Intravitreous Injection: Maximizing the Benefits and Minimizing the Risks
DONALD J. D'AMICO, MD
With the recent Food and Drug Administration approval of Macugen (pegaptanib sodium; Eyetech/Pfizer Inc, New York, NY) for the treatment of neovascular AMD and the investigational use of triamcinolone acetonide in patients with AMD and diabetic retinopathy, retina specialists are presented with the decision to incorporate the therapeutic use of intravitreous injections into their daily practice. Intravitreous injection has several advantages over other routes of drug administration especially for disorders affecting the posterior segment of the eye. The most significant is the avoidance of systemic toxicity. The drug is introduced precisely to the target tissue and therapeutic intraocular concentrations are achieved soon after the injection. The blood-ocular barrier is bypassed allowing the use of agents that would be excluded due to their systemic effects at the doses that would be otherwise necessary.
During the past 20 years, the use of intravitreous injection has gained increasing acceptance. It began as the pathway for the successful treatment of endophthalmitis and is now used extensively for pneumatic retinopexy in the treatment of primary rhegmatogenous retinal detachment. Nevertheless, it is not without risks, and these risks include retinal toxicity from injected agents as well as mechanical damage to the retina and lens.1 Other risks of significance include endophthalmitis, acute intraocular pressure (IOP) rises, intraocular inflammation, retinal detachment, cataract, intraocular lens dislocation, hemorrhage, retinal vascular occlusion, cystoid macular edema, and hypotony. Injection-related pain, inconvenience to the patient, and, for some agents, the need to repeat the injection frequently in order to maintain effective drug concentrations are other disadvantages of intravitreal injection. Despite these limitations, proper technique and care in adhering to aseptic procedures have allowed safe administration of new intravitreous therapies with high patient acceptance levels.2
GUIDELINES FOR SAFE INTRAVITREOUS INJECTION
With anticipation that the number of intravitreous injection indications would grow based on promising results from ongoing clinical studies, a group of retina specialists recognized the need to identify specific strategies for the delivery of intravitreous injection that reduce risks and improve outcomes. In 2004, this panel developed practice guidelines based on its review of published and unpublished studies and case series regarding intravitreous injection.3 It must be emphasized that these guidelines should be viewed as suggestions and not rules, because the data that entered into their formulation is far from complete. Nevertheless, the guidelines provide a series of recommendations concerning intravitreal injection technique for a broad range of indications. The panel's key recommendations are summarized in the Table and discussed below.
Prior to performing an intravitreous injection, the physician should conduct a thorough risk assessment and manage any disorders, conditions, or abnormalities. Since the use of povidone-iodine is recommended for antisepsis during the procedure, it is important to not exclude patients who give a vague or uncertain history of allergy. Allergies to povidone-iodine are extremely rare; in patients reporting a history of allergy to iodine, a skin-patch test may be performed, but it is quite rare to find a positive result, and in almost all cases, povidone-iodine may be used. Active external infections, including blepharitis, should be treated, and the injection should not be administered under any circumstances until the infection is cleared. Any eyelid abnormalities such as entropion and the like should be considered to be a risk factor for the development of endophthalmitis, and warrant increased attention and follow-up.
After careful exclusion of infected patients, and the extensive and liberal use of povidone-iodine, the third most important item is the use of a lid speculum to keep the needle from contacting the lashes. As part of universal precautions, the use of gloves and draping of the surgical field are appropriate, but draping of the periorbital region and eyelashes are not essential. The physician may use discretion with regard to the use of preinjection antibiotics. Excessive lid manipulation should not be performed. If preinjection globe softening is desired, pressure should be applied directly to the globe, not to the lids or adnexa; in short, the meibomian gland material should not be massaged on to the ocular surface.
