Eric M. Shrier
Intravitreal injections (IVIs) are one of the most common surgical procedures performed in the world,1 with an estimated 5.9 million IVI in the United States in 2016.2 These injections are the foundation of modern retinal treatment and are used in a wide variety of disorders such as diabetic retinopathy, exudative macular degeneration, and retinal vein occlusions.
The injection techniques vary among injectors, with the goal being prevention of infectious endophthalmitis (IE) while providing for patient comfort. IE is rare after IVI, with an incidence of only 0.028% (1/3,544),3 but it is the most feared complication of IVI due to the potential for devastating outcomes, even with prompt treatment. We briefly summarize the evidence for different techniques of providing IVI in a safe and comfortable manner.
Patient comfort is of the utmost importance since many patients will need to receive many IVIs to have maximal visual benefit. Thus, the goal of any technique is to increase compliance through comfort. Methods of anesthesia include topical proparacaine, tetracaine, lidocaine gel, soaked pledgets, and subconjunctival lidocaine injection. All of these methods have been shown to have a relatively low level of associated pain. A subconjunctival injection of 2% lidocaine has been shown to have benefit for certain patients who are sensitive to pain;4 however, this technique requires a second injection.
It should be noted that when anesthetic gel is used, povidone iodine (PI) should be applied to the ocular surface prior to application of the gel to prevent bacteria from being sequestered by the gel.5
No trial has demonstrated benefit with topical antibiotics and, thus, they are not presently recommended.6 The incidence of IE has been shown to increase with topical antibiotic prophylaxis.7 It is hypothesized that antibiotic use increases resistance of the ocular flora or that the repeated use of antibiotics, such as fluoroquinolones, have a detrimental effect on the ability of the ocular surface to prevent infection.8,9
Injection-related IE is most commonly from Staphylococcus and Streptococcus species. Streptococcus is not normally found on the ocular surface, yet it is found in the normal flora of the upper respiratory tract and oral cavities. That is why it has been hypothesized that oropharyngeal droplets could be the origin of these cases of endophthalmitis.10 This is supported by the fact that post injection IE with streptococcal isolates after IVI are approximately three-times more prevalent than when compared to intraocular surgery performed in an operating room.11 In light of this, a face mask should be considered12 or a no-talk policy13,14 be instituted during the setup and injection to help prevent aerosolization of oropharyngeal pathogens from contaminating the IVI.
Hand hygiene is essential before every patient contact, but there is a significant variation with the use of gloves for IVI. In the United States, 27% percent of physicians use no gloves at all during IVI.15 There are no studies that show decreased rates of IE with the use of sterile or nonsterile gloves. In our experience, the use of gloves seems sensible but not necessarily mandated by the evidence in the literature.
PI is considered standard of care due to its effectiveness, low cost, and low incidence of microorganism resistance. PI has broad-spectrum microbicidal activity and has been shown to be bactericidal in as short as 30 seconds for concentrations between 2.5% to 10%.1,16 Most physicians use 5% PI on the ocular surface; however, with sensitive patients, it has been documented that 1.25% PI is safe, as well.17 Periocular lid scrubs with PI are not recommended.1,18
Irritation from PI is the most common complaint, and patients may develop a contact dermatitis, but there have been no reported cases of anaphylaxis due to PI during ophthalmic use.16 If a patient has anxiety, we offer to place a drop of PI on the back of their hand or forearm for 5 minutes and let them observe if a reaction will occur. Prior to attempting a subsequent injection, this sometimes alleviates their anxiety and improves compliance in our experience.
As an alternative to PI, chlorhexidine gluconate (0.1%) may be used and well tolerated with comparably low IE rates to PI. Clinical studies on the ideal ocular contact time have yet to be established.19
Eyelashes and the eyelid margin are a main source of infection with ocular procedures, so it is essential to have them retracted during IVI to ensure the needle or ocular surface not be contaminated.5 An eyelid speculum is a commonly used method; however, more comfortable methods exist such as the bimanual20 or unimanual cotton-tipped applicator21 and lid-splinting22 techniques (Figure 1).
Methods for eyelid retraction during intravitreal injections include use of unimanual (A) or bimanual eyelid retraction (B), lid splinting (C), speculum (D), or cotton-tipped applicator eyelid retraction (E) techniques.
Some physicians in our practice use the cotton-tipped applicator methods for eyelid retraction technique,20 and we have shown these methods to be significantly more comfortable than a speculum in a prospective, randomized study (unpublished data). With a visual analog scale (VAS) of pain, which ranges from 0 (no pain) to 100 (worst pain), we were able to show that eyelid retraction with a speculum had a VAS of 18, unimanual had a VAS of 6.5 VAS, and the cotton-tipped applicator method of eyelid retraction had a VAS of 8.
