Prior to 2007, the only corticosteroid that was available for intraocular use was off-label preserved intravitreal triamcinolone acetonide (IVTA; Kenalog, Bristol-Myers Squibb). Since the US Food and Drug Administration (FDA) approval of and availability of preservative-free triamcinolone (Triesence, Alcon Laboratories, Inc.) and the dexamethasone sustained-delivery device (Ozurdex, Allergan, Inc.), we have more options for patients when considering utilizing steroids as therapeutic agents.

Additionally, steroids may also be applied as visualization agents in surgery, and the therapeutic effect against postoperative inflammation can be an added benefit. Compared with indocyanine green (ICG; IC-Green, Akorn, Lake Forest, IL), and Trypan blue (Vision Blue, Dutch Ophthalmic Research Center, Zuidland, The Netherlands), steroids have low toxicity, require less preparation time, and are typically less expensive.

The question is: How does one decide between these three steroids for treating retinal disease and between steroids and dyes for visualization? It is important to consider three factors: safety, efficacy, and cost. This article weighs the evidence for all three in both therapeutic application and surgery.

THERAPEUTIC APPLICATION OF CORTICOSTEROIDS
When considering safety of the available corticosteroids, there are factors beyond pressure increases and risk of cataract. In the therapeutic arena, there have been published case series and retrospective reports concerning sterile endophthalmitis after intravitreal injection with preserved triamcinolone acetonide1-14 and it has been suggested that this complication is in part caused by the preservative agent, benzyl alcohol. 2,3,12 Because both the dexamethasone sustaineddelivery device and the on-label IVTA do not contain preservatives, they may have a distinct advantage over the former in regard to this complication.

Additionally, although preserved IVTA has been used for some time by ophthalmologists with good results, its use remains off label and the agent often must be compounded before use in the eye. Alternatively, both the FDA-approved preservative-free IVTA and the dexamethasone sustaineddelivery device come in sterile packs, which reduces the risk of contamination with these agents.

I will use the off-label preserved IVTA in situations such as when I do not have the preservative-free IVTA available, which I do not in one of the satellite offices in which I practice. Additionally, when the situation is such that the patient will be paying for the injection out of pocket, the off-label preserved IVTA is more cost effective at $14 per injection. Regarding cost, the dexamethasone sustained-delivery device is only FDA-approved for the treatment of macular edema secondary to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO), and outside of these indications, the use of the implant is prohibitively expensive. The FDAapproved IVTA represents a good balance of an on-label steroid specifically formulated for intraocular use that is available for a reasonable cost.

VISUALIZATION AGENTS FOR SURGERY
Currently, the available agents for visualization in vitreoretinal surgery include ICG, Trypan blue, preserved IVTA, and preservative-free IVTA. There are benefits and shortcomings to each visualization agent. For example, the preserved and preservative-free IVTA agents are more advantageous when considering visualization of the cortical vitreous, vitreous base, epiretinal membrane, and internal limiting membrane (ILM). In terms of ease of preparation, Trypan blue and preservative-free IVTA have a slight advantage over the preserved preparation of IVTA, and a distinct advantage over ICG. The costs of vital dyes such as ICG and Trypan blue are typically more expensive than steroids. With ICG and Trypan Blue, there is a higher risk of toxicity than with the other agents,15-27 and so this must be taken into careful consideration when choosing an agent for visualization. Furthermore, ICG should not be used in patients who have an iodine allergy. The off-label preserved IVTA must be compounded for use in the eye so, as with therapeutic use, it does not come in a sterilized pack, as does preservative-free IVTA, ICG, and Trypan blue. Finally, only Trypan blue and preservative-free IVTA are FDA-approved for staining in vitreoretinal surgery.

CORTICOSTEROID-ASSISTED VITRECTOMY
In my experience, corticosteroids offer an advantage in vitrectomy for the visualization of vitreous in the anterior chamber, such as in retained lens fragment cases where corneal haze may limit the view. There are three techniques for using steroids for this purpose:

1. inject diluted steroid just anterior to the limbus using a 27-gauge needle;

2. create a paracentesis site and inject using a cannula;,/p>

3. or inject through the sclerotomy up into the anterior chamber.

Corticosteroids are also useful for visualization of the core vitreous, which is important for training fellows and residents (Figure 1) and having an FDA-approved agent for this purpose is a plus.

POSTERIOR HYALOID ELEVATION/CORTICAL VITREOUS REMOVAL
Additionally, corticosteroids offer an advantage in posterior hyaloid elevation and cortical vitreous removal. The use of IVTA for posterior hyaloid removal was first described by Peyman et al28 in 2000. IVTA-assisted posterior hyaloid elevation allows the surgeon to identify or create a break in the posterior hyaloid. Once the break or Weiss ring is created, the posterior hyaloid can be easily separated from the retina using low suction pressure. This technique is most useful when performing microincisional vitrectomy surgery, particularly 25-gauge vitrectomy.

