Intravitreal drug delivery has become the gold standard for treatment of many retinal diseases, including neovascular age-related macular degeneration (AMD), diabetic retinopathy, and retinal vein occlusion. The frequency of intravitreal injections has significantly increased since the introduction of anti-vascular endothelial growth factor (VEGF) medications. The technique involved in properly performing this procedure is important to master in order to optimize patient safety and reduce the risk of complications.
Common Diseases Treated by Intravitreal Injections
- Neovascular AMD
- DME/NPDR/PDR (diabetic macular edema/non-proliferative diabetic retinopathy/proliferative diabetic retinopathy)
- RVO (retinal vein occlusions)
- CME (cystoid macular edema)
- CNVM (choroidal neovascular membrane) secondary to multiple retinal diseases
Informed Consent and Risks of Intravitreal Injections
Discuss the indications, risks, benefits, and alternatives with patients. Obtain informed consent and have the patient's signature on the consent form witnessed.
The RISKS of intravitreal injections include:
- Pain / foreign body sensation / epiphora (possibly due to dry eye, corneal abrasion, infection)
- Bleeding (subconjunctival, vitreous hemorrhage)
- Retinal tear / detachment
- Cataract (from inadvertently hitting the lens)
- Infection (endophthalmitis)
- Uveitis / retinal vasculitis (higher risk with brolucizumab)
- Loss of vision (from any of above)
- Loss of the eye (from a severe infection)
- Increased intraocular pressure with damage to optic nerve (primarily with steroids but may also occur after higher numbers of anti-VEGF injections)
- Need for surgery (to address some of the complications above)
- Stroke/heart attack (with anti-VEGF medications, controversial)
- Off-label use (for bevacizumab, triamcinolone, other medications)
- Need for additional injections in future (patients need to understand this)
BENEFITS of intravitreal injections depend on the ocular pathology being treated, but typically include improvement in vision or prevention of worsening vision (in the case of AMD, DR, RVO). In the case of an infection, the benefit is also direct delivery of the antibiotic/antifungal into the eye close to the nidus of the infection.
ALTERNATIVES to intravitreal injections can include observation, surgery (pars plana vitrectomy), or laser treatment (e.g., laser photocoagulation or photodynamic therapy) depending on the ocular disease.
Common Intravitreal Medications
- Bevacizumab (Avastin, off-label) 1.25mg/0.05mL (0.675mg/0.03mL if considering using for treatment of Zone I+ ROP in an infant)
- Ranibizumab (Lucentis) 0.5mg/0.05mL (for neovascular AMD, RVO, myopic CNVM) or 0.3mg/0.05mL (for diabetic retinopathy/DME)
- Aflibercept (Eylea) 2.0 mg /0.05 mL
- Brolucizumab (Beovu) 6 mg/0.05 mL
- Triamcinolone acetonide (Kenalog, off-label) 2mg/0.05mL or 4mg/0.1mL (Triesence/ Trivaris is alcohol-free preparation that is FDA-approved for intraocular use)
- Ganciclovir 4mg/0.1mL - administer 2 mg in 0.05 mL (twice weekly for cytomegalovirus retinitis for 14 days for induction)
- Clindamycin 1mg/0.1mL
- Foscarnet 2.4mg/0.1mL - administer 1.2 mg in 0.05 mL
- Fomivirsen - 330 micrograms/0.05mL
- Methotrexate - 400 micrograms/0.1mL
- Vancomycin 1mg/0.1mL
- Ceftazidime 2.25mg/0.1mL
- Amikacin 0.4mg/0.1mL
- Amphotericin B 5 micrograms/0.1mL
- Voriconazole 50-100 micrograms/0.1mL
- Dexamethasone 0.4mg/0.1mL
Topical, subconjunctival, or pledgets are commonly used routes of local anesthesia for in-office intravitreal injections. The choice of anesthetic depends on physician preference, and is also dictated by how the patient tolerated prior injections. Retrobulbar block may need to be used for an inflamed eye, such as in the case of endophthalmitis requiring a tap and injection. However, subconjunctival anesthetic is usually adequate and less painful than a retrobulbar block in an already inflamed eye. An acute inflamed eye is generally a contraindication for intravitreal anti-VEGF injections, especially with brolucizumab.
Several studies have looked at the different anesthetic choices for intravitreal injections. One randomized controlled trial found that topical anesthesia was effective for most patients. In this study, patients felt the least pain with the actually injection when a subconjunctival anesthetic was given. However, patients felt more pain when the actual anesthetic was being administered subconjunctivally. Therefore the collective pain score (anesthesia pain + intravitreal injection pain) was greater for the subconjunctival group compared to the topical group (in which patients had less pain during the administration of the anesthetic, but slightly higher pain score during the actual intravitreal injection).