Pupillary dilation is the preferred method of achieving adequate visualization. Topical anesthetics should be applied according to standard practice, and supplemental subconjunctival anesthetic or topical gel may be administered as well, and probably will be appreciated by the majority of patients. Before the injection is administered, povidone-iodine drops or wash should be applied directly to the ocular surface, lid margins, and lashes using a sterile applicator, drops, or a flush. As mentioned, the use of a speculum is recommended. After the speculum is in place, an additional drop of povidone-iodine should be applied to the intended injection site. The injection should be placed through the pars plana in the inferotemporal quadrant 3.0 mm (pseudophakic eyes) to 4 mm (phakic eyes) from the limbus. A 27-g needle or smaller with a length of 0.5 inch to 5/8 of an inch is preferred, and the needle should be inserted 6 mm toward the eye's center.
Antibiotics may be administered postinjection at the physician's discretion, but within 72 hours of treatment. Typically, several drops of a topical fourth-generation quinolone are given, and many physicians use a day or 2 of additional postinjection topical antibiotics, although the data for their benefit is nonexistent. For the typical patient, a 0.1 mL injection will produce only a very transient pressure rise, and the patients should be monitored for the return of light perception vision within a minute or 2, as well as examined for return of perfusion of the optic disc by ophthalmoscopy. Paracentesis is to be avoided in virtually all cases, and even applanation tonometry may be avoided post injection, since both of these items may pose additional risk of infection, and are invariably unnecessary. Patients and caregivers should be educated to recognize the symptoms of endophthalmitis, retinal detachment, and intraocular hemorrhage, and they must be instructed to call at once if they develop pain or loss of vision. It is useful to have all patients call in to the physician's office on the first post injection day simply to verify that they are free of any worrisome symptoms. In addition, all patients should be contacted for a second time within 1 week of the procedure, again perhaps by phone, with further follow-up dictated by their individual needs. However, most patients will not require an interval examination.
Over the next few years, the rapid and substantial expansion of clinical applications using intravitreous injection can be expected given the increasing body of evidence that demonstrates the safety and benefits of access through the vitreous. Implementation of these guidelines will allow ophthalmologists to benefit from the clinical experiences of their peers to reduce the risks associated with intravitreous injection.
Donald D�Amico is professor of ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA. He is a consultant to Eyetech Pharmaceuticals, Alcon, and Iridex. He can be reached by e-mail at DJDAMICO@MEEI.HARVARD.EDU.
1.�Jager RD, Aiello LP, Patel SC, Cunningham ET Jr. Risks of intravitreous injection: a comprehensive review. Retina. 2004;24:676-698.
2.�Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR; VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805-2816.
3.�Aiello LP, Brucker AJ, Chang S, et al. Evolving guidelines for intravitreous injections. Retina. 2004;24(Suppl 5):S3-S19.
Table. Key Consensus Panel Recommendations for Intravitreous Injection.3
The strongest panel recommendations were:
Screen patients for disorders, conditions, or abnormalities that may increase risks.
Exclude patients with active lid or ocular adnexal infection.
Use gloves for the injection procedure.
Avoid extensive massage of the eyelids either pre- or postinjection (to avoid expressing meibomian glands).
In patients with glaucoma: monitor/manage IOP both before and after injection; avoid paracentesis (prophylactic or postinjection) unless absolutely necessary.
Dilate the pupil unless otherwise contraindicated; single-use or fresh bottles are recommended.
Use adequate anesthetic (topical drops and/or subconjunctival injection [single-use bottles recommended]).
Liberally use povidone-iodine on the ocular surface, lid margins, and eye lashes.
Use a lid speculum to avoid contamination of the needle with the eye lashes or eyelid margin.
Educate patients and caregivers to recognize symptoms of endophthalmitis, retinal detachment, and intraocular hemorrhage.
Contact patients within 1 week of the injection to inquire about vision loss and complications.
Recommendations for which there was no clear panel consensus were:
Use of a sterile drape.
Use of immediate pre- or postinjection antibiotics (little evidence to support their value as prophylaxis for endophthalmitis).
Use of an additional 10-cc povidone-iodine as a preinjection flush.
Technique for monitoring postinjection IOP in the eye without glaucoma or underlying optic disc disease (applanation tonometry vs. verifying optic disc perfusion by ophthalmoscopy).