Intravitreal administration

Intravitreal administration is a route of administration of a drug, or other substance, in which the substance is delivered into the vitreous humor of the eye. "Intravitreal" literally means "inside an eye". Intravitreal injections were first introduced in 1911 when Ohm gave an injection of air into the vitreous humor to repair a detached retina. In the mid 1940s, intravitreal injections became a standard way to administer drugs to treat endophthalmitis and cytomegalovirus retinitis.

Intravitreal injections were proposed over a century ago however the number performed remained relatively low until the mid 2000s. Until 2001, intravitreal injections were mainly used to treat end ophthalmitis. The number of intravitreal injections stayed fairly constant, around 4,500 injections per year in the US. The number of injections tripled to 15,000 in 2002 when triamcinolone injections were first used to treat diabetic macular oedema. This use continued to drive an increase to 83,000 injections in 2004. These three drugs bind to VEGF molecules preventing them from binding to VEGF receptors on the surface of endothelial cells thereby stopping the abnormal angiogenesis that causes wet AMD. All three of these therapies have vastly improved outcomes for sufferers who had limited treatment options prior to their invention but must be administered via intravitreal injection.

Steroids may be administered via intravitreal injection to treat diabetic and vasculo occlusive macular edema, exudative macular degeneration, pseudophakic cystoid macular edema, and posterior uveitis. Common steroids used to treat these conditions include dexamethasone and triamcinolone acetonide (Triescence, Alcon Laboratories, Inc.). Steroid implants, such as the dexamethasone implant (Ozurdex, Allergan, Inc.), are used for long term treatment of macular edema. Both of these steroid work by modulating inflammatory cytokines.

Endophthalmitis, or a bacterial infection within the eye causing inflammation of the sclera, is one of the most severe complications due to intravitreal injections. Incidence of endophthalmitis after intravitreal injection per patient has been reported to range from 0.019 to 1.6%. Endophthalmitis can also result in white or yellow discharge inside the eyelid, and a white, cloudy cornea. A layer of white blood cells called hypopyon may develop between the iris and the cornea. Endophthalmitis is considered an ophthalmological emergency and requires immediate treatment in many cases. It is treated with injections of antibiotics and antifungal compounds as appropriate. In severe cases a vitrectomy, or removal of vitreous humor, may be required to surgically remove infectious debris. Another complication of intravitreal medication administration is inflammation. Intraocular inflammation is one of the main causes of temporary pain and vision loss after an intravitreal injection. Severe inflammation can cause permanent damage to the eye. The risk of inflammation varies based on the specific drug being administered. One clinical trial of ranibizumab for age related macular degeneration administered intravitreally reported intraocular inflammation rates between 1.4% and 2.9%. Bevacizumab, another medication for the same purpose, resulted in an incidence between 0.09% and 0.4%. Subconjunctival hemorrhage is the most common type of hemorrhage following intravitreal injection with a reported incidence of nearly 10% of injections. People taking aspirin may be at higher risk for hemorrhage after intravitreal injection. Choroidal hemorrhage and subretinal hemorrhage are less common than subconjunctival hemorrhage, but both have been reported to occur following intravitreal injection.

Treatments administered via intravitreal injection are not cures and therefore repeated injections are necessary for managing conditions. For example, anti VEGF therapies must be injected monthly or bi monthly for the rest of their lives in order to treat wet age related macular degeneration. A growing body of evidence has shown repeat intravitreal injections have their own increased risks and complications. A 3x rise in intraocular pressure after an intravitreal injection is expected and usually only lasts a few minutes. Studies have shown an increased risk of sustained elevated intraocular pressure due to repeated intravitreal injections. Mount Sinai researchers have developed a method to measure retina damage from long term intravitreal injection using optimal coherence tomography angiography (OCTA). OCTA captures the motion of red blood cells in blood vessels noninvasively allowing researchers to measure blood flow in the macula and optic nerve. From this data they were able to show areas of cumulative damage.

In 2004 with the rise of intravitreal injections, a group of experts established the first general guidelines for administering intravitreal injections. Until an update in 2014 these were consensus guidelines in the US. In 2014 a panel of 16 health professionals with expertise in different aspects of the injection reviewed and revised the original guidelines. Together they released areas of general agreement, areas with no clear consensus, and recommended sequence of steps for intravitreal injection. For these reasons in 2014 the committee decided against recommending routine antibiotics. The new guidelines include hand washing and glove use consistent with the modern day medical practice of universal precautions. Although the use of gloves was agreed upon by the committee some panelists cited studies showing no impact of glove use on endophthalmitis rate. This is likely due to aerosolized droplet contamination from either the practitioners' or patients' mouth. The 2014 guidelines were updated to address these findings recommending both clinicians and patients wear face masks during the procedure. The new guidelines recommend monitoring intraocular pressure both pre and post injection. This recommendation stemmed from new evidence showing that routine intravitreal administration of anti VEGF therapies may increase intraocular pressure for a sustained time period. The 2014 guidelines addressed bilateral injections done in the same visit. The committee recommended treating each eye as a separate procedure and use different lots or batches of medication whenever possible. The panel was not able to support the use of sterile drapes in the procedure as retrospective studies showed no increased rate of endophthalmitis in injections done without drapes.

Intravitreal injections have vastly improved outcomes for patients with retinal diseases however the risk and patient burden associated with repeated injections has prompted researchers to pursue less invasive methods of application. There has been significant emphasis on finding methods to administer treatments topically over the last 50 years. This research has garnered more attention thanks to the increase in intravitreal injections and the growing evidence linking repeat injections to adverse events.