Build A Safer Intravitreal Injection Protocol

Caroline Tate is injected with Lucentis to treat macular deg
Applying an evidence-based, standard operating protocol for intravitreal injections can help keep their complication and error rates low. Image: Getty Images
Nitish Mehta, MD, explains the steps you need to take to assure injections are delivered safely.

Intravitreal injections (IVI) have become one of the most common procedures in outpatient medicine, with an estimated 5.9 million performed in the United States in 2016.1 IVI is an invaluable method of vision-saving drug delivery. Often, these medications are delivered repeatedly to patients in 1 or both eyes for the treatment of chronic retinal disease such as macular edema and neovascularization. There must be an extremely low tolerance for adverse safety events, given the possibility of severe harm to the patient with IVI. When an evidence-based, standard operating protocol is in place, IVI is a safe procedure with low complication and error rates. Nevertheless, there is a variation in the technique for IVI among physicians and practices. Studies have highlighted a few crucial elements to any IVI protocol that must be adhered to for safety. 

Think of adverse events associated with these injections in 2 major categories: those related to technique of the procedure (i.e., minimizing pain and risk of infection), and those related to the practice of the procedure (i.e., avoiding medical error). 

Using the tools researchers have established, the risks from both categories can be significantly reduced, and patients can have a better experience undergoing these treatments.

Endophthalmitis 

The single most important adverse event to minimize is endophthalmitis, which has potential to result in severe permanent visual disability. Fortunately, the rate of endophthalmitis is low (1:2,659 in a recent single center study of around 150,000 injections) due to the sterilization of the ocular surface with the use of 5% or 10% topical povidone iodine, a 2019 report shows.2 The same study reports no significant predictive ability of the use of lid speculum, injection location, conjunctival displacement, use of gloves, employment of a strict no-talking policy, use of subconjunctival lidocaine, and topical antibiotic use on the rate of endophthalmitis. However, the use of both 2% lidocaine jelly and 0.5% Tetravisc are both independent risk factors for post-IVI endophthalmitis.2 The researchers suggest that the viscous anesthetics create a barrier on the ocular surface preventing direct antiseptic action of the povidone iodine. 

Povidone iodine 5% significantly reduces bacterial colony forming units after 30 seconds of exposure, but not 15 seconds.3 It likely does not promote bacterial resistance or change conjunctival flora.4 The application of povidone iodine has repeatedly been confirmed as an effective form of antisepsis. Consensus guidelines encourage the use of direct application to the site of injection along with broader bathing of the fornix and lid margins. The use of lid speculum does not seem to affect infection risk; however, aggressive lid scrubbing is discouraged to minimize dispersion of lid and lash microbes.5 

The application of povidone iodine may result in ocular surface dysfunction and contact dermatitis, which may be minimized by thoroughly irrigating the ocular surface after the injection procedure. True allergy to povidone-iodine is rare. But for those situations, an alternative antiseptic, aqueous chlorhexidine, can perform favorably in terms of conjunctival sterilization, ocular surface dysfunction measures, and reduction of endophthalmitis risk.6 However, this is not widely commercially available in the United States at this time. 

The use of topical antibiotic prophylaxis is controversial due to lack of prospective data guiding use. Large single-center studies show no decrease in the rate of endophthalmitis with antibiotic use.7,8 In fact, 2 meta-analyses found a paradoxical increase risk of endophthalmitis with the use of topical antibiotic prophylaxis (a 1.7 higher risk in 1 paper and an increased rate of 0.09% vs 0.03% in the other).9,10 It seems reasonable to assume that the large scale use of topical antibiotic would breed widespread resistance — 1 small study reports an 87.5% fluoroquinolone resistance rate compared with 25% in control eyes with use of the 4 days of topical fluoroquinolone post-injection prophylaxis.11 It would be most prudent, given the data available, not to employ the use of topical antibiotic prophylaxis. Nevertheless, it is still relatively commonly done; a 2019 ‘real-world’ survey of 218 practicing retinal physicians reports that approximately 30% use of pre- and postinjection antibiotics.1 

