C)phthaln1ic Pearls
`
`RETINA
`
`How to Give
`I ntravitreal Injections
`
`BY MICHELLE E . WILSON, BS, AND ADRIENNE W . SCOTT, MD
`
`EDITED BY INGRID U . SCOTT, MD, MPH, AND SHARON FEKRAT, MD
`
`ntravitreal injection enables
`highly targeted drug therapy,
`maximizing therapeutic drug
`delivery to the posterior pole
`while minimizing systemic
`toxicity. With the increasing use of
`intravitreal anti-VEGF agents in the
`treatment of neovascular age-related
`macular degeneration (AMD), dia(cid:173)
`betic macular edema, retinal vein
`occlusion, and various other retinal
`vascular disorders, intravitreal injec(cid:173)
`tion has become the most common
`ophthalmic procedure performed in
`the United States.
`This review offers practical guid(cid:173)
`ance for the delivery of intravitreal
`injections based on published, peer(cid:173)
`reviewed literature, and expert consen(cid:173)
`sus where evidence is lacking.
`
`Overview
`Background and indications. Intra(cid:173)
`vitreal injection was first described
`in 1911 with the use of an air bubble
`to tamponade a retinal detachment.
`Triamcinolone acetonide (Kenalog)
`became the first intravitreal agent
`with widespread application, used as a
`treatment for macular edema associ(cid:173)
`ated with a variety of etiologies, such
`as diabetic retinopathy and retinal vein
`occlusion. It also was used as an ad(cid:173)
`junct to photodynamic therapy in the
`treatment of choroidal neovasculariza(cid:173)
`tion (CNV) related to AMD.
`Potential complications. These
`include intraocular inflammation,
`retinal detachment or perforation,
`traumatic lens damage, intraocular
`
`hemorrhage, sustained ocular hyper(cid:173)
`tension, and hypotony. 1
`Of all postinjection complications,
`endophthalmitis has greatest potential
`to be visually devastating. According
`to studies assessing the safety profile
`of intravitreal injection, the rate of en(cid:173)
`dophthalmitis has been found to be as
`low as 0.05 percent per injection.2
`Contraindications. Active external
`eye infection (including conjuncti(cid:173)
`vitis, meibomianitis, and significant
`blepharitis) is a contraindication to
`intravitreal injection and should be
`treated prior to injection.3 Glaucoma is
`common among patients requiring in(cid:173)
`travitreal injection and is not a contra(cid:173)
`indication to therapy despite the tran(cid:173)
`sient rise in intraocular pressure (IOP)
`that may occur following injection.
`Despite the theoretical increased risk
`of intraocular hemorrhage in patients
`on long-term anticoagulation who
`receive intravitreal injection, that risk
`has not been substantiated in studies.
`
`Preinjection Risk Management
`We recommend the following steps:
`1) Apply a topical anesthetic; 2) apply
`5 percent or 10 percent povidone(cid:173)
`iodine drops and/or periocular povi(cid:173)
`done-iodine eyelid preparation; 3) in(cid:173)
`sert a sterile speculum to separate the
`lids; and 4) reapply povidone-iodine
`immediately over the injection site
`prior to injection.
`Local anesthetic. Nearly all injec(cid:173)
`tions are performed with local anes(cid:173)
`thesia, with topical anesthetic drops
`employed most commonly. Studies
`
`show no significant difference in injec(cid:173)
`tion-related pain with the use of topi(cid:173)
`cal drops, subconjunctival anesthesia,
`or topical anesthetic gel. There is some
`concern that viscous anesthetic gel
`may prevent adequate sterilization of
`the ocular surface.
`Povidone-iodine. Povidone-iodine
`is the only agent shown to decrease
`bacterial colonization as well as the
`risk of endophthalmitis. Application
`ofpovidone-iodine to the conjunctival
`surface, eyelids, and lashes is recom(cid:173)
`mended prior to introducing the sterile
`speculum. (The speculum prevents
`the needle tip from touching the lids
`or lashes prior to needle insertion.)
