Randomized Controlled Study of Cooled Versus Room-Temperature Artificial Tears for Reducing Surface Irritation Following Intravitreal Injection
Phase: PHASE4
Conditions: Diabetic Retinopathy With Macular Edema of Both Eyes (Diagnosis), Central Retinal Vein Occlusion With Macular Edema, Exudative Age-Related Macular Degeneration, Unspecified Eye, Cystoid Macular Edema, Ocular Surface Disease, Dry Eye Sensation, Eye Pain
Sponsor: University of Iowa

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Study Title: Randomized Controlled Study of Cooled Versus Room-Temperature Artificial Tears for 
Reducing Surface Irritation Following Intravitreal Injection 
NCT05832996 
Document Date: 04/25/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Project Title: The Effect of Cooled Artificial Tears in Reducing Ocular Surface Irritation after 
Povidone-Iodine Preparation of Intravitreal Injection. 
Principle Investigator: Douglas Jin, MD 
Purpose:  
The use of Povidone-iodine (PVI) is the standard of care when preparing for intravitreal injections. 
However, PVI is also known to be toxic to the corneal epithelium and delays ocular surface healing. 
Although guidelines on pre and peri-injection antiseptic techniques are well-studied, there has 
been a relative lack of consensus on ocular surface management to reduce the severity and 
duration of post-injection pain and discomfort. Patients frequently report post-injection ocular 
discomfort (e.g. tearing, burning, redness, and foreign body sensation) similar to symptoms of dry 
eye disease, and the main culprit is the application of PVI to prevent eye infections. Many have 
studied the effect of cooling eye drops, such as certain glaucoma and anesthetic drops to alleviate 
their initial stinging sensation upon instillation. Similarly, people have tried cooling the eye itself as 
an effective numbing effect to dull the pain associated with intravitreal injections. Oftentimes 
patients are advised to try using artificial tears on an as-needed basis to alleviate any dry-eye 
sensation post-injection, and we propose that cooling the artificial tears will further reduce 
patients' ocular discomfort level associated with eye injections. 
Study aims or hypotheses:  
Does the use of cooled artificial tears (4 C) reduce ocular discomfort compared to that of room-
temperature artificial tears (~23C) measured by the standard questionnaires (e.g. Ocular Surface 
Disease Index and subjective stinging feeling scale) in patients who receive intravitreal injections? 
Procedure:  
Any patient who comes to the injection clinic and reports subjective sensation of ocular discomfort 
will be allowed to participate in the study. The subject will be randomized into either the room-
temperature group or the cooled group, and they will use the respective artificial tears for up to 12 
hours in the immediate post-injection period. A telephone survey will be administered within 48 
hours of the clinic visit to administer a standard questionnaire to assess their ocular discomfort 
level. 
Background and significance: 
Intravitreal injection (IVI) is the most commonly performed ophthalmic procedure (2.5 million in 
2011) in the United States. Povidone-iodine (PVI) has been widely studied as an antiseptic agent 
and its application is considered the standard of care when preparing for IVI. PVI is also known to 
be toxic to the corneal epithelium and delays ocular surface healing. Although guidelines on pre 
and peri-injection antiseptic techniques are well-studied, there has been a relative lack of 
consensus on ocular surface management to reduce the severity and duration of post-injection 
pain and discomfort. Patients frequently report post-injection ocular discomfort (e.g. tearing, 
burning, redness, and foreign body sensation) similar to symptoms of dry eye disease. Many have 
studied the effect of cooling eye drops, such as certain glaucoma and anesthetic drops to alleviate 
their initial stinging sensation upon instillation. Similarly, people have tried cooling the eye itself as 

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an effective numbing effect to dull the pain associated with intravitreal injections. Oftentimes 
patients are advised to try using artificial tears on an as-needed basis to alleviate any dry-eye 
sensation post-injection, and we propose that cooling the artificial tears will further reduce 
patients' ocular discomfort level associated with eye injections. 
Target Enrollment: 300 
Age of Subjects: 18-105 years 
Inclusion Criteria:  
Patients were eligible if they were receiving standard intravitreal injections for their exudative age-
related macular degeneration, cystoid macular edema, diabetic macular edema, proliferative 
diabetic retinopathy, retinal vein occlusion with macular edema, or retinal neovascularization.  
Exclusion criteria 
• 
Inability or lack of willingness to participate in the study 
• 
Active ocular infection including infectious uveitis 
• 
First time receiving intravitreal injection 
• 
Those who reported never having ocular discomfort following intravitreal injections on the 
pre-injection questionnaire 
• 
Less than 18 years of age. 
Arms and Interventions:  
 
 
 
 
 
 
 
 
Outcome Measure:  
1) The Efficacy of Cooled Versus Room Temperature Artificial Tears in Reducing Post 
Intravitreal Injection Ocular Discomfort as Measured by Pain Scale Survey. The level of 
subjectively reported pain scale from 1 to 10, where 1 is minimal pain and 10 is extreme 
pain measured within 72 hours of the intervention. 
 
 
Arms 
Assigned Interventions 
Experimental: Cooled artificial tear 
group 
Stored at 4 degree Celsius 
Drug: Refresh Plus Preservative-free Lubricant Eye Drops 
Refresh Plus Preservative-free Lubricant Eye Drops at 
either 4 or 25 degree Celsius 
Active Comparator: Room temperature 
artificial tear group 
Stored at 25 degree Celsius 
Drug: Refresh Plus Preservative-free Lubricant Eye Drops 
Refresh Plus Preservative-free Lubricant Eye Drops at 
either 4 or 25 degree Celsius 

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