Intravitreal injections (IVIs) may be required for a variety of vitreoretinal disorders affecting infants, including retinopathy of prematurity (ROP) and rarely other retinal vascular disorders, endophthalmitis, viral retinitis, and intraocular inflammation. While efficacious for the treatment of many vitreoretinal disorders, IVIs generally carry the local risk of retinal break, retinal detachment, ocular perforation, cataract, and infection (with possible loss of vision and/or the loss of the eye).

Although the incidence is low, endophthalmitis is the most severe complication of IVI, and neonates may be particular vulnerable due to impaired host defense mechanisms, limited protective endogenous flora at time of birth, reduced barrier function of neonatal skin, and exposure to invasive procedures, devices, and broad-spectrum antibiotics.¹ The prospective RAINBOW (Ranibizumab Compared with Laser Therapy for the Treatment of Infants Born Prematurely With Retinopathy of Prematurity) trial² reported 2 cases of neonatal endophthalmitis, and subsequent cases have been reported following intravitreal bevacizumab³ and intravitreal ranibizumab.⁴

INJECTION PROTOCOL

The authors developed the acronym SAFER⁵ to describe the intravitreal injection protocol in neonates which comprises the following: Short needle, Antiseptic/antibiotic, Follow-up, Extra attention to detail, and Recheck every 1-2 weeks after injection (in the setting of ROP) until complete retinal vascularization or additional laser has been administered to avascular retina. This article will describe the related injection technique and methods to maximize safety and sterility during neonatal IVI.

Due to the unique anatomy of the infant eye having a smaller size, absent or immature pars plana, and larger crystalline lens relative to the volume of the eye, there are 3 needle-related considerations that are important when administering IVIs to infants: (1) distance of needle insertion from the corneal limbus, (2) angle of needle insertion into the vitreous cavity, and (3) the length of chosen needle. The chosen distance from the limbus may be guided by the ora serrata nomogram⁶ developed to simultaneously minimize retinal perforation and crystalline lens strike. If an infant is receiving anti-VEGF therapy for ROP for example, the eye is typically marked with calipers 1 mm posterior the corneal limbus and the needle inserted through the sclera roughly 0.75 mm to 1.0 mm posterior to the limbus (at or just anterior to the mark). We typically prefer to inject temporally, as the anatomic approximation of the ora serrata is more posterior temporally compared to nasally, but the specific ergonomics and ocular or eyelid anatomy often dictates the quadrant of entry.

The angle of the needle insertion is also very important to minimize perforation of the retina or globe and strike of the lens. It is recommended to keep the needle tip parallel with the visual pupillary axis during the injection to avoid the infant lens.⁷

The needle that is preferred is a 32-gauge thin-walled stainless steel hypodermic needle 4 mm in length (TSK SteriJect; Air-Tite Products)^8,9 because it has been demonstrated that the 30-g 0.5-inch needle can anatomically reach the nasal side of the eye when injected temporally if inserted deeply into the eye.⁸ If the 4-mm 32-gauge needle is not available, the authors prefer the 30-gauge 0.5-inch needle with care being taken to insert the needle roughly one-third of the needle length into the eye and not to the “hub” of the needle to avoid this complication. When administering the injection, a sterile lens loop or nasopharyngeal calcium alginate tipped applicator (Puritan Medical Products Company LLC) may be used to stabilize the eye at the discretion of the treating physician.

ANTISEPSIS

Antisepsis is critically important to decrease the incidence of endophthalmitis secondary to IVI. There is a high incidence of bacterial conjunctival colonization in the NICU; one study found that 58% of infants had conjunctival colonization with a variety of bacterial organisms, with a longer stay in the NICU increasing risk for colonization.¹⁰ Although rare, colonization can lead to severe exogenous endophthalmitis with virulent organisms.¹¹ Moshfeghi et al found that the rate of endophthalmitis decreased 6% per year in the United States between 1998 and 2006, and that neonates with endophthalmitis were more likely to have systemic bacteremia, candidemia, a birth weight of less than 1,500 grams, and ROP.¹² The treating physician should therefore assess the infants for signs of infection including conjunctivitis and dacryocystitis prior to treatment.

The concentration of medicine injected varies depending on disease and medication of choice, but if the medication is compounded for a specific dose, one should ensure the reliability of the compounding pharmacy to avoid contamination. If administering anti-VEGF therapy, it does not appear that the choice of anti-VEGF agent affects the rate of endophthalmitis.¹³

The antiseptic is typically topical 5%¹⁴ or 10% povidone-iodine (PI; betadine), which works by releasing iodine resulting in the death of microorganisms. Lower concentrations (1%) have been investigated with evidence of higher bactericidal efficacy in vitro, but it appears that 5% PI is more effective in vivo.¹⁵ Reibaldi et al investigated treatment with 0.6% PI drops 3 days prior to IVI and found that this was effective in reducing bacterial load but did not alter the rate of endophthalmitis (perhaps related to sample size of 507 eyes).¹⁶

Aqueous chlorhexidine (AqCHX) (0.05% or 0.1%) has also been demonstrated to be safe and efficacious in the prevention of endophthalmitis secondary to intravitreal injections.^17,18 A recent study compared 5% PI to 0.1% AqCHX for endophthalmitis prophylaxis in adults undergoing same-day bilateral IVIs and found that 5% PI resulted in greater ocular surface discomfort and corneal epitheliopathy than 0.1% AqCHX without difference in positive microbial cultures or adverse events (no endophthalmitis in either group).¹⁹ If a definite iodine or PI allergy is documented, it is safer to administer AqCHX than to reduce or limit PI exposure.²⁰ Whatever the choice of antiseptic, it should be instilled both before and after the IVI.

ADDITIONAL MEASURES

Other methods to decrease infection include the use of clean instruments,²¹ gloves, and masks for all involved in the injection procedure, including those holding the infant. A separate eye kit with individual lid speculums and scleral depressors is used for each eye of each patient. To decrease the risk of transmission of infectious agents between infants, it is worth drawing attention to the indirect ophthalmoscope as well as using sterile wipes to clean the rim of examination lenses allowed to dry between patients.²² Ventilation masks can transfer contaminated air from the nasopharynx to the injection field, so unsheathed needles are not held for an extended period of time while the physician is maneuvering into position for the injection. If acceptable given the pulmonary status, nasal prongs may be temporarily used instead of a ventilation mask to decrease the spread of contaminated air.

Sedation may be given at the discretion of the NICU, but often a sweetened pacifier in conjunction with preinjection topical proparacaine hydrochloride 0.5% or tetracaine hydrochloride 0.5% is sufficient. During the injection, the infant should be kept flat on their back. After the injection, another drop of antiseptic solution is given, and binocular indirect ophthalmoscopy is performed using the speculums for their respective eyes, noting optic nerve perfusion, the absence of sequential retinal breaks, retinal detachment, hemorrhage, and/or cataract, and that the drug is inside the eye. The speculums are removed, and the eyes are irrigated with normal saline solution. While the role of topical antibiotics following intravitreal injection is debated,²³ the authors typically prescribe topical moxifloxacin ophthalmic solution 4 times a day for 3 to 5 days. The infant is typically examined again within 72 hours to ensure no development of cataract or early endophthalmitis. With these techniques, the safety of intravitreal injections can be maximized for one of our most vulnerable patient populations. RP

References

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