clin* NEAR/3 trial*):ab,ti
#14 ((singl* OR doubl* OR trebl* OR tripl*) NEAR/3 (blind* OR mask*)):ab,ti
#15 'placebo'/exp
#16 placebo*:ab,ti
#17 random*:ab,ti
#18 'experimental design'/exp
#19 'crossover procedure'/exp
#20 'control group'/exp
#21 'latin square design'/exp
#22 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21
#23 #22 NOT #10
#24 #23 NOT #11
#25 'comparative study'/exp
#26 'evaluation'/exp
#27 'prospective study'/exp
#28 control*:ab,ti OR prospectiv*:ab,ti OR volunteer*:ab,ti
#29 #25 OR #26 OR #27 OR #28
#30 #29 NOT #10
#31 #30 NOT (#11 OR #23)
#32 #11 OR #24 OR #31
#33 'cataract'/exp
#34 'cataract extraction'/exp
#35 ((extract* OR aspirat* OR operat* OR remov* OR surg* OR excis* OR implant*) NEAR/4 (cataract*)):ab,ti
#36 ((extract* OR aspirat* OR operat* OR remov* OR surg* OR excis* OR implant* OR emulsif*) NEAR/4 (lens*)):ab,ti
#37 (phakectom* OR lensectom* OR zonulolys* OR catarectom*):ab,ti
#38 (pha*oemulsif* OR ("pha*o emulsif*") OR facoemulsif* OR ("faco emulsif*")):ab,ti
#39 (Capsulorhexis OR Capsulorrhexis):ab,ti
#40 #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39
#41 'mydriasis'/exp
#42 'miotic agent'/exp
#43 'miosis'/exp
#44 (Miotic* OR Miosis OR myosis OR mydriasis OR Mydriasert OR (pupil* NEAR/3 dilat*)):ab,ti
#45 'mydriatic agent'/exp
#46 mydriatic*:ti,ab
#47 cycloplegic*:ti,ab
#48 (Atropine OR atrinal OR "atro‐polygyl" OR atrop OR atropen OR atropin OR atropina OR "atropini sulfas" OR atropinol OR atropisol OR atropt OR atroptol OR atrospan OR "atrosulf‐1" OR "bar bropin" OR "bellpino‐artin" OR "cendo tropine" OR "dextro levo hyosciamine" OR "ichtho bellol" OR "isopto" OR isoptoAtropine OR "ocu‐tropine" OR "sal‐tropine" OR skiatropine OR "tropine dextro levo tropate" OR ximex OR "51‐55‐8" OR "55‐48‐1"):ab,ti,tn
#49 (berefrine OR POPD OR "105567‐83‐7"):ab,ti,tn
#50 (Cyclopentolate OR "ak‐pentolate" OR akpentolate OR "bell pentolate" OR ciclolux OR cyclogyl OR cyclomydri OR cyclopentol OR cyclopentolat OR cylate OR cyplegin OR diopentolate OR midriodavi OR mydrilate OR "ocu‐pentolate" OR ocucyclo OR "oftan‐syklo" OR pentolair OR "refractyl ofeno" OR skiacol OR zyklolat OR "512‐15‐2" OR "5870‐29‐1"):ab,ti,tn
#51 'adrenalin'/exp
#52 (Epinephrine OR Adrenaline OR adrenalin OR Epitrate OR Lyophrin OR Epifrin OR adnephrin OR adnephrine OR "adrenal hydrochloride" OR adrenalina OR adrenamine OR adrenapax OR adrenazin OR adrenine OR adrin OR adrine OR advaradin OR balmadren OR biorenine OR bosmin OR chelafrin OR dylephrin OR epiglaufrin OR epimephrine OR epinefrina OR epinephran OR epinephrin OR epirenamine OR epirenan OR exadrin OR glaucon OR glaucosan OR glaufrin OR "glin epin" OR glycirenan OR haemostatin OR hemisine OR hemostasin OR hemostatin OR hypernephrin OR "isopto epinal" OR levoadrenalin OR levoadrenaline OR levoepinephrine OR levorenin OR levorenine OR methylaminoethanolcatechol OR methylarterenol OR mucidrina OR myosthenine OR "n methylnoradrenalin" OR nephridine OR nieraline OR paranephrin OR posumin OR renaglandin OR renaglandulin OR renaleptine OR renalina OR renaline OR renoform OR renostypticin OR renostyptin OR scurenaline OR simplene OR soladren OR sphygmogenin OR styptirenal OR supracapsulin OR supranephrane OR supranephrin OR supranol OR suprarenaline OR suprarenin OR suprarenine OR suprel OR surenine OR surrenine OR "sus‐phrine sulfite‐free" OR susphrine OR "sympathin I" OR takamina OR tonogen OR vasoconstrictine OR vasodrine OR vasotonin OR weradren OR "51‐43‐4" OR "55‐31‐2" OR "6912‐68‐1"):ab,ti,tn
#53 (Ethylmorphine OR Ethomorphine OR Trachyl OR codethyline OR diolan OR dionine OR "ethyl morphine" OR ethylmorfine OR ethylmorphin OR "morphine ethyl ether" OR "125‐30‐4" OR "76‐58‐4"):ab,ti,tn
#54 (Eucatropine OR euphthalmine OR "100‐91‐4" OR "536‐93‐6"):ab,ti,tn
#55 (Homatropine OR homatro OR homatrocil OR homatropaire OR homatropin OR homatropina OR isoptoHomatropine OR "I Homatrine" OR "mandelyl tropeine" OR mandelyltropeine OR "mydryn eye" OR "omatropina lux" OR "tropine mandelate" OR "51‐56‐9" OR "87‐00‐3"):ab,ti,tn
#56 'hyoscyamine'/exp
#57 (Hyoscyamine OR anaspaz OR cystospaz OR cytospaz OR daturine OR donnamar OR duboisine OR egacen OR hyoscamine OR hyosciamine OR hyoscyanin OR hyosyne OR "ib‐stat" OR levbid OR levsin OR "levsinex sr" OR neosol OR nulev OR spasdel OR "symax sl" OR "symax sr" OR "tropine l tropate" OR "101‐31‐5" OR "306‐03‐6"):ab,ti,tn
#58 'ibopamine'/exp
#59 (Ibopamine OR "N‐methyldopamine diisobutyrate" OR "SB 7505" OR "SB7505" OR Escandine OR Inopamil OR "diisobutyric n methyldopamine ester" OR scandine OR "skf 100168" OR "skf 100168 a" OR "66195‐31‐1" OR "75011‐65‐3"):ti,ab,tn
#60 (Methylatropine OR "8‐methylatropinium nitrate" OR "31610‐87‐4"):ti,ab,tn
#61 (Naphazoline OR "Afazol Grin" OR "AK Con" OR AKCon OR Albalon OR albasol OR "All Clear" OR allersol OR antan OR benil OR cefasan OR "Clear Eyes" OR coldan OR "Colirio Alfa" OR "comfort eye drops" OR dazolin OR "degest 2" OR derinox OR Idril OR imidin OR minha OR Miraclar OR mirafrin OR Nafazair OR nafazoline OR naftazolina OR "naphacel ofteno" OR naphasal OR naphazolin OR Naphcon OR "naphozoline hydrochloride" OR naphtears OR naphthazoline OR naphthizine OR naphthyzin OR nastizol OR "nazil ofteno" OR niazol OR "ocu‐zoline" OR opcon OR Optazine OR Privin OR privina OR Privine OR privine OR Proculin OR rhinantin OR rhinazin OR rhinoperd OR rimidol OR sanorin OR sanotin OR Siozwo OR strictylon OR "Tele Stulln" OR TeleStulln OR Vasoclear OR Vasocon OR "Vasoconstrictor Pensa" OR VasoNit OR vistalbalon OR vistobalon OR "5144‐52‐5" OR "550‐99‐2" OR "835‐31‐4"):ti,ab,tn
#62 (Oxedrine OR Synephrine OR Sympaethamin OR Synephrin OR aetaphen OR pentedrine OR vasoton OR "94‐07‐5"):ti,ab,tn
#63 'oxyphenonium bromide'/exp
#64 (Oxyphenonium OR Methacin OR Oxyphenon OR Atrenyl OR Spastrex OR antrenyl OR "ba 5473" OR ba5473 OR "c 5473" OR c5473 OR helkamon OR metacin OR metacinum OR oxyphenium OR "oxyphenomium bromide" OR spasmofen OR spasmophen OR "14214‐84‐7" OR "50‐10‐2"):ab,ti,tn
#65 (Phenylephrine OR adrianol OR "af‐taf" OR "ak‐dilate" OR "albalon relief" OR alconefrin OR almefrin OR altafrin OR biomidrin OR biomydrin OR derizene OR "despec‐sf" OR drosin OR "efrin‐10" OR efrisel OR fenylephrine OR idrianol OR isonefrine OR isophrin OR isophrine OR "isopto frin" OR isoptofrin OR lexatol OR "m synephrine" OR mesaton OR "meta sympathol" OR "meta synephrine" OR Metaoxedrin OR metaoxedrine OR Metasympatol OR metasynephrine OR Mezaton OR "murucoll 2" OR mydfrin OR "n 105 to" OR "nefrin‐ofteno" OR "Neo Synephrine" OR neofrin OR neooxedrine OR neophryn OR neosynephrin OR Neosynephrine OR "neosynephrin‐pos" OR neosynesin OR neosynesine OR "ocu‐phrin" OR "oftan‐metaoksedrin" OR optistin OR phenoptic OR phenylefrine OR phenylephedrine OR prefrin OR "pupiletto forte" OR rectasol OR "rhinall 10" OR "slv 325" OR slv325 OR sucraphen OR vazculep OR visadron OR vistafrin OR vistosan OR "532‐38‐7" OR "59‐42‐7" OR "61‐76‐7"):ti,ab,tn
#66 (Pholedrine OR "4 hydroxy n methylamphetamine" OR "4 hydroxymethamphetamine" OR adyston OR "para hydroxymethamphetamine" OR "p‐hydroxymethamphetamine" OR paredrinol OR "Pholedrin liquidum" OR "Pholedrin‐longo‐Isis" OR pulsotyl OR venosan OR veritol OR "370‐14‐9"):ti,ab,tn
#67 'hydroxyamphetamine'/exp
#68 (p‐Hydroxyamphetamine OR "1 para hydroxyphenyl 2 propylamine" OR "alpha methyl para tyramine" OR "alpha methyl tyramine" OR "dl 1 p hydroxyphenyl 2 propylamine" OR "dl 1 para hydroxyphenyl 2 propylamine" OR "dl p hydroxy alpha methylphenethylamine" OR "dl para hydroxy alpha methylphenethylamine" OR "h 66 37" OR "para hydroxy alpha methylphenethylamine" OR Hydroxyamfetamine OR Hydroxyamphetamin OR Hydroxyamphetamine OR Hydroxyphenylisopropylamine OR Methyltyramine OR Norpholedrin OR norpholedrine OR oxamphetamine OR Oxyamphetamine OR paradrine OR parahydroxyamphetamine OR Paredrine OR paredrinea OR paredrinex OR pedrolone OR pulsoton OR "103‐86‐6" OR "1518‐86‐1" OR "306‐21‐8"):ab,ti,tn
#69 'racepinefrine'/exp
#70 (Racepinephrine OR Micronefrin OR micronefrine OR Micronephrine OR mikronephrin OR racadrenalin OR "Racepinefrine Hydrochloride" OR racinephrine OR Vaponefrin OR vaponefrine OR vaponephrin OR "329‐65‐7"):ti,ab,tn
#71 'scopolamine bromide'/exp
#72 (Scopolamine OR "Boro Scopol" OR BoroScopol OR Hyoscine OR Kwells OR "levo hyoscinehydrobromide" OR Scoburen OR Scopace OR scopos OR "Travacalm HO" OR Vorigeno OR "114‐49‐8" OR atrochin OR atroquin OR atroscine OR hyosceine OR hysco OR "l epoxytropine tropate" OR "n methylhyoscine" OR oscine OR scopalamine OR "scopine tropate" OR scopolamin OR transcop OR "tropic acid ester with scopine" OR "138‐12‐5" OR "51‐34‐3" OR "55‐16‐3"):ab,ti,tn
#73 (Tropicamide OR "alcon‐mydril" OR bistropamide OR "cendo mydriatyl" OR "Colircusi Tropicamida" OR midriaticum OR mydiacyl OR mydral OR mydramide OR mydriacyl OR Mydriafair OR Mydriaticum OR "mydrin m" OR "mydrin p" OR Mydrum OR "n ethyl 2 phenyl n pyrid 4 ylmethylhydracrylamide" OR "n ethyl n 4 picolyltropamide" OR "n ethyl n gamma picolyltropamide" OR "n ethyl n pyrid 4 ylmethyltropamide" OR "Ocu‐Tropic" OR OcuTropic OR opticyl OR sandol OR sintropic OR "tropamid forte" OR "tropic acid n ethyl n gamma picolyl amide" OR Tropicacyl OR tropicamid OR "tropico eye" OR tropicol OR tropikamid OR tropimil OR visumidriatic OR "1508‐75‐4"):ab,ti,tn
#74 (Tyramine OR "4 hydroxyphenethylamine" OR lyramine OR mydrial OR "para hydroxyphenethylamine" OR paratyramine OR systogene OR tiramine OR tocosine OR tyramin OR tyrosamine OR uteramine OR "51‐67‐2" OR "60‐19‐5"):ti,ab,tn
#75 (Vibrocil OR "8059‐14‐1"):ti,ab,tn
#76 'yohimbine'/exp
#77 (Yohimbine OR actibine OR aphrodine OR aphrodyne OR Corynanthine OR "corynine hydrochloride" OR "dayto‐himbin" OR "methyl yohimbine 16alpha carboxylate" OR "methylyohimbane 16alpha carboxylate" OR Pluriviron OR quebrachin OR "quebrachine hydrochloride" OR Rauhimbine OR Rauwolscine OR urobine OR yobin OR yobinol OR yocan OR yocaral OR Yocon OR yocon OR yohimbe OR "yohimbic acid methyl ester" OR yohimbin OR Yohimex OR yohimex OR yohimibin OR yovital OR "146‐48‐5" OR "65‐19‐0"):ti,ab,tn
#78 #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55 OR #56 OR #57 OR #58 OR #59 OR #60 OR #61 OR #62 OR #63 OR #64 OR #65 OR #66 OR #67 OR #68 OR #69 OR #70 OR #71 OR #72 OR #73 OR #74 OR #75 OR #76 OR #77
#79 #40 AND #78
#80 #32 AND #79

