Retinal Physician - Steps for a Safe Intravitreal Injection Technique
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`l\(•li11al
`P~VSICIAN Article
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`Steps for a Safe Intravitreal Injection Technique
`A look at how European and American approaches compare
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`July 1, 2009
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`Steps for a Safe Intravitreal Injection Technique
`
`A look at how European and American approaches compare.
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`CARSTEN H. MEYER, MD · ANNE FUNG, MD · SANDEEP SAXENA, MD · FRANK G. HOLZ, MD
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`In recent years, significant advances have been made in optimizing the delivery of drugs to target tissues within the
`eye and in maintaining effective drug doses within those tissues. However, retinal drug delivery is still a challenging
`area in the field of ophthalmic drug delivery.
`
`A variety of approaches have been described for drug delivery into the vitreous cavity. lntravitreal injection was first
`reported by Ohm in 1911 as a technique to introduce air for retinal tamponade and repair of retinal detachment. 1
`lntravitreal administration of pharmacotherapies dates to the mid-1940s with the use of penicillin to treat
`endophthalmitis. Since that time, use of the intravitreal injection technique has progressively increased, with its
`usage being focused primarily on the treatment of retinal detachment, endophthalmitis, and cytomegalovirus
`retinitis.
`
`Carsten H. Meyer, MD, is professor of ophthalmology at the University of Bonn in Germany. Anne E. Fung, MD, is
`a medical retina consultant at Pacific Eye Associates in San Francisco. Sandeep Saxena, MD, is professor of
`ophthalmology at King George's Medical University in Lucknow, India. Frank G. Holz, MD, is professor and chair
`of ophthalmology at the Universitats-Augenklinik mit Poliklinikin in Bonn. Dr. Meyer reports minimal financial
`interest in Pfizer, Novartis, and GlaxoSmithKline. Ors. Fung, Holz, and Saxena report no financial interest in any
`products mentioned in this article. Dr. Meyer can be reached via e-mail at Meyer_eye@yahoo.com.
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`The increasing efficacy and safety of intravitreal injections, in conjunction with the development of
`pharmacotherapies, has led to a recent rapid increase in the use of this technique for the administration of various
`pharmacotherapies, including bevacizumab, ranibizumab, pegaptanib sodium, and intravitreal triamcinolone
`acetonide. 2 An intravitreal drug application has been suggested to achieve therapeutic levels locally, with prolonged
`effective concentrations (Figure 1 ). 1 Retinal specialists in Europe and the United States have varied approaches
`within their countries and between the continents. We will highlight consensus and differences in practices here.
`
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`Retinal Physician - Steps for a Safe Intravitreal Injection Technique
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`Figure 1. lntravitreal injections via the pars plana route into the mid-vitreous.
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`INTRAVITREAL DRUG DELIVERY
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`The advantage of intravitreal administrations is an immediate therapeutic effect at the intended tissue. With the
`widespread use of intravitreal injections, there has been an increased interest regarding the best application
`technique. Clinical experience with intravitreal injection has provided physicians with an outline of avoidable risks.
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`All injections should be performed under sterile conditions. While European countries recommend applying the
`injection in an operating room, other countries, including the United States and India, perform the injection in minor
`surgery or conventional examining rooms under sterile conditions. 5
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`ANTICOAGULATION AND INTRAVITREAL INJECTIONS
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`A major concern associated with preoperative discontinuation of anticoagulation therapy is the increased risk of
`thromboembolic or cerebrovascular events. 6 The ranibizumab study trials observed a low incidence of ocular
`hemorrhages in patients maintaining warfarin. In the MARINA trial, there were a total of 60 warfarin-treated
`participants, receiving a mean of 22.0 (SD, 3.6) injections. 7 No ocular bleeding was observed during the 1318
`consecutive injections. All the authors agree that intraocular injections in warfarin-treated patients are unlikely to
`cause ocular hemorrhages.