Topical tetracaine or proparacaine eyedrops can be effective. In a similar fashion, pledgets soaked with proparacaine or tetracaine can be placed in the fornix and allowed to rest on the globe over the area of planned injection for a short period of time. Another option is to use a gel type anesthetic, such as lidocaine 2% or 4% jelly or Tetravisc. Some recent reports indicate that the gel may result in trapping of microbes on the ocular surface, so if gel is used it may be best to apply betadine before and after the gel is placed. For subconjunctival anesthesia, typically lidocaine 1% or 2% without epinephrine is effective.
Other points to remember:
- Subconjunctival anesthesia has a higher risk of causing subconjunctival hemorrhage
- Allow adequate time for anesthetic to take effect (can be as fast as 1 - 2 minutes for subconj, but would wait longer for topical lidocaine jelly, such as 5 min)
- If a patient is very nervous or "jumpy" consider a subconjunctival injection so that the injection itself is not felt or minimally felt. Still use topical anesthetics prior to performing the subconjunctival injection to minimize discomfort.
- If using topical anesthesia (since patients feel the injection more), remind them immediately before the injection that they will feel pressure, so that they do not move with the unanticipated sensation.
Preparation for Intravitreal Injection
- Patient should be at least slightly supine with neck well supported
- Ensure that the headrest is secure and will not unlock during the injection (as patients have a tendency to get nervous, extending their necks and pushing back on the headrest)
- Close the door and make sure there are no distractions during the injection which could cause the patient to have an ocular saccade
- Ensure that you have all required instruments before starting, as it is very uncomfortable for patient to wait once Betadine is instilled into the eye
- Do a surgical "timeout" before the procedure to confirm the correct patient, correct eye, and any allergies. Preferably the timeout should be done with a technician or a nurse to help confirm with the patient prior to the procedure.
- Superotemporally or inferotemporal for ease of access, though any quadrant can be used.
- Some retina specialists prefer the superotemporal quadrant, since should a complication such as a retinal detachment occur, it can be treated with a pneumatic retinopexy. Others prefer the inferior quadrant as patients tend to look up with any squeezing of the lids (Bell's phenomenon).
- Most important is povidone-iodine 5% solution as it has evidence based data showing risk reduction for endophthalmitis in ocular surgery.
- Antibiotic use is controversial, and most retina specialists do not pre-treat with antibiotics. Historically, post-procedure antibiotics were given for approximately 3 days (likely for medico-legal reasons). Several studies have demonstrated that post-injection antibiotics do not reduce the incidence of endophthalmitis. More importantly, studies show increased antibiotic resistance with the use of post-procedure antibiotics.
- 5% povidone-iodine solution should be placed on the globe and allowed to sit on the eye for at least 30-60 seconds. One may also use 10% Betadine swabs to gently clean the eye and eyelashes. However, 10% Betadine is associated with more corneal toxicity so care should be taken to avoid getting it in the eye.
- Sterile lid speculum with closed blades (to isolate lashes better) or bimanual lid retraction by an assistant
- Gloves are optional. However, patients may feel more comfortable if the surgeon uses gloves.
- Do not talk (or cough or sneeze) while preparing or performing the intravitreal injection as studies suggest that there may be a higher risk of oral flora-associated endophthalmitis during intravitreal injections due to talking . If you must talk, turn your head away from the surgical field and speak before uncapping the needle.
- Consider wearing a mask if there is a need to speak or instruct the patient during the injection as one study suggested that this may yield equivalent outcomes to a no talking policy with potentially a lower incidence of oral flora-associated endophthalmitis. However, if wearing a surgical mask it may be best to face the surgical field as exhalations will exit the mask to the sides and back of the surgical mask.
Many variations in technique exist, and the following is one example:
- Confirm informed consent obtained
- Surgical time-out to confirm correct medication and correct eye
- Place patient in near supine position; make sure the headrest of the chair is stable
- Topical proparacaine (wait 10-15 seconds before placing povidone-iodine)
- 5% povidone-iodine drops; ask patient to blink multiple times to spread the povidone-iodine
- If necessary, place 2% lidocaine gel on the eye, focusing on the planned injection quadrant. (Note: use povidone-iodine prior to lidocaine gel to sterilize the globe prior to placing the gel so as not to have bacteria trapped in the gel and possibly increase risk of endophthalmitis).
- Ask patient to close their eyes, and return in 2-5 minutes.
- Apply 5% povidone-iodine drops again to planned injection quadrant and inferior cul-de-sac.
- Place sterile closed-blade eyelid speculum (be careful not to cause a corneal abrasion) or have an assistant retract both lids.
- Mark the location of injection: 3-3.5mm for pseudophakes, 3.5-4.0 mm for phakic patients. Tip: Can use the end of a TB syringe (without needle attached) to mark 3.5-4.0 mm. After marking and causing an indentation with the TB syringe, consider placing 5% povidone-iodine again. It will slightly pool in the indentation ring and nicely highlight the injection site.