Recently, due to the increased use of face coverings in the setting of the pandemic, a repeat interest in the utility of face mask use during IVI has arisen. No randomized data exists describing the potential risk reduction provided by masking. A patient with a face covering may exhale oral flora upwards towards the periocular area; thus, potentially increasing the rates of endophthalmitis. In a 15-person study, the use of tight-fitting mask with tape by the patient was demonstrated to have less bacterial dispersion than a loose-mask or no mask during a simulated injection.12 However, a review of a large number of injections noted no impact of the use of universal masking (patient, physician, and staff) on the rate of endophthalmitis. A fewer number of culture-positive cases were found in the masking group.13 Consistently, maintaining a ‘no talking’ policy results in less bacterial dispersion on the patient’s periocular area as well.14,15 

In summary, the key steps to reducing endophthalmitis rates include providing topical antisepsis with an application of 5% povidone iodine to the ocular surface for at least 30 seconds, avoiding postinjection antibiotic prophylaxis, and, at least, minimizing speaking during the procedure. 

Pain, Pressure and Safety Considerations 

Although anesthetic gel use is discouraged as described above, the choice of topical vs subconjunctival anesthetic is provider-dependent, due to equivocal scores on reducing pain scores for each technique.16,17 The velocity and angle of the injection do not seem to affect pain scores, and 1 study shows that injection in the superonasal quadrant may the least painful site.18.19 Optimization of ocular surface health can also improve the tolerability of the procedure. 

Repeat injection of small volumes of fluid into the vitreous also raises concerns regarding the immediate and long-term complications secondary to rise in intraocular pressure (IOP). It is well established that the injection procedure results in a transient increase in IOP to the mid-forties that returns below thirty in around fifteen minutes.20,21 Although a few studies have reported a decrease in retinal nerve fiber layer thickness on optical coherence tomography (OCT) after of intravitreal injections, the absolute reduction appears to be between 2 and 3 µm, and the clinical relevance of this finding is unclear.22 Interestingly, data from the Intelligent Research in Sight (IRIS) Registry shows a small decrease in IOP compared with baseline in patients receiving anti-VEGF agents for more than 1 year. However, a greater proportion of treated eyes had a clinically significant sustained IOP rise compared with their fellow untreated eyes.23 Patients with preexisting glaucoma or ocular hypertension, or both, must be optimally managed prior to initiation of IVI and close monitoring of their optic nerve and IOP must be performed during treatment with IVI for any patient. However, unless there is concern for severe vision impairment with transient rise in IOP (in advanced glaucoma, for example); withholding IVI and/or utilizing anterior chamber paracentesis to reduce postinjection IOP is not routinely recommended. 

Another safety consideration is the risk of the development of rhegmatogenous retinal detachment and cataract after IVI. Fortunately, these rates are very low.24,25 Clinicians must take care to inject 3 to 4 mm posterior to the limbus perpendicular to the sclera, pointed to the center of the vitreous cavity to avoid contact with the retina or lens. Noninfectious intraocular inflammation has been rarely reported, ranging from mild anterior chamber inflammation to vision-threating hemorrhagic occlusive retinal vasculitis. Any presence of intraocular inflammation must raise suspicion for endophthalmitis and must be treated with caution.26 Lastly, IVI is not contraindicated in patients receiving anticoagulation due to minimal risk of severe ocular hemorrhagic event.5 

Standard Operating Procedure 

As with any interventional procedure, critical attention must be placed on minimizing the risk of medical error. These include injection on the wrong patient or the wrong eye, and injection of incorrect or expired medication. It is the responsibility of the physician and the practice to adhere to a standard operating procedure (SOP) that takes into account vulnerabilities for error. 