Eyelid retraction with speculum is known to be more uncomfortable23,24 than less-invasive methods of eyelid retraction. The main driving factor to not using a speculum is patient comfort.20,22
IVI are commonly placed in the superior temporal and inferior temporal quadrants; however, they may be placed safely when performed 360° through the pars plana.1 Injections in the each of the four quadrants have all been shown to be similarly comfortable.25,26 There is general agreement that injections should be placed posterior to the limbus less than 4.0 mm in phakic eyes, 3.5 mm in pseudophakic eyes,2,16 and 3.0 mm in aphakic eyes.
Other Comfort Measures
Classical music before and during IVI has been shown to decrease anxiety during.27 Penetrating the sclera perpendicular rather than doing a tunneled injection causes less pain.28 Topical nonsteroidal anti-inflammatory drugs (NSAIDs) such as bromfenac29 and ketorolac30,31 have been shown to decrease the pain during the IVI, whereas bromfenac29 and nepafenac32,33 decrease post-injection pain at 6 hours. Studies have shown that needle diameter is correlated to discomfort during the injection process, with comfort levels improving as needle size decreases from 26 to 33 gauge.34–37
IVI have become the most common intraocular procedure, surpassing even cataract surgery, which is why this topic is of such importance.1 There are many different techniques for doing these injections, many lacking randomized studies due to the enormous numbers required due to the low incidence of endophthalmitis. We present a concise, up-to-date review on the major methods to decrease the risk while attempting to maximize patient comfort.
- Grzybowski A, Told R, Sacu S, et al. Euretina Board. 2018 Update on Intravitreal Injections: Euretina Expert Consensus Recommendations. Ophthalmologica. 2018;239(4):181–193. https://doi.org/10.1159/000486145 PMID: doi:10.1159/000486145 [CrossRef]29393226
- Williams GA. IVT Injections: Health Policy Implications. Review of Ophthalmology website. https://www.reviewofophthalmology.com/article/ivt-injections-health-policy-implications. Published June 5, 2014. Accessed June 9, 2019.
- Merani R, Hunyor AP. Endophthalmitis following intravitreal anti-vascular endothelial growth factor (VEGF) injection: a comprehensive review. Int J Retina Vitreous. 2015;1(1):9. https://doi.org/10.1186/s40942-015-0010-y PMID: doi:10.1186/s40942-015-0010-y [CrossRef]27847602
- Shiroma HF, Takaschima AKK, Farah ME, et al. Patient pain during intravitreal injections under topical anesthesia: a systematic review. Int J Retina Vitreous. 2017;3(1):23. https://doi.org/10.1186/s40942-017-0076-9 PMID: doi:10.1186/s40942-017-0076-9 [CrossRef]28680703
- Avery RL, Bakri SJ, Blumenkranz MS, et al. Intravitreal injection technique and monitoring: updated guidelines of an expert panel. Retina. 2014;34(suppl 12):S1–S18. https://doi.org/10.1097/IAE.0000000000000399 PMID: doi:10.1097/IAE.0000000000000399 [CrossRef]25489719
- Benoist d'Azy C, Pereira B, Naughton G, Chiambaretta F, Dutheil F. Antibioprophylaxis in prevention of endophthalmitis in intravitreal injection: a systematic review and meta-analysis. PLoS One. 2016;11(6):e0156431. https://doi.org/10.1371/journal.pone.0156431 PMID: doi:10.1371/journal.pone.0156431 [CrossRef]27257676
- Reibaldi M, Pulvirenti A, Avitabile T, et al. Pooled estimates of incidence of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents with and without topical antibiotic prophylaxis. Retina. 2018;38(1):1–11. https://doi.org/10.1097/IAE.0000000000001583 PMID: doi:10.1097/IAE.0000000000001583 [CrossRef]
- Hsu J, Gerstenblith AT, Garg SJ, Vander JF. Conjunctival flora antibiotic resistance patterns after serial intravitreal injections without postinjection topical antibiotics. Am J Ophthalmol. 2014;157(3):514–8.e1. https://doi.org/10.1016/j.ajo.2013.10.003 PMID: doi:10.1016/j.ajo.2013.10.003 [CrossRef]