Appendix 4. PubMed search strategy

#1  ((randomized controlled trial[pt]) OR (controlled clinical trial[pt]) OR (randomised[tiab] OR randomized[tiab]) OR (placebo[tiab]) OR (drug therapy[sh]) OR (randomly[tiab]) OR (trial[tiab]) OR (groups[tiab])) NOT (animals[mh] NOT humans[mh])
#2  (Cataract*[tw] AND (extract*[tw] OR aspirat*[tw] OR operate*[tw] OR operation*[tw] OR operating*[tw] OR remov*[tw] OR surg*[tw] OR excis*[tw] OR implant*[tw])) NOT Medline[sb]   
#3  (lens*[tw] AND (extract*[tw] OR aspirat*[tw] OR operate*[tw] OR operation*[tw] OR operating*[tw] OR remov*[tw] OR surg*[tw] OR excis*[tw] OR implant*[tw] OR emulsif*[tw])) NOT Medline[sb]   
#4  (phakectom*[tw] OR lensectom*[tw] OR zonulolys*[tw] OR catarectom*[tw]) NOT Medline[sb]   
#5  (phacoemulsif*[tw] OR phaco emulsif*[tw] OR phakoemulsif*[tw] OR phako emulsif*[tw] OR facoemulsif*[tw] OR faco emulsif*[tw]) NOT Medline[sb]   
#6  (Capsulorhexis[tw] OR Capsulorrhexis[tw]) NOT Medline[sb]
#7  #2 OR #3 OR #4 OR #5 OR #6    
#8  (Miotic*[tw] OR Miosis[tw] OR myosis[tw] OR mydriasis[tw] OR Mydriasert[tw] OR (pupil*[tw] AND dilat*[tw])) NOT Medline[sb]
#9  mydriatic*[tw] NOT Medline[sb]   
#10  cycloplegic*[tw] NOT Medline[sb]
#11  (Atropine [tw] OR atrinal [tw] OR "atro‐polygyl" [tw] OR atrop [tw] OR atropen [tw] OR atropin [tw] OR atropina [tw] OR "atropini sulfas" [tw] OR atropinol [tw] OR atropisol [tw] OR atropt [tw] OR atroptol [tw] OR atrospan [tw] OR "atrosulf‐1" [tw] OR "bar bropin" [tw] OR "bellpino‐artin" [tw] OR "cendo tropine" [tw] OR "dextro levo hyosciamine" [tw] OR "ichtho bellol" [tw] OR "isopto" [tw] OR isoptoAtropine [tw] OR "ocu‐tropine" [tw] OR "sal‐tropine" [tw] OR skiatropine [tw] OR "tropine dextro levo tropate" [tw] OR ximex [tw] OR "51‐55‐8" [tw] OR "55‐48‐1"[tw]) NOT Medline[sb]
#12  (berefrine [tw] OR POPD [tw] OR "105567‐83‐7"[tw]) NOT Medline[sb]   
#13  (Cyclopentolate [tw] OR "ak‐pentolate" [tw] OR akpentolate [tw] OR "bell pentolate" [tw] OR ciclolux [tw] OR cyclogyl [tw] OR cyclomydri [tw] OR cyclopentol [tw] OR cyclopentolat [tw] OR cylate [tw] OR cyplegin [tw] OR diopentolate [tw] OR midriodavi [tw] OR mydrilate [tw] OR "ocu‐pentolate" [tw] OR ocucyclo [tw] OR "oftan‐syklo" [tw] OR pentolair [tw] OR "refractyl ofeno" [tw] OR skiacol [tw] OR zyklolat [tw] OR "512‐15‐2" [tw] OR "5870‐29‐1"[tw]) NOT Medline[sb]   
#14  (Epinephrine [tw] OR Adrenaline [tw] OR adrenalin [tw] OR Epitrate [tw] OR Lyophrin [tw] OR Epifrin [tw] OR adnephrin [tw] OR adnephrine [tw] OR adrenaclick [tw] OR "adrenal hydrochloride" [tw] OR adrenalina [tw] OR adrenamine [tw] OR adrenapax [tw] OR adrenazin [tw] OR adrenine [tw] OR adrin [tw] OR adrine [tw] OR advaradin [tw] OR balmadren [tw] OR biorenine [tw] OR bosmin [tw] OR chelafrin [tw] OR dylephrin [tw] OR epiglaufrin [tw] OR epimephrine [tw] OR epinefrina [tw] OR epinephran [tw] OR epinephrin [tw] OR epirenamine [tw] OR epirenan [tw] OR exadrin [tw] OR glaucon [tw] OR glaucosan [tw] OR glaufrin [tw] OR "glin epin" [tw] OR glycirenan [tw] OR haemostatin [tw] OR hemisine [tw] OR hemostasin [tw] OR hemostatin [tw] OR hypernephrin [tw] OR "isopto epinal" [tw] OR levoadrenalin [tw] OR levoadrenaline [tw] OR levoepinephrine [tw] OR levorenin [tw] OR levorenine [tw] OR methylaminoethanolcatechol [tw] OR methylarterenol [tw] OR mucidrina [tw] OR myosthenine [tw] OR "n methylnoradrenalin" [tw] OR nephridine [tw] OR nieraline [tw] OR paranephrin [tw] OR posumin [tw] OR renaglandin [tw] OR renaglandulin [tw] OR renaleptine [tw] OR renalina [tw] OR renaline [tw] OR renoform [tw] OR renostypticin [tw] OR renostyptin [tw] OR scurenaline [tw] OR simplene [tw] OR soladren [tw] OR sphygmogenin [tw] OR styptirenal [tw] OR supracapsulin [tw] OR supranephrane [tw] OR supranephrin [tw] OR supranol [tw] OR suprarenaline [tw] OR suprarenin [tw] OR suprarenine [tw] OR suprel [tw] OR surenine [tw] OR surrenine [tw] OR "sus‐phrine sulfite‐free" [tw] OR susphrine [tw] OR "sympathin I" [tw] OR takamina [tw] OR tonogen [tw] OR vasoconstrictine [tw] OR vasodrine [tw] OR vasotonin [tw] OR weradren [tw] OR "51‐43‐4" [tw] OR "55‐31‐2" [tw] OR "6912‐68‐1"[tw]) NOT Medline[sb]   
#15  (Ethylmorphine[tw] OR Ethomorphine[tw] OR Trachyl[tw] OR codethyline[tw] OR diolan[tw] OR dionine[tw] OR "ethyl morphine"[tw] OR ethylmorfine[tw] OR ethylmorphin[tw] OR "morphine ethyl ether"[tw] OR "125‐30‐4"[tw] OR "76‐58‐4"[tw]) NOT Medline[sb]   
#16  (Eucatropine[tw] OR euphthalmine[tw] OR "100‐91‐4"[tw] OR "536‐93‐6"[tw]) NOT Medline[sb]   
#17  (Homatropine[tw] OR homatro[tw] OR homatrocil[tw] OR homatropaire[tw] OR homatropin[tw] OR homatropina[tw] OR isoptoHomatropine[tw] OR "I Homatrine"[tw] OR "mandelyl tropeine"[tw] OR mandelyltropeine[tw] OR "mydryn eye"[tw] OR "omatropina lux"[tw] OR "tropine mandelate"[tw] OR "51‐56‐9"[tw] OR "87‐00‐3"[tw]) NOT Medline[sb]   
#18  (Hyoscyamine[tw] OR anaspaz[tw] OR cystospaz[tw] OR cytospaz[tw] OR daturine[tw] OR donnamar[tw] OR duboisine[tw] OR egacen[tw] OR hyoscamine[tw] OR hyosciamine[tw] OR hyoscyanin[tw] OR hyosyne[tw] OR "ib‐stat"[tw] OR levbid[tw] OR levsin[tw] OR "levsinex sr"[tw] OR neosol[tw] OR nulev[tw] OR spasdel[tw] OR "symax sl"[tw] OR "symax sr"[tw] OR "tropine l tropate"[tw] OR "101‐31‐5"[tw] OR "306‐03‐6"[tw]) NOT Medline[sb]   
#19  (Ibopamine[tw] OR "N‐methyldopamine diisobutyrate"[tw] OR "SB 7505"[tw] OR "SB7505"[tw] OR Escandine[tw] OR Inopamil[tw] OR "diisobutyric n methyldopamine ester"[tw] OR scandine[tw] OR "skf 100168"[tw] OR "skf 100168 a"[tw] OR "66195‐31‐1"[tw] OR "75011‐65‐3"[tw]) NOT Medline[sb]   
#20  (Methylatropine[tw] OR "8‐methylatropinium nitrate"[tw] OR "31610‐87‐4"[tw]) NOT Medline[sb]   
#21  (Naphazoline[tw] OR "Afazol Grin"[tw] OR "AK Con"[tw] OR AKCon[tw] OR Albalon[tw] OR albasol[tw] OR "All Clear"[tw] OR allersol[tw] OR antan[tw] OR benil[tw] OR cefasan[tw] OR "Clear Eyes"[tw] OR coldan[tw] OR "Colirio Alfa"[tw] OR "comfort eye drops"[tw] OR dazolin[tw] OR "degest 2"[tw] OR derinox[tw] OR Idril[tw] OR imidin[tw] OR minha[tw] OR Miraclar[tw] OR mirafrin[tw] OR Nafazair[tw] OR nafazoline[tw] OR naftazolina[tw] OR "naphacel ofteno"[tw] OR naphasal[tw] OR naphazolin[tw] OR Naphcon[tw] OR "naphozoline hydrochloride"[tw] OR naphtears[tw] OR naphthazoline[tw] OR naphthizine[tw] OR naphthyzin[tw] OR nastizol[tw] OR "nazil ofteno"[tw] OR niazol[tw] OR "ocu‐zoline"[tw] OR opcon[tw] OR Optazine[tw] OR Privin[tw] OR privina[tw] OR Privine[tw] OR privine[tw] OR Proculin[tw] OR rhinantin[tw] OR rhinazin[tw] OR rhinoperd[tw] OR rimidol[tw] OR sanorin[tw] OR sanotin[tw] OR Siozwo[tw] OR strictylon[tw] OR "Tele Stulln"[tw] OR TeleStulln[tw] OR Vasoclear[tw] OR Vasocon[tw] OR "Vasoconstrictor Pensa"[tw] OR VasoNit[tw] OR vistalbalon[tw] OR vistobalon[tw] OR "5144‐52‐5"[tw] OR "550‐99‐2"[tw] OR "835‐31‐4"[tw]) NOT Medline[sb]   
#22  (Oxedrine[tw] OR Synephrine[tw] OR Sympaethamin[tw] OR Synephrin[tw] OR aetaphen[tw] OR pentedrine[tw] OR vasoton[tw] OR "94‐07‐5"[tw]) NOT Medline[sb]   
#23  (Oxyphenonium[tw] OR Methacin[tw] OR Oxyphenon[tw] OR Atrenyl[tw] OR Spastrex[tw] OR antrenyl[tw] OR "ba 5473"[tw] OR ba5473[tw] OR "c 5473"[tw] OR c5473[tw] OR helkamon[tw] OR metacin[tw] OR metacinum[tw] OR oxyphenium[tw] OR "oxyphenomium bromide"[tw] OR spasmofen[tw] OR spasmophen[tw] OR "14214‐84‐7"[tw] OR "50‐10‐2"[tw]) NOT Medline[sb]   
#24  (Phenylephrine[tw] OR adrianol[tw] OR "af‐taf"[tw] OR "ak‐dilate"[tw] OR "albalon relief"[tw] OR alconefrin[tw] OR almefrin[tw] OR altafrin[tw] OR biomidrin[tw] OR biomydrin[tw] OR derizene[tw] OR "despec‐sf"[tw] OR "disneumon pernasal"[tw] OR drosin[tw] OR "efrin‐10"[tw] OR efrisel[tw] OR fenylephrine[tw] OR idrianol[tw] OR isonefrine[tw] OR isophrin[tw] OR isophrine[tw] OR "isopto frin"[tw] OR isoptofrin[tw] OR lexatol[tw] OR "m synephrine"[tw] OR mesaton[tw] OR "meta sympathol"[tw] OR "meta synephrine"[tw] OR Metaoxedrin[tw] OR metaoxedrine[tw] OR Metasympatol[tw] OR metasynephrine[tw] OR Mezaton[tw] OR "murucoll 2"[tw] OR mydfrin[tw] OR "n 105 to"[tw] OR "nefrin‐ofteno"[tw] OR "Neo Synephrine"[tw] OR neofrin[tw] OR neooxedrine[tw] OR neophryn[tw] OR neosynephrin[tw] OR Neosynephrine[tw] OR "neosynephrin‐pos"[tw] OR neosynesin[tw] OR neosynesine[tw] OR "ocu‐phrin"[tw] OR "oftan‐metaoksedrin"[tw] OR optistin[tw] OR phenoptic[tw] OR phenylefrine[tw] OR phenylephedrine[tw] OR prefrin[tw] OR "pupiletto forte"[tw] OR rectasol[tw] OR "rhinall 10"[tw] OR "slv 325"[tw] OR slv325[tw] OR sucraphen[tw] OR vazculep[tw] OR visadron[tw] OR vistafrin[tw] OR vistosan[tw] OR "532‐38‐7"[tw] OR "59‐42‐7"[tw] OR "61‐76‐7"[tw]) NOT Medline[sb]   
#25  (Pholedrine[tw] OR "4 hydroxy n methylamphetamine"[tw] OR "4 hydroxymethamphetamine"[tw] OR adyston[tw] OR "para hydroxymethamphetamine"[tw] OR "p‐hydroxymethamphetamine"[tw] OR paredrinol[tw] OR "Pholedrin liquidum"[tw] OR "Pholedrin‐longo‐Isis"[tw] OR pulsotyl[tw] OR venosan[tw] OR veritol[tw] OR "370‐14‐9"[tw]) NOT Medline[sb]   
#26  (p‐Hydroxyamphetamine [tw] OR "1 para hydroxyphenyl 2 propylamine" [tw] OR "alpha methyl para tyramine" [tw] OR "alpha methyl tyramine" [tw] OR "dl 1 p hydroxyphenyl 2 propylamine" [tw] OR "dl 1 para hydroxyphenyl 2 propylamine" [tw] OR "dl p hydroxy alpha methylphenethylamine" [tw] OR "dl para hydroxy alpha methylphenethylamine" [tw] OR "h 66 37" [tw] OR "para hydroxy alpha methylphenethylamine" [tw] OR Hydroxyamfetamine [tw] OR Hydroxyamphetamin [tw] OR Hydroxyamphetamine [tw] OR Hydroxyphenylisopropylamine [tw] OR Methyltyramine [tw] OR Norpholedrin [tw] OR norpholedrine [tw] OR oxamphetamine [tw] OR Oxyamphetamine [tw] OR paradrine [tw] OR parahydroxyamphetamine [tw] OR Paredrine [tw] OR paredrinea [tw] OR paredrinex [tw] OR pedrolone [tw] OR pulsoton [tw] OR "103‐86‐6" [tw] OR "1518‐86‐1" [tw] OR "306‐21‐8"[tw]) NOT Medline[sb]   
#27  (Racepinephrine[tw] OR asthmanefrin [tw] OR Micronefrin[tw] OR micronefrine[tw] OR Micronephrine[tw] OR mikronephrin[tw] OR racadrenalin[tw] OR "Racepinefrine Hydrochloride"[tw] OR racinephrine[tw] OR Vaponefrin[tw] OR vaponefrine[tw] OR vaponephrin[tw] OR "329‐65‐7"[tw]) NOT Medline[sb]
#28  (Scopolamine[tw] OR "Boro Scopol"[tw] OR BoroScopol[tw] OR Hyoscine[tw] OR Kwells[tw] OR "levo hyoscinehydrobromide"[tw] OR Scoburen[tw] OR Scopace[tw] OR scopos[tw] OR "Travacalm HO"[tw] OR Vorigeno[tw] OR "114‐49‐8"[tw] OR atrochin[tw] OR atroquin[tw] OR atroscine[tw] OR hyosceine[tw] OR hysco[tw] OR "kimite‐patch"[tw] OR "l epoxytropine tropate"[tw] OR "n methylhyoscine"[tw] OR oscine[tw] OR scopalamine[tw] OR "scopine tropate"[tw] OR scopoderm[tw] OR scopolamin[tw] OR transcop[tw] OR "transderm scop"[tw] OR "transderm v"[tw] OR "tropic acid ester with scopine"[tw] OR "138‐12‐5"[tw] OR "51‐34‐3"[tw] OR "55‐16‐3"[tw]) NOT Medline[sb]   
#29  (Tropicamide[tw] OR "alcon‐mydril"[tw] OR bistropamide[tw] OR "cendo mydriatyl"[tw] OR "Colircusi Tropicamida"[tw] OR midriaticum[tw] OR mydiacyl[tw] OR mydral[tw] OR mydramide[tw] OR mydriacyl[tw] OR Mydriafair[tw] OR Mydriaticum[tw] OR "mydrin m"[tw] OR "mydrin p"[tw] OR Mydrum[tw] OR "n ethyl 2 phenyl n pyrid 4 ylmethylhydracrylamide"[tw] OR "n ethyl n 4 picolyltropamide"[tw] OR "n ethyl n gamma picolyltropamide"[tw] OR "n ethyl n pyrid 4 ylmethyltropamide"[tw] OR "Ocu‐Tropic"[tw] OR OcuTropic[tw] OR opticyl[tw] OR sandol[tw] OR sintropic[tw] OR "tropamid forte"[tw] OR "tropic acid n ethyl n gamma picolyl amide" [tw] OR  Tropicacyl[tw] OR tropicamid[tw] OR "tropico eye"[tw] OR tropicol[tw] OR tropikamid[tw] OR tropimil[tw] OR visumidriatic[tw] OR "1508‐75‐4"[tw]) NOT Medline[sb]   
#30  (Tyramine[tw] OR  "4 hydroxyphenethylamine"[tw] OR lyramine[tw] OR mydrial[tw] OR "para hydroxyphenethylamine"[tw] OR paratyramine[tw] OR systogene[tw] OR tiramine[tw] OR tocosine[tw] OR tyramin[tw] OR tyrosamine[tw] OR uteramine[tw] OR "51‐67‐2"[tw] OR "60‐19‐5"[tw]) NOT Medline[sb]   
#31  (Vibrocil[tw] OR "8059‐14‐1"[tw]) NOT Medline[sb]   
#32  (Yohimbine[tw] OR actibine[tw] OR aphrodine[tw] OR aphrodyne[tw] OR Corynanthine[tw] OR "corynine hydrochloride"[tw] OR "dayto‐himbin"[tw] OR "methyl yohimbine 16alpha carboxylate"[tw] OR "methylyohimbane 16alpha carboxylate"[tw] OR Pluriviron[tw] OR quebrachin[tw] OR "quebrachine hydrochloride"[tw] OR Rauhimbine[tw] OR Rauwolscine[tw] OR urobine[tw] OR yobin[tw] OR yobinol[tw] OR yocan[tw] OR yocaral[tw] OR Yocon[tw] OR yocon[tw] OR yohimbe[tw] OR "yohimbic acid methyl ester"[tw] OR yohimbin[tw] OR Yohimex[tw] OR yohimex[tw] OR yohimibin[tw] OR yovital[tw] OR "146‐48‐5"[tw] OR "65‐19‐0"[tw]) NOT Medline[sb]   
#33  #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32
#34  #7 AND #33
#35  #1 AND #34