- Have the patient look away from the injection site. For example, if injecting the right eye in the superotemporal quadrant, ask the patient to look down and to the left.
- Hold syringe in dominant hand, and a cotton-tipped applicator in the non-dominant hand
- Do not talk and ask patient not to talk during the injection. Alternatively, wear a mask. Make sure the needle tip (which is usually a short 30g) is always kept absolutely sterile.
- Using your dominant hand, rest your wrist or pinky finger on the patient's face (forehead for superior and cheek for inferior injection sites) for hand stabilization
- Insert the needle at the marked site in a smooth and single motion, aiming for the mid-vitreous cavity
- Insert the short 30g needle about 1/2 length in (to make sure you are in the vitreous cavity and not in the suprachoroidal space)
- Swing over with your non-dominant hand to push down on the plunger in a smooth fashion. (Note: some surgeons prefer to inject with one-hand; the author feels that using two hands is more stable). Do not move the needle while inside the eye so as to not cause traction on the vitreous and potentially cause a retinal tear/detachment.
- As you remove the needle, cover the injection site with a cotton-tipped applicator that is in your non-dominant hand
- Rinse the povidone-iodine out of the patient's eye
- Ensure optic nerve perfusion (patient should be at least light perception). Paracentesis is usually not required unless a large volume of medication is injected. Some physicians prefer to check and document the IOP and do not let the patient leave until the IOP has reduced to an acceptable level. Glaucoma patients may need an anterior chamber paracentesis as their outflow may be compromised. Injecting Kenalog or Triesence 0.1cc causes a rapid and high IOP and it is not uncommon for patients to be temporarily NLP after the injection. Warn patients about this. Tip: One can try to place pressure on the globe (e.g., anesthetic solution on a cotton-tipped applicator at the proposed injection site) to squeeze some aqueous out of the eye and lower the IOP prior to injection and possibly prevent transient NLP vision.
Post-Injection Care Tips
- Make sure to wash off povidone-iodine well so the patient does not have irritation/corneal toxicity
- Reassure patients that they may see floaters which are due to air bubbles or the medication itself (in the case of Kenalog, Triesence, or Dexamethasone implant)
- Review endophthalmitis and retinal detachment symptoms and precautions
- Consider a follow-up phone call with patients 3-7 days after the injection
- A one week in-office follow-up is at the physician's discretion, but is not typically needed.
Bilateral Intravitreal Anti-VEGF Injections
Intravitreal injections of anti-VEGF are traditionally given unilaterally. More recently, there has been an increase in the use of these medications in a bilateral fashion in patients with pathology in both eyes. Common diseases that may need bilateral injections include diabetic macular edema and neovascular AMD, and there is evidence that the rate of bilateral involvement increases with the follow-up and disease duration.  A survey of retina specialists in the US in 2011 found that 46% of retina specialists perform bilateral same-day injections.  The purpose of bilateral same-day injections is to decrease both physician and patient burden in terms of office visits. In one study, more than 90% of patients strongly preferred bilateral injections to unilateral injections. However, some physicians will avoid bilateral injections for fear of bilateral endophthalmitis. Other local complications should be considered when administering bilateral injections, including inflammation/uveitis, raised intraocular pressure, retinal detachment and subretinal hemorrhages. Separate eyedrops, speculum, needle, and syringe are typically used for each eye to minimize risks.
There have been several large-scale studies of endophthalmitis in bilateral same-day intravitreal anti-VEGF injections. Overall, bilateral injections appear to have a similar safety profile to unilateral injections. The largest study of 101,932 same-day bilateral intravitreal anti-VEGF injections in 5890 patients at a large academic private practice over 5 years found 28 cases of endophthalmitis (0.027% of total injections) with no cases of bilateral endophthalmitis. Other similar studies have found the incidence of endophthalmitis from 0-0.01% to 0.065%.  
- Depends on the disease being treated and duration of treatment. Early on, patients may require monthly injections and follow-up. Later in the course as the disease is stabilized, some advocate extending the interval between injections permitting less frequent injections and follow-up visits.
Similar safety and efficacy of intravitreal bevacizumab compared to ranibizumab
Numerous trials (CATT, IVAN, GEFAL, MANTA, LUCAS) conducted worldwide have shown intravitreal bevacizumab to be non-inferior to ranibizumab in terms of efficacy and safety in AMD. Bevacizumab has the advantage of significantly reducing the cost of therapy. However, intravitreal bavacizumab injection has not been approved by the Food and Drug Administration (FDA) and the use in the eye is hence 'off label'. All patients need to be clearly informed of this when obtaining written consent for intravitreal bevacizumab injection.
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