Intravitreal drug delivery has become a popular method of treatment of many retinal diseases, commonly including AMD, Diabetic Retinopathy, and Retinal Vein Occlusions. The frequency of intravitreal injections has significantly increased since the introduction of Anti-VEGF medications. This is an important procedure that Retina Specialists use on a daily basis, and it is important to master the techniques of effective injections for patient safety and reduction of complications.
- 1 Common Diseases Treated by Intravitreal Injections
- 2 Informed Consent and Risks of Intravitreal Injections
- 3 Common Intravitreal Medications
- 4 Anesthesia
- 5 Preparation for Intravitreal Injection
- 6 Injection Site
- 7 Asepsis
- 8 Injection Technique
- 9 Post-Injection Care Tips
- 10 Bilateral Intravitreal Anti-VEGF Injections
- 11 Follow up
- 12 Similar safety and efficacy of intravitreal bevacizumab compared to ranibizumab
- 13 Additional Resources
- 14 References
Common Diseases Treated by Intravitreal Injections
- AMD (neovascular age related macular degeneration)
- CSME/PDR (clinically significant macular edema/ proliferetive diabetic retinopathy)
- 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:
- Bleeding (subconjunctival, vitreous hemorrhage)
- Retinal tear / detachment
- Cataract (from inadvertently hitting the lens)
- Infection (Endophthalmitis)
- Loss of vision (from any of above)
- Loss of the eye (from a severe infection)
- Increased IOP, with damage to optic nerve (steroids)
- Need for surgery (to address some of the complications above)
- Stroke/Heart-Attack (with Anti-VEGF medications, controversial)
- Off-label use (for Avastin, Kenalog, other medications)
- Need for multiple injections in future (patients need to understand this)
BENEFITS of Intravitreal Injections depend on the ocular pathology being treated, but mainly include improvement of vision or prevention of worsening of the vision (in the case of AMD, DR, RVO). In the case of an infection, the benefit is direct delivery of the antibiotic/antifungal into the eye close to the nidus of the infection.
ALTERNATIVES to intravitreal injection can include observation, surgery (pars plana vitrectomy), or laser treatment (e.g. photodynamic therapy) depending on the ocular disease.
Common Intravitreal Medications
- Bevacizumab (Avastin) 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
- Aflibercept (Eylea) 2.0 mg /0.05 ml
- Brolucizumab (Beovu) 6 mg/ 0.05 ml
- Triamcinolone acetonide (Kenalog) 0.1cc of 4mg/ml (Triesence/ Trivaris is alcohol-free preparation that is FDA approved for intraocular use)
- Ganciclovir Intravitreal 4mg/0.1mL - administer 2 mg in 0.05 mL (twice weekly for CMV Retinitis for 14 days for induction)
- Clindamycin 1mg/0.1mL
- Foscarnet Intravitreal 2.4mg/0.1ml - administer 1.2 mg in 0.05 mL
- Cidofovir - 20 micrograms
- Fomvirsen - 330 micrograms
- Methotrexate - 400 micrograms
- Vancomycin 1mg/0.1ml
- Ceftazidime 2.25mg/0.1ml
- Amikacin 0.4mg/0.1ml
- Amphotericin B; 5 micrograms/0.1 mL
- Voriconazole - 50-100 micrograms/0.1 mL
- Dexamethasone 0.4mg/0.1ml
Retina Specialists usually use topical, subconjunctival, or pledgets for common in-office intravitreal injections. The choice of anesthetic depends on the Retina Specialists' preference, and 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. In case of intravitreal bevacizumab or ranibizumab an acute inflamed eye is an contraindication for intravitreal injection.
Several studies have looked at the different choices of intravitreal injections. One randomized controlled trial found that topical anesthesia was effective for most patientsIn 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 also be effective. In a similar fashion, pledgets soaked with lidocaine or tetracaine can be placed in the inferotemporal fornix and allowed to rest on the globe. 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 some retina specialists advocate betadine before and after application.
Other points to remember:
- Subconjunctival anesthesia has higher risk of a 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 they injection itself is not felt or minimally felt
- 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 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 and extend their necks and push 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 upon an 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 confirm with the patient the procedure.
- Superotemporally or inferotemporal for ease of access
- 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.
