MARK E. HAMMER
Table Of Contents
AQUEOUS VITREOUS SUBSTITUTES|
VISCOELASTIC SUBSTANCES AS VITREOUS SUBSTITUTES
INTRAOCULAR GASES AS VITREOUS SUBSTITUTES
ABSORPTION AND KINETICS OF GASES
INDICATIONS FOR INTRAOCULAR GASES
COMPLICATIONS OF INTRAOCULAR GASES
AVAILABILITY OF GASES
SILICONE OIL AS A VITREOUS SUBSTITUTE
PERFLUOROCARBON LIQUIDS AS VITREOUS SUBSTITUTES
SEMIFLOURONINATED ALKANE LIQUIDS AS A VITREOUS SUBSTITUTE
|In 1895, Deutschmann injected rabbit vitreous into the vitreous of a human
to successfully treat retinal detachment.1 Intraocular air was first used for treatment of retinal detachment by
Ohm in 1911; Rosengren revived its use in 1938.2 The use of intraocular air and gas for retinal reattachment declined with
the advent of Gonin's discovery that scleral buckling or indentation
beneath the retinal break resulted in a high success rate for
retinal reattachment. In the 1950s, Cibis began using silicone oil as
a dissecting tool for proliferative vitreoretinopathy (PVR) detachments
and also noted its tamponading effect. Further development
of silicone oil was delayed by the advent of vitrectomy surgery for direct
attack on the traction forces of PVR. As use of the vitrectomy procedure
increased, aqueous substitutes for infusion during lengthy vitrectomy
were developed. Long-acting gases for ocular tamponade
after vitrectomy were developed in the 1970s.|
Although silicone oil was never completely abandoned, it became much more popular for endstage detachments not responding to vitrectomy and tamponade with long-acting gases. In the 1980s heavier-than-water immiscible perfluorocarbon liquids were investigated for tamponade of inferior retinal tears and reattachment of the retina, especially for giant retinal tears. In 2001, semiflourinated alkanes were developed that were heavier than water and immiscible but possessed a lesser specific gravity than the perflourocarbons, which allowed mechanical rotation of the partially flattened retina without gross mechanical damage to the retina.
A classification of vitreous substitutes based on their physical mechanism divides them into aqueous miscible vitreous substitutes, (such as balanced salt solution, hyaluronic acid solutions, and other viscoelastic substances) and aqueous immiscible substances such as fluorinated silicone oils, perfluorocarbon liquids, air, and other gases. The immiscible substances depend on their surface tension to seal retinal breaks either temporarily or on a long-term basis. They can be subdivided into gases (such as air, sulfur hexafluoride, perfluoro-propane, and many other less frequently used gases) and liquids, including those that are lighter than water (polydimethylsiloxane, which we shall call silicone oil) and those heavier than water (such as fluorinated silicone oils, perfluorocarbon liquids and semifluorianted alkanes) (Table 1).
Several factors are important for a thorough understanding of each of these vitreous substitutes. The mode of action and physical properties such as surface tension and viscosity must be considered. Biocompatibility, including direct toxicity, immune response, inflammatory response, and, in some cases, foreign body response, is important. The absorption or necessity for removal, indications for use (including clinical studies and special surgical methods), additives, and complications of use must also be considered.
Manufacturers of these vitreous substitutes and brand names when they exist are listed in this chapter. Many are still undergoing investigation by the U.S. Food and Drug Administration (FDA). The purity, quality, and cost of these vitreous substitutes are important considerations.
|AQUEOUS VITREOUS SUBSTITUTES|
|The perfect vitreous substitute would be regrowth of the human vitreous
with all of its hyaluronic acid (sodium hyaluronate), collagen
fibrils, and electrolytes. This seems an unlikely achievement even
in the distant future. In the stable postvitrectomy unicameral eye months
after surgery, the vitreous component is likely to resemble that
of aqueous, because the bulk of the fluid entering the eye will come from
the ciliary body. From clinical experience, we know that eyes containing
this aqueous secretion can survive indefinitely with good corneal
and retinal function. For the present time, the ideal aqueous vitreous
substitute would then approximate the human aqueous secretion.|
The present vitreous substitutes used as infusion fluid during a vitrectomy approximate the aqueous humor. These infusions evolved from ocular irrigation fluids used during anterior segment surgery. Initially, normal saline was used, but corneal edema was found after even brief irrigation with this solution. Small volumes of a more finely tuned fluid called balanced salt solution (BSS) were then developed and were adequate for the relatively short procedures. In the 1970s, longer procedures such as vitrectomy, phacoemulsification, and anterior segment reconstruction developed. Larger solution volumes were required for these procedures. Plasma-Lyte 148 and lactated Ringer's solution were used but caused corneal edema.3 BSS was superior to these two agents, but it still resulted in corneal edema and electroretinographic changes in surgery lasting more than 1 hour.4 It was discovered that by fortifying BSS with bicarbonate, glucose, adenosine, and glutathione, corneal endothelial integrity, electroretinographic changes, and retinal edema could be maintained for operations lasting longer than 1 hour.5,6 In the 1980s, BSS Plus became commercially available. Reduced glutathione is substituted for adenosine and oxidized glutathione, but otherwise BSS Plus is quite similar to the glutathione bicarbonate Ringer's solution. To have a commercially acceptable shelf life, BSS Plus comes in a two-part solution and must be mixed at the time of surgery.