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`SURFACE PREPARATION WITH POVIDONE-IODINE
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`There is general agreement that the risk of infectious endophthalmitis following intravitreal injection is small. The
`role of topical antibiotics to prevent postinjection endophthalmitis remains controversial around the world. Topical
`antibiotics may be applied after the injection for a few days, as the break in the conjunctiva and sclera takes time to
`completely heal and water-seal. In addition, there may be a synergistic effect between topical antibiotics and
`povidone-iodine. However, Frank Holz, MD, emphasized that there is no study demonstrating that reduced
`conjunctiva! bacteria may result in a lower risk for endophthalmitis. 8
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`Sandeep Saxena, MD, emphasized that treatment of any active external infection, including significant blepharitis, is
`mandatory prior to each intravitreal injection. 4,8 The primary goal of any infectious prophylaxis is to minimize the
`present bacterial flora around the surgical entry site. This can be achieved with the topical application of povidone(cid:173)
`iodine, eyelid hygiene, proper isolation of the surgical site, and optional postoperative antibiotics. 9-11
`
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`Retinal Physician - Steps for a Safe Intravitreal Injection Technique
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`One key step to reducing the risk of endophthalmitis is a sufficient disinfection of the skin, eyelashes, and
`conjunctiva. The eyelids and lashes are usually disinfected with a povidone-iodine (10%) scrub. A sterile speculum
`is placed between the lids. Various methods of applying povidone-iodine preoperatively have been studied.
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`Most US sites apply 2 drops of 0.5% povidone-iodine placed on the ocular surface over the intended site of the
`injection. Some physicians place 3 drops of povidone-iodine (5%) 3 times, several minutes apart, over the ocular
`surface, preventing dessication and abrasion of the cornea with antibiotic eyedrops or sterile saline solution.
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`German investigators have advocated irrigating the conjunctiva! sac with 1 % or 5% povidone-iodine to decrease
`conjunctiva! colonization; however, it remains unknown whether the application of povidone-iodine drops vs a flush
`is more effective in preventing endophthalmitis.
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`There is no consensus among the 4 authors as to whether topical antibiotics should be used preoperatively.
`Preinjection antibiotic drops may be applied according to the label of the applied drug, although there is no evidence
`supporting their use before intravitreal injections.
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`LOCAL TOPICAL ANESTHESIA
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`Satisfactory pain relief may be achieved with topical lidocaine. Local anesthesia may be induced by applying 3 to 4
`sterile cotton swabs soaked in sterile 4% lidocaine to the injection area (for 30 seconds each). 12 Alternatively,
`lidocaine may be applied with 2% eyedrops, as a gel, or as a subconjunctival injection. The effective relief of pain
`with lidocaine for intravitreal injection seems to be independent of its mode of application (gel vs subconjunctival
`injection). However, topical applications of lidocaine cause less chemosis compared with subconjunctival
`anaesthesia. Most centers have stopped using gel on a regular basis, as topical eyedrops seem to induce a
`sufficient anesthesia.
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`THE INJECTION PROCEDURE AND RECOMMENDED TECHNIQUE
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`There is general agreement that the injection site should be located 3.5 to 4 mm posterior to the limbus. Dr. Saxena
`emphasizes that the injection site may differ in repeated injections by approximately 1 clock hour.4,13 This avoids a
`double penetration through the same site, inducing a persisting scleral hole with consecutive leaking or vitreous
`incarceration "vitreous wick."
`
`The angle of the incision through the sclera may be directed in an oblique, tunneled fashion (Figures 2 and 3), as
`rectangular radial incisions may remain open, inducing vitreous or drug reflux under the conjunctiva, as well as
`severe chemosis and even hypotony in vitrectomized eyes. 14,15 Dr. Meyer observes persistent unsealed
`sclerotomies following radial injections using a 30-gauge needle, requiring secondary suturing to seal the
`penetrating scleral wound. 16 The depth of the insertion may vary between 5 to 7 mm according to Anne Fung, MD,
`so that the tip of the needle is placed in the mid-vitreous. The drug is then gently injected into the vitreous cavity.
`
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`Figure 2. Schematic drawing of the injection procedure: The conjunctiva is moved upwards so that the
`conjunctiva! hole and the site of the scleral penetration are not on top of each other. After an initial lamellar
`penetration of the outer sclera, the needle is moved upwards for a full-thickness penetration.
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`Figure 3. Examination of the injections site 15 minutes after the injection with the anterior-segment OCT
`scan (Visante): The radial injection remains open and visible, whereas the tangential oblique injection is not
`detected on OCT.
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`The needle diameter should be smaller than 27-gauge to reduce risk of wound leakage or injury. Injections with
`crystalline TA are frequently applied with 27-gauge needles, while most liquid injections use 30-gauge needles. The
`required force to penetrate the sclera is almost twice as much using 27-gauge needles compared with 30- or even
`31-gauge.17 Dr. Holz explains that larger needles may not necessarily induce more pain to the patient; however,
`they may induce more reflux or subconjunctival hemorrhage. In addition, blunting of the needle tip, as found in some
`prefilled syringes, was observed to cause a deeper in pouching and visible indentation of the eye wall during the
`injection that may have caused the patient more discomfort. 18,19
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`The injected volume should be limited up to 0.15 ml without a routine paracentesis releasing an elevated ocular
`pressure, according to Dr. Meyer's clinical experience. Administration of rTPA, anti-VEGF agents, and SF6 gas as
`triple injection for the management of subretinal hemorrhage frequently require a paracentesis to release the
`elevated eye pressure. 20
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`OCULAR COMPLICATIONS
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`Retinal Physician - Steps for a Safe Intravitreal Injection Technique
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`Dr. Fung published a survey on ocular complications reporting an overall prevalence for retinal detachments of 3.9%
`per eye or 0.9% per injection and a prevalence of endophthalmitis (including pseudo-endophthalmitis) of 0.3% per
`injection and 0.9% per eye. 2
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`CONCLUSION
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`The rationale for intravitreal drug application is an immediate and increased therapeutic delivery to the targeted
`tissue. Some parts of the injection procedure (use of adequate anesthetics, povidone-iodine, and a lid speculum; not
`injecting patients with active eyelid or ocular infections; avoiding extensive massage of eyelid meibomian glands;
`avoiding prophylactic or postinjection paracentesis) are supported by consensus agreement in all countries, while
`other aspects have less agreement (eg, most investigators advocate gloves, most prefer povidone-iodine drops over
`flush, most use no sterile drape). There is no agreement regarding the use of pre- or postinjection topical antibiotics,
`as well as a specific intraocular pressure level that should not be exceeded before the injection. lntravitreal drug
`application is a safe and effective procedure. Side effects, eg, elevated IOP, cataract formation, and
`endophthalmitis, are limited. RP
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`REFERENCES
`
`1. Ohm J. Ober die Behandlung der Netzhautabli:isung durch operative Entleerung der subretinalen Fli.issigkeit
`und Einspritzen vom Luft in den Glaski:irper. Graefe Arch Klin Ophthalmol. 1911 ;79:442-450.
`2. Fung AE, Rosenfeld PJ, Reichel E. The International lntravitreal Bevacizumab Safety Survey: using the
`internet to assess drug safety worldwide. Br J Ophthalmol. 2006;90: 1344-1349.
`3. Kaiser PK, Brown OM, Zhang K, Hudson HL, Holz FG, Shapiro H, Schneider S, Acharya NR. Ranibizumab
`for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year
`ANCHOR results. Am J Ophthalmol. 2007;144:850-857.
`4. Fung AE, Lalwani GA, Rosenfeld PJ, Dubovy SR, Michels S, Feuer WJ, Puliafito CA, et al. An optical
`coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for
`neovascular age-related macular degeneration. Am J Ophthalmol. 2007; 143:566-583.
`5. Schmidt-Erfurth UM, Richard G, Augustin A, Aylward WG, Sandella F, Corcostegui B, Cunha-Vaz J, Gaudric
`A, Leys A, Schlingemann RO; European Society for Retina Specialists' Guidelines Committee (EURETINA).
`Guidance for the treatment of neovascular age-related macular degeneration. Acta Ophthalmol Scand.
`2007;85:486-494.
`6. Meyer CH, Callizo J, Mennel S, Kussin A. Perioperative management of anticoagulated patients undergoing
`repeated intravitreal injections. Arch Ophthalmol. 2007; 125:994.
`7. Charles S, Rosenfeld PJ, Gayer S. Medical consequences of stopping anticoagulant therapy before
`intraocular surgery or intravitreal injections. Retina. 2007;27:813-815.
`8. Scott IU, Flynn HW. Reducing the risk of endophthalmitis following intravitreal injections. Retina. 2007;27:10-
`12.
`9. Safar A, Dellimore MC. The effect of povidone iodine flush versus drops on conjunctiva! colonization before
`intravitreal injections. Int Ophthalmol. 2007;27:307-312.
`10. Meyer CH, Mennel S, Eter N. Incidence of endophthalmitis after intravitreal Avastin injection with and without
`postoperative topical antibiotic application. Ophthalmologe. 2007;104:952-957.
`11. Ta CN, Egbert PR, Singh K, Shriver EM, Blumenkranz MS, Mino De Kaspar H. Prospective randomized
`comparison of 3-day versus 1-hour preoperative ofloxacin prophylaxis for cataract surgery. Ophthalmology.
`2002; 109:2036-2041.
`12. Kaderli B, Avci R. Comparison of topical and subconjunctival anesthesia in intravitreal injection
`administrations. Eur J Ophthalmol. 2006;16:718-721.
`13. Aiello LP, Brucker AJ, Chan Set al. Evolving guidelines for intravitreous injections. Retina. 2004;24;S3-19.
`14. Rodrigues EB, Meyer CH, Grumann A Jr, Shiroma H, Aguni JS, Farah ME. Tunneled scleral incision to
`prevent vitreal reflux after intravitreal injection. Am J Ophthalmol. 2007;143:1035-1037.
`
`10/1/2018
`https://www.retinalphysician.com/issues/2009/july-aug/steps-for-a-safe-intravitreal-injection-technique
`Regeneron Exhibit 1059.005
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`15. Rodrigues EB, Meyer CH, Schmidt JC, Hi:irle S, Kroll P. Unsealed sclerotomy after intravitreal injection with a
`30-gauge needle. Retina. 2004;24:810-812.
`16. Meyer CH, Rodrigues EB, Aguni JS, Farah ME. Scleral incisions evaluated by with anterior segment optical
`coherence tomography. Am J Ophthalmol. 2009 (in press)
`17. Pulido JS, Pulido CM, Bakri SJ, McCannel CA, Cameron JD. The use of 31-gauge needles and syringes for
`intraocular injections. Eye. 2007;21 :829-830.
`18. Kozak I, Dean A, Clark TM, et al. Prefilled syringe needles versus standard removable needles for
`intravitreous injection. Retina. 2006;26:679-683.
`19. Hochman MN, Friedman MJ. An in vitro study of needle force penetration comparing a standard linear
`insertion to the new bidirectional rotation insertion technique. Quintessence Int. 2001 ;32:789-796.
`20. Meyer CH, Scholl HP, Eter N, Helb HM, Holz FG. Combined treatment of acute subretinal haemorrhages with
`intravitreal recombined tissue plasminogen activator, expansile gas and bevacizumab: a retrospective pilot
`study. Acta Ophthalmol. 2008;86:490-494.
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`Retinal Physician, Issue: July/ Aug 2009
`Table of Contents
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