Intravitreal injections have become the most commonly performed medical procedure in the United States, now at nearly twice the rate of cataract surgery. The expanding use of intravitreal triamcinolone acetate, introduced nearly 15 years ago, can be said to have opened the era of widespread intravitreal pharmacotherapy. The introduction of intravitreal anti-VEGF therapy with the approval of pegaptinib (Macugen) in 2004, followed by the off-label use of bevacizumab (Avastin), and approvals of ranibizumab (Lucentis) and aflibercept (Eylea) for expanding indications led to staggering growth in the use of intravitreal injection therapies now seen.

Prior to the approval of Macugen, and in anticipation that the number of intravitreal injections would increase dramatically, an expert panel convened in New York City to establish general guidelines for performing intravitreal injections. The results of this panel meeting were published as a supplement to the journal Retina in 2004,¹ and have stood since as consensus guidelines.¹ Since then, a vast body of scientific literature relating to various aspects of the procedure has emerged. In December of 2014, a panel of 16 health professionals with expertise in various aspects of the injection procedure convened to review and revise the intravitreal injection guidelines published in 2004. As part of that effort, each participant reviewed the publications on a particular aspect of the intravitreal injection process, and all reported their findings to the group as the basis for discussion and possible recommendation for revision, or establishment of updated guidelines. The areas of agreement with and without clear consensus are summarized in Tables 1 and 2. Important highlights and general rationale for the recommended changes are summarized here.

 • Items of the 2004 recommendations that have been dropped or have been significantly altered:

Table 1. Areas of General Agreement by Committee Members (2014)* 1. Povidone-iodine (5-10%) should be the last agent applied to the intended injection site before injection. If a gel anesthetic is used, povidone-iodine should be applied both before and after application of gel, as retained gel may prevent povidone-iodine from contacting the conjunctival surface of the injection site. 2. Pre-, peri- or post-injection topical antibiotics are unnecessary. 3. There is no evidence to support the routine use of a sterile drape. 4. Avoid contamination of the needle and injection site by the eyelashes or the eyelid margins. 5. Avoid extensive massage of the eyelids either pre- or post-injection (to avoid meibomian gland expression). 6. Use adequate anesthetic for a given patient (topical drops, gel and/or subconjunctival injection). 7. Use of sterile or nonsterile gloves as consistent with modern office practice, combined with strong agreement regarding the need for handwashing before and after patient contact. 8. Either surgical masks should be used or both the patient and providers should minimize speaking during the injection preparation and procedure to limit aerosolized droplets containing oral contaminants from the patient and/or provider. 9. Monitor IOP both pre- and post-injection. 10. Routine anterior chamber paracentesis is not recommended. * Reproduced from Avery RL, Bakri SJ, Blumenkranz MS, et al.  Retina 2014 Dec; 34 Suppl 12:S1-S18.

1. Use of a lid speculum is not essential. Unlike 2004, use of a lid speculum is no longer required in the updated 2014 guidelines. However, the panel stressed the importance of paying careful attention to the eyelid margin as a source of possible needle or ocular surface contamination.^3,4 The panel recommended that a lid speculum, manual lid retraction or some similar maneuver be used to keep the eyelid margins away from the injection site and needle during the injection procedure.

2. Routine dilation of the pupil is not essential. There was strong consensus in the 2004 guidelines that the pupil should be dilated to facilitate full examination of the posterior segment following intravitreal injections. The 2014 panel could not achieve agreement on this topic, as many panelists do not dilate the pupil for all injections, while others consider dilation and full post-injection examination to be important. Given the lack of consensus, the recommendation for routine dilation was dropped.

 • New 2014 recommendations:

1. Peri-injection antibiotics are not necessary. In 2004, no clear consensus regarding the use of peri-injection antibiotics could be achieved. Since then, a growing body of evidence has emerged that strongly suggests peri-injection antibiotics do not meaningfully lower the risk of post-injection endophthalmitis.^5-9 In addition, there is strong evidence that periodic multi-day administration of topical ophthalmic antibiotics results in the development of, and colonization with, drug-resistant bacteria. Facilitating the colonization of patients with drug-resistant bacteria is generally undesirable, especially since such organisms tend to show increased virulence.^10,11 Thus, the panel did not recommend routine use of pre-, peri- or postinjection antibiotics.

Recommended Sequence of Steps for IVT Injection*

1. Take a procedural time-out to verify patient, agent and laterality; 2. Apply liquid anesthetic drops to the ocular surface; 3. Apply povidone-iodine to the eyelashes and eyelid margins (optional, most use 10%); 4. Retract the eyelids away from the intended injection site for the duration of the procedure; 5. Apply povidone-iodine to the conjunctival surface, including the intended injection site (most use 5%); 6. If additional anesthetic is applied, reapply povidone-iodine to the intended injection site immediately prior to injection (most use 5%); 7. Insert the needle perpendicular to the sclera, 3.5 to 4 mm posterior to the limbus, between the vertical and horizontal rectus muscles. Application of a sterile cotton-tip applicator over the injection site immediately following removal of the needle may reduce vitreous reflux. * Reproduced from Avery RL, Bakri SJ, Blumenkranz MS, et al. Retina 2014 Dec; 34 Suppl 12:S1-S18.

