37 Intravitreal Injections
37.1 Introduction
Intravitreal injection was reported by Ohm in 1911 as a technique to introduce air for retinal tamponade and repair of retinal detachment. 1 Intravitreal administration of pharmacotherapies dates back to the mid-1940s with the use of penicillin to treat endophthalmitis. 2 , 3 Since that time, use of the intravitreal injection technique has steadily increased, with its usage for the treatment of retinal detachment, 4 , 5 endophthalmitis, 6 , 7 and cytomegalovirus (CMV) retinitis. 8 , 9 The introduction of anti–vascular endothelial growth factor (anti-VEGF) agents resulted in a dramatic increase in intravitreal injections. 10 An analysis of the United States Medicare claims database revealed that fewer than 5,000 intravitreal injections were performed in 2001, and 812,413 intravitreal injections were performed in 2007. 10 Currently, intravitreal injection is one of the most commonly performed medical procedures in the United States with well over 1 million injections performed annually. 11
Pearls
Although the intravitreal injection procedure dates back to 1911, the recent development of pharmacotherapies for various posterior segment diseases has led to a rapid increase in the use of this technique.
37.2 Risk of Endophthalmitis Associated with the Intravitreal Injection Procedure
With the widespread use of the intravitreal injection technique, there has been increased concern regarding the risk of endophthalmitis following intravitreal injection. The risk of endophthalmitis in eyes with CMV retinitis treated with intravitreal injection has been estimated to be 1.3% per eye and 0.1% per injection. 12 The risk of endophthalmitis following intravitreal triamcinolone acetonide injection has been estimated to be approximately 0.8% for noninfectious endophthalmitis 12 , 13 , 14 and 0.6 to 0.16% for infectious endophthalmitis. 12 , 15 Because most patients treated with anti-VEGF agents receive a series of injections over months or years, it is important to distinguish between per-injection rates of endophthalmitis versus per-patient (or cumulative) rates of endophthalmitis over the course of treatment. While reported per-injection rates of endophthalmitis are generally very low in series of patients treated with anti-VEGF agents, per-patient rates may be close to 1% over a 2-year course of therapy. Recent series from Florida (20 cases of endophthalmitis out of 121,285 intravitreal injections, or a rate of 0.016%), 16 Denmark (2 cases out of 7,584 injections, or a rate of 0.026%), 17 Australia (2 cases out of 9.162 injections, 0.022%), 18 and Massachusetts (3 cases out of 10,208 injections, 0.029%) 19 indicate an endophthalmitis rate of 1 per 3,000 intravitreal anti-VEGF injections or less. A population-based study in the United Kingdom estimated the per-injection rate of endophthalmitis following intravitreal anti-VEGF injection to be 0.025%. 20 A review of the United States Medicare claims database revealed a per-injection rate of 0.09% for endophthalmitis associated with intravitreal anti-VEGF injections administered to patients with age-related macular degeneration (AMD). 21 In the Comparison of Age-related Macular Degeneration Treatments Trials (CATT), a prospective, multicenter, randomized clinical trial comparing intravitreal ranibizumab (Lucentis, Genentech) and intravitreal bevacizumab (Avastin, Genentech) in 1,107 patients with neovascular AMD, the per-patient rate of endophthalmitis over 2 years was 0.7% with intravitreal ranibizumab and 1.2% with intravitreal bevacizumab (p = 0.38). 22 A recent meta-analysis of 43 studies reported that endophthalmitis occurred after 197 of 350,535 intravitreal anti-VEGF injections, for an endophthalmitis rate of 0.056%. 23
37.3 Endophthalmitis after Intravitreal Injection: Spectrum of Causative Organisms Compared to Postsurgical Cases of Endophthalmitis
While the majority of postsurgical cases of endophthalmitis are believed to be related to the patient’s baseline ocular surface flora, many cases of endophthalmitis associated with the intravitreal injection procedure may be related to droplet transmission from the patient or from the health care providers involved with the intravitreal injection. Several studies provide evidence that the patient’s ocular surface flora may be the most common source of bacteria causing postoperative endophthalmitis, with the most common causative organisms being coagulase-negative Staphylococcus species. 24 , 25 , 26 , 27 Streptococcus species, which comprise at least 41% of culturable adult salivary flora, 28 , 29 are believed to contaminate operative fields by aerosolization or droplet spread. 30 , 31 , 32 , 33 , 34 Several studies have reported that Streptococcus species are significantly more likely to be the causative organism of endophthalmitis after intravitreal injection than of endophthalmitis after intraocular surgery. McCannel 35 summarized 54 cases of endophthalmitis following 105,532 intravitreal injections of anti-VEGF agents, and found that, of the culture-positive cases, Staphylococcus (n = 17; 65%) and Streptococcus (n = 8; 31%) were the most common causative organisms. In contrast, in series of postsurgical endophthalmitis cases, the proportion of culture-positive cases that were Streptococcus species ranged from 0 to 9%. 35 Similarly, Gregori et al 16 reported a series of 20 patients with endophthalmitis after 121,285 intravitreal injections of anti-VEGF agents; of the 9 (45%) culture-positive cases, 5 (56%) were Streptococcus species, 3 (33%) were coagulase-negative Staphylococcus, and 1 (11%) was nonanthracis Bacillus. Fileta et al 23 reported a meta-analysis which included 197 cases of endophthalmitis out of 350,535 intravitreal anti-VEGF injections; the most common organisms isolated were coagulase-negative Staphylococcus (38%) and Streptococcus (29%). An analysis of conjunctival flora in patients undergoing intravitreal injections identified Streptococcus species in only 3 of 71 (4.2%) cultured isolates, supporting the hypothesis that such organisms come from respiratory droplets instead of the patient’s conjunctival flora. 36
Special Considerations
Several studies have reported that Streptococcus species are significantly more likely to be the causative organism of endophthalmitis after intravitreal injection than of endophthalmitis after intraocular surgery. Thus, an important source for some cases of endophthalmitis after intravitreal injection may be respiratory droplets from the patient or the health care providers involved with the intravitreal injection procedure.