`Studies have found that a 5 percent
`povidone-iodine solution is as effec(cid:173)
`tive as 10 percent and is less irritating
`to the eye. There is controversy as to
`
`EYE N ET
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`I a
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`Novartis Exhibit 2305.001
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`

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`whether using drops or a flush is more
`effective. We recommend reapplication
`of povidone-iodine immediately over
`the injection site prior to injection.
`Antibiotics. The use of preinjection
`antibiotics is controversial. There is
`evidence showing decreased coloniza-
`tion of the ocular surface with the use
`of preinjection antibiotics, particularly
`in conjunction with povidone-iodine;
`however, there is no evidence to sug-
`gest that the use of preinjection anti-
`biotics actually decreases the risk of
`endophthalmitis. Moreover, repeat
`injections are associated with more
`resistant flora.
`Using a face mask. The use of a
`face mask for the injecting physician,
`injection assistants, and the patient is
`not currently considered standard of
`care.4 However, recovery of common
`respiratory flora from vitreous culture
`aspirates in patients diagnosed with
`endophthalmitis after intravitreal
`injection strongly supports efforts to
`minimize talking, coughing, or sneez-
`ing during the injection procedure.5
`Bilateral injections. For bilateral
`injections, we recommend separate
`preparation of each eye. Separate in-
`struments and medication vials should
`be used for each eye to decrease the risk
`of potential bilateral contamination.
`IOP rise. A transient, volume-relat-
`ed rise in IOP is common following in-
`jection. There is no evidence to suggest
`that prophylactic IOP-lowering agents
`are effective in preventing the post-
`injection volume-mediated IOP spike,
`and their use is not recommended.
`
`Peri-injection Risk Management
`Injection volume. An injection volume
`of 0.05 mL is most commonly used.
`The maximum safe volume to inject
`without preinjection paracentesis is
`believed to be 0.1 mL to 0.2 mL. Larger
`injection volumes are uncommon,
`with two exceptions: the injection of
`gas for pneumatic retinopexy and the
`injection of multiple intravitreal agents
`in one session.
`Needle selection. Needle size varies
`according to the substance injected,
`with 27-gauge needles often used for
`crystalline substances such as triam-
`
`46 a p r i l 2 0 1 3
`
`cinolone acetonide and 30-gauge nee-
`dles commonly used for the anti-VEGF
`agents ranibizumab, bevacizumab,
`and aflibercept. Studies suggest that
`smaller, sharper needles require less
`force for penetration and result in less
`drug reflux. Some physicians have
`begun using 31-gauge needles (the size
`commonly used by diabetic patients to
`test blood sugar and inject insulin), as
`smaller needle size may decrease pa-
`tient discomfort.
`Needle length between 0.5 and
`0.62 inches (12.7 to 15.75 mm) is rec-
`ommended, as longer needles may
`increase risk of retinal injury if the
`patient accidentally moves forward
`during the procedure.
`Injection site. The patient should
`be instructed to direct his or her gaze
`away from the site of needle entry (Fig.
`1). The injection is placed 3 to 3.5 mm
`posterior to the limbus for an aphakic
`or pseudophakic eye, and 3.5 to 4 mm
`posterior to the limbus for a phakic
`eye. Injection in the inferotemporal
`quadrant is common, although any
`quadrant may be used.
`Sterile ophthalmic calipers or the
`hub of a sterile tuberculin syringe may
`be used to mark the injection site and
`to verify that adequate anesthesia has
`been achieved.
`Injection technique. Some guide-
`lines suggest pulling the conjunctiva
`over the injection site with forceps or a
`sterile cotton swab to create a steplike
`entry path. While this approach may,
`in theory, decrease reflux and risk of
`infection, a straight injection path is
`most commonly employed.6
`After the sclera is penetrated, the
`needle is advanced toward the center
`of the globe and the solution is gently
`injected into the midvitreous cavity.
