|Year : 2018 | Volume
| Issue : 1 | Page : 63-66
Intravitreal injections: A brief note
Fellow - Medical Retina, Department of Ophthalmology, Little Flower Hospital and Research Centre, Ernakulam, Kerala, India
|Date of Web Publication||7-Jun-2018|
Fellow - Medical Retina, Department of Ophthalmology, Little Flower Hospital and Research Centre, Angamaly, Ernakulam - 683 572, Kerala
Source of Support: None, Conflict of Interest: None
The delivery of medications directly into the vitreous cavity through an injection or implant has become a commonplace in ophthalmology. Common diseases treated by intravitreal injections include neovascular age-related macular degeneration, clinically significant macular edema/proliferative diabetic retinopathy, cystoid macular edema following retinal vein occlusions and uveitis, endophthalmitis, and choroidal neovascular membrane secondary to multiple retinal diseases. Intravitreal injection procedure as per VRSI guidelines has been described in detail. Complications of intravitreal injections include those related to the technique and those related to the drug being used. It is important for the retina specialists to master the right technique of intravitreal injection in an effective way for patient safety as well as for reduction of complications.
Keywords: Age-related macular degeneration, anti-vascular endothelial growth factor, intravitreal
|How to cite this article:|
Joseph A. Intravitreal injections: A brief note. Kerala J Ophthalmol 2018;30:63-6
The delivery of medications directly into the vitreous cavity through an injection or implant has become a commonplace in ophthalmology. It allows for higher concentrations in the eye with lesser chance for systemic absorption compared to other modes of drug delivery. It also bypasses the blood-retinal barrier in the eye.
History began in 1911 when Ohm gave injection of air into the vitreous cavity for retinal detachment (RD) repair. In 1944, Von Sallmansuccessfully cured endophthalmitis in rabbits by intravitreal penicillin injection. In next two decades, intravitreal antibiotics and steroids were the main mode for the treatment of endophthalmitis. Fomivirsen (Vitravene) became the first intravitreal medication to be approved by the Food and Drug Administration (FDA) for treatment of cytomegalovirus (CMV) retinitis in 1998. Pegaptanib (Macugen), ranibizumab (Lucentis), and aflibercept (Eylea) have all since been FDA approved for use in exudative age-related macular degeneration (ARMD). Bevacizumab (Avastin) is commonly used off-label in choroidal neovascularization and macular edema.
Common diseases treated by intravitreal injections include neovascular ARMD (AMD), clinically significant macular edema/proliferative diabetic retinopathy, cystoid macular edema (CME) following retinal vein occlusions and uveitis, endophthalmitis, and choroidal neovascular membrane secondary to multiple retinal diseases.
Intravitreal injection guidelines as per VRSI guidelines  are as follows:
Preoperative preparation and precautions
The need and choice of intravitreal injection should be based on individual patient and best clinical judgment of the attending/injecting eye specialist. Proper screening should be done to ensure a patent nasolacrimal duct (NLD) and negative regurgitation test.
Any active infection (blepharitis and Meibomitis More Details) or a blocked NLD/positive regurgitation test has a high risk for postinjection endophthalmitis. Any active infection should be treated first and injection should be scheduled only after that.
The patient's name, intravitreal agent, and laterality ought to be verified before injection. Bilateral injections are not recommended, and injection for the other eye should be planned at least 1 week later. Uncontrolled systemic conditions such as diabetes should first be treated. Routine use of topical antibiotics for a day prior and 3 days postinjection is mandatory.
An informed written consent explaining the procedure and the risks involved should be obtained from the patient. Off-label use of bevacizumab should be included in the consent and explained to the patient specifically.
For each patient, a cleaned operation theatre gown, protective cap, and booties should be provided before entering the preoperative holding area/operating room.
Steps of injection
It is always carried out in an operation theater or a sterile room. Intravitreal injection in an office setting is not recommended though it's a practice in Western world. Mandatory cleaning and draping should be done. Skin and periocular adnexa are cleansed with 10% povidone-iodine and 5% povidone-iodine drops instilled in conjunctival sac for a contact period of 3 min after application of local anesthetic (proparacaine) eye drops. Evidence suggests that prophylactic antibiotics are no better than the use of povidone-iodine 5% drops. For patients with known povidone allergy, fluoroquinolone eye drops may be instilled 3 times in the eye starting 30 min before the injection. Draping should be done after a minimum of 2–3 min of povidone-iodine painting. The surgical area should be draped using sterile linen and a separate plastic sticking eye drape. After placing, the sterile speculum topical anesthetic drops instilled. Povidone-iodine is reapplied after anesthetic drop use. The injecting physician must scrub and wear cap and mask. Take a final timeout to confirm the name of the patient and the correct eye to be injected. It is preferable to inject under an operating microscope. Prepare the caliper marking and make the final adjustment of volume of drug with a fresh 29/30 G needle. Any quadrant (superotemporal or inferotemporal) can be chosen for injection. Sterile calipers should be used to mark 3–4 mm from limbus (depending on lens status) to mark the injection site.