Appendix 5. LILACS search strategy

(MH:C11.510.245$ OR MH:E04.540.825.249$ OR MH:E04.943.875$ OR phacoemulsif$ OR phakoemulsif$ OR phaco$ OR phako$ OR capsulorhexis or capsulorrhexis OR phakectom$ OR lensectom$ OR zonulolys$ OR catarectom$ OR cataract$) AND (MH:C11.710.570$ OR MH:D27.505.696.663.050.495$ OR MH:C10.597.690.362$ OR MH:C11.710.528$ OR MH:C23.888.592.708.362$ OR MH:D27.505.696.663.050.500$ OR Miotic$ OR Miosis OR Miose OR myosis OR mydriasis OR Midrias$ OR Mydriasert OR (pupil$ AND dilat$) OR mydriatic$ OR Midriáticos OR cycloplegic$ OR Atropin$ OR MH:D02.145.074.722.229.199$ OR MH:D03.132.760.180.572.199$ OR MH:D03.132.889.180.648.199$ OR MH:D03.605.869.229.199$ OR MH:D04.075.080.875.099.722.229.199 OR berefrine OR Cyclopentolate OR Ciclopentolato OR MH:D02.241.223.601.200$ OR Epinephrine OR Epinefrina OR MH:D02.033.100.291.310$ OR MH:D02.092.063.291.310$ OR MH:D02.092.211.215.311.461$ OR MH:D02.092.311.461$ OR Ethylmorphine OR Etilmorfina OR MH:D03.132.577.249.562.430$ OR MH:D03.549.686.607.460$ OR MH:D03.605.497.607.460$ OR MH:D04.615.723.795.576.430$ OR Eucatropine OR Homatropine OR Hyoscyamine OR Hiosciamina OR MH:D02.145.074.722.229.199.500$ OR MH:D03.132.760.180.572.199.500$ OR MH:D03.132.889.180.648.199.500$ OR MH:D03.605.869.229.199.500$ OR MH:D04.075.080.875.099.722.229.199.500$ OR Ibopamine OR Methylatropine OR Naphazoline OR Nafazolina OR MH:D03.383.129.308.585$ OR Oxedrine OR Synephrine OR Sinefrina OR MH:D02.033.100.291.870$ OR MH:D02.092.063.291.870$ OR MH:D02.092.211.215.811.875$ OR Oxyphenonium OR Oxifenonio OR MH:D02.092.877.648$ OR MH:D02.675.276.648$ OR Phenylephrine OR Fenilefrina OR MH:D02.033.100.291.617$ OR MH:D02.092.063.291.617$ OR Pholedrine OR "p‐Hydroxyamphetamine" OR "p‐Hidroxianfetamina" OR MH:D02.092.471.683.152.500$ OR Racepinephrine OR Racepinefrina OR MH:D02.033.100.291.310.500$ OR MH:D02.092.063.291.310.500$ OR MH:D02.092.211.215.311.461.700$ OR MH:D02.092.311.461.825$ OR Scopolamine OR Escopolamina OR MH:D02.145.074.722.822.775$ OR MH:D03.132.760.180.848$ OR MH:D03.132.889.601.775$ OR MH:D03.605.869.822.775$ OR MH:D04.075.080.875.099.722.822.775$ OR Tropicamide OR Tropicamida OR MH:D03.383.725.942$ OR Tyramine OR Tiramina OR MH:D02.092.211.215.811$ OR Vibrocil OR Yohimbine OR Yohimbina OR Ioimbina OR MH:D03.132.436.681.933$ OR MH:D03.438.473.402.681.933$)

Appendix 6. ClinicalTrials.gov search strategy

(Cataract OR Phacoemulsification OR Capsulorhexis) AND (mydriatics OR miotics OR miosis OR myosis OR mydriasis OR atropine OR berefrine OR cyclopentolate OR epinephrine OR ethylmorphine OR eucatropine OR homatropine OR hyoscyamine OR ibopamine OR oxyphenonium OR methylatropine OR naphazoline OR oxedrine OR p‐hydroxyamphetamine OR phenylephrine OR pholedrine OR scopolamine OR tropicamide OR tyramine OR vibrocil OR yohimbine)

Appendix 7. WHO ICTRP search strategy

Cataract AND mydriatics OR Cataract AND miotics OR Cataract AND miosis OR Cataract AND myosis OR Cataract AND mydriasis OR Cataract AND atropine OR Cataract AND berefrine OR Cataract AND cyclopentolate OR Cataract AND epinephrine OR Cataract AND ethylmorphine OR Cataract AND eucatropine OR Cataract AND homatropine OR Cataract AND hyoscyamine OR Cataract AND ibopamine OR Cataract AND oxyphenonium OR Cataract AND methylatropine OR Cataract AND naphazoline OR Cataract AND oxedrine OR Cataract AND p‐hydroxyamphetamine OR Cataract AND phenylephrine OR Cataract AND pholedrine OR Cataract AND scopolamine OR Cataract AND tropicamide OR Cataract AND tyramine OR Cataract AND vibrocil OR Cataract AND yohimbine

Phacoemulsification AND mydriatics OR Phacoemulsification AND miotics OR Phacoemulsification AND miosis OR Phacoemulsification AND myosis OR Phacoemulsification AND mydriasis OR Phacoemulsification AND atropine OR Phacoemulsification AND berefrine OR Phacoemulsification AND cyclopentolate OR Phacoemulsification AND epinephrine OR Phacoemulsification AND ethylmorphine OR Phacoemulsification AND eucatropine OR Phacoemulsification AND homatropine OR Phacoemulsification AND hyoscyamine OR Phacoemulsification AND ibopamine OR Phacoemulsification AND oxyphenonium OR Phacoemulsification AND methylatropine OR Phacoemulsification AND naphazoline OR Phacoemulsification AND oxedrine OR Phacoemulsification AND p‐hydroxyamphetamine OR Phacoemulsification AND phenylephrine OR Phacoemulsification AND pholedrine OR Phacoemulsification AND scopolamine OR Phacoemulsification AND tropicamide OR Phacoemulsification AND tyramine OR Phacoemulsification AND vibrocil OR Phacoemulsification AND yohimbine