`The needle is removed, and a sterile
`cotton swab is immediately placed over
`the injection site to prevent reflux.
`
`Postinjection Risk Management
`Antibiotics. These are used by many
`physicians postinjection and often
`consist of a fourth-generation fluoro-
`quinolone. However, as with preinjec-
`tion antibiotics, there is no evidence
`showing clinical benefit of use. Ex-
`
`perimental evidence suggests insuf-
`ficient penetration into the vitreous
`to prevent infection. There is also an
`increase in resistant bacterial strains
`with repeated use.
`IOP measurement. Postinjection
`IOP may be measured, especially
`for patients who have glaucoma,
`who are receiving large injection vol-
`umes, or who complain of pain or
`reduced vision. Some guidelines rec-
`ommend a funduscopic examination
`after each injection to assess central
`retinal artery perfusion and identify
`injection-related hemorrhage or retinal
`detachment. Instead, many physicians
`employ functional tests such as a de-
`termination of at least counting fingers
`vision or assessment of absence of light
`perception.
`Central retinal artery occlusion is
`indicated by the absence of light per-
`ception. In this case, paracentesis is in-
`dicated in an attempt to restore central
`retinal artery perfusion immediately.
`Vision is typically recovered quickly
`after decreasing IOP with rapid para-
`centesis. Routine pre- or postinjection
`paracentesis is not recommended for
`standard 0.05 mL intravitreal injec-
`tions.
`Complications. Transient, mild
`elevations of IOP are common, al-
`though IOP usually drops below 30
`mmHg 15 to 20 minutes postinjection
`and returns to within 4 to 5 mmHg
`of baseline after 30 minutes. IOP nor-
`malization may take slightly longer in
`patients with glaucoma.
`As noted above, endophthalmitis is
`the most feared complication of intra-
`vitreal injection, because of the poten-
`tial for severe vision loss.
`If postinjection endophthalmitis is
`suspected, recommended management
`includes immediate vitreous tap (for
`culture) and injection of intravitreal
`antibiotics (vancomycin 1 mg/0.1 mL
`and ceftazidime 2.25 mg/0.1 mL). Ur-
`gent vitrectomy may be considered.
`Pseudoendophthalmitis is a sterile
`inflammatory reaction that does not
`involve true microbial infection. This
`has been reported most commonly
`following injection of triamcinolone
`acetonide and bevacizumab. Unlike
`
`O p h t h a l m i c Pe a r l s
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`Novartis Exhibit 2305.002
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`
`

`

`true endophthalmitis, pseudoendo(cid:173)
`phthalmitis occurs earlier, typically
`within one day of injection, and often
`subsides without specific treatment.
`Follow-up. After the injection,
`all patients should be provided with
`information regarding the signs and
`symptoms of complications, such as
`eye pain or discomfort, redness, pho(cid:173)
`tophobia, and diminished vision. Pa(cid:173)
`tients should be instructed to contact
`the physician's office immediately if
`symptoms develop.
`
`NOTE: For a slideshow of images illustrating
`the steps outlined in this article, go to www.
`eyenet.org. lt will be available in mid-April.
`
`1 Jager RD et al. Retina. 2004;24(5):676-698.
`2 Bhavsar AR et al. Am J Ophthalmol. 2007;
`144(3):454-456.
`3 Aiello LP et al. Retina. 2004;24(5 suppl):
`S3-S19.
`4 Schimel AM et al. Arch Ophthalmol. 2011;
`129 (12) :1607-1609.
`5 McCannel CA. Retina. 2011;31( 4):654-661.
`6 Knecht PB et al. Retina. 2009;29(3):1175-
`1181.
`
`Ms. Wilson is a medical st11dent and research
`assistant, and Dr. Scott is assistant professor
`of ophthalmology; both are at the Wilmer Eye
`Institllte. The authors report no related finan(cid:173)
`cial interests.
`
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