Sodium is the major extracellular ion required for maintenance of cellular tonicity and volume regulation of cells.7 Low potassium ion concentration (on the order of 3 to 6 mOsm/liter) is required to maintain the transmembrane cellular potential. Magnesium is necessary for many cellular biochemical reactions in all cells. Absence of the calcium ion during prolonged surgery will result in corneal edema caused by endothelial junctional breakdown.8 Calcium is also important in retinal functioning as well as retinal adhesion.9 Bicarbonate ion is a natural extracellular buffer that is important for both corneal functioning and maintenance of the electroretinogram during prolonged surgery. The bicarbonate ion may be required for intracellular functioning because specific adenosine triphosphatases depend on it.10–12 Citrate, phosphate, N-2-hydroxyethyl-piperazine-N-2-ethane-sufonic acid (HEPES), and other buffers have been tried but are not adequate substitutes for bicarbonate ion.
Glutathione, which is metabolized by adenosine triphosphate for energy, is important in maintaining the clarity of the lens and the cornea and also retinal function during longer procedures. Glutathione has been shown to be helpful in maintaining corneal integrity in procedures lasting up to 6 hours. Although glutathione can be helpful in maintaining intracellular adenosine triphosphate, glucose alone is capable of accomplishing this. The unique feature of glutathione is that it may detoxify injurious free radicals generated during intraocular surgery.13 Ascorbate, which is a naturally occurring antioxidant in aqueous fluid, may protect against retinal-pigmented epithelial light damage.14
The cornea has been shown to tolerate osmolalities ranging between 200 and 400 mOsm, but the osmolality of normal anterior chamber fluid is 305 mOsm. It is best to have a fluid of normal osmolality because in many surgical cases, the corneal epithelium is already compromised. The pH range tolerated by the cornea has been shown to be 6.8 to 8.2. Because the pH of the normal anterior chamber fluid is 7.4, ocular infusion fluid is usually adjusted to a pH of approximately 7.4.15 The pH is vulnerable to additions to the irrigating solution. Surgeons should be aware that additives to irrigating solution might create a pH value leading to lenticular, corneal, and retinal damage.16
Glucose has been used to fortify BSS Plus in phakic diabetic vitrectomy.17 It was found that a posterior capsular-type cataract would occur during prolonged vitrectomy with BSS Plus.18 It is important to maintain a clear lens and avoid lensectomy in diabetic persons. Lensectomy was found to increase the risk of developing postoperative neovascular glaucoma by a factor of more than 4 in diabetics. Additional glucose is usually given in the form of injection of a small aliquot of 50% glucose into a 500-ml bottle of BSS Plus. This has the effect of increasing the osmolality of the infusion fluid. Lenses of a diabetic person have polyols trapped within them. When the vitreous fluid osmolality is lowered to 305 mOsm, a transcapular osmotic gradient tends to draw in extra fluid, creating an osmotic stress and a posterior subcapsular cataract. Fortified BSS Plus can be prepared by adding 3 mL of a 50% dextrose solution in sterile water with no preservatives to the standard 500 mL bottle of BSS Plus.19 This results in increasing the glucose concentration to between 300 and 400 mg/mL and gives a pH of 7.5 and an osmolality of approximately 320 mOsm. In an animal model, up to 6 mL of 50% glucose has been added, yielding an osmolality of 330 mOsm and a pH of 7.5. The resulting solution had a concentration of 650 to 750 mg/dL. One series using a fortified glucose solution cited only two occurrences of posterior subcapsular lens changes in 1,000 vitrectomy cases (Table 2).20
Epinephrine is frequently added to BSS Plus infusion solutions to maintain pupillary mydriasis during prolonged surgery (see Table 2). 21 In undiluted and weakly diluted solutions, the bisulfite preservative included in most epinephrine preparations is shown to cause corneal endothelial damage and subsequent corneal haziness.22 The corneal damage, however, can be prevented by diluting bisulfite-containing solutions to 1:5,000 or greater or by actually preparing an epinephrine bitartrate solution 1:1,000 concentration.23, 24 It has been shown that extremely diluted concentrations of epinephrine (on the order of 1:96,000 or less) are effective in maintaining mydriasis during intraocular surgery. In practice, 0.3 to 0.5 mL of 1:1,000 epinephrine is usually added to a 500-mL bottle of BSS Plus for vitrectomy surgery. Concentrations of 1:1,000 Parke Davis epinephrine and 1:1,000 Elkin Sinn epinephrine in the amount of 1 mL to 500 mL of BSS Plus produced no toxic effects on endothelial tissue.