37.4 Injection Procedure Guidelines
Strategies that may be important in reducing the risk of complications associated with intravitreal injection include attention to issues before, during, and after the injection. Guidelines developed as a result of round-table deliberations conducted after a review of published and unpublished studies and case series are summarized, and an appropriate sequence of events for the administration of intravitreal injection is provided in the following. 37
Special Considerations
Injection procedure guidelines include consideration of preexisting conditions, such as active external infection and eyelid abnormalities, povidone-iodine, lid speculum, gloves, anesthesia, injection site location, needle selection, intraocular pressure (IOP) and vision monitoring postinjection, patient counselling postinjection regarding signs and symptoms of complications, and follow-up.
Guideline Areas with General Agreement among Committee Members
Povidone-iodine (5–10%) should be the last agent applied to the intended injection site before injection. If a gel anesthetic is used, povidone-iodine should be applied both before and after application of gel, as retained gel may prevent povidone-iodine from contacting the conjunctival surface of the injection site.
Pre- peri-, or postinjection topical antibiotics are unnecessary.
There is no evidence to support the routine use of a sterile drape.
Avoid contamination of the needle and injection site by the eyelashes or the eyelid margins.
Avoid extensive massage of the eyelids either pre- or postinjection (to avoid meibomian gland expression).
Use adequate anesthetic for a given patient (topical drops, gel, and/or subconjunctival injection).
Use of sterile or nonsterile gloves as consistent with modern office practice, combined with strong agreement regarding the need for handwashing before and after patient contact.
Either surgical masks should be used or both the patient and providers should minimize speaking during the injection preparation and procedure to limit aerosolized droplets containing oral contaminants from the patient and/or provider.
Monitor IOP both pre- and postinjection.
Routine anterior chamber paracentesis is not recommended.
Source: Adapted from Avery et al. 37
Guideline Areas with No Clear Consensus among Committee Members
Need for povidone-iodine application to the eyelids, including the eyelashes and eyelid margins. All agreed that when povidone-iodine is applied to the eyelashes and eyelid margins, eyelid scrubbing or eyelid pressure adequate to express material from the meibomian gland should be avoided.
Use of a speculum (some prevent contact between the needle/injection site and the eyelashes and eyelids with manual lid retraction).
Need for pupillary dilation and postinjection dilated examination of the posterior segment (although some viewed the return of formed vision as sufficient, others routinely dilate the pupil and examine the posterior segment after injection).
Use of povidone-iodine flush (most preferred drops only and saw no benefit to allowing the povidone-iodine to dry before injection).
(Adapted from Avery et al. 37 )
Intravitreal Injection Procedure: An Appropriate Sequence of Events
Either surgical masks should be used or both the patient and providers should minimize speaking during the injection preparation and procedure.
Take a procedural time-out to verify patient, agent, and laterality.
Apply liquid anesthetic drops to the ocular surface.
Apply povidone-iodine to the eyelashes and eyelid margins (optional, most use 10%).
Retract the eyelids away from the intended injection site for the duration of the procedure
Apply povidone-iodine (most use 5%) to the conjunctival surface including the intended injection site, at least 30 seconds before injection.
If additional anesthetic is applied, reapply povidone-iodine to the intended injection site immediately before injection (most use 5%).
Insert the needle perpendicular to the sclera, 3.5 to 4.0 mm posterior to the limbus (3.0–3.5 mm in pseudophakic or aphakic eyes) between the vertical and horizontal rectus muscles.
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