- 3 mm-aphakic
- 3.5 mm-pseudophakic
- 4 mm-phakic.
Postinjection the cul-de-sac is flushed with povidone iodine or the injection site dabbed with a povidone-iodine soaked sterile swab. Routine anterior chamber paracentesis is not recommended. The eye can be patched with povidone iodine 5% drops for 2–4 h after injection. The patient is asked to avoid head bath for 1 day postinjection and swimming for 3 days postinjection. Topical postinjection antibiotic eyedrops for 5 days is recommended in patients with poor lid hygiene or debilitating systemic status.
Proper lid hygiene should be maintained. Postinjection intraocular pressure (IOP) is monitored on follow-up visit and topical antiglaucoma may be prescribed for postinjection IOP spike. The patient discharge card-injection details, postoperative instructions, symptoms of infection (pain, redness, dimness of vision, swelling, discharge, etc.), and 24-h emergency contact information.
After each day, all the instruments and linen after thorough cleaning and drying should be autoclaved for the next day.
Patients may be examined within 3 days after injection. They are advised to report to the nearest ophthalmologist immediately if there is unusual pain, redness, or drop in vision at any time. A good slit-lamp examination of anterior segment should be done to look for any cells in the anterior chamber/anterior vitreous. Fundus should be examined using indirect ophthalmoscope for any exudates, floaters, or new onset peripheral retinal hemorrhages or vasculitis. Check the IOP at each visit.
Injections for ROP are not covered in these guidelines. Antivascular endothelial growth factor (VEGF) injections are deferred in pregnant women and in those with uncontrolled diabetes (no evidence-based guideline for a cutoff of blood sugar or glycated hemoglobin level).
| Intravitreal Antibiotics|| |
Bactericidal agents are more preferred than other groups. Combination of drugs are given to cover broad spectrum of organisms, for examples (vancomycin + ceftazidime), (vancomycin + amikacin), etc. The clearance of drugs occurs through two routes-anterior→passive diffusion into aqueous (cationic-vancomycin and aminoglycoside) and posterior→active transport by retinal pigment epithelial pumps. Dose regimens of some intravitreal antibiotic preparations  are as follows: vancomycin (1000 μg in 0.1 ml), ceftazidime (dose: 2.25 mg in 0.1 ml), cefazolin (Dose: 2.25 mg in 0.1 ml), amikacin sulfate (Dose: 400 μg in 0.1 ml), gentamicin sulfate (dose: 200 μg in 0.1 ml), and amphotericin B (dose: 5 μg in 0.1 ml).
Major use is in the treatment of CMV Retinitis (particularly in HIV patients). Other uses – varicella zoster virus retinitis, and acute retinal necrosis. Some commonly used drugs include Ganciclovir (2000 mcg in 0.05–0.1 ml) given on a weekly basis, foscarnet (2.4 mg/0.1 ml) twice weekly injections for induction and once a week for maintenance as in resistant CMV disease. Combinations of high-dose intravitreal ganciclovir (3.0 mg twice a week) and foscarnet (2.4 mg twice a week) is used in conditions intolerant to conventional therapy, cidofovir (20 mcg) in the treatment of CMV retinitis in AIDS patients.
First used dexamethasone intravitreally in 1979 by Machemer  to halt cellular proliferation after RD surgery. Dexamethasone (Dose: 400 μg in 0.1 ml) is even given along with antibiotics in the treatment of bacterial endophthalmitis to reduce the inflammation. Triamcinolone (4 mg in 0.1 ml) inhibits the production of VEGF molecules. It stabilizes endothelial and basement membranes and decreases vascular permeability and vascular leakage through their inhibitory effect on plasmin. It also downregulates intercellular adhesion molecule in neovascular membrane. Various clinical applications of intravitreal steroids include anti-edematous effect, anti-angiogenic, effect and for intra operative use in visualization of vitreous. Anti-edematous effect of intravitreal triamcinolone acetonide (IVTA) is made use in diabetic macular edema, in edema secondary to retinal vein occlusions and in pseudophakic CME, uveitic CME, macular edema in retinitis pigmentosa, radiation-induced macular edema, CME following penetrating corneal graft. IVTA also has antiangiogenic and antiproliferative action that made it effective in Iris neovascularization, Exudative ARMD, proliferative vitreo Retinopathy, chronic prephthisical ocular hypotony, and resistant cases of chronic uveitis.
Intravitreal antivascular endothelial growth factor agents
Aptamers are RNA/DNA oligonucleotides that bind to proteins with high affinity and specificity→prevent binding of VEGF to human VEGF receptors (VEGFRs)→inhibit activity of pathogenic VEGF molecules. SELEX technique  is employed in the manufacture of these drugs. Nucleic acids alone is unstable. Hence, F and NH2 substituted ribonucleotides are used which are stable (nuclease resistant aptamers). They have a short halflife (t 1/2) of few minutes. When aptamer is linked to a polyethylene Glycol moiety, t 1/2 is increased. These molecules are immunologically nonreactive. Examples of such an aptamer include pegaptanib sodium.