Capsulorhexis AND mydriatics OR Capsulorhexis AND miotics OR Capsulorhexis AND miosis OR Capsulorhexis AND myosis OR Capsulorhexis AND mydriasis OR Capsulorhexis AND atropine OR Capsulorhexis AND berefrine OR Capsulorhexis AND cyclopentolate OR Capsulorhexis AND epinephrine OR Capsulorhexis AND ethylmorphine OR Capsulorhexis AND eucatropine OR Capsulorhexis AND homatropine OR Capsulorhexis AND hyoscyamine OR Capsulorhexis AND ibopamine OR Capsulorhexis AND oxyphenonium OR Capsulorhexis AND methylatropine OR Capsulorhexis AND naphazoline OR Capsulorhexis AND oxedrine OR Capsulorhexis AND p‐hydroxyamphetamine OR Capsulorhexis AND phenylephrine OR Capsulorhexis AND pholedrine OR Capsulorhexis AND scopolamine OR Capsulorhexis AND tropicamide OR Capsulorhexis AND tyramine OR Capsulorhexis AND vibrocil OR Capsulorhexis AND yohimbine

Data and analyses

Comparison 1. Topical mydriatics versus intracameral mydriatics.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Mean pupillary diameter	7		Mean Difference (IV, Random, 95% CI)	Totals not selected
1.1.1 At the time the surgeon performs capsulorhexis	4		Mean Difference (IV, Random, 95% CI)	Totals not selected
1.1.2 At the beginning of the procedure	4		Mean Difference (IV, Random, 95% CI)	Totals not selected
1.1.3 At the end of procedure	5		Mean Difference (IV, Random, 95% CI)	Totals not selected
1.2 Intraoperative surgical time	5		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.2.1 Total intraoperative time	5		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.3 Total time it took for the surgeon to perform phacoemulsification (seconds)	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.4 AE: participant‐reported ocular discomfort	1		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only
1.4.1 Week 1	1	555	Risk Ratio (IV, Fixed, 95% CI)	10.57 [1.37, 81.34]
1.4.2 Month 1	1	543	Risk Ratio (IV, Fixed, 95% CI)	2.51 [1.36, 4.65]
1.5 AE: posterior capsule rupture	1		Risk Ratio (IV, Fixed, 95% CI)	Totals not selected
1.5.1 Any time point during or after surgery	1		Risk Ratio (IV, Fixed, 95% CI)	Totals not selected
1.6 AE: cystoid macular edema	1		Risk Ratio (IV, Fixed, 95% CI)	Totals not selected
1.6.1 Any time point during or after surgery	1		Risk Ratio (IV, Fixed, 95% CI)	Totals not selected

1.5. Analysis.

Comparison 1: Topical mydriatics versus intracameral mydriatics, Outcome 5: AE: posterior capsule rupture

1.6. Analysis.

Comparison 1: Topical mydriatics versus intracameral mydriatics, Outcome 6: AE: cystoid macular edema

Comparison 2. Topical mydriatics versus depot delivery systems.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Mean pupillary diameter	6		Mean Difference (IV, Random, 95% CI)	Totals not selected
2.1.1 At the beginning of the procedure	6		Mean Difference (IV, Random, 95% CI)	Totals not selected
2.1.2 At the end of procedure	3		Mean Difference (IV, Random, 95% CI)	Totals not selected
2.2 Intraoperative surgical time	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.2.1 Total intraoperative time	1	58	Mean Difference (IV, Fixed, 95% CI)	0.88 [‐0.64, 2.40]
2.3 AE: vitreous loss	1		Risk Ratio (IV, Fixed, 95% CI)	Subtotals only
2.3.1 Any time point during or after surgery	1	58	Risk Ratio (IV, Fixed, 95% CI)	Not estimable

2.3. Analysis.

Comparison 2: Topical mydriatics versus depot delivery systems, Outcome 3: AE: vitreous loss

Comparison 3. Intracameral mydriatics versus depot delivery systems.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Mean pupillary diameter	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
3.1.1 At the beginning of the procedure	1	60	Mean Difference (IV, Fixed, 95% CI)	‐1.90 [‐2.45, ‐1.35]
3.1.2 At the end of procedure	1	60	Mean Difference (IV, Fixed, 95% CI)	‐1.60 [‐2.13, ‐1.07]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bäckström 2013.

Study characteristics
Methods	Study design: randomized controlled trial, parallel group Exclusion after randomization: 2 Loss to follow‐up: none Intention‐to‐treat: all participants were analyzed in the group to which they had been randomly assigned, but 2 were excluded from analysis Sample size estimation: not reported
Participants	Country: Sweden Setting: hospital Enrollment year: not reported Baseline characteristics: Topical mydriatics group Number randomized: 30 Mean age, years (SD): 78 (8) Women, n (%): NR (53) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): 2.9 (0.6) Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists at baseline, n (%): not reported Pseudoexfoliation syndrome, n (%): 10 (33) Diabetes mellitus, n (%): 6 (20) Pre‐existing cardiac conditions, n (%): not reported Pre‐ and intraoperative NSAIDs, n (%): not reported Intracameral mydriatics group Number randomized: 30 Mean age, years (SD): 77 (10) Women, n (%): NR (60) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): 3.1 (0.5) Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists at baseline, n (%): not reported Pseudoexfoliation syndrome, n (%): 9 (30) Diabetes mellitus, n (%): 4 (13) Pre‐existing cardiac conditions, n (%): not reported Pre‐ and intraoperative NSAIDs, n (%): not reported Overall Number randomized: 60 Mean age, years (SD): not reported Women, n (%): NR (57) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists at baseline, n (%): not reported Pseudoexfoliation syndrome, n (%): 19 (32) Diabetes mellitus, n (%): 10 (17) Pre‐existing cardiac conditions, n (%): not reported Pre‐ and intraoperative NSAIDs, n (%): not reported Inclusion criteria: patients with age‐related cataracts planned for unilateral phacoemulsification and IOL implantation Exclusion criteria: synechia or other mechanical obstacles for free pupil movement Pretreatment: no preoperative differences between the topical mydriatics and the intracameral mydriatics groups
Interventions	Intervention group: 3 drops of a saline solution 0.9% with 5‐minute interval (placebo drops); for surface anesthesia, 3 drops of tetracaine 1% with 5‐minute interval prior to surgery; and intracameral mydriatics (150 μL of cyclopentolate 0.1%, phenylephrine 1.5%, and xylocaine 1% intracamerally) at the beginning of the surgical procedure Comparator: 3 drops of a mixture of cyclopentolate 0.85% and phenylephrine 1.5% with 5‐minute interval; for surface anesthesia, 3 drops of tetracaine 1% with 5‐minute interval prior to surgery; and 150 μL of preservative‐free lidocaine 1% intracamerally at the beginning of the surgical procedure
Outcomes	Primary outcome and secondary outcomes: not specified Measured outcomes: mean pupillary diameter at the beginning and end of procedure intraoperative surgical time in minutes total time in seconds to perform phacoemulsification adverse events
Identification	Author name: Gunnie Backstrom Institution: Eye Clinic, Ornskoldsviks Hospital Email: gunnie.backstrom@lvn.se Clinical Trials Registration Number: not reported
Notes	Sponsorship source: not reported Declaration of interest: the authors have no financial interest in any product mentioned in this paper
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants assigned to treatment groups using a list of randomization prepared by the R&D department (FoU Cenntrum) of the county council.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking of participants and personnel (performance bias)	Low risk	Authors stated that treatment was masked for participants but not for the surgeon.
Masking of outcome assessment (detection bias)	Unclear risk	Masking of outcome assessors not reported.
Incomplete outcome data (attrition bias) All outcomes	Low risk	2 participants were excluded from the study: 1 had preoperative synechia comprising a mechanical obstacle for free pupil movement, and 1 was excluded due to technical administrative problems.
Selective reporting (reporting bias)	Unclear risk	No trial registration; although outcomes specified at the methods section were reported in the results section, selective outcome reporting may still exist.

Dubois 2006.

Study characteristics
Methods	Study design: randomized controlled trial, parallel group Exclusion after randomization: 20 Loss to follow‐up: none Intention‐to‐treat: all participants were analyzed in the group to which they had been randomly assigned Sample size estimation: sample size was obtained from a power calculation, looking for a medium effect size (0.5), with P = 0.05, aiming for α = 0.8, allowing for a dropout rate. Participants were randomized into 2 groups of 65 cases and 65 controls.
Participants	Country: United Kingdom Setting: Eye Unit, Royal United Hospital Enrollment year: not reported Baseline characteristics: Topical mydriatics Number randomized: 65 Mean age, years (SD): not reported Women, n (%): not reported Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists at baseline, n (%): not reported Pseudoexfoliation syndrome, n (%): not reported Diabetes mellitus, number (%): not reported Pre‐existing cardiac conditions, n (%): not reported Pre‐ and intraoperative NSAIDs, n (%): 65 (100) Depot delivery systems Number randomized: 65 Mean age, years (SD): not reported Women, n (%): not reported Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists at baseline, n (%): not reported Pseudoexfoliation syndrome, n (%): not reported Diabetes mellitus, n (%): not reported Pre‐existing cardiac conditions, n (%): not reported Pre‐ and intraoperative NSAIDs, n (%): 65 (100) Overall Number randomized: 130 Mean age, years (SD): not reported Women, n (%): not reported Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists at baseline, n (%): not reported Pseudoexfoliation syndrome, n (%): not reported Diabetes mellitus, number (%): not reported Pre‐existing cardiac conditions, n (%): not reported Pre‐ and intraoperative NSAIDs, n (%): 130 (100) Inclusion criteria: patients scheduled for routine cataract surgery Exclusion criteria: history of diabetes, uveitis, any pupillary abnormalities, pseudoexfoliation, use of miotics (but not other glaucoma medications), and very dark irides Pretreatment: there was no significant difference between the observed pupil sizes in the 2 groups of participants
Interventions	Intervention group: immediate dose of proparacaine followed by insertion of a mydriatic‐soaked wick (BD Visidrain eye fluid wick, cut into 1‐centimeter strips; soaked in equal part mixture of diclofenac sodium 0.1%, tropicamide 1%, and phenylephrine 2.5%) into the lower fornix Comparator: immediate dose of diclofenac sodium 0.1%, and then alternate tropicamide 1% and phenylephrine 2.5% at 15‐minute intervals in the preoperative hour
Outcomes	Primary outcome: not reported Secondary outcome: not reported Measured outcome: pupil size Adverse events: none
Identification	Author name: Vincent Dubois Institution: Eye Unit, Royal United Hospital Email: vincent_dubois@doctors.org.uk Clinical Trials Registration Number: ISRCTN78047760
Notes	Sponsorship source: Royal United Hospital NHS Trust (UK) Conflict of interest: the authors have no financial interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors did not describe how random sequence was generated.
Allocation concealment (selection bias)	Unclear risk	While authors reported that after the participant signed the consent form, an envelope was opened which contained either the word WICK (for the cases), or DROPS (for the controls), and the participant was assigned to the respective group, this is not quite sealed, opaque envelopes and could still be subverted.
Masking of participants and personnel (performance bias)	Unclear risk	Masking of participants, personnel, and surgeons not reported.
Masking of outcome assessment (detection bias)	Low risk	All participants had measurement of horizontal pupil diameter with a pair of calipers to within half a millimeter by a masked observer (who was the doctor administering the local anesthetic).
Incomplete outcome data (attrition bias) All outcomes	High risk	15% (n = 20) eyes excluded from analysis because of loss of wick (n = 1), and a further 12 in WICK group and 8 in DROPS group due to improper or incomplete "filling of forms."
Selective reporting (reporting bias)	Unclear risk	Trial was registered, however outcome assessed not reported in registered protocol.

Hargitai 2013.

