The Status of Vitreous Substitutes
BY TORSTEN W. WIEGAND, MD, PHD, & CAROLINE R. BAUMAL, MD

Current and Future

While vitreous substitutes have been in use for almost a century, the advent of modern vitrectomy techniques pioneered by Machemer in the 1970s produced a tremendous increase in demand for intraoperative and long-term artificial vitreous replacements. Advances in vitreoretinal surgical techniques, instrumentation, and vitreous substitutes have improved anatomic and functional success rates greatly over the past few decades.

Vitreoretinal surgeons now have an array of agents available that are optimized for specific tasks. The three most common types of vitreous substitutes available in North America are intraocular gas, silicone oil, and perfluorocarbon liquid. In this article, the properties, indications, and complications associated with each group of vitreous substitutes are reviewed.

One of the earliest descriptions of vitreous substitutes dates to 1911 when Ohm treated retinal detachment with injection of sterile air into the vitreous cavity.¹ However, it was Rosengren who established the concept of internal gas tamponade in 1938.² Due to the high surface tension of the gas bubble, an effective seal of the retinal break can be established, allowing the retinal pigment epithelium (RPE) to pump the subretinal fluid into the choroids and re-establish the natural retinal architecture.³ The buoyancy of the bubble helps to push the retina against the scleral wall while the surface tension prevents breakup of the bubble and entering of the subretinal space. For this tamponade to be effective with low-volume gas fills, such as those used during pneumatic retinopexy, the patient needs to be positioned so that the retinal break is located at the apex of the eye.

The role of intraocular gases broadened with expansile gases as investigated by Lincoff.⁴ The most commonly used gases are sulfur hexafluoride (SF₆, Figure 1a) and perfluoropropane (C₃F₈, Figure 1b). These gases are colorless, odorless, heavier than air, and nontoxic to the human eye. During the life cycle of the intraocular gas bubble, three

When preparing the gas for injection, using a filter (0.22 μm, Millipore, Billerica, Mass) is recommended to sterilize the gas, although there have not been demonstrated reports of intraocular infection secondary to omitting this step. Flushing the syringe several times with the gas is recommended to avoid dilution of the desired concentration with residual air. The gas should not be left in the syringe for a prolonged period of time prior to injection, as diffusion will alter the effective gas concentration.¹⁰

The most common postoperative complication after fluid-gas exchange with expansile gases is elevation of the intraocular pressure (IOP), with up to 60% of patients experiencing a measurable pressure spike.^11,12 Predisposing factors for IOP elevation include pre-existing glaucoma, anterior synechiae, and compromise of the outflow angle by pigment, hemorrhage, or neovascularization. Patients should be screened for these factors and the concentration, amount, and choice of gas should be modified accordingly. In the majority of eyes, temporary IOP control with antiglaucoma agents is sufficient. If the gas bubble expands to such a degree that the lens iris diaphragm is pushed forward, resulting in pupillary block and angle-closure glaucoma that is not controllable with medications, gas aspiration from the posterior compartment by pars plana approach may be indicated.¹³

Acute IOP increase can occur under special circumstances with overexpansion of the gas bubble. Nitrous oxide is a highly water-soluble inhalation agent that may be used during general anesthesia and will rapidly diffuse into an intraocular gas bubble. Patients with intraocular gas should be provided with an identification bracelet to alert medical personnel if subsequent anesthesia needs to be administered. During eye surgery nitrous oxide must be discontinued 20 minutes prior to intraocular gas injection to allow clearance of the nitrous oxide from the bloodstream and tissues.¹⁴

Air travel with intraocular gas is unsafe because the cabin pressure in airliners is reduced during flight. This leads to initial expansion of the intraocular gas bubble and subsequent increased trans-scleral pressure manifested as pain and decreased vision. Should a patient experience this situation the pilot needs to lower the plane to allow normalization of the cabin pressure. Experimental studies and clinical observations indicate that 0.6 to 1.0 mL of residual gas are safe for air travel.^15-17

Prolonged contact of the intraocular gas with the lens can lead to gas-induced cataracts, presenting typically as feathery posterior subcapsular lens opacifications. These lens changes can be reversible if the patient is positioned to break the gas lens contact, but some of these patients will retain permanent lens changes.¹⁸

In aphakic eyes, contact of gas with the corneal endothelium can lead to decompensation and stromal edema by limiting diffusion of nutrients from the anterior chamber fluid to the corneal endothelial layer.¹⁹ To limit these anterior segment complications, patients with intraocular gas need to be reminded not to sleep in a supine position.