- Pegaptanib sodium (Macugen)-bind specifically to only one VEGF-A isoform  (target-VEGF 165). FDA approved in the treatment of wet AMD. Administered in 0.3 mg dose once every 6 weeks. It effective in all forms of exudative AMD and its effect is seen as early as 6 weeks after 1st injection
- Bevacizumab (Avastin)-it's a monoclonal antibody that binds all VEGF-A isoforms. Still not FDA approved for ophthalmological use, though its approved for metastatic colon cancer. Typical dose is 1.25 mg in 0.05 ml in adults
- Ranibizumab (lucentis/accentrix)-its an antibody fragment which binds all VEGF-A isoforms with higher affinity than bevacizumab. Dosage is 0.5 mg/0.05 ml (10 mg/ml)
- Aflibercept (eylea)-it's a recombinant fusion protein consisting of VEGF binding portions from extracellular domains of human VEGFRs 1 and 2 that are fused to Fc portion of human IgG1. It binds VEGF-A dimer like a trap with higher affinity than bevacizumab and ranibizumab. It also binds VEGF-B and placenta growth factor. Dosage is 2 mg/0.05 ml.
Newer anti-vascular endothelial growth factor agents
- Brolucizumab – smallest active unit of a human monoclonal antibody, which allows for concentrated molar dosing. It's a humanized single-chain antibody fragment body inhibitor of VEGF-A used in wet AMD with very low molecular weight of 26 kDa. Dosage is 6 mg in 0.05 ml
- Conbercept  (Lumitin) is an anti-VEGF agent that has been approved in China for the treatment of neovascular AMD. Similar to aflibercept, conbercept is a fusion protein consisting of the extracellular domain 2 of VEGFR 1 and extracellular domains 3 and 4 of VEGFR2 combined with the Fc portion of the human immunoglobulin G1. The additional domains may allow conbercept to have a longer halflife than other anti-VEGF agents, which could mean that optimal treatment may be achieved with less-than-monthly or even bimonthly dosing. It also gives conbercept a higher binding affinity for VEGF than aflibercept.
Complications of intravitreal injections
Those related to the technique  include acute rise of IOP, endophthalmitis, rhegmatogenous RD, ocular hemorrhage, lens damage, etc. Complications related to drug being injected as in case of steroids such as increased risk of IOP elevation and increased risk of cataract formation. For anti-VEGF injections, there is again an increased risk of IOP elevation, intraocular inflammation, and systemic side effects (gastroenterology bleeds, subdural hemorrhage, transient ischemic attack, cerebral vascular accident), etc.
| Conclusion|| |
The frequency of intravitreal medications has significantly increased since the introduction of these anti-VEGF agents. Hence, it is important for the retina specialists to master the right technique of intravitreal injection in an effective way for patient safety as well as for reduction of complications.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Raichand M, Peyman GA. Endophthalmitis: Diagnosis and management. Indian J Ophthalmol 1982;30:635-40. [Full text]
de Smet MD, Meenken CJ, van den Horn GJ. Fomivirsen – A phosphorothioate oligonucleotide for the treatment of CMV retinitis. Ocular Immunol Inflamm 1999;7:189-98.
John B. Ocular pharmacology – Intravitreal Injections. Kerala J Ophthalmol 2007;19:46-56.
Machemer R, Sugita G, Tano Y. Treatment of intraocular proliferations with intravitreal steroids. Trans Am Ophthalmol Soc 1979;77:171-80.
Danis RP, Ciulla TA, Pratt LM, Anliker W. Intravitreal triamcinolone acetonide in exudative age-related macular degeneration. Retina 2000;20:244-50.
Trujillo CA, Nery AA, Alves JM, Martins AH, Ulrich H. Development of the anti-VEGF aptamer to a therapeutic agent for clinical ophthalmology. Clin Ophthalmol 2007;1:393-402.
Chappelow AV, Schachat AP. Neovascular age-related macular degeneration. Retinal Pharmacother 2010;18:128-32.
Abou-Ltaif S. Aflibercept in refractory wet AMD treated with ranibizumab: Anatomical and visual outcome. Saudi J Ophthalmol 2016;30:227-32.
Chexal S, Gunderson I, Berger BS, Jhaveri C. A novel compound for treatment of wet AMD. Retina Today 2016;4:72-8.
Li X, Ding X, Kaiser PK. Another anti-VEGF agent for treatment of neovascular AMD. Retina Today 2015;4:94-6.
Xu Y, Tan CS. Safety and complications of intravitreal injections performed in an Asian population in Singapore. Int Ophthalmol 2017;37:325-32.