Study characteristics
Methods	Study design: randomized controlled trial, parallel group Loss to follow‐up: not reported Intention‐to‐treat: all participants were analyzed in the groups to which they had been assigned Sample size estimation: with 25 participants in each of 2 groups, a 0.8‐millimeter difference between groups will be recognized by an unpaired t‐test with 80% probability assuming a within‐group standard deviation of approximately 1 mm
Participants	Country: Denmark Setting: hospital Enrollment year: 2012 Baseline characteristics: Topical mydriatics Number randomized: 28 Mean age, years (SD): 76.64 (6.85) Women, n (%): 0 (0) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): 7.30 (1.55) Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, n (%): 28 Pseudoexfoliation syndrome, n (%): 0 Diabetes mellitus, n (%): 10 Pre‐existing cardiac conditions, n (%): not reported Pre‐ and intraoperative NSAIDs at baseline, n (%): 28 Depot delivery systems Number randomized: 30 Mean age, years (SD): 78.6 (10.35) Women, n (%): 0 (0) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): 7.52 (1.21) Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, n (%): 30 Pseudoexfoliation syndrome, n (%): 0 Diabetes mellitus, n (%): 10 Pre‐existing cardiac conditions, n (%): not reported Pre‐ and intraoperative NSAIDs at baseline, n (%): 30 Overall Number randomized: 58 Mean age, years (SD): 78.6 (10.35) Women, n (%): 0 (0) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): 7.52 (1.21) Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, n (%): 58 Pseudoexfoliation syndrome, n (%): 0 Diabetes mellitus, n (%): 20 Pre‐existing cardiac conditions, n (%): not reported Pre‐ and intraoperative NSAIDs at baseline, n (%): 58 Inclusion criteria: male patients taking tamsulosin due to benign prostatic hypertrophy, attending elective cataract surgery Exclusion criteria: previous ocular surgery, posterior synechiae, and the use of drops other than artificial tears Pretreatment: 1‐way ANOVA showed no significant difference between the groups in terms of age
Interventions	Intervention group: oxybuprocaine 0.4%, cocaine 4%, tropicamide 1%, phenylephrine 10%, diclofenac 0.1%, and chloramphenicol 0.5% eyedrops were used preoperatively. Cellulose wicks were prepared and submerged in a mix of the above solutions with 1:1:1:1:1:1 ratio. Comparator: oxybuprocaine 0.4%, cocaine 4%, tropicamide 1%, phenylephrine 10%, diclofenac 0.1%, and chloramphenicol 0.5% eyedrops were used preoperatively. Drops were supplied 3 times with 10‐minute intervals.
Outcomes	Primary outcome: pupil diameter (mm), after nucleus delivery, and before IOL implantation Secondary outcome: not reported Measured outcomes: total intraoperative miosis (mm), mean (SD)
Identification	Author name: János Hargitai Institution: Thy‐Mors Hospital Email: janos.hargitai@rn.dk Address: Department of Ophthalmology, Thy‐Mors Hospital, Højtoftevej 2, Thisted7700, Denmark Clinical Trials Registration Number: not reported
Notes	Comments: 30 participants were dilated using the mydriatics cocktail‐soaked sponge (group 1), and 30 participants were dilated using conventional repeated eyedrops regimen (group 2); there was an additional "control" (non‐randomized) group of 31 participants not receiving any α1 adrenergic receptor antagonist medication who also were dilated with mydriatic‐cocktail soaked sponge. Minor (3/30, 2/28, and 1/31 respectively) and major (1/30, 0/28, and 0/31 respectively) complication rate was similar among all groups. Sponsorship source: not reported Conflict of interest: the authors declare that they have no competing interests
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors did not describe how the random sequence was generated.
Allocation concealment (selection bias)	Low risk	The study group was subdivided randomly into 2 equal‐sized groups (n = 30), using sealed envelope method.
Masking of participants and personnel (performance bias)	High risk	Masking of participants not described; surgeons were masked.
Masking of outcome assessment (detection bias)	Unclear risk	Identity and masking of outcome assessors not reported.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data reported for all randomized participants, except for 2 who were excluded because they could not lie flat.
Selective reporting (reporting bias)	Low risk	Outcomes stated in trial registry same as reported in paper.

Johansson 2007.

Study characteristics
Methods	Study design: randomized controlled trial, parallel group Loss to follow‐up: no losses to follow‐up Intention‐to‐treat: participants were analyzed in the groups to which they had been assigned Sample size estimation: not reported
Participants	Country: Sweden Setting: hospital Enrollment date: not reported Baseline characteristics Topical mydriatics Number randomized: not reported Mean age, years (SD): not reported Women, n (%): not reported Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, n (%): not reported Pseudoexfoliation syndrome, n (%): not reported Diabetes mellitus, n (%): not reported Pre‐existing cardiac conditions, n (%): not reported Pre‐ and intraoperative NSAIDs at baseline, n (%): not reported Intracameral mydriatics Number randomized: 11 Mean age, years (SD): not reported Women, n (%): not reported Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, n (%): not reported Pseudoexfoliation syndrome, n (%): not reported Diabetes mellitus, n (%): not reported Pre‐existing cardiac conditions, n (%): not reported Pre‐ and intraoperative NSAIDs at baseline, n (%): not reported Overall Number randomized: 22 Mean age, years (SD): 79.6 (8.3) Women, n (%): 12 (55) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, n (%): not reported Pseudoexfoliation syndrome, n (%): not reported Diabetes mellitus, n (%): not reported Pre‐existing cardiac conditions, n (%): not reported Pre‐ and intraoperative NSAIDs at baseline, n (%): not reported Inclusion criteria: patients with age‐related cataract scheduled for unilateral phacoemulsification and IOL implantation were included Exclusion criteria: patients on medication containing topical mydriatics or miotics or with proliferative diabetic retinopathy, previous intraocular surgery, history of uveitis, previous eye trauma, malformations of the anterior segment, only 1 functioning eye, signs of corneal disease, "serious general disease," or cognitive insufficiency were not included Pretreatment: baseline data were similar between groups
Interventions	Intervention group: intracameral administration of 150 mL of a preservative‐free mixture of phenylephrine 1.5% and lidocaine 1% at the beginning of the surgical procedure Comparator: the control group was given 3 drops each of cyclopentolate 1% and phenylephrine 10% at 15‐minute intervals before surgery and 150 mL of preservative‐free lidocaine 1% intracamerally at the beginning of the procedure
Outcomes	Primary outcome: not reported Secondary outcome: not reported Other outcomes: pupillary dilation and total surgical time
Identification	Author name: Anders Behndig, MD, PhD, Department of Clinical Science/Ophthalmology, Umeå University Hospital, Umeå, SE‐901 85, Sweden Institution: Department of Clinical Science/Ophthalmology, Umeå University Hospital, Umeå Email: anders.behndig@ophthal.umu.se Address: Department of Clinical Science/Ophthalmology, Umeå University Hospital, Umeå, SE‐901 85, Sweden Clinical Trials Registration Number: not reported
Notes	Sponsorship source: supported by grants from the Umeå University research funds and the KMA fund Conflict of interest: no author has a financial or proprietary interest in any material or method mentioned
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation was not described.
Allocation concealment (selection bias)	Unclear risk	Method of treatment allocation not reported.
Masking of participants and personnel (performance bias)	Low risk	"neither the operating surgeon nor the patient was aware of which treatment was given"
Masking of outcome assessment (detection bias)	Low risk	"The same observer reviewed the videos of all surgical procedures in a masked fashion; subjective evaluations of the surgical performance and pupil dilation were done using the same criteria"
Incomplete outcome data (attrition bias) All outcomes	Low risk	There were no losses to follow‐up.
Selective reporting (reporting bias)	Unclear risk	No trial registration; however, while outcomes specified at the methods section were reported in the results section, selective outcome reporting may still exist.

Labetoulle 2016.

Study characteristics
Methods	Study design: randomized controlled trial, parallel group Loss to follow‐up: 12 participants were withdrawn after randomization, 6 from each group. In mydriatics group: 1 participant was lost to follow‐up and 5 non‐medical/other reasons; in the comparator group: 1 participant was withdrawn due to adverse events and 5 for non‐medical or other reasons Intention‐to‐treat: participants were analyzed in the groups to which they had been assigned Sample size estimation: data were required for 246 evaluable participants in each treatment group to have 95% power for showing non‐inferiority of mydriatics to the reference treatment
Participants	Country: multicenter, international (France, Germany, Belgium, Portugal, Italy, Spain, Algeria, Austria, Sweden) Setting: hospital Enrollment date: June 2011 to January 2013 Baseline characteristics Topical mydriatics Number randomized: 296 Mean age, years (SD): 70.6 (9.2) Women, n (%): 162 (54.7) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): at least 7 mm Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, n (%): not reported Pseudoexfoliation syndrome, n (%): not reported Diabetes mellitus, n (%): not reported Pre‐existing cardiac conditions, n (%): not reported Pre‐ and intraoperative NSAIDs at baseline, n (%): not reported Intracameral mydriatics Number randomized: 295 Mean age, years (SD): 69.2 (9.4) Women, n (%): 175 (59.3) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): at least 7 mm Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, n (%): not reported Pseudoexfoliation syndrome, n (%): not reported Diabetes mellitus, n (%): not reported Pre‐existing cardiac conditions, n (%): not reported Pre‐ and intraoperative NSAIDs at baseline, n (%): not reported Overall Number randomized: 591 Mean age, years (SD): not reported Women, n (%): 337 (57.0) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): at least 7 mm Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, n (%): not reported Pseudoexfoliation syndrome, n (%): not reported Diabetes mellitus, n (%): not reported Pre‐existing cardiac conditions, n (%): not reported Pre‐ and intraoperative NSAIDs at baseline, n (%): not reported Inclusion criteria: aged 40 to 88 years old, scheduled to undergo phacoemulsification with foldable IOL implantation under topical anesthesia with clear self‐sealing corneal incisions Exclusion criteria: history of intraocular surgery or combined procedures; iatrogenic, traumatic, or congenital cataract; corneal, epithelial, stromal, or endothelial residual or progressive corneal disease; history of ocular trauma, infection, or inflammation within the previous 3 months; pseudoexfoliation and exfoliation syndrome Pretreatment: baseline data were similar between groups
Interventions	Intervention group: injected with 200 μL of Mydrane in the anterior chamber just after the first corneal incision. Subsequently, a waiting time of 1.5 min (with the surgical microscope light switched off) was required by the protocol after injection of Mydrane and before delivery of viscoelastic. If mydriasis was considered inadequate after 1.5 min, a supplementary injection of 100 μL was permitted at the surgeon’s discretion. Comparator: participants received 1 drop each of tropicamide 0.5% and phenylephrine 10%, repeated 3 times at 10‐minute intervals beginning 30 min before surgery
Outcomes	Primary outcome: achievement of capsulorhexis without the use of any additive mydriatic treatment Secondary outcomes: pupil size measured, assessment of participant's discomfort during cataract surgery, time necessary for obtaining sufficient mydriasis
Identification	Author name: Marc Labetoulle Institution: Service d’Ophtalmologie, Hôpital Bicêtre, APHP, Université Paris Email: marc.labetoulle@bct.aphp.fr Address: Service d ’Ophtalmologie, Hôpital Bicêtre, APHP, Université Paris Sud. 94275 Le Kremlin‐Bicêtre, France Clinical Trials Registration Number: NCT02101359
Notes	Sponsorship source: this clinical study was sponsored by Laboratoires THEA (Clermont‐Ferrand, France), manufacturers of 1 of the interventions compared (standard topical regimen was tropicamide). The sponsor participated in the design of the study, conducting the study, data collection, data management, data analysis, interpretation of the data, and preparation of the manuscript. Conflict of interest: ML has served as a consultant for Allergan, Alcon, Bausch & Lomb, MSD, Santen/Novagali and Théa. OF is a scientific advisor to Abbott Medical Optics, Carl Zeiss Meditec AG, and Croma‐Pharma. M‐JT is consultant for Théa, Ellex Medical Lasers and Morcher GmbH. BC has financial interests with Abbott Medical Optics, Alcon, and Bausch & Lomb.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomized, at end of selection visit (7 to 60 days before surgery), but method of random sequence generation not reported.
Allocation concealment (selection bias)	Unclear risk	The surgeon and surgical team were masked to the type of regimen and group enrollment until 30 to 60 minutes preoperatively.
Masking of participants and personnel (performance bias)	Unclear risk	Masking of participants and investigators not reported.
Masking of outcome assessment (detection bias)	Low risk	Pupillary diameter was performed by an independent and masked operator.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Exclusion numbers were reported, and reasons for exclusion given. Analysis was done in an intention‐to‐treat manner.
Selective reporting (reporting bias)	High risk	Discrepancies between adverse events reported in ClinicalTrials.gov and adverse events reported in study (e.g. retinal detachment)

Lay Suan 2017.

Study characteristics
Methods	Study design: randomized controlled trial Study grouping: parallel group Loss to follow‐up: none Intention‐to‐treat: participants were analyzed in the groups to which they had been assigned Sample size estimation: not reported
Participants	Country: Malaysia Setting: hospital Enrollment date: not reported Baseline characteristics Topical mydriatics Number randomized: 56 Mean age, years (SD): 63.20 (5.22) Women n (%): 129 (51.8) Race, n (%): Asian, n (%): 56 (100) Preoperative pupillary diameter, mean, mm (SD): 1.94 (0.29) Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): 0 Diabetes mellitus, number (%): 0 Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Intracameral mydriatics Number randomized: 56 Mean age, years (SD): 62.66 (6.45) Women n (%): 35 (62.5) Race, n (%): Asian, n (%): 56 (100) Preoperative pupillary diameter, mean, mm (SD): 1.98 (0.33) Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): 0 Diabetes mellitus, number (%): 0 Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Overall Number randomized: 112 Mean age, years (SD): 62.66 (6.45) Women n (%): 64 (57.1) Race, n (%): Asian, n (%): 112 (100) Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): 0 Diabetes mellitus, number (%): 0 Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Inclusion criteria: "Patients were eligible if they were older than 18 years and able to provide informed consent" Exclusion criteria: "Patients with pupil abnormalities, narrow anterior chambers, previous intraocular surgery, past ocular trauma, ocular inflammation with posterior synechiae, pseudoexfoliation, complicated or dense cataracts, scheduled for combined surgery (e.g., cataract and glaucoma), chronic miotic or a‐blocker use or systemic comorbidities that were thought to affect pupil dilation (e.g., DM and single eyed) were excluded" Pretreatment: "All baseline parameters were comparable between the 2 groups"
Interventions	Topical mydriatics: "Topical tropicamide 1.0%, and phenylephrine 2.5% at 15‐minute intervals for 1 hour before the surgery" Intracameral mydriatics: "Intracameral injection of 0.2 mL preservative‐free mixture of lidocaine 1.0% and phenylephrine 1.5% at the beginning of the surgery"
Outcomes	Primary: not reported Secondary: not reported Measured outcome: before capsulorhexis, before IOL implantation, at end of surgery, surgical time (min)
Identification	Author name: Amelia Lim Lay Suan Institution: Department of Ophthalmology, Faculty of Medicine, Universiti Kebangsaan Malaysia Email: jemaima@ppukm.ukm.edu.my Address: Jemaima Che Hamzah, MD, Department of Ophthalmology, Faculty of Medicine, Universiti Kebangsaan Malaysia, JalanYaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia Clinical Trials Registration Number: not reported
Notes	Sponsorship source: not reported Conflict of interest: none of the authors has a financial or proprietary interest in any material or method mentioned
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors did not describe method of random sequence generation.
Allocation concealment (selection bias)	Unclear risk	Method of treatment allocation concealment before randomization not reported.
Masking of participants and personnel (performance bias)	Unclear risk	Stated to be a prospective randomized single‐masked trial, but did not state whether it was participants or investigators who were masked.
Masking of outcome assessment (detection bias)	Unclear risk	Masking of outcome assessors not reported.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Authors did not report any attrition, and it is unclear whether number randomized were also analyzed.
Selective reporting (reporting bias)	Unclear risk	No trial registration; however, while outcomes specified in the methods section were reported in the results section, selective outcome reporting may still exist.

