Intravitreal administration

The most common reason intravitreal injections are used is to administer anti-vascular endothelial growth factor (anti-VEGF) therapies to treat wet age related macular degeneration (AMD) and diabetic retinopathy. Both of these conditions cause damage to the retina leading to vision loss. There are three widely used Anti-VEGF drugs to treat these conditions: ranibizumab (Lucentis®; Genentech), bevacizumab (Avastin®; Genentech), and aflibercept (Eylea®; Regeneron Pharmaceuticals). Bevacizumab has not been FDA approved to treat wet AMD however in the US it is the first line anti-VEGF therapy for over half of ophthalmologists due to its efficacy and drastically lower cost.[4]  These three drugs bind to VEGF molecules preventing them from binding to VEGF receptors on the surface of endothelial cells thereby stopping the abnormal angiogenesis that causes wet AMD.  All three of these therapies have vastly improved outcomes for sufferers who had limited treatment options prior to their invention but must be administerd via intravitreal injection.

Steroids may be administered via intravitreal injection to treat diabetic and vasculo-occlusive macular edema, exudative macular degeneration, pseudophakic cystoid macular edema, and posterior uveitis. Common steroids used to treat these conditions include dexamethasone and triamcinolone acetonide (Triescence, Alcon Laboratories, Inc.). Steroid implants, such as the dexamethasone implant (Ozurdex, Allergan, Inc.), are used for long term treatment of macular edema. Both of these steroid work by modulating inflammatory cytokines.[5]

Endophthalmitis is one of the most severe complications due to intravitreal injections. Incidence of endophthalmitis after intravitreal injection per patient has been reported to range from 0.019 to 1.6% these rates are similar across injection settings and geographic locations.[6] Endophthalmitis is an bacterial infection within the eye which causes the white of the eye to be inflamed, white or yellow discharge inside the eyelid, and a white clouded cornea. A layer of white cells called hypopyon may develop between the iris and the cornea. Endophthalmitis is incredibly dangerous and treatment is often an emergency. Injections of antibiotics and antifungal compounds are used to treat endophthalmitis. In more severe cases a vitrectomy may be required to surgically remove infectious debris.[7]

Intraocular inflammation is one of the main causes of temporary pain and vision loss after an intravitreal injection. Severe inflammation can cause damage to the eye. Rate of inflammation is dependent upon the drug administered via intravitreal injections. A large clinical trial of ranibizumab for AMD reported intraocular inflammation rates between 1.4–2.9%. Clinical trials of a similar drug administered via intravitreal injection, bevacizumab, reported a much lower incidence ranging from 0.09-0.4%.[6]

Rhegmatogenous retinal detachment after intravitreal injection is low between 0 to 0.67%.[6] A rhegmatogenous retinal detachment is basically when there is a retinal break that allows fluid from the vitreous chamber into the subretinal space. This fluid causes sensory tissues to pull away from the retina and their nutrition source slowly killing the cells.[8]

Subconjunctival hemorrhage is the most common type of hemorrhage following intravitreal injection with a reported incidence of nearly 10% of injections. Aspirin may increase these chances. Massive choroidal hemorrhage and massive subretinal hemorrhage are uncommon but have been reported.[6]

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.

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.

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.[10]

Use of a lid speculum is no longer essential. Now a lid speculum, manual lid retraction or a similar maneuver can be used to keep the eyelids out of the way during the procedure.

The strong 2004 consensus that the pupil should be routinely dilated to examine the posterior segment of the eye post injection was dropped. Some of the 2014 panelists did not dilate the pupil for routine injections while others found this examination to be highly important. As no consensus was reached this recommendation was dropped from the 2014 guidance.

In 2004 the committee did not come to a consensus on routine use of pre-, peri- or postinjection antibiotics. Since then evidence has emerged suggesting that peri-injection antibiotics do not meaningfully lower the risk of post-injection infection and periodic multi-day administration of topical ophthalmic antibiotics facilitates the colonization of drug-resistant bacteria.[11][12][13][14][15][16] For these reasons in 2014 the committee decided against recommending routine antibiotics.

The new guidelines include hand washing and glove use consistent with the modern-day medical practice of universal precautions. Although the use of gloves was agreed upon by the committee some panelists cited studies showing no impact of glove use on endophthalmitis rate.[11][14]

In 2004, the topic of droplet contamination was not addressed. Since then new evidence has come to light showing that streptococcal species cause a disproportionate number of post intravitreal injection endophthalmitis cases compared to other forms of ocular surgery.[17][18] This is likely due to aerosolized droplet contamination from either the practitioners’ or patients’ mouth.[19] The 2014 guidelines were updated to address these findings recommending both clinicians and patients wear face masks during the procedure.

The new guidelines recommend monitoring intraocular pressure both pre- and post-injection. This recommendation stemmed from new evidence showing that routine intravitreal administration of anti-VEGF therapies may increase intraocular pressure for a sustained time period.[20]

The 2014 guidelines addressed bilateral injections done in the same visit. The committee recommended treating each eye as a separate procedure and use different lots or batches of medication whenever possible. The panel was not able to support the use of sterile drapes in the procedure as retrospective studies showed no increased rate of endophthalmitis in injections done without drapes.[21]