`
`Retinal Physician - Steps for a Safe Intravitreal Injection Technique
`
`Article
`
`Steps for a Safe Intravitreal Injection Technique
`A look at how European and American approaches compare
`
`July 1, 2009
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`19
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`Steps for a Safe Intravitreal Injection Technique
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`A look at how European and American approaches compare.
`
`CARSTEN H. MEYER, MD · ANNE FUNG, MD · SANDEEP SAXENA, MD · FRANK G. HOLZ, MD
`
`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. Intravitreal injection was first reported by Ohm in 1911 as a
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`technique to introduce air for retinal tamponade and repair of retinal detachment. Intravitreal 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 Universitäts-Augenklinik mit Poliklinikin in Bonn. Dr. Meyer reports minimal
`financial interest in Pfizer, Novartis, and GlaxoSmithKline. Drs. 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.
`
`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
`2
`intravitreal triamcinolone acetonide. An intravitreal drug application has been suggested to achieve therapeutic levels locally, with prolonged effective
`concentrations (Figure 1). Retinal specialists in Europe and the United States have varied approaches within their countries and between the
`1
`continents. We will highlight consensus and differences in practices here.
`
`Figure 1. Intravitreal injections via the pars plana route into the mid-vitreous.
`
`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.
`
`All injections should be performed under sterile conditions. While European countries recommend applying the injection in an operating room, other
`5
`countries, including the United States and India, perform the injection in minor surgery or conventional examining rooms under sterile conditions.
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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
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`events. The ranibizumab study trials observed a low incidence of ocular hemorrhages in patients maintaining warfarin. In the MARINA trial, there were
`7
`a total of 60 warfarin-treated participants, receiving a mean of 22.0 (SD, 3.6) injections. 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.
`
`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 conjunctival bacteria may result in a lower
`8
`risk for endophthalmitis.
`
`Sandeep Saxena, MD, emphasized that treatment of any active external infection, including significant blepharitis, is mandatory prior to each intravitreal
`4,8
`injection.
` The primary goal of any infectious prophylaxis is to minimize the present bacterial flora around the surgical entry site. This can be achieved
`9-11
`with the topical application of povidone-iodine, eyelid hygiene, proper isolation of the surgical site, and optional postoperative antibiotics.
`
`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.
`
`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.
`
`German investigators have advocated irrigating the conjunctival sac with 1% or 5% povidone-iodine to decrease conjunctival 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
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`sterile 4% lidocaine to the injection area (for 30 seconds each).
` 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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`Retinal Physician - Steps for a Safe Intravitreal Injection 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.
` This avoids a double penetration through the same site, inducing a persisting scleral
`4,13
`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.
` Dr.
`14,15
`Meyer observes persistent unsealed sclerotomies following radial injections using a 30-gauge needle, requiring secondary suturing to seal the
`penetrating scleral wound.
` 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
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`in the mid-vitreous. The drug is then gently injected into the vitreous cavity.
`
`Figure 2. Schematic drawing of the injection procedure: The conjunctiva is moved upwards so that the conjunctival 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.
` Dr. Holz explains that larger needles may not necessarily induce more pain to the patient;
`17
`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 inpouching 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.
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`OCULAR COMPLICATIONS
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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
`
`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. Intravitreal 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. Über die Behandlung der Netzhautablösung durch operative Entleerung der subretinalen Flüssigkeit und Einspritzen vom Luft in den
`Glaskörper. Graefe Arch Klin Ophthalmol. 1911;79:442-450.
`2. Fung AE, Rosenfeld PJ, Reichel E. The International Intravitreal Bevacizumab Safety Survey: using the internet to assess drug safety worldwide.
`Br J Ophthalmol. 2006;90:1344-1349.
`3. Kaiser PK, Brown DM, 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, Bandello F, Corcòstegui 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 conjunctival 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, Miño 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 S et 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.
`15. Rodrigues EB, Meyer CH, Schmidt JC, Hörle 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 - Steps for a Safe Intravitreal Injection Technique
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