Li 2006.

Study characteristics
Methods	Study design: randomized controlled trial Study grouping: parallel group Loss to follow‐up: not reported Intention‐to‐treat: participants were analyzed in the groups to which they had been assigned Sample size estimation: not reported
Participants	Country: China Setting: ophthalmology center of a teaching hospital Enrollment date: not reported Baseline characteristics Topical mydriatics Number randomized: 46 Mean age, years (SD): 68.8 (NR) Women n (%): 32 (57.1) Race, n (%): Asian, n (%): 46 (100) Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): 0 Diabetes mellitus, number (%): 0 Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Intracameral mydriatics Number randomized: 34 Mean age, years (SD): 69 (NR) Women n (%): 24 (42.9) Race, n (%): Asian, n (%): 34 (100) Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): 0 Diabetes mellitus, number (%): 0 Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Overall Number randomized: 80 Mean age, years (SD): not reported Women n (%): 56 (70) Race, n (%): Asian, n (%): 34 (100) Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): 0 Diabetes mellitus, number (%): 0 Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported ("NOTE: Some values published as "SDs" may be "SEs".) Inclusion criteria: continuous cases of phacoemulsification and intraocular lens implantation were performed at the Zhongshan Ophthalmic Center of Sun Yat‐sen University from January 2004 to June 2004. The inclusion criteria included: (1) medium nuclear hardness (II) ~ III grade cataract patients, because of the high risk of hard or hard nuclear phacoemulsification itself, affecting the trial; (2) no glaucoma, uveitis, fundus lesions, and other eye abnormalities; (3) no surgery complications such as uveitis and fulminant choroidal hemorrhage Exclusion criteria: (1) patients with eye abnormalities, such as glaucoma, uveitis, fundus lesion, etc.; (2) patients with complications of surgery origin, such as uveitis, choroidal expulsive hemorrhage Pretreatment: not reported
Interventions	Topical mydriatics: compound tropicamide eyedrops Intracameral mydriatics: 1% hydrochloride lidocaine
Outcomes	Primary: not reported Secondary: not reported Measured outcome: pupillary size at time of capsulorhexis, at the beginning of procedure
Identification	Author name: Xiumei Li Institution: Ophthalmology center of Sun Yat‐sen University Email: zhenpinz@hotmail.com Address: Ophthalmology center of Sun Yat‐sen University, Guangzhou, China 510060 Clinical Trials Registration Number: not reported
Notes	Sponsorship source: not reported Conflict of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors mentioned random number generation, but it is unclear how this was generated.
Allocation concealment (selection bias)	Unclear risk	Method of treatment allocation concealment before assignment not reported.
Masking of participants and personnel (performance bias)	Unclear risk	Masking of participants and study personnel not reported.
Masking of outcome assessment (detection bias)	Unclear risk	Masking of outcome assessors not reported.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Participant attrition not reported.
Selective reporting (reporting bias)	Unclear risk	No trial registration; however, while outcomes specified in the methods section were reported in the results section, selective outcome reporting may still exist.

Lundberg 2003.

Study characteristics
Methods	Study design: randomized controlled trial Study grouping: parallel group Loss to follow‐up: not reported Intention‐to‐treat: participants were analyzed in the groups to which they had been assigned Sample size estimation: not reported
Participants	Country: Sweden Setting: hospital Enrollment date: not reported Baseline characteristics Topical mydriatics Number randomized: 30 Mean age, years (SD): 72 (10) Women n (%): not reported Race, n (%): Asian, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): not reported Diabetes mellitus, number (%): not reported Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Intracameral mydriatics Number randomized: 30 Mean age, years (SD): 72 (7) Women n (%): not reported Race, n (%): Asian, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): not reported Diabetes mellitus, number (%): not reported Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Overall Number randomized: 60 Mean age, years (SD): not reported Women n (%): not reported Race, n (%): Asian, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): not reported Diabetes mellitus, number (%): not reported Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Inclusion criteria: "Patients with age‐related cataract scheduled for unilateral phacoemulsification and intraocular lens (IOL) implantation were included" Exclusion criteria: NR Pretreatment: no significant difference between groups
Interventions	Topical mydriatics: "3 drops each of cyclopentolate 1% and phenylephrine 10% at 15‐minute intervals. In addition, they received 150 μL of preservative‐free lidocaine hydrochloride 1% (Xylocaine®) intracameral" Intracameral mydriatics: "Preservative‐free mixture of cyclopentolate 0.1%, phenylephrine 1.5%, and Xylocaine 1% intracameral"
Outcomes	Primary: not reported Secondary: not reported Measured outcome: pupil size and the central, nasal, and temporal corneal thicknesses
Identification	Author name: Anders Behndig Institution: Department of Clinical Science/Ophthalmology, Umeå University Hospital Email: anders.behndig@ophthal.umu.se Address: Department of Clinical Science/Ophthalmology, Umeå University Hospital, Umeå, SE‐901 85, Sweden Clinical Trials Registration Number: not reported
Notes	Sponsorship source: not reported Conflict of interest: neither author has any financial or proprietary interest in any material
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not reported.
Allocation concealment (selection bias)	Unclear risk	Method of treatment allocation concealment before assignment not reported.
Masking of participants and personnel (performance bias)	Low risk	Double‐masked randomized controlled trial; neither operating surgeon nor participant was aware of treatment assignment.
Masking of outcome assessment (detection bias)	Unclear risk	Masking of outcome assessors not reported, but pupil size was measured from video recordings.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Participant attrition not reported. However, no missing data observed.
Selective reporting (reporting bias)	Unclear risk	No trial registration; however, while outcomes specified in the methods section were reported in the results section, selective outcome reporting may still exist.

McCormick 2006.

Study characteristics
Methods	Study design: randomized controlled trial Study grouping: parallel group Loss to follow‐up: no losses to follow‐up; all 56 randomized participants were included in the analysis Intention‐to‐treat: participants were analyzed in the groups to which they had been assigned Sample size estimation: a power calculation was carried out prior to commencing the study to determine the appropriate sample size. A difference in horizontal pupil diameter of 1 mm was felt to be clinically significant. In order to estimate the standard deviation of pupil diameter, measurements were taken from a separate cohort of 20 preoperative cataract patients.
Participants	Country: United Kingdom Setting: hospital Enrollment date: not reported Baseline characteristics Topical mydriatics Number randomized: 31 Mean age, years (SD): 77 (NR) Women n (%): 21 (67.7) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): 0 Diabetes mellitus, number (%): not reported Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Depot delivery systems Number randomized: 25 Mean age, years (SD): 70 (NR) Women n (%): 13 (52) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): 0 Diabetes mellitus, number (%): not reported Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Overall Number randomized: 56 Mean age, years (SD): 70 (NR) Women n (%): 34 (60.7) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): 0 Diabetes mellitus, number (%): not reported Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Inclusion criteria: "Patients due to attend for routine local anaesthetic phacoemulsification cataract surgery in our unit under a single consultant during a 2‐month period (13 May to 12 July 2004) were included" Exclusion criteria: "Patients with pseudoexfoliation syndrome and ocular cicatricial pemphigoid whose fornix precluded the placement of a pledget" Pretreatment: no differences in baseline characteristics were reported
Interventions	Topical mydriatics: "2 drops each of Tropicamide 1%, phenylephrine 2.5% and atropine 1% administered to the lower conjunctival fornix spaced 3 min apart" Depot delivery systems: 3‐millimeter pledget trimmed, soaked in tropicamide 1%, phenylephrine 2.5%, and atropine 1%, and placed in the inferior fornix for 20 min
Outcomes	Primary: horizontal pupil diameter measured in millimetres immediately prior to surgery Secondary: tolerability of the pledget, cornea abrasion
Identification	Author name: Dr Austin McCormick Institution: Department of Ophthalmology, Faculty of Medical and Health Sciences, The University of Auckland Email: amccormick@slingshot.co.nz Address: Department of Ophthalmology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand Clinical Trials Registration Number: ISRCTN63768137
Notes	Comment: in the topical mydriatics, the analysis of participant stinging gave a range of 0 to 5, median of 2 (95% CI: 0 to 3) and mean of 1.9 (95% CI 1.17 to 2.63). In the depot delivery, the range was 0 to 4, median of 1 (95% CI 0 to 2) and mean of 1.52 (95% CI 0.95 to 2.09). Sponsorship source: not reported Conflict of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	See below. Number of cards, whether draws were with or without replacement, and other details not reported.
Allocation concealment (selection bias)	Low risk	On the day of surgery, small pieces of card were placed in a bag with the words ‘trial’ or ‘control.’ Once the participant had consented to be part of the study, a card was picked from the bag by a nurse not involved in the study.
Masking of participants and personnel (performance bias)	High risk	It was not possible to conceal the arm of the trial from the participant due to the nature of the intervention.
Masking of outcome assessment (detection bias)	Low risk	Outcome assessors were masked.
Incomplete outcome data (attrition bias) All outcomes	Low risk	There were no losses to follow‐up, and all 56 randomized participants were included in the analysis.
Selective reporting (reporting bias)	Low risk	Outcomes specified in trial registry as well as the methods section of the paper were reported in the results.

Morgado 2010.

Study characteristics
Methods	Study design: randomized controlled trial Study grouping: parallel group Loss to follow‐up: not reported Intention‐to‐treat: participants were analyzed in the groups to which they had been assigned Sample size estimation: not reported
Participants	Country: Portugal Setting: Hospital Pedro Hispano Enrollment date: not reported Baseline characteristics: not reported Topical mydriatics Number randomized: 30 Mean age, years (SD): 77.3 (NR) Women n (%): 20 (66.6) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): systolic 139.6 mmHg (16), diastolic 76.3 mmHg (9) Alpha‐adrenergic agonists, number (%): 3 (10) Pseudoexfoliation syndrome, number (%): 2 (6.6) Diabetes mellitus, number (%): 7 (23.3) Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Intracameral mydriatics Number randomized: 30 Mean age, years (SD): 79.3 (NR) Women n (%): 21 (70.0) Race, n (%): n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): systolic 138.5 mmHg (13), diastolic 77.7 mmHg (12) Alpha‐adrenergic agonists, number (%): 3 (10) Pseudoexfoliation syndrome, number (%): 3 (10.0) Diabetes mellitus, number (%): 9 (30.0) Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Depot delivery systems Number randomized: 30 Mean age, years (SD): 80.1 (NR) Women n (%): 22 (73.3) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): systolic 140.5 mmHg (18), diastolic 79.3 mmHg (11) Alpha‐adrenergic agonists, number (%): 2 (6.6) Pseudoexfoliation syndrome, number (%): 4 (13.3) Diabetes mellitus, number (%): 8 (26.6) Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Overall Number randomized: 90 Mean age, years (SD): not reported Women n (%): 63 (70.0) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): 8 (9) Pseudoexfoliation syndrome, number (%): 9 (10) Diabetes mellitus, number (%): 24 (27) Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Inclusion criteria: "Eyes with senile cataract undergoing phacoemulsification surgery" Exclusion criteria: "Eyes with iris posterior synechiae, prior eye surgery, and anterior segment malformation" Pretreatment: "Demographic data, comorbidities, and eye parameters were considered homogenous between groups"
Interventions	Topical mydriatics: "1% tropicamide and 10% phenylephrine drop, applied 3 times with 5‐minute intervals, initiated 60 minutes before surgery" Intracameral mydriatics: "Intracameral mydriasis with1% lidocaine (already performed in the anesthesia protocol) and 2.5% phenylephrine, administered into the anterior chamber, in a sequential manner (0.3 mL each drug)" Depot delivery systems: "Mydriasert mydriasis, with the device being placed in the inferior conjunctival sac, at least 1 hour before surgery. The insert contains 0.28 mg tropicamide and 5.4 mg phenylephrine hydrochloride equivalent to 1 0.5% tropicamide and 10% phenylephrine drop"
Outcomes	Primary: not reported Secondary: not reported Measured outcome: pupillary diameter at the beginning of procedure and at the end of procedure, intraoperative surgical time
Identification	Author name: Gabriel Morgado Institution: Department of Ophthalmology, Hospital Pedro Hispano, Porto, Portugal Email: gabrielmorgado@iol.pt Address: Rua do Monte 588 4405‐812 Vila Nova de Gaia Portugal Clinical Trials Registration Number: not reported
Notes	Sponsorship source: not reported Conflict of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not reported.
Allocation concealment (selection bias)	Unclear risk	Method of treatment allocation concealment not reported.
Masking of participants and personnel (performance bias)	Unclear risk	Masking of study participants and personnel not reported.
Masking of outcome assessment (detection bias)	Unclear risk	Masking of outcome assessors not reported.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Participant attrition not reported, but number randomized is the same as number analyzed, and there is no evidence of participants lost to follow‐up.
Selective reporting (reporting bias)	Unclear risk	No trial registration; however, while outcomes specified in the methods section were reported in the results section, selective outcome reporting may still exist.