2. Hand washing and glove use are important. Consistent with the modern-day medical practice of universal precautions, hand washing before and after patient contact, as well as the use of sterile or non-sterile gloves during procedures are generally recommended. Although this item was agreed upon nearly uniformly by the panelists, some panelists do not use gloves, citing studies that showed no impact of glove use on endophthalmitis rate.^5,12

3. Use of a surgical face mask or avoiding talking during the procedure is recommended. In the 2004 guidelines, the topic of droplet contamination was not addressed. Since then, evidence has emerged from multiple studies that streptococcal species are responsible for a disproportionate number of cases of endophthalmitis following intravitreal injection compared to endophthalmitis following intraocular surgery.^13,14 The increased rate of Streptococcus species is likely from aerosolized droplet contamination from either the practitioners’ or patients’ oral flora.¹⁵ Thus, it is recommended that clinicians and patients avoid talking during the procedure unless wearing a face mask.

4. Monitoring intraocular pressure both pre- and post-injection is important. Following intravitreal injection, IOP can be assessed by the presence or absence of formed vision, or by IOP measurement. In some patients the IOP elevates acutely to the level that formed vision is not present, suggesting a pressure-induced occlusion of the central retinal artery, and these patients need to be managed accordingly. IOP should be measured before the injection, as recent evidence suggests that chronic intravitreal administration of anti-VEGF agents can result in a sustained elevation in IOP.^16,17

5. Bilateral injections during the same visit may require special precautions. Some practitioners inject both eyes during the same visit.^18-21 In such situations it is recommended that each eye be treated as a separate procedure, and that when a compounded medication is used, such as bevacizumab, different compounding lots or batches be used for each eye. For commercially packaged unit dose medications, such as ranibizumab and aflibercept, different lots for each eye may not be feasible due to the very large production lot sizes.

6. There is no evidence to support the routine use of a sterile drape. The panel identified no evidence to support routine use of sterile drapes for the injection. In fact, studies not requiring a drape during injection have not reported increased rates of endophthlamitis.^5,22

Table 2. Areas with No Clear Consensus by Committee Members (2014)

1. Need for povidone-iodine application to the eyelids, including the eyelashes and eyelid margins. All agreed that when povidone-iodine is applied to the eyelashes and eyelid margins, eyelid scrubbing or eyelid pressure adequate to express material from the meibomian glands should be avoided. 2. Use of an eyelid speculum (some prevent contact between the needle/injection site and the eyelashes and eyelids with manual lid retraction). 3. Need for pupillary dilation and post-injection dilated examination of the posterior segment (although some viewed the return of formed vision as sufficient, others routinely dilate the pupil and examine the posterior segment after injection). 4. Use of povidone-iodine flush (most preferred drops only and saw no benefit to allowing the povidone-iodine to dry before injection). * Reproduced from Avery RL, Bakri SJ, Blumenkranz MS, et al. Retina 2014 Dec; 34 Suppl 12:S1-S18.

Moreover, controlled studies addressing the use of sterile drapes in a non-ophthalmic setting found higher rates of infection when adhesive drapes were used.²⁶

 • Recommendations without change from 2004:

1. The routine use of povidone-iodine as a topical antiseptic remains important. Extensive evidence supports the potent antiseptic properties of povidone iodine.^24,25 There was strong consensus among the group that povidone-iodine solution application is probably the single most important step for reducing the risk of endophthalmitis following IVT injection. Specifically, it was agreed that before injection, povidone-iodine solution (5 to 10%) should be the last agent applied to the intended injection site. In situations that viscous or gel topical anesthetic agents are used, the povidone-iodine solution should be applied to the ocular surface both before and after the viscous agents.²⁶

2. Extensive massage of the eyelids either pre- or post-injection should be avoided. If the eyelids and eyelashes are prepped with povidone-iodine solution, this should be done carefully. Excessive pressure may lead to expression of the meibomian glands and contamination of the ocular surface. Generally, the panel felt that the risk of adding a lid and lash prep with povidone-iodine outweighed any potential benefit, and did not recommend this step.

3. Adequate anesthesia is important. The use of topical anesthetics is usually required, whether or not an additional subconjunctival injection of an anesthetic agent is performed. While there are a number of studies comparing various anesthesia techniques for intravitreal injection, no consistently preferred approach has been identified.^29-31 Some panelists preferred localized anesthetic application with a cotton pledget. The panelists unanimously agreed that adequate anesthesia should be used to minimize patient discomfort.

4. Routine anterior chamber paracentesis is not recommended. As was the case in 2004, there was consensus among the 2014 panel that routine anterior chamber paracentesis either before or after the injection is not recommended. In most instances the IOP normalizes rapidly, and performing a paracentesis is not entirely risk-free, as complications such as endophthalmitis can occur.^32,33 However, in select circumstances, paracentesis may be necessary, and should be done at the treating physician’s discretion.  REVIEW


Dr. McCannel is a professor of clinical ophthalmology at the Jules Stein Eye Institute, University of California, Los Angeles.

Dr. Flynn is J. Donald M. Gass Chair of Ophthalmology and a professor of ophthalmology at Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine.

Dr. Cunningham is director of the Uveitis Service at California Pacific Medical Center, San Francisco; an adjunct clinical professor of ophthalmology at Stanford University School of Medicine; a research associate at the Francis I. Proctor Foundation, UCSF School of Medicine; and a partner at West Coast Retina Medical Group, San Francisco.

Inquires can be directed to Dr. McCannel at CMcCannel@jsei.ucla.edu.




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