In patients who are diabetic, vitreoschesis is frequent, and residual cortical vitreous may cause persistent tangential traction, serving as a scaffold for neovascular proliferation or proliferative vitreoretinopathy (PVR). So, when performing cortical vitreous removal, I use preservative-free IVTA to visualize islands of thin cortical vitreous that may be left behind on the retinal surface after a “complete” hyaloid separation. Enaida et al29 also showed the benefits to IVTAassisted pars plana vitrectomy in both an interventional, nonrandomized study and case reports of surgeries for proliferative diabetic retinopathy, diabetic macular edema, rhegmatogenous retinal detachment, and branch retinal vein occlusion. The studies also showed that the use of IVTA when removing cortical vitreous resulted in lower rates of reoperation and postoperative epiretinal membrane formation. They found no serious complications associated with the use of IVTA and no significant differences in postoperative intraocular pressure (IOP). Furino et al30 found similar results with cortical vitreous removal in PVR. Figure 2 shows the use of IVTA in posterior cortical vitreous removal.

MEMBRANE PEELING AND VITREOUS BASE DISSECTION
Membrane peeling is often used as an adjunct in macular surgery for macular hole, epiretinal membrane (ERM)/macular pucker, and macular edema. ICG dye has facilitated visualization and removal of the ILM, but both preserved IVTA and preservative-free IVTA are able to highlight both the ILM and the ERM. Additionally, as earlier stated, concerns exist as to the toxicity of ICG dye.15-27 IVTA has the advantage of being able to be reapplied after ERM removal and even ILM removal; whereas with ICG, one must be cautious of reapplying this agent to the bare retina.

For certain surgical situations, good vitreous base dissection may be necessary and IVTA can be used as an aid to highlight the vitreous base. I recommend injecting steroid into the posterior segment using a cannula. Next, the vitrector can be applied to spread the steroid throughout the posterior segment. Dilution is essential for this technique.

CORTICOSTEROIDS VS ICG
When comparing the benefits of IVTA to those of ICG dye for use in vitreoretinal surgical procedures, IVTA requires minimal preparation and can be reapplied once ILM peeling has begun. IVTA is not a photosensitizer, as is ICG and is not contraindicated for patients with iodine allergy. Additionally, IVTA may have a beneficial postoperative inflammatory affect, and may stabilize the blood-ocular barrier, benefitting eyes with DME or cystoid macular edema. Finally, IVTA is inexpensive.31

PRESERVED VS PRESERVATIVE-FREE IVTA
When comparing preserved vs preservative-free IVTA, it is important to consider that the preservative-free IVTA is FDA-approved and also is available in a sterile pack. Regarding cost, the preserved IVTA is less expensive, but the preservative-free agent is certainly affordable and reimbursable. Preservative-free IVTA contains no benzyl alcohol, and so in theory, the risk of sterile endophthalmitis is lower.2,3,12 Finally, and not least important, the particles in preservative-free IVTA are finer than in the preserved agent, and can potentially adhere more effectively to membranes.

TIPS FOR INTRAOPERATIVE USE OF CORTICOSTEROIDS
When using preserved and preservative-free IVTA in surgery, the following are some tips to ensure a successful outcome.

Dilution.The ratio of preserved TA to BSS should be about 4:1. For preservative-free TA, the ratio is about 8:1. Surgeons can dilute to personal preference.

Mixing.After appropriate ratio of steroid:BSS is drawn into the syringe, a 0.1 cc air bubble should be placed to aid in the mixing of particles as the syringe is turned upside down several times.

IOP.Lower the IOP when the particles are on the surface of the macula to reduce the likelihood of the infusion line blowing the crystals off the retinal surface.

Needle size. The needle size should be 27 gauge for preserved TA and 30 gauge for preservative-free TA.

SUMMARY
Having an option for a steroid to use in clinic and in surgery that is FDA approved, nontoxic, and cost effective is obviously an advantage. There is not one solution that fits every situation, therefore, the clinician needs to make a decision as to which agent makes most sense in a particular scenario. For therapy, in particular, we are finding that a combination of agents works for our patients, so having one more option is certainly beneficial.

The versatility of corticosteroids makes their use in therapeutics and vitrectomy surgery appealing. These agents are inexpensive, easy to use, have no proven retinal/choroidal toxicity, and may potentially lead to superior visual outcomes.

Seenu M. Hariprasad, MD, is an Associate Professor and Director of Clinical Research at the University of Chicago Department of Surgery Section of Ophthalmology and Visual Science. He serves as Chief of the Vitreoretinal Service and Director of the Surgical Retina Fellowship Program. Dr. Hariprasad can be reached by e-mail: retina@uchicago.edu.

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