Other additives such as atropine, chymotrypsin, acetylcholine, and carbachol have specifically been demonstrated to have low corneal endothelial toxicity when used in diluted solution.25, 26 These are not in general usage or certainly are used infrequently by vitreoretinal surgeons. Dilute solutions of bovine thrombin have been used to prevent hemorrhage during vitrectomy for diabetic retinopathy but were abandoned after frequent inflammatory and fibrinous responses occurred, possibly related to the nonhuman source of the thrombin. Dilute solutions of heparin were also used but again found not to have significant advantage in controlling hemorrhage during vitrectomy. Antibiotics placed in the infusion fluids have been used by some surgeons to decrease the risk of endophthalmitis. Use of dextran has been suggested by some vitrectomists to dehydrate the cornea, but this is not in wide usage.
It has been suggested that hypothermia of ocular fluids protects the retina from light toxicity during vitrectomy.27 Retinal adhesiveness is increased by hypothermia. In a sense, infusion fluids are usually relatively hypothermic because they are administered at room temperature, which is considerably below body temperature. Some attempts have been made to further cool intraocular fluids during vitrectomy, but cooling is not widely used at this time.
Retinal adhesion both postmortem and in vivo has been shown to be affected by several factors in infusion fluids. For example, low calcium ion concentration weakens retinal adhesions significantly. This may be applicable to newer techniques that require the surgical creation of retinal detachments, such as macular rotation surgery. Factors that increased retinal adhesion are ouabain, hyperosmolar solution, and darkness rather than light.28 Factors weakening retinal adhesion were normal saline, low pH, and solutions without calcium. There was little effect on retinal adhesion by removing magnesium, potassium, sulfate, and orthophosphate. 29 These factors require more investigation before clinical application.
|VISCOELASTIC SUBSTANCES AS VITREOUS SUBSTITUTES|
|Use of hyaluronic acid as a vitreous substitute was first proposed by Balazs
in 1960. The development of hyaluronic acid has been most successful
in anterior segment surgery. It was first used in implant surgery
in 1979. Fechner used methylcellulose 1% solution to coat intraocular
implants in 1977, and in the 1980s, it was used for the maintenance
of anterior chamber depth. A combination of chondroitin sulfate
and hyaluronic acid for use as an anterior segment viscoelastic substance
became available in the 1980s. The vitreous surgeon uses viscoelastic
substances to maintain the clarity and integrity of the anterior segment
during vitrectomy surgery. Many important posterior segment uses
of viscoelastic substances have developed mainly around hyaluronic acid. Except
in a few special circumstances, viscoelastic substances are
not used as bulk or volume vitreous substitutes.|
The relatively high viscosity or resistance to flow of these commercially available viscous agents is their most striking characteristic. At the molecular level, viscosity arises from the interactions of relatively large molecules as their concentration increases. Pseudoplasticity is an important concept that explains how some of the relatively thick solutions can be extruded through a small-gauge cannula.30 A pseudoplastic fluid is one in which the viscosity actually decreases as the shear rate of the fluid increases.31, 32 The relationship of shear rate to flow through the needle can be understood by visualizing the velocity profile of the fluid as it flows through the lumen of the needle. At the wall of the needle, the velocity is zero. In the center of the fluid, velocity is maximum. In between a parabolic curve represents the velocity, which is zero at each wall and maximal at the center of the needle. The tangent to this curve, which is the slope at any given distance, x, across the lumen of the needle, is the shear rate and is expressed as dv / dx (Fig. 1). Thus, the shear rate is much higher, and the apparent viscosity is vastly lower near the wall of the needle for extremely pseudoplastic fluids such as hyaluronic acid. The vastly lower viscosity near the wall of the needle decreases the resistance to flow enormously. This allows the pseudoplastic fluid in the central channel of the needle to flow almost as a plug. This explains the paradox that concentrated hyaluronic acid has high apparent viscosity at rest but can still be injected through a 30-gauge needle. The pluglike flow through a small-diameter needle also explains the extruded appearance of the hyaluronic acid from the end of the needle. Hyaluronic acid at a 1% concentration is the most pseudoplastic of the commercially available substances and therefore can be injected with 27- to 30-gauge needles. Hydroxypropyl methylcellulose (HPMC) is less pseudoplastic and requires a larger (23 to 25) gauge needle for injection.