SILICONE OIL

Silicone oil is transparent and has a refractive index of 1.404. This is slightly higher than that of vitreous gel and thus induces a mild hyperopic shift in phakic patients. However, in an aphakic eye, the steep anterior curvature of the silicone oil fill causes an increase in refractive power and lessens aphakic hyperopia.²⁴ Compared to a gas fill that allows little useful vision until the meniscus clears the visual axis, a postsurgical eye with oil has a shortened visual rehabilitation time, which is important to consider in monocular patients.

At a specific gravity of 0.97, silicone oil is slightly lighter than water and a silicone globule will float on a residual aqueous base inside the eye. The resulting buoyant force is only one-thirtieth of that contained within a corresponding gas bubble.²⁵ Because silicone oil is not miscible with the aqueous phase, the resulting interface develops surface tension, but at 20 to 40 mN/m this tension is one-half to one-third of a gas bubble's surface tension. In combination, these 2 forces are sufficient to postsurgically support the reattached, tension-free retina, but residual or recurrent radial traction, especially in the inferior half of the retina, can lead to re-detachment under oil.²⁶ This is important to consider in cases of PVR, when pathology tends to be concentrated inferiorly or can recur in this location.^27,28 Table 2 summarizes the physical properties of common silicone oils.

Silicone oils are used when long-term need for stabilization of the retina with internal tamponade is anticipated. The Silicone Study Report, comparing the use of intraocular gas and silicone oil in surgical management of PVR, concluded that silicone oil was equivalent to C₃F₈ but superior to SF₆.^30-32 Subgroup analysis showed a benefit for oil use over gas in patients with anteriorly located PVR and patients without prior vitrectomy who received retinotomy during surgical repair. In management of severe diabetic tractional retinal detachment, silicone oil may have the added benefit of suppression of future neovascularization; however, prospective trials have not been performed. A small prospective trial of silicone oil in the management of traumatic endophthalmitis suggests a benefit possibly due to concentration of intravitreal antibiotic or through bactericidal properties of silicone oil.³³ In cases of endophthalmitis refractive to initial intravitreal antibiotics, this approach should be considered. Other surgical indications for silicone oil include complicated retinal detachment, giant retinal breaks, hypotony due to chronic uveitis, infectious retinitis, and finally, retinal detachments where postoperative positioning would not be possible.

Postsurgical and late complications of intraocular silicone oil fills are common and may require removal of the oil earlier than the desired duration. Prolonged contact of silicone oil with the posterior capsule of the lens will inevitably induce cataract formation,³⁴ likely due to prevention of nutrient diffusion rather than a direct toxic effect. Some surgeons may remove the crystalline lens during vitrectomy; however, retention of an intact posterior capsule is desirable to keep the oil confined to the posterior compartment. The increased use of silicone intraocular lenses (IOLs) during cataract extraction poses a challenge for use of intraocular silicone oil when a retinal detachment develops after cataract surgery. If the posterior capsule was violated during surgery or an yttrium aluminum garnet (YAG) capsulotomy has been performed, silicone oil droplets may adhere to the posterior lens surface, necessitating lens removal.³⁵ Thus use of a silicone IOL is not recommended in an eye that has any predisposing risk factors for retinal detachment.

Silicone oil migration into the anterior chamber may result in keratopathy or corneal endothelial decompensation. Interestingly, according to the Silicone Study Report, the rate of corneal complications is comparable to the
2-year complication rate in eyes that received a gas fill (26% vs 28%, respectively).³⁶ If severe corneal decompensation occurs, ethylenediaminetetraacetic acid (EDTA) chelation can be performed to reduce band keratopathy, or a corneal transplantation can be considered. If possible, the silicone oil should be removed at that time, as 68% of penetrating keratoplasties fail in oil-filled eyes.³⁶

Increased IOP after silicone oil use in treatment of PVR occurs in up to 40% of patients.^37,38 Emulsification of silicone oil can directly clog the trabecular mesh, or recruitment of macrophages and other inflammatory components can lead to open-angle glaucoma. If the silicone globule remains intact, pupillary block with angle closure can occur when the silicone oil occupies the pupillary sphincter and prevents aqueous fluid from passing into the anterior chamber. An inferior peripheral iridectomy is therefore routinely created in aphakic eyes prior to silicone oil fill. Spontaneous closure of the iridectomy may occur postsurgically in up to one-third of patients.³⁹

While hypotony occurs in about one-fifth of silicone filled eyes within 3 years of surgery, this complication is significantly less frequent than in comparable gas-filled eyes.³⁷ Hypotony can be managed with peeling of membranes of the ciliary body, subtenon steroid injection, or long-term retention of the oil to prevent phthisis.

