Nora Muakkassa, MD; Kendra Klein, MD; and Elias Reichel, MD

Intravitreal injection of medication was first described in 1947 with the use of penicillin for late postoperative endophthalmitis.¹ Antiviral agents were first injected intravitreally for the treatment of cytomegalovirus retinitis in the late 1980s.² Intravitreal injection of corticosteroids for diabetic macular edema was first described in 2002 and became commonplace for the treatment of retinal vein occlusion and diabetic macular edema.^3–5

In 2004, pegaptanib became the first anti-vascular endothelial growth factor (VEGF) agent the United States (US) Food and Drug Administration (FDA) approved for intravitreal injection for the treatment of neovascular age-related macular degeneration (AMD). Since then, additional anti-VEGF agents have become available and include bevacizumab, ranibizumab, and aflibercept. Currently, ranibizumab and aflibercept are FDA approved for the treatment of neovascular AMD, macular edema due to retinal vein occlusion, diabetic macular edema, and diabetic retinopathy. Large, randomized, controlled trials to assess injection technique are lacking; however, there have been many large studies to help establish general guidelines.⁶

Preexisting Conditions

Guidelines based on roundtable deliberations conducted after a review of published studies of intravitreal injections from 2004 to 2014 addressed several issues related to the injection process, including preexisting ocular conditions. The authors suggest that there are no absolute contraindications to intravitreal injection, but there are several clinical scenarios that warrant special consideration.⁶

Patients with preexisting ocular hypertension or glaucoma should be managed by the treating physician according to the standard of care or preferred practice pattern. Intravitreal injection should not be withheld secondary to ocular hypertension or glaucoma if treatment is necessary for preservation of vision. In these patients, the injecting physician should consider monitoring intraocular pressure after injection, but routine anterior chamber paracentesis is not recommended. It may be beneficial, however, in those with highly elevated intraocular pressure due to neovascular glaucoma.

In addition, previous ocular surgery does not preclude a patient from receiving an intravitreal injection, although the physician should avoid the site of prior incisional glaucoma surgery. Anticoagulation does not need to be withheld prior to injection. Patients with active external infection, including severe blepharitis, hordeolum, or cellulitis, should have the injection postponed until the infection has been adequately treated and cleared.6 In reviewing our cases of endophthalmitis after intravitreal injection, we found approximately one-third had an underlying systemic infection. Therefore, we recommend deferring injection, if possible, until after the infection has been adequately treated.

There are no data in the literature discussing the safety of intravitreal injections of anti-VEGF agents in the setting of active uveitis. If possible, we recommend controlling intraocular inflammation prior to injection.

Anesthesia

Many patients who receive intravitreal injections of anti-VEGF agents require frequent injections on a regular basis, and in some, the fear of pain and discomfort may lead to considerable anxiety. A pain-free injection is paramount in maintaining comfort and ensuring compliance to a treatment regimen. An ideal anesthetic provides maximum pain reduction without inflicting additional discomfort or increasing the risk of side effects. Other considerations include the ease of anesthetic application, the time required to administer the anesthetic, and cost.⁷

There has been no consensus as to which mode of anesthesia is optimal for pain control in intravitreal injections. Commonly used methods of topical anesthesia include topical drops (0.5% proparacaine, 0.5% tetracaine, 2% aqueous lidocaine), topical 2% lidocaine jelly, topical 3.5% lidocaine gel, or subconjunctival 2% lidocaine. In the 2008 American Society of Retina Specialists (ASRS) Preferences and Trends (PAT) survey, 36% of practitioners used a pledget or cotton-tip applicator soaked with anesthetic, 24% used subconjunctival lidocaine, 21% used topical anesthetic drops, and 18% used a viscous anesthetic.⁸

In a prospective, masked, randomized study, Blaha et al⁷ compared the effectiveness of 4 different anesthetic methods for intravitreal injection: 0.5% proparacaine, 0.5% tetracaine, a pledget of 4% lidocaine, or subconjunctival injection of 2% lidocaine. There was no statistically significant difference between the subjective patient pain scores.⁷ Furthermore, the use of subconjunctival lidocaine is associated with chemosis and subconjunctival hemorrhage.^7,9 In another randomized study, there was no significant difference in patient pain scales in patients receiving 0.5% tetracaine hydrochloride drops and a 4% lidocaine pledget, 0.5% tetracaine hydrochloride drops alone, or 4% cocaine drops alone.¹⁰