Another important concept is the Reynolds number, the dimensionless number that can be used to determine whether a fluid system is more likely or less likely to develop a turbulent or rough fluid flow. Fluid systems that have a Reynolds number of more than 2,000 may develop turbulent flow, those with a Reynolds number less than 2,000 generally will not. The Reynolds number is equal to the characteristic velocity of fluid, multiplied by a characteristic length, multiplied by the fluid density, and divided by its viscosity. An eye filled with BSS has a Reynolds number of around 5,700 (Table 3). When 0.4 mL of 1% hyaluronic acid is added the Reynolds number is reduced to approximately 250 once the hyaluronic acid goes into a uniform solution in the vitreous. Thus, relatively small amounts of hyaluronic acid in the posterior segment can result in reducing turbulent and rough fluid motions at the retinal surface.
Reynolds number = Velocity × length × fluid density
The viscosity of hyaluronic acid/sodium hyaluronate (Healon) when it is not moving or is at zero shear is as high as 300,000 cp, but viscosity falls to around 200 cp at shear rates of 1,000 inverse seconds. Viscoat is a hyaluronic acid and chondroitin sulfate mixture that has a viscosity of approximately 40,000 cp at rest and of approximately 300 cp at a shear rate of 1,000 inverse seconds. The viscosity of Amvisc parallels that of Healon but appears to be less at very low shear rates. The viscosity of Amvisc Plus appears to be slightly greater than that of Healon at very low or zero shear rates. The zero shear rate viscosity predicts the ability of the viscoelastic substance to maintain the anterior chamber depth. The viscosity of Occucoat is 4,000 cp at zero shear and about 300 cp at 1,000 inverse seconds. Occucoat, a commercially available HPMC, shows less pseudoplasticity.
The hyaluronic acid and chondroitin sulfate substance has a greater affinity to coat instruments and stick to tissues than 1% hyaluronate.33 This is usually attributed to the fact that the hyaluronate-chondroitin complex carries three negative charges for every one that the hyaluronate molecule carries. HPMC solutions also have good coating properties. The pH of commercially available solutions is in the range of 6.5 to 7.5; it should be adjusted to a pH of 7.4 wherever possible. The osmolality of commercially available viscous solutions ranges from 285 to 340 mOsm/kg H2O. Chondroitin sulfate was developed as a viscous solution; however, its osmolality is 1,000 mOsm in a 50% solution, which is required for higher viscosity. This is damaging to the corneal endothelium.
The FDA-approved viscoelastic substances that are nontoxic to the ocular tissues (Table 4). The substances must be highly purified to prevent inflammatory reactions, presumably of a foreign antigen type. HPMC solutions can be autoclaved without damaging their molecular structure, but hyaluronate solutions must not be autoclaved. Autoclaving and reuse of cannulas not properly cleaned after hyaluronic acid injection has been thought to lead to inflammatory reactions in subsequent operations. Viscoat, the commercially available chondroitin sulfate and hyaluronate solution, was reformulated in 1987 to contain a smaller amount of phosphate buffer. The higher phosphate concentration in the earlier formulations led to the precipitation of calcium in the cornea, seen as an acute band keratopathy.34 This was noted to occur in association with the use of BSS Plus but not BSS, which contains a citrate buffer that probably prevented potassium precipitation by high amounts of phosphate.
When injected into the unicameral eye the viscoelastic solutions leave the eye through the trabecular meshwork. Hyaluronic acid injected into the vitreous probably also leaves through the trabecular meshwork, but it takes a great deal longer.1 In the owl monkey, hyaluronic acid flows out of the anterior chamber within 72 hours. When injected into the vitreous of the phakic eye, however, it may take more than 2 months to flow out. There are no reports of commercially available chondroitin sulfate or HPMC solutions used in the posterior segment of aphakic eyes. Early reports of white precipitates and inflammation occurring after HPMC injection into the posterior segment of rabbits were based on laboratory rather than commercial preparations of HPMC.35 Early reactions may have resulted from inadequate purification. Vegetable fibers and other impurities were found in HPMC preparations made by pharmacies from non–medical-grade products. The human body has enzymes to degrade hyaluronate and chondroitin sulfate, but hyaluronate at least is not