Saenz‐de‐Viteri 2013.

Study characteristics
Methods	Study design: randomized controlled trial Study grouping: parallel group Loss to follow‐up: not reported Intention‐to‐treat: participants were analyzed in the groups to which they had been assigned Sample size estimation: not reported
Participants	Country: Spain Setting: hospital Enrollment date: not reported Baseline characteristics Topical mydriatics Number randomized: 40 Mean age, years (SD): 70.10 (10.22) Women n (%): 28 (70) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): 8.77 (0.63) Blood pressure, mean (SD): systolic 140.25 mmHg (21.93), diastolic 75.33 mmHg (8.69) Alpha‐adrenergic agonists, number (%): 8 (9) Pseudoexfoliation syndrome, number (%): 0 Diabetes mellitus, number (%): 0 Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Depot delivery systems Number randomized: 40 Mean age, years (SD): 67.95 (9.52) Women n (%): 17 (42.50) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): 8.75 (0.76) Blood pressure, mean (SD): systolic 135 mmHg (17.10), diastolic 76.97 mmHg (10.58) Alpha‐adrenergic agonists, number (%): 8 (9) Pseudoexfoliation syndrome, number (%): 0 Diabetes mellitus, number (%): 0 Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Overall Number randomized: 80 Mean age, years (SD): 69 (NR) Women n (%): 45 (56.0) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): 0 Diabetes mellitus, number (%): 0 Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Inclusion criteria: "Patients with Lens Opacities Classification System III (LOCS‐III) nuclear opacity (NO) nuclear color (NC) score of 3 or higher who were scheduled for routine unilateral cataract surgery" Exclusion criteria: "Patients with pseudoexfoliation syndrome, diabetes, intraoperative floppy iris syndrome (IFIS) associated with systemic alpha‐1 blockers, and previous ophthalmic surgery were excluded. Patients with intra surgical requirements of iris retractors, or intracameral phenylephrine or acetylcholine, were also excluded" Pretreatment: cataract surgery group were similar at baseline
Interventions	Topical mydriatics: "One drop of 10% phenylephrine and one drop of 1% tropicamide" Depot delivery systems: "Mydriasert (MY) is anophthalmic drug insert containing 0.28mg tropicamide and 5.4mg phenylephrine inserted into the inferior conjunctival sac one hour before surgery"
Outcomes	Primary: mean pupil diameter obtained by either tropicamide drops or the MY insert. Secondary: mean near best spectacle corrected visual acuity (NBSCVA), which is an indirect measurement of cycloplegia, and objective signs such as keratitis, conjunctiva redness, conjunctiva swelling, reading capacity, and light adaptation. Subjective symptoms such as foreign body sensation, itchiness, stinging, irritation, and tearing were also scored by participants at 0‐, 30‐, 60‐, and 90‐minute time points (scores 0 to 4: 0: none, 1: mild, 2: moderate, 3: severe, 4: incapacitating). 6 hours after dilation, reading capacity recovery was assessed, and subjective preferred dilation method was recorded.
Identification	Author name: Manuel Saenz‐de‐Viteri Institution: Department of Ophthalmology, University of Navarra Email: msaenzdevit@unav.es Address: Department of Ophthalmology, University of Navarra, 36th Pio XII Ave, Pamplona 31008, Spain Clinical Trials Registration Number: not reported
Notes	Comments: 2 trials in 1: first group OPD (n = 40), second group patients undergoing cataract surgery (n = 80) Sponsorship source: not reported Conflict of interest: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not reported.
Allocation concealment (selection bias)	Unclear risk	Method of treatment allocation concealment not reported.
Masking of participants and personnel (performance bias)	Unclear risk	Masking of participants and study personnel not reported.
Masking of outcome assessment (detection bias)	Unclear risk	Masking of outcome assessment not reported.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No indication that attrition occurred, and number randomized was analyzed.
Selective reporting (reporting bias)	Unclear risk	No trial registration; however, while outcomes specified in the methods section were reported in the results section, selective outcome reporting may still exist.

Sengupta 2010.

Study characteristics
Methods	Study design: randomized controlled trial Study grouping: parallel group Loss to follow‐up: not reported Intention‐to‐treat: participants were analyzed in the groups to which they had been assigned Sample size estimation: not reported
Participants	Country: India Setting: hospital Enrollment date: not reported Baseline characteristics Topical mydriatics Number randomized: 75 Mean age, years (SD): 55 (NR) Women n (%): 36 (48) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): not reported Diabetes mellitus, number (%): not reported Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Depot delivery systems Number randomized: 150 Mean age, years (SD): 58 (NR) Women n (%): 378 (52) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): not reported Diabetes mellitus, number (%): not reported Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Overall Number randomized: 225 Mean age, years (SD): not reported Women n (%): 114 (51) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): not reported Diabetes mellitus, number (%): not reported Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Inclusion criteria: "All patients enrolled for cataract surgery with grade II and III nuclear sclerosis as per the Lens Opacification Classification System III (LOCS III) as well as patients expected to have poor mydriasis, such as diabetics, and those with pseudoexfoliation (PXF)" Exclusion criteria: patients with posterior synechiae due to long‐standing uveitis, glaucoma, those with corneal pathologies, phacotoxic uveitis, and so on were excluded. Individuals with systemic hypertension and ischemic heart disease were also excluded. Pretreatment: participants did not differ in terms of age and baseline levels of mydriasis in the 2 groups
Interventions	Topical mydriatics: 1% cyclopentolate, 2.5% phenylephrine, 0.03% flurbiprofen, and 0.5% moxifloxacin. These were instilled topically as 1 drop from standard droppers. A single drop from each group was instilled every 3 min in succession, and the procedure was repeated every 15 min for 45 min. Depot delivery systems: "A mydriatic cocktail regimen consisting of 1 : 1 : 1: 1 ratio of 2.5% phenylephrine, 0.5% moxifloxacin, 1% cyclopentolate, and 0.03% flurbiprofen eye drops was prepared. A standard sized wick (1 cm X 2 mm) made of Weck cell sponge was soaked in the cocktail for a minute and placed in the lower fornix with sterile forceps"
Outcomes	Primary: pupillary diameters at the end of 15, 30, and 45 min, and intraoperative maintenance Secondary: not reported
Identification	Author name: Sengupta Institution: Jawaharlal Institute of Post graduate Medical Education and Research Email: sengupta_sunny@rediffmail.com Address: Department of Ophthalmology, Jawaharlal Institute of Post graduate Medical Education and Research (JIPMER), Pondicherry, India Clinical Trials Registration Number: not reported
Notes	Sponsorship source: "no sources of support" Conflict of interest: the authors declare no conflicting interests
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	See below. Number of cards, whether draws were with or without replacement, and other details not reported.
Allocation concealment (selection bias)	Low risk	Small pieces of folded card paper were placed in a bag with the word ‘trial’ or ‘control’ written on them. Once the participant had consented to be a part of the study, a card was picked from the bag by a nurse who was not involved in the study.
Masking of participants and personnel (performance bias)	High risk	Surgeon was masked. It was not possible to conceal the arm of the trial from the participant due to the nature of the intervention.
Masking of outcome assessment (detection bias)	Low risk	Outcome assessors were masked.
Incomplete outcome data (attrition bias) All outcomes	Low risk	CONSORT diagram indicates no attrition after randomization; data reported for all participants.
Selective reporting (reporting bias)	Unclear risk	No trial registration; however, while outcomes specified in the methods section were reported in the results section, selective outcome reporting may still exist.

Torrón 2013.

Study characteristics
Methods	Study design: randomized controlled trial Study grouping: parallel group Loss to follow‐up: not reported Intention‐to‐treat: participants were analyzed in the groups to which they had been assigned Sample size estimation: not reported
Participants	Country: Spain Setting: hospital Enrollment date: not reported Baseline characteristics Topical mydriatics Number randomized: 35 Mean age, years (SD): 75.53 (NR) Women n (%): 20 (55.6) Race, n (%): white: 35 (100) Preoperative pupillary diameter, mean, mm (SD): 9.44 (1.17) Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): 2 (6.5) Pseudoexfoliation syndrome, number (%): 1 (2.8) Diabetes mellitus, number (%): not reported Pre‐existing cardiac conditions, number (%): 17.5 (50) Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Depot delivery systems Number randomized: 35 Mean age, years (SD): 75.44 (NR) Women n (%): 24 (67.9) Race, n (%): white: 35 (100) Preoperative pupillary diameter, mean, mm (SD): 9.05 (1.54) Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): 2 (6.5) Pseudoexfoliation syndrome, number (%): 5 (15.4) Diabetes mellitus, number (%): 7 (24.8) Pre‐existing cardiac conditions, number (%): 17.5 (50) Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Overall Number randomized: 70 Mean age, years (SD): not reported Women n (%): 44 (63) Race, n (%): white: 70 (100) Preoperative pupillary diameter, mean, mm (SD): not reported Blood pressure, mean (SD): not reported Alpha‐adrenergic agonists, number (%): 3 (4.3) Pseudoexfoliation syndrome, number (%): 6 (8.6) Diabetes mellitus, number (%): 16 (230) Pre‐existing cardiac conditions, number (%): 35 (50) Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Inclusion criteria: "subjects who were scheduled for routine cataract surgery were prospectively enrolled. We wanted to show the reality of routine cataract surgery, so we did not exclude any type of cataract" Exclusion criteria: "Any allergy to mydriatic agents was the only exclusion criterion" Pretreatment: both groups were similar at baseline
Interventions	Topical mydriatics: "Combination of tropicamide 1%, phenylephrine 10%, and cyclopentolate 1% was instilled at 15‐minute intervals for 1 hour preoperatively" Depot delivery systems: "Mydriasert insert was placed in the lower fornix 1 hour and removed before the surgery by the nurse"
Outcomes	Primary: not reported Secondary: not reported Measured outcome: mean pupillary diameter at the beginning and end of the procedure
Identification	Author name: Torrón, P Calvo Institution: Department of Ophthalmology, Miguel Servet University Hospital, Aragon ´es Institute of Health Sciences, University of Zaragoza Email: xenatrance@yahoo.es Address: Department of Ophthalmology, Miguel Servet University Hospital, Aragon ´es Institute of Health Sciences, University of Zaragoza, Isabel la Cat ´olica 1‐3, 50009 Zaragoza, Spain Clinical Trials Registration Number: not reported
Notes	Sponsorship source: this research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors Conflict of interest: the authors declare having no conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not reported.
Allocation concealment (selection bias)	Unclear risk	Method of treatment allocation concealment not reported.
Masking of participants and personnel (performance bias)	Low risk	Personnel were masked to treatment. Masking of participants not reported.
Masking of outcome assessment (detection bias)	Low risk	Outcome assessors were masked to treatment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	3 participants did not provide informed consent, and 2 did not complete the tests included in the exploration protocol. However, it was unclear whether these participants had been randomized.
Selective reporting (reporting bias)	Unclear risk	No trial registration; however, while outcomes specified in the methods section were reported in the results section, selective outcome reporting may still exist.

Yu 2016.