Viscous anesthetics have been shown to provide adequate anesthesia for cataract surgery and are frequently used as an anesthetic for intravitreal injection.^11,12 They are reported to be equally efficacious as subconjunctival injections in providing anesthesia with less patient discomfort and fewer side effects.9,13 Lidocaine jelly (2%), formulated for urogenital use, has been used off-label as an ocular anesthetic. The viscous nature of lidocaine jelly is beneficial in maintaining prolonged anesthetic contact with the ocular surface. Concerns have been raised over the jelly anesthetic forming a physical barrier over the conjunctiva, thus preventing povidone-iodine from contacting the conjunctival surface. In laboratory experiments, culture plates showed increased numbers of colony-forming units on plates treated with povidone-iodine after application of lidocaine jelly in comparison to application of povidone-iodine alone.¹⁴ However, there is no clinical evidence suggesting higher rates of endophthalmitis with the use of lidocaine jelly.^15,16 In 2008, preservative-free lidocaine gel 3.5% (Akten, Akorn) was FDA approved for ocular use. It is 50% less viscous than lidocaine jelly, potentially lowering the risk of bacterial entrapment and allowing better penetration of povidone-iodine.¹²

Allergy to topical anesthetics is rare, with an incidence of less than 1% of the general population. Allergic episodes attributed to topical anesthetics are typically adverse reactions rather than true hypersensitivities, but documented cases of contact dermatitis to anesthetics have been reported. Alternatives include a trial of anesthetic from another class (ie, amides such as lidocaine vs benzoic acid esters such as proparacaine or tetracaine), skin patch testing to verify true allergy, or trial of a preservative-free formula if allergy to preservative is suspected. Ice in a sterile glove has also been reported as an effective anesthetic for intravitreal injection in a patient with a severe lidocaine allergy.¹⁷

Setting

There is a large variability in practice patterns regarding sterility of injections, ranging from an operating room setting under sterile conditions to office-based injections without the use of lid speculums, gloves, or masks (Figure 5-1). According to the 2013 ASRS PAT survey, 98.2% of retina specialists in the US perform their injections in the office while only 47.3% of their international colleagues do the same. The large remainder of injections performed internationally are given in a surgery center (33.2%) or a hospital (16.4%).¹⁸

In 2014, Brynskov et al¹⁹ reported a 0.00% incidence of endophthalmitis in 20,293 injections performed in a positive-pressure ventilated operating room under sterile conditions. The authors compared results of major studies of rates of endophthalmitis after intravitreal injection. In 5 studies in which intravitreal injections were performed in the operating room, the rate of endophthalmitis was 0.014% and in 11 studies with an office setting, the rate was 0.038%.¹⁹ Another study reported no difference in the rate of endophthalmitis between injections performed in the operating room vs the office.²⁰

Masks

There is concern for oropharyngeal droplet transmission during intravitreal injection potentially increasing the risk of endophthalmitis. This is supported by data from a meta-analysis in which Streptococcus species were 3 times more commonly isolated after intravitreal injection as compared to postoperative endophthalmitis.²¹ Speaking while not wearing a face mask, by either the patient or physician, has been shown to increase bacterial dispersal in a setting simulating an intravitreal injection.²² There is significantly less bacterial dispersal either when a face mask is worn or when talking is avoided.22,23 Given the evidence above, published guidelines recommend either using a surgical mask or minimizing speaking during preparation and injection.^6,24 According to the 2013 ASRS PAT survey, 78% of US members follow these guidelines.¹⁸

Gloves

In a survey of US retina specialists, 58% reported using gloves, and of those, 58% use sterile gloves.²⁵ However, there is no evidence to support the use of gloves to prevent endophthalmitis. In general, the use of nonsterile or sterile gloves is recommended as part of routine infection control in the office setting.⁶

Sterile Drapes

There is no evidence in the literature to suggest the use of sterile drapes decreases the risk of endophthalmitis.⁶ In one retrospective study that did not use sterile gloves or drapes, the rate of endophthalmitis was 0.057%, comparable with the overall rates reported in the literature.²⁶ A 2011 survey found that only 12% of retina specialists in the US use a sterile drape for intravitreal injections.²⁵

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