- Milder E, Vander J, Shah C, Garg S. Changes in antibiotic resistance patterns of conjunctival flora due to repeated use of topical antibiotics after intravitreal injection. Ophthalmology. 2012;119(7):1420–1424. https://doi.org/10.1016/j.ophtha.2012.01.016 PMID: doi:10.1016/j.ophtha.2012.01.016 [CrossRef]22420958
- Chen E, Lin MY, Cox J, Brown DM. Endophthalmitis after intravitreal injection: the importance of viridans streptococci. Retina. 2011;31(8):1525–1533. https://doi.org/10.1097/IAE.0b013e318221594a PMID: doi:10.1097/IAE.0b013e318221594a [CrossRef]21878800
- McCannel CA. Meta-analysis of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents: causative organisms and possible prevention strategies. Retina. 2011;31(4):654–661. https://doi.org/10.1097/IAE.0b013e31820a67e4 PMID: doi:10.1097/IAE.0b013e31820a67e4 [CrossRef]21330939
- Doshi RR, Leng T, Fung AE. Reducing oral flora contamination of intravitreal injections with face mask or silence. Retina. 2012;32(3):473–476. https://doi.org/10.1097/IAE.0B013E31822C2958 PMID:22374155
- Wen JC, McCannel CA, Mochon AB, Garner OB. Bacterial dispersal associated with speech in the setting of intravitreous injections. Arch Ophthalmol. 2011;129(12):1551–1554. https://doi.org/10.1001/archophthalmol.2011.227 PMID: doi:10.1001/archophthalmol.2011.227 [CrossRef]21825179
- Garg SJ, Dollin M, Hsu J, Storey P, Vander JF. Effect of a Strict ‘No-Talking’ Policy During Intravitreal Injection on Post-Injection Endophthalmitis. Ophthalmic Surg Lasers Imaging Retina. 2015;46(10):1028–1034. https://doi.org/10.3928/23258160-20151027-07 PMID: doi:10.3928/23258160-20151027-07 [CrossRef]26599245
- Chaturvedi R, Wannamaker K, Riviere P, Khanani A, et al. Real-World Trends in Intravitreal Injection Practices among American Retina Specialists. Ophthalmol Retina. 2019;3(8):656–662. https://doi.org/10.1016/j.oret.2019.03.023 PMID: doi:10.1016/j.oret.2019.03.023 [CrossRef]31133544
- Berkelman RL, Holland BW, Anderson RL. Increased bactericidal activity of dilute preparations of povidone-iodine solutions. J Clin Microbiol. 1982;15(4):635–639. PMID:7040461
- Peden M, Hammer M, Suner I. Dilute povidone-iodine prophylaxis maintains safety while improving patient comfort after intravitreal injections. Retina. 39(11):2219–2224. https://doi.org/10.1097/IAE.0000000000002290 PMID:30142109
- Aiello LP, Brucker AJ, Chang S, et al. Evolving guidelines for intravitreous injections. Retina. 2004;24(5)(suppl):S3–S19. https://doi.org/10.1097/00006982-200410001-00002 PMID: doi:10.1097/00006982-200410001-00002 [CrossRef]15483476
- Merani R, McPherson ZE, Luckie AP, et al. Aqueous Chlorhexidine for Intravitreal Injection Antisepsis. Ophthalmology. 2016;123(12):2588–2594. https://doi.org/10.1016/j.ophtha.2016.08.022 PMID: doi:10.1016/j.ophtha.2016.08.022 [CrossRef]27720552
- Fineman MS, Hsu J, Spirn MJ, Kaiser RS. Bimanual assisted eyelid retraction technique for intravitreal injections. Retina. 2013;33(9):1968–1970. https://doi.org/10.1097/IAE.0b013e318287da92 PMID: doi:10.1097/IAE.0b013e318287da92 [CrossRef]23609121
- Shrier EM. Cotton-tip applicator lid retraction technique for controlled intravitreal injection. Retina. 2014;34(6):1244–1246. https://doi.org/10.1097/IAE.0000000000000219 PMID: doi:10.1097/IAE.0000000000000219 [CrossRef]24849702
- Munro M, Williams GR, Ells A, et al. Lid splinting eyelid retraction technique: a minimised sterile approach for intravitreal injections. Br J Ophthalmol. 2018;102(9):1254–1258. https://doi.org/10.1136/bjophthalmol-2017-311081 PMID: doi:10.1136/bjophthalmol-2017-311081 [CrossRef]
- Rahimy E, Fineman MS, Regillo CD, et al. Speculum versus Bimanual Lid Retraction during Intravitreal Injection. Ophthalmology. 2015;122(8):1729–1730. https://doi.org/10.1016/j.ophtha.2015.02.001 PMID: doi:10.1016/j.ophtha.2015.02.001 [CrossRef]25726752