Study characteristics
Methods	Study design: randomized controlled trial Study grouping: parallel group Loss to follow‐up: not reported Intention‐to‐treat: participants were analyzed in the groups to which they had been assigned Sample size estimation: the calculated sample size was 12 participants to offer 90% statistical power at the 5% level to detect a 0.3‐millimeter difference in pupil diameters between the 2 groups, when the SD of the mean difference was 0.25 mm. The level of significance was P < 0.05.
Participants	Country: China Setting: hospital Enrollment date: December 2010 Baseline characteristics Topical mydriatics Number randomized: 18 participants (36 eyes) Mean age, years (SD): 63.78 (3.10) Women: not reported Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): 7.98 (0.15) Blood pressure, mean (SD): systolic 128.1 mmHg (2.4), diastolic 74.1 mmHg (1.4) Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): not reported Diabetes mellitus, number (%): not reported Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Intracameral mydriatics Number randomized: 18 Mean age, years (SD): not reported Women: not reported Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): 2.20 (0.08) Blood pressure, mean (SD): systolic 128.1 mmHg (2.4), diastolic 74.1 mmHg (1.4) Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): not reported Diabetes mellitus, number (%): not reported Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported Overall Number randomized: 18 Mean age, years (SD): 63.78 (3.10) Women n (%): 7 (39) Race, n (%): not reported Preoperative pupillary diameter, mean, mm (SD): 2.20 (0.08) Blood pressure, mean (SD): systolic 128.1 mmHg (2.4), diastolic 74.1 mmHg (1.4) Alpha‐adrenergic agonists, number (%): not reported Pseudoexfoliation syndrome, number (%): not reported Diabetes mellitus, number (%): not reported Pre‐existing cardiac conditions, number (%): not reported Pre‐ and intraoperative NSAIDs at baseline, number (%): not reported ("NOTE: Some values published as "SDs" may be "SEs".). Inclusion criteria: "Subjects scheduled for bilateral phacoemulsification and IOL implantation" Exclusion criteria: "The exclusion criteria included the following: (1) the patient with asymmetrical lens classification of the two eyes according to the Lens Opacities Classification System III who was excluded to keep lens density homogeneity in cataract between the 2 groups, (2) patients using eye drops or taking systemic medications that could affect pupil dilation, (3) ocular pathologies other than cataract, such as corneal disease, anisocoria, malformations of the anterior segment, glaucoma, uveitis, and diabetic retinopathy, and (4) a history of previous intraocular surgery or ocular trauma" Pretreatment: insufficient information to judge
Interventions	Topical mydriatics: "The contralateral eye, as the topical group, received 3 drops of topical mydriatics (Mydrin, Santen, China), comprising a mixture of tropicamide 0.5% and phenylephrine 0.5%, given topically at 5‐minute intervals 30 minutes before surgery" Intracameral mydriatics: "intracameral group received 0.1mL epinephrine hydrochloride 0.01% (adrenaline hydrochloride, Tianjin Jinyao Amino Acid, China) in 0.9mL of balanced salt solution (BSS Plus, Alcon, USA), giving a concentration of 1: 100000, prepared at the start of surgery by the surgeon (A‐Yong Yu), given intracamerally just after cornea incision, and stayed at anterior chamber for 1 minute. It took approximately 3 minutes to complete the whole procedure"
Outcomes	Primary: not reported Secondary: not reported Measured outcomes: the mean pupil diameter was calculated for each eye before corneal incision (T1), before the ophthalmic viscoelastic device (OVD) injection (T2), after the OVD injection (T3), before IOL implantation (T4), and at the end of surgery (T5); corneal thicknesses, corneal endothelial density, refraction and best spectacle corrected visual acuity (BSCVA)
Identification	Author name: A‐Yong Yu Institution: The Eye Hospital of Wenzhou Medical University, Wenzhou, China Email: yaybetter@hotmail.com Address: The Eye Hospital of Wenzhou Medical University, Wenzhou 325000, China Clinical Trials Registration Number: NCT01264653
Notes	Sponsorship source: "This material is based upon work funded by Zhejiang Provincial Natural Science Foundation of China under Grant no.Y2110784 and by Zhejiang Provincial Foundation of China for Distinguished Young Talents in Medicine and Health under Grant no. 2010QNA018" Conflict of interest: the authors declare that there is no conflict of interest regarding the publication of this paper
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Method of randomization was done using SPSS software to generate random numbers.
Allocation concealment (selection bias)	Unclear risk	Method of treatment allocation concealment before assignment was not reported.
Masking of participants and personnel (performance bias)	High risk	This was said to be a double‐masked randomized controlled trial. The participant was masked, but not the surgeon, who prepared the topical drops.
Masking of outcome assessment (detection bias)	Low risk	Outcome assessor was masked.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Participant attrition not reported; however, there appears to be no attrition.
Selective reporting (reporting bias)	Low risk	Outcomes stated in trial registry the same as those reported in paper.

ANOVA, analysis of variance, a statistical analysis method
CI, confidence interval, given as lower and upper values
IOL, intraocular lens
mm Hg, millimeters of mercury, common units for blood pressure measurements
NR, not reported
NSAIDs, non‐steroidal anti‐inflammatory drugs
OPD, outpatient department
SD, standard deviation
SE, standard error
 

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Ajay 2017	Not population of interest, includes patients undergoing manual small incision cataract surgery
CTRI202012030145	Not a randomized clinical trial, single arm with no comparator group
Cuan Aguilar 2020	Not a randomized clinical trial, prospective comparative case series
Davey 2018	Not a randomized clinical trial, modeling study (budget impact analysis)
de Faria 2019	Not a randomized clinical trial, observational study
Donnenfeld 2017	Not a comparator of interest; compared different drugs, same route of administration (intracameral)
EUCTR2010 021188 34 DE	Not intervention of interest; compared fixed combination of lidocaine, phenylephrine, and tropicamide with individual eyedrops
EUCTR2017 003277 34 ES	Not outcome of interest; compared effect of topical and intracameral mydriatics on ocular surface after cataract surgery instead of before or during cataract surgery
EUCTR2018 00233923	Not a randomized clinical trial, multicenter non‐randomized trial
Ezhilvendhan 2020	Not a randomized clinical trial, prospective observational study
Gimbel 1989	Not intervention of interest; compared 2 different non‐steroidal anti‐inflammatory drugs, Ocufen (flurbiprofen) or Indocid (indomethacin)
Labetoulle 2020	Not a randomized clinical trial, post hoc analysis of Labetoulle 2016
Mouly 2006	Not population of interest; healthy volunteers, no cataract surgery performed
Nazim‐Lipski 2020	Not a comparator of interest; pupil size is measured pre‐ and postsurgery in the same eye (first in clinic using topical, then in operating room using intracameral), therefore pupil size during surgery is never compared between groups
NCT03375996	Not a randomized clinical trial, observational design
NCT03831984	Not intervention of interest; compared 0.09% bromfenac with 0.1% sodium hyaluronate in femtosecond laser‐assisted cataract surgery
Ng 2016	Not a randomized clinical trial, prospective unblinded trial not published as a full text, only as a conference abstract
PACTR201608001739424	Not a randomized clinical trial
Sharma 2020	Not a comparator of interest; compared different drugs, same route of administration (intracameral)
Vazquez‐Ferreiro 2017	Not a randomized clinical trial, review of intracameral phenylephrine in phacoemulsification
Wilson 2020	Not a comparator of interest; compared different drugs, same route of administration (intracameral)

Characteristics of studies awaiting classification [ordered by study ID]

EUCTR2013 000292 33 ES.

Methods	Not reported
Participants	Not reported
Interventions	Not reported
Outcomes	Not reported
Study	Comparative study of the mydriatic effect of Mydriasert vs the use of topical instillation of phenylephrine (10%) and tropicamide (1%) before cataract surgery
Notes	Not reported

NCT00690222.

Methods	Randomized parallel‐group design
Participants	Inclusion criteria: ability to give consent, age ≥ 18 years, planned clear cornea cataract extraction and placement of foldable posterior chamber intraocular lens, no secondary procedure planned (i.e. trabeculectomy, keratectomy, corneal transplant, vitreo‐retinal procedure, etc.), systemic condition capable of undergoing topical anesthesia, no previous intraocular surgery, pseudoexfoliation syndrome (PXF) for group 1, no pseudoexfoliation syndrome for group 2 Exclusion criteria: not fulfilling inclusion criteria, any iris pathology including but not limited to posterior synechia, iridocorneal endothelial syndrome, corectopia, traumatic mydriasis, Horner's syndrome, Adie's pupil, cyclodialysis, iridodialysis, previous or concurrent use of Flomax or similar alpha‐antagonist medication, corneal pathology affecting pupil magnification or measurement (keratoconus, peripheral thinning, sclerocornea, scarring), uncontrolled hypertension (greater than 170/90 on preoperative assessment on day of surgery as measured by automated DATEX monitor)
Interventions	Topical mydriasis without pseudoexfoliation
Outcomes	Primary outcome: Pupil size (time frame: at beginning and completion of cataract surgery) Secondary outcomes: Blood pressure (time frame: perioperatively) Heart rate (time frame: perioperatively)
Study	Intracameral mydriasis versus topical mydriasis in cataract surgery
Notes	None

Characteristics of ongoing studies [ordered by study ID]

NCT03638726.

Study name	Subconjunctival atropine and intracameral epinephrine for pupil dilation in phacoemulsification
Methods	Randomized parallel‐group design
Participants	Inclusion criteria: individuals aged 18 to 80 years who had bilateral visually significant cataract Exclusion criteria: patients with poor pupil dilation (less than 6‐millimeter diameter), history of previous eye surgery or trauma, history of use of eyedrops affecting pupil size such as pilocarpine, known drug allergy to cyclopentolate, phenylephrine, atropine sulfate, or epinephrine, pediatric age group (less than 18 years old), pupil abnormalities such as anisocoria or neurological disorders, associated glaucoma, uveitis, corneal, retinal, or optic nerve disease, cases scheduled for phacoemulsification under general anesthesia (to exclude possible ocular and systemic effects or interactions of anesthetic agents), patients with bleeding tendency or on anticoagulant therapy (because peribulbar and subconjunctival injections are used)
Interventions	Intervention: combined use of subconjunctival atropine sulfate 0.6 mg (parasympathetic antagonist) and intracameral epinephrine 1:100000 (sympathetic agonist). Comparator intervention: topical cyclopentolate and phenylephrine. Control arm: topical mydriatics are used for pupil dilation. Other name: atropine (Misr.co), epinephrine (Misr.co)
Outcomes	Primary outcomes: Intraoperative pupil diameter (time frame: 1 day), intraoperative pupil diameter measurements of involved eye (mm) Secondary outcome: Postoperative complications (starting from first postoperative day till 1 month), complications such as subconjunctival hemorrhage or corneal edema (starting from the first postoperative day till 1 month) Postoperative corneal thickness (from 1 month after surgery), measured by specular microscopy (mm) Postoperative corneal endothelial density (1 month after surgery), measured by specular microscopy (cell number/mm2) Postoperative pupil diameter (1 day, 1 week, and 1 month after surgery), postoperative diameter of involved eye (mm) Postoperative visual acuity (day 1, week 1, and month 1 after surgery), postoperative best corrected distance visual acuity in logMAR units Postoperative intraocular pressure (IOP) (1 day, 1 week, and 1 month after surgery), postoperative IOP measured in mmHg Maximum follow‐up: not reported
Starting date	7 November 2013 Estimated end date: June 2019
Contact information	clinicaltrials.gov/ct2/show/NCT03638726
Notes

NCT04396301.

Study name	Effect of intracameral injection of mydriatic plus anaesthetic combination on corneal endothelial count in phaco
Methods	Randomized parallel‐group design
Participants	Inclusion criteria: adults 60 to 75 years with medium‐density cataract (nuclear II to III) Exclusion criteria: individuals with soft‐ or hard‐density cataract (nuclear I or IV), history of ocular trauma or previous intraocular surgery, iatrogenic, congenital, or traumatic cataract, associated eye disease (e.g. pseudoexfoliation syndrome), associated pre‐existing corneal endothelial disease (e.g. Fuchs dystrophy), and associated systemic disease that can affect endothelium
Interventions	Intervention: Fydrane (manufacturer Delpharm Tours, France). The active substances in Fydrane are: tropicamide 0.04 mg (anticholinergic), phenylephrine hydrochloride 0.62 mg (alpha sympathomimetic), and lidocaine hydrochloride 2 mg (amide type local anesthetics) for each 0.2 mL dose, equivalent to 0.2 mg of tropicamide, 3.1 mg of phenylephrine hydrochloride, and 10 mg of lidocaine hydrochloride for 1 mL Comparator intervention 1: Fydrane (manufacturer Delpharm Tours, France) is injected intracamerally at the beginning of cataract surgery after the first incision, at a dose of 0.2 mL of solution, in only 1 injection. No preoperative topical eyedrops are used. Comparator intervention 2: not injected with intracameral Fydrane. Pupillary dilatation in this group is achieved using preoperative topical eyedrops: cyclopentolate hydrochloride 1% and tropicamide 1% 1 drop every 15 min for 1 hour preoperatively.
Outcomes	Primary outcome: safety of Fydrane on corneal endothelium, assessed by calculating percentage of endothelial cell loss Secondary outcome: Fydrane efficacy in achieving and maintaining mydriasis is evaluated by measuring pupil diameter using surgical caliper at certain timings during surgery (before capsulorhexis and before intraocular lens implantation) Maximum follow‐up: 3 weeks postoperative
Starting date	1 February 2019 Estimated end date: September 2019
Contact information	clinicaltrials.gov/ct2/show/NCT04396301
Notes

Differences between protocol and review

We did not contact study authors for missing data. However, we contacted authors of reports from two studies for clarification of reported data. We added the following authors to the author team: Mustafa Iftikhar, Samuel A Abariga, Barbara S Hawkins, and Sidra Zafar.

Contributions of authors

Conception and design of study: Fasika A Woreta, Henry Jampel, Tahreem A Mir

Screening search results and extraction of data for included studies: Mustafa Iftikhar, Samuel A Abariga, Barbara Hawkins

Drafting the review or commenting on it critically for intellectual content: Mustafa Iftikhar, Samuel A Abariga, Barbara Hawkins, Sidra Zafar, Tahreem A Mir, Henry Jampel, Fasika A Woreta

Final approval of the document to be published: Mustafa Iftikhar, Samuel A Abariga, Barbara Hawkins, Sidra Zafar, Tahreem A Mir, Henry Jampel, Fasika A Woreta

Sources of support

Internal sources

• No sources of support provided

External sources

• Cochrane Eyes and Vision US Project, supported by cooperative agreement 1 U01 EY020522, National Eye Institute, National Institutes of Health, USA

• Queen's University Belfast, UK

  Gianni Virgili, Co‐ordinating Editor for Cochrane Eyes and Vision’s work is funded by the Centre for Public Health, Queen’s University of Belfast, Northern Ireland

• National Institute for Health Research (NIHR), UK, UK

  This review was supported by the NIHR, via Cochrane Infrastructure funding to the CEV UK editorial base.

Declarations of interest

• Mustafa Iftikhar: none

• Samuel A Abariga: none

• Barbara Hawkins: none

• Sidra Zafar: none

• Tahreem A Mir: none

• Henry Jampel: none

• Fasika A Woreta: none

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