PERFLUOROCARBON LIQUIDS

In contrast to other vitreous substitutes, perfluorocarbon liquids have a specific density greater than water and are therefore unique in applying gravitational force onto the dependant portion of the retina.⁴⁰ These liquids had been developed as blood substitutes based on their inert nature and ability to carry oxygen. In contrast to silicone oil, perflurocarbon liquids have low viscosity and can be easily injected and withdrawn through standard vitrectomy instruments. Perflurocarbon liquids are optically clear and do not absorb wavelengths of lasers used in retinal surgery, allowing application of endolaser during tamponade with perfluorocarbons. The commonly used agents are perfluoro-n-octane (C₈F₁₈), perfluorodecaline (C₁₀F₁₈), perfluoroperhydrophenanthrene (C₁₄F₂₄), and perfluorohexyloctane (C₆F₁₃C₈H₁₈).

In 1987, Chang⁴¹ reported on the use of perfluorocarbon liquids for repair of giant retinal tears, which previously required placing the patients into a prone position during surgery. Application of the heavier-than-water perflurocarbon liquids displaces subretinal fluid anteriorly, and the inverted flap of the retinal tear can be flattened with minimal manipulation. Because perfluorocarbon liquids are not used as long-term vitreous substitutes, exchange of the perfluorocarbon liquid with air and gas or directly with silicone oil is required. Bypassing the perfluorocarbon-air exchange and going directly to silicone oil has the advantage of reducing the risk of retinal slippage and the formation of folds.⁴² The use of perflurocarbon liquids in management of severe PVR has improved the anatomic success rate.⁴³ Funnel detachments may on occasion be opened up, and epiretinal membranes and gliotic tractional bands can be visualized and dissected with progressive perflurocarbon injection and flattening. Posterior retinotomies may be avoided since subretinal fluid is forced anteriorly and allowed to escape through pre-existing breaks. Other indications for the use of perfluorocarbon liquids include repair of detachments secondary to ocular trauma, removal of dislocated crystalline lenses, and management and displacement of suprachoroidal hemorrhage.

Due to the low viscosity of these liquids, long-term intraocular tolerance is limited by dispersion into microdroplets over time, which leads to decrease in vitreous clarity, compromise of the trabecular meshwork with subsequent IOP rise, and subretinal migration of droplets through residual breaks. Perfluorocarbon liquids are therefore used primarily as a temporary intraoperative vitreous substitute and long-term complications are rare. In up to 10% of surgical cases, small amounts of retained perflurocarbon liquids were identified.⁴⁴ While small amounts of residuals in the vitreous are usually well tolerated, subretinal migration of perfluorocarbon liquids can result in persistent focal retinal detachments with possible direct toxic effects to the photoreceptor layer.⁴⁵ Perfluorocarbon liquid droplets found in the anterior chamber in aphakic patients should be removed by small-gauge needle aspiration to prevent possible corneal endothelium toxicity.

Perflurocarbon liquids represent the only class of heavier-than-water vitreous substitutes, but current agents cannot safely remain in the eye for an extended time. Research efforts are therefore focusing on long-term tamponading vitreous substitutes that can support the inferior retina. This would reduce the need for prolonged postsurgical face-down positioning and may increase the anatomic success rate in management of PVR by displacing proliferative cells from the inferior quadrants of the retina. Partially fluorinated alkanes, used either as pure liquids or in mixtures with silicone oil to create low viscosity oils with a density greater than water, have been tested in vitro^46,47 and used in vitreoretinal surgery. Initial reports appeared encouraging, but long-term complications, including severe emulsification,⁴⁸ intractable uveitis,⁴⁹ and pathologic responses of the retina,⁵⁰ have been reported recently. While this novel class of heavy tamponading agents holds promise, further investigational work is needed to address these complications. Based on the use of semifluorinated alkanes in rabbit eyes, the persistent gravitational force on the inferior retina alone does not appear to be deleterious.⁵¹

SUMMARY

The intraocular vitreous body is a highly complex macromolecular structure, and despite significant progress over the past few decades, the ideal, universal vitreous substitute does not exist. The array of artificial substitutes available for short- and long-term replacements each have specific advantages and drawbacks. A thorough understanding of the properties, indications, and potential complications of intraocular gas, silicone oil, and perflurocarbon liquids is essential to utilize these adjuncts successfully during vitreoretinal surgery. RP

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Torsten W. Wiegand, MD, PhD, and Caroline R Baumal, MD, are both ophthalmologists at the Vitreoretinal Department of the New England Eye Center at the Tufts University School of Medicine in Boston. You can reach them at (617) 636-1486. Neither author has any financial interest in any of the products mentioned here.

ALL FIGURES IN THIS ARTICLE APPEAR COURTESY OF THE AUTHORS.