A single center retrospective analysis of 4 safety events out of 147,000 injections in 2 years and found the mistakes were associated with inaccurate reviews of the medical record, poor staff and physician focus, and inconsistent use of timeouts and/or checklists.27 In response to safety events, another single center reported their experience with implantation of an intravitreal injection SOP. Some important features of their SOP included daily staff huddles identifying potential issues in a clinic day (high patient volumes, staffing shortages), use of 2-point identifiers at every point of patient progression through the clinic (from waiting room to photography to injection), increased attention to identifying and correcting errors in the medical chart, and the use of a six-point time out prior to injections.28 The time out procedure required confirmation of the patient name, date of birth, last chart note and plan, name and expiration of the medication, and marking of the correct eye by the physician prior to performing the injection. Zero safety events were noted after 18-month follow-up period. 

Implementation of standard operating protocols for intravitreal injection can be performed rapidly without increase in patient time-in-clinic or wait time.29 It is strongly recommended for every practice and institution to have an intravitreal injection standard operating procedure that is specific to the unique features to their practice and features a standard time out protocol. 

Step-by-Step Guide

It is clear that some of the components in the intravitreal injection technique such as anesthetic choice, use of speculum, and the use of gloves are free to the providers discretion. However, we can summarize the critical and immutable steps for IVI: 

  1. Utilization of a standard operating procedure featuring a time out that confirms patient, laterality, medication and expiration date. 
  2. Universal masking or a minimizing of speaking during the injection preparation and procedure. 
  3. Applying anesthetic to the ocular surface. 
  4. Retracting eyelids from the injection site by use of speculum or manual retraction. 
  5. Applying povidone-iodine to the ocular surface and eyelid margins for at least 30 seconds prior to injection. 

With the use of these simple steps, we can maintain a very high level of safety of the intravitreal injection procedure even as the number of injections continues to rise. 

References:

  1. Chaturvedi R, Wannamaker KW, Riviere PJ, Khanani AM, Wykoff CC, Chao DL. Real world trends in intravitreal injection practices among American retina specialists. Ophthalmol Retina. 2019;3(8):656–662. doi:10.1016/j.oret.2019.03.023ons
  2. Stem MS, Rao P, Lee IJ, et al. Predictors of endophthalmitis after intravitreal injection: a multivariable analysis based on injection protocol and povidone iodine strength. Ophthalmol Retina. 2019;3(1):3-7. doi:10.1016/J.ORET.2018.09.013
  3. Friedman DA, Mason JO, Emond T, McGwin G. Povidone-iodine contact time and lid speculum use during intravitreal injection. Retina. 2013;33(5):975-981. doi:10.1097/IAE.0B013E3182877585
  4. 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). doi:10.1016/j.ajo.2013.10.003
  5. 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. doi:10.1097/IAE.0000000000000399
  6. Ali FS, Jenkins TL, Boparai RS, et al. Aqueous chlorhexidine compared with povidone-iodine as ocular antisepsis before intravitreal injection: a randomized clinical trial. Ophthalmol Retina. 2021;5(8):788-796. doi:10.1016/J.ORET.2020.11.008
  7. Storey P, Dollin M, Pitcher J, et al. The role of topical antibiotic prophylaxis to prevent endophthalmitis after intravitreal injection. Ophthalmol. 2014;121(1):283-289. doi:10.1016/J.OPHTHA.2013.08.037
  8. Cheung CSY, Wong AWT, Lui A, Kertes PJ, Devenyi RG, Lam WC. Incidence of endophthalmitis and use of antibiotic prophylaxis after intravitreal injections. Ophthalmology. 2012;119(8):1609-1614. doi:10.1016/J.OPHTHA.2012.02.014
  9. Bande MF, Mansilla R, Pata MP, et al. Intravitreal injections of anti-VEGF agents and antibiotic prophylaxis for endophthalmitis: A systematic review and meta-analysis. Sci Rep. 2017;7(1). doi:10.1038/S41598-017-18412-9
  10. 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. doi:10.1097/IAE.0000000000001583
  11. 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. doi:10.1016/J.OPHTHA.2012.01.016
  12. Patel SN, Mahmoudzadeh R, Salabati M, et al. Bacterial dispersion associated with various patient face mask designs during simulated intravitreal injections. Am J Ophthalmol. 2021;223:178-183. doi:10.1016/J.AJO.2020.10.017
  13. Patel SN, Tang PH, Storey PP, et al. The influence of universal face mask use on endophthalmitis risk after intravitreal anti-vascular endothelial growth factor injections. Ophthalmol. 2021;128(11):1620-1626. doi:10.1016/J.OPHTHA.2021.05.010
  14. Doshi RR, Leng T, Fung AE. Reducing oral flora contamination of intravitreal injections with face mask or silence. Retina. 2012;32(3):473-476. doi:10.1097/IAE.0B013E31822C2958
  15. 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. doi:10.1001/ARCHOPHTHALMOL.2011.227
  16. Davis MJ, Pollack JS, Shott S. Comparison of topical anesthetics for intravitreal injections : a randomized clinical trial. Retina. 2012;32(4):701-705. doi:10.1097/IAE.0B013E31822F27CA
  17. Kaderli B, Avci R. Comparison of topical and subconjunctival anesthesia in intravitreal injection administrations. Eur J Ophthalmol. 2006;16(5):718-721. doi:10.1177/112067210601600509
  18. Sternfeld A, Schaap-Fogler M, Dotan A, et al. Effect of penetration angle and velocity during intravitreal injection on pain. Semin Ophthalmol. 2021;36(5-6):437-443. doi:10.1080/08820538.2021.1906914
  19. Karimi S, Mosavi SA, Jadidi K, Nikkhah H, Kheiri B. Which quadrant is less painful for intravitreal injection? A prospective study. Eye. 2019;33(2):304. doi:10.1038/S41433-018-0208-Y
  20. Lee JW, Park H, Choi JH, et al. Short-term changes of intraocular pressure and ocular perfusion pressure after intravitreal injection of bevacizumab or ranibizumab. BMC Ophthalmol. 2016;16(1):1-7. doi:10.1186/S12886-016-0255-8/TABLES/5
  21. Kim JE, Mantravadi A v., Hur EY, Covert DJ. Short-term intraocular pressure changes immediately after intravitreal injections of anti-vascular endothelial growth factor agents. Am J Ophthalmol. 2008;146(6). doi:10.1016/J.AJO.2008.07.007
  22. de Vries VA, Bassil FL, Ramdas WD. The effects of intravitreal injections on intraocular pressure and retinal nerve fiber layer: a systematic review and meta-analysis. Sci Rep. 2020;10(1). doi:10.1038/S41598-020-70269-7
  23. Atchison EA, Wood KM, Mattox CG, Barry CN, Lum F, MacCumber MW. The real-world effect of intravitreous anti-vascular endothelial growth factor drugs on intraocular pressure: an analysis using the IRIS Registry. Ophthalmol. 2018;125(5):676-682. doi:10.1016/J.OPHTHA.2017.11.027
  24. Kitchens JW, Do D v, Boyer DS, et al. Comprehensive review of ocular and systemic safety events with intravitreal aflibercept injection in randomized controlled trials. Ophthalmol. 2016;123(7):1511-1520. doi:10.1016/j.ophtha.2016.02.046
  25. Vounotrypidis E, Freissinger S, Cereda M, et al. Intravitreal injection associated rhegmatogenous retinal detachment: outcomes of a European analysis. Graefes Arch Clin Exp Ophthalmol. 2021;259(12):3655-3664. doi:10.1007/S00417-021-05261-6
  26. Falavarjani KG, Nguyen QD. Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature. Eye. 2013;27:787-794. doi:10.1038/eye.2013.107
  27. Vora RA, Patel A, Seider MI, Yang S. Evaluation of a series of wrong intravitreous injections. JAMA Ophthalmol. 2021;139(10):1123-1125. doi:10.1001/JAMAOPHTHALMOL.2021.3311
  28. John DA, Hansemann B, Lieu P, Weizer J. Reducing injection-related safety events in retina clinics. Clinical Ophthalmology. 2022;16:1255-1259. doi:10.2147/OPTH.S360628
  29. van Calster J, Willekens K, Seys D, van Elderen P, Spileers W, Vanhaecht K. Standardized care by redesign of an intravitreal injection pathway. Eur J Ophthalmol. 2019;29(1):92-99. doi:10.1177/1120672117754169