- 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). More and more Retina Specialists are abandoning the use of post-injection antibiotics, and this practice may be stopped in the near future. A study from Bascom-Palmer suggested 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.
- Sterile lid speculum with closed blades (to isolate lashes better)
- 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 Dr. McCannel from UCLA showed at AAO (Chicago 2010) that the most common source of the bacteria causing endophthalmitis was from the surgeon's mouth. One should consider wearing a mask if there is a need to speak or instruct the patient during the injection, especially if its the first time and the patient needs direction. If you must talk, turn your head away from the surgical field. However, if wearing a surgical mask it is best to face the surgical field as exhalations will exit the mask to the sides and back of the surgical mask.
Variations in technique exist, and the following is an example of how the author does intravitreal injections:
- Confirm informed consent obtained
- Confirm the eye.
- Do not talk during injection.
- 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 Betadine)
- 10% Betadine swab to inferior cul-de-sac, to allow the Betadine to start working; ask patient to blink multiple times to spread the Betadine
- Place 2% lidocaine jelly on the eye, focusing on inferotemporal quadrant. (Note: Betadine placed prior to lidocaine jelly to sterilize the globe prior to placing the jelly so as not to have bacteria trapped in the jelly and possibly increase risk of endophthalmitis).
- Ask patient to close their eyes, and return in 2-5 minutes.
- Apply Betadine swab again to inferotemporal quadrant and inferior cul-de-sac, as well as to eyelashes (do not manipulate much so as not to liberate bacteria from the lashes)
- Place sterile closed-blade eyelid speculum (careful not to cause corneal abrasion and save yourself a phone call from the patient with a painful corneal abrasion).
- Clean again with Betadine
- 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, you can place Betadine again -- the Betadine will slightly pool in the indentation ring and nicely highlight the injection site. Careful with subconj anesthesia so as not to cause too much chemosis or subconj hemorrhage as this case affect your visibility of the injection site mark.
- 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 Q-tip in the non-dominant hand
- Do not talk and ask patient not to talk during the injection. Alternatively, wear a mask and place a mask on the patient too (or use a drape to cover the patient's face). Make sure the needle tip (which is usually a short 30g) is always kept absolutely sterile.
- Using your dominant hand, rest your wrist 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 subretinal 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 Q-tip that is in your non-dominant hand
- Rinse the Betadine off of the patients 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 Retina Specialists 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 a 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., Lidocaine 4% anesthetic solution on a Q-tip 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.
- Optional: Place topical antibiotic and have patient use the antibiotic qid x 3 days - please consider antibiotic resistance risk
- Review endophthalmitis and retinal detachment precautions with the patient.
Post-Injection Care Tips
- Make sure to wash off Betadine 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 or Triesence)
- Review endophthalmitis and RD symptoms and precautions
- Consider a phone follow-up with patients 3-7 days after the injection
- A one week in-office follow-up is at the physician's discretion, but is not likely 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 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, but is usually in the order of 4-6 weeks.
Similar safety and efficacy of intravitreal bevacizumab compared to ranibizumab
Numerous trials (CATT trial, IVAN trial, GEFAL, MANTA, LUCAS) conducted worldwide have shown Bevacizumab injection in the eye to be non-inferior to Ranibizumab injection in the eye in terms of efficacy and safety in AMD. Bevacizumab on the other hand 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 when taking written consent for intraocular bevacizumab.
The possible drawback of AvastinTM may be that as the company does not manufacture and pack it for ocular use the drug does not come in a single use vial. Despite all the precautions there is an increased risk of serious eye infection to a small extent after intravitreal injection.
- Video: Univeristy of Iowa, Intravitreal Injection Technique: http://video.google.com/videoplay?docid=-4029538953224029219
- Article: Preventing infections: injection technique: http://dx.doi.org/10.4172/2327-5073.1000118
- Boyd K, Janigian RH. Eye Injections. American Academy of Ophthalmology. EyeSmart® Eye health. https://www.aao.org/eye-health/treatments/eye-injections-list. Accessed March 11, 2019.
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- Survey of intravitreal injection techniques among retinal specialists in the United States Am J Ophthalmol, 151 (2) (2011), pp. 329-332).
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