- Alattas K. Patients' tolerance of bimanual lid retraction versus a metal speculum for intravitreal injections. Clin Ophthalmol. 2016;10:1719–1721. https://doi.org/10.2147/OPTH.S113326 PMID: doi:10.2147/OPTH.S113326 [CrossRef]27660408
- Massamba N, Elluard M, Agoune W, et al. Assessment of ocular pain following ranibizumab intravitreal injection. Acta Ophthalmol. 2015;93(3):e231–e232. https://doi.org/10.1111/aos.12531 PMID: doi:10.1111/aos.12531 [CrossRef]
- Moisseiev E, Regenbogen M, Bartfeld Y, Barak A. Evaluation of pain in intravitreal bevacizumab injections. Curr Eye Res. 2012;37(9):813–817. https://doi.org/10.3109/02713683.2012.681335 PMID: doi:10.3109/02713683.2012.681335 [CrossRef]22667326
- Chen X, Seth RK, Rao VS, Huang JJ, Adelman RA. Effects of music therapy on intravitreal injections: a randomized clinical trial. J Ocul Pharmacol Ther. 2012;28(4):414–419. https://doi.org/10.1089/jop.2011.0257 PMID: doi:10.1089/jop.2011.0257 [CrossRef]22506884
- Knecht PB, Michels S, Sturm V, Bosch MM, Menke MN. Tunnelled versus straight intravitreal injection: intraocular pressure changes, vitreous reflux, and patient discomfort. Retina. 2009;29(8):1175–1181. https://doi.org/10.1097/IAE.0b013e3181aade74 PMID: doi:10.1097/IAE.0b013e3181aade74 [CrossRef]19734766
- Georgakopoulos CD, Tsapardoni F, Makri OE. Effect of Bromfenac on pain related to intravitreal injections: A Randomized Crossover Study. Retina. 2017;37(2):388–395. https://doi.org/10.1097/IAE.0000000000001137 PMID: doi:10.1097/IAE.0000000000001137 [CrossRef]
- Rifkin L, Schaal S. Shortening ocular pain duration following intravitreal injections. Eur J Ophthalmol. 2012;22(6):1008–1012. https://doi.org/10.5301/ejo.5000147 PMID: doi:10.5301/ejo.5000147 [CrossRef]22562296
- Georgakopoulos CD, Vasilakis PT, Makri OE, Beredima E, Pharmakakis NM. Effect of ketorolac 0.5% drops on patients' pain perception during intravitreal injection procedure. J Ocul Pharmacol Ther. 2012;28(5):455–458. https://doi.org/10.1089/jop.2012.0023 PMID: doi:10.1089/jop.2012.0023 [CrossRef]22587573
- Ulrich JN. Topical nepafenac after intravitreal injection: a prospective double-masked randomized controlled trial. Retina. 2014;34(3):509–511. https://doi.org/10.1097/IAE.0b013e3182a0e611 PMID: doi:10.1097/IAE.0b013e3182a0e611 [CrossRef]
- Makri OE, Tsapardoni FN, Plotas P, Aretha D, Georgakopoulos CD. Analgesic Effect of Topical Nepafenac 0.1% on Pain Related to Intravitreal Injections: A Randomized Crossover Study. Curr Eye Res. 2018;43(8):1061–1064. https://doi.org/10.1080/02713683.2018.1461908 PMID: doi:10.1080/02713683.2018.1461908 [CrossRef]29634375
- Rodrigues EB, Grumann A Jr, Penha FM, et al. Effect of needle type and injection technique on pain level and vitreal reflux in intravitreal injection. J Ocul Pharmacol Ther. 2011;27(2):197–203. https://doi.org/10.1089/jop.2010.0082 PMID: doi:10.1089/jop.2010.0082 [CrossRef]21314588
- van Asten F, van Middendorp H, Verkerk S, et al. Are intravitreal injections with ultrathin 33-G needles less painful than the commonly used 30-G needles?Retina. 2015;35(9):1778–1785. https://doi.org/10.1097/IAE.0000000000000550 PMID: doi:10.1097/IAE.0000000000000550 [CrossRef]25901838
- Haas P, Falkner-Radler C, Wimpissinger B, Malina M, Binder S. Needle size in intravitreal injections - pain evaluation of a randomized clinical trial. Acta Ophthalmol. 2016;94(2):198–202. https://doi.org/10.1111/aos.12901 PMID: doi:10.1111/aos.12901 [CrossRef]
- Güler M, Bilgin B, Çapkın M, Şimşek A, Bilak Ş. Assessment of patient pain experience during intravitreal 27-gauge bevacizumab and 30-gauge ranibizumab injection. Korean J Ophthalmol. 2015;29(3):190–194. https://doi.org/10.3341/kjo.2015.29.3.190 PMID: doi:10.3341/kjo.2015.29.3.190 [CrossRef]26028948