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`DHVS‘C‘AN Art'c'e
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`Steps for a Safe Intravitreal Injection Technique
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`A look at how European and American approaches compare
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`July 1, 2009
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`6*
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`4Share
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`Steps for a Safe Intravitreal Injection Technique
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`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
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`eye and in maintaining effective drug doses within those tissues. However, retinal drug delivery is still a challenging
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`area in the field of ophthalmic drug delivery.
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`A variety of approaches have been described for drug delivery into the vitreous cavity. Intravitreal injection was first
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`reported by Ohm in 1911 as a technique to introduce airfor retinal tamponade and repair of retinal detachment.1
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`Intravitreal administration of pharmacotherapies dates to the mid-1940s with the use of penicillin to treat
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`endophthalmitis. Since that time, use of the intravitreal injection technique has progressively increased, with its
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`usage being focused primarily on the treatment of retinal detachment, endophthalmitis, and cytomegalovirus
`retinitis.
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`Carsten H. Meyer, MD, is professor of ophthalmology at the University of Bonn in Germany. Anne E. Fung, MD, is
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`a medical retina consultant at Pacific Eye Associates in San Francisco. Sandeep Saxena, MD, is professor of
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`ophthalmology at King George's Medical University in Lucknow, India. Frank G. Holz, MD, is professor and chair
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`of ophthalmology at the Universitéts-Augenklinik mit Poliklinikin in Bonn. Dr. Meyer reports minimal financial
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`interest in Pfizer, Novartis, and GlaxoSmithKline. Drs. Fung, Holz, and Saxena report no financial interest in any
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`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
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`pharmacotherapies, has led to a recent rapid increase in the use of this technique forthe administration of various
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`pharmacotherapies, including bevacizumab, ranibizumab, pegaptanib sodium, and intravitreal triamcinolone
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`acetonide.2 An intravitreal drug application has been suggested to achieve therapeutic levels locally, with prolonged
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`effective concentrations (Figure 1).1 Retinal specialists in Europe and the United States have varied approaches
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`within their countries and between the continents. We will highlight consensus and differences in practices here.
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`https://www.retina1physician.com/issues/2009/july-aug/steps-for-a-safe-intraVitrea1-injection-technique
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`Regeneron Exhibit 1059.001
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`Retinal Physician - Steps for a Safe Intravitreal Injection Technique
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`Page 2 of 6
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`Figure 1. Intravitreal 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. V\fith the
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`widespread use of intravitreal injections, there has been an increased interest regarding the best application
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`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
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`injection in an operating room, other countries, including the United States and India, perform the injection in minor
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`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
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`thromboembolic or cerebrovascular events.6 The ranibizumab study trials observed a low incidence of ocular
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`hemorrhages in patients maintaining warfarin. In the MARINA trial, there were a total of 60 warfarin-treated
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`participants, receiving a mean of 22.0 (SD, 3.6) injections.7 No ocular bleeding was observed during the 1318
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`consecutive injections. All the authors agree that intraocular injections in warfarin-treated patients are unlikely to
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`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
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`role of topical antibiotics to prevent postinjection endophthalmitis remains controversial around the world. Topical
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`antibiotics may be applied after the injection for a few days, as the break in the conjunctiva and sclera takes time to
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`completely heal and water-seal. In addition, there may be a synergistic effect between topical antibiotics and
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`povidone-iodine. However, Frank Holz, MD, emphasized that there is no study demonstrating that reduced
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`conjunctival 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
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`mandatory priorto each intravitreal injection“:8 The primary goal of any infectious prophylaxis is to minimize the
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`present bacterial flora around the surgical entry site. This can be achieved with the topical application of povidone-
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`iodine, eyelid hygiene, proper isolation of the surgical site, and optional postoperative antibiotics?-11
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`One key step to reducing the risk of endophthalmitis is a sufficient disinfection of the skin, eyelashes, and
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`conjunctiva. The eyelids and lashes are usually disinfected with a povidone-iodine (10%) scrub. A sterile speculum
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`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 overthe intended site of the
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`injection. Some physicians place 3 drops of povidone-iodine (5%) 3 times, several minutes apart, over the ocular
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`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 conjunctival sac with 1% or 5% povidone-iodine to decrease
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`conjunctival colonization; however, it remains unknown whether the application of povidone-iodine drops vs a flush
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`is more effective in preventing endophthalmitis.
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`There is no consensus among the 4 authors as to whethertopical antibiotics should be used preoperatively.
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`Preinjection antibiotic drops may be applied according to the label of the applied drug, although there is no evidence
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`supporting their use before intravitreal injections.
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`LOCAL TOPICAL AN ESTH ESIA
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`Satisfactory pain relief may be achieved with topical lidocaine. Local anesthesia may be induced by applying 3 to 4
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`sterile cotton swabs soaked in sterile 4% lidocaine to the injection area (for 30 seconds each).12 Alternatively,
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`lidocaine may be applied with 2% eyedrops, as a gel, or as a subconjunctival injection. The effective relief of pain
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`with lidocaine for intravitreal injection seems to be independent of its mode of application (gel vs subconjunctival
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`injection). However, topical applications of lidocaine cause less chemosis compared with subconjunctival
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`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 posteriorto the limbus. Dr. Saxena
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`emphasizes that the injection site may differ in repeated injections by approximately 1 clock hour.413 This avoids a
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`double penetration through the same site, inducing a persisting scleral hole with consecutive leaking or vitreous
`incarceration "vitreous wick."
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`The angle of the incision through the sclera may be directed in an oblique, tunneled fashion (Figures 2 and 3), as
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`rectangular radial incisions may remain open, inducing vitreous or drug reflux under the conjunctiva, as well as
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`severe chemosis and even hypotony in vitrectomized eyes.i4x15 Dr. Meyer observes persistent unsealed
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`sclerotomies following radial injections using a 30-gauge needle, requiring secondary suturing to seal the
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`penetrating scleral wound.16 The depth of the insertion may vary between 5 to 7 mm according to Anne Fung, MD,
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`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 he injection procedure: The conjunctiva is moved upwards so that the
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`conjunctival hole and the site of the scleral penetration are not on top of each other. After an initial lamellar
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`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
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`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
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`crystalline TA are frequently applied with 27-gauge needles, while most liquid injections use 30-gauge needles. The
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`required force to penetrate the sclera is almost twice as much using 27-gauge needles compared with 30- or even
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`31-gauge.17 Dr. Holz explains that larger needles may not necessarily induce more pain to the patient; however,
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`they may induce more reflux or subconjunctival hemorrhage. In addition, blunting of the needle tip, as found in some
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`prefilled syringes, was observed to cause a deeper inpouching and visible indentation of the eye wall during the
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`injection that may have caused the patient more discomfortflB'19
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`The injected volume should be limited up to 0.15 ml without a routine paracentesis releasing an elevated ocular
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`pressure, according to Dr. Meyer's clinical experience. Administration of rTPA, anti-VEGF agents, and SF6 gas as
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`triple injection for the management of subretinal hemorrhage frequently require a paracentesis to release the
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`elevated eye pressure.20
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`OCULAR COMPLICATIONS
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`https://www.retina1physician.com/issues/2009/july-aug/steps-for-a-safe-intraVitrea1-injection-technique
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`Retinal Physician - Steps for a Safe lntravitreal Injection Technique
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`Dr. Fung published a survey on ocular complications reporting an overall prevalence for retinal detachments of 3.9%
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`per eye or 0.9% per injection and a prevalence of endophthalmitis (including pseudo-endophthalmitis) of 0.3% per
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`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
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`tissue. Some parts of the injection procedure (use of adequate anesthetics, povidone-iodine, and a lid speculum; not
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`injecting patients with active eyelid or ocular infections; avoiding extensive massage of eyelid meibomian glands;
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`avoiding prophylactic or postinjection paracentesis) are supported by consensus agreement in all countries, while
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`other aspects have less agreement (eg, most investigators advocate gloves, most prefer povidone-iodine drops over
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`flush, most use no sterile drape). There is no agreement regarding the use of pre- or postinjection topical antibiotics,
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`as well as a specific intraocular pressure level that should not be exceeded before the injection. lntravitreal drug
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`application is a safe and effective procedure. Side effects, eg, elevated IOP, cataract formation, and
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`endophthalmitis, are limited. RP
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`REFERENCES
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`1. Ohm J. Uber die Behandlung der Netzhautablosung durch operative Entleerung der subretinalen Fliissigkeit
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`und Einspritzen vom Luft in den Glaskorper. Graefe Arch Klin Ophthalmol. 1911;79:442-450.
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`2. Fung AE, Rosenfeld PJ, Reichel E. The International lntravitreal Bevacizumab Safety Survey: using the
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`internet to assess drug safety worldwide. BrJ Ophthalmol. 2006;90:1344-1349.
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`3. Kaiser PK, Brown DM, Zhang K, Hudson HL, Holz FG, Shapiro H, Schneider S, Acharya NR. Ranibizumab
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`for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year
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`ANCHOR results. Am J Ophthalmol. 2007;144:850-857.
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`4. Fung AE, Lalwani GA, Rosenfeld PJ, Dubovy SR, Michels S, Feuer WJ, Puliafito CA, et al. An optical
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`coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for
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`neovascular age-related macular degeneration. Am J Ophthalmol. 2007;143:566—583.
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`5. Schmidt-Erfurth UM, Richard G, Augustin A, Aylward WG, Bandello F, Corcostegui B, Cunha-Vaz J, Gaudric
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`A, Leys A, Schlingemann RO; European Society for Retina Specialists' Guidelines Committee (EURETINA).
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`Guidance for the treatment of neovascular age-related macular degeneration. Acta Ophthalmol Scand.
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`2007;85:486-494.
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`6. Meyer CH, Callizo J, Mennel S, Kussin A. Perioperative management of anticoagulated patients undergoing
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`repeated intravitreal injections. Arch Ophthalmol. 2007;125:994.
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`7. Charles S, Rosenfeld PJ, Gayer S. Medical consequences of stopping anticoagulant therapy before
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`intraocular surgery or intravitreal injections. Retina. 2007;27:813-815.
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`8. Scott lU, Flynn HW. Reducing the risk of endophthalmitis following intravitreal injections. Retina. 2007;27:10-
`12.
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`9. Safar A, Dellimore MC. The effect of povidone iodine flush versus drops on conjunctival colonization before
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`intravitreal injections. Int Ophthalmol. 2007;27:307-312.
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`10. Meyer CH, Mennel S, Eter N. Incidence of endophthalmitis after intravitreal Avastin injection with and without
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`postoperative topical antibiotic application. Ophthalmologe. 2007;104:952-957.
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`11. Ta CN, Egbert PR, Singh K, Shriver EM, Blumenkranz MS, Mifio De Kaspar H. Prospective randomized
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`comparison of 3-day versus 1-hour preoperative ofloxacin prophylaxis for cataract surgery. Ophthalmology.
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`2002;109:2036-2041.
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`12. Kaderli B, Avci R. Comparison of topical and subconjunctival anesthesia in intravitreal injection
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`administrations. EurJ Ophthalmol. 2006;16:718-721.
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`13. Aiello LP, BruckerAJ, Chan S et al. Evolving guidelines for intravitreous injections. Retina. 2004;24;S3-19.
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`14. Rodrigues EB, Meyer CH, Grumann A Jr, Shiroma H, Aguni JS, Farah ME. Tunneled scleral incision to
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`prevent vitreal reflux after intravitreal injection. Am J Ophthalmol. 2007;143:1035-1037.
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`15.
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`16.
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`17.
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`18.
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`19.
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`20.
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`Rodrigues EB, Meyer CH, Schmidt JC, Hérle S, Kroll P. Unsealed sclerotomy after intravitreal injection with a
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`30-gauge needle. Retina. 2004;24:810-812.
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`Meyer CH, Rodrigues EB, Aguni JS, Farah ME. Scleral incisions evaluated by with anterior segment optical
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`coherence tomography. Am J Ophthalmol. 2009 (in press)
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`Pulido JS, Pulido CM, Bakri SJ, McCannel CA, Cameron JD. The use of 31-gauge needles and syringes for
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`intraocular injections. Eye. 2007;21:829-830.
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`Kozak I, Dean A, Clark TM, et al. Prefilled syringe needles versus standard removable needles for
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`intravitreous injection. Retina. 2006;26:679-683.
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`Hochman MN, Friedman MJ. An in vitro study of needle force penetration comparing a standard linear
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`insertion to the new bidirectional rotation insertion technique. Quintessence Int. 2001 ;32:789-796.
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`Meyer CH, Scholl HP, Eter N, Helb HM, Holz FG. Combined treatment of acute subretinal haemorrhages with
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`intravitreal recombined tissue plasminogen activator, expansile gas and bevacizumab: a retrospective pilot
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`study. Acta Ophthalmol. 2008;86:490-494.
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`Retinal Physician, Issue: July / Aug 2009
`Table of Contents
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`Archives
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`Regeneron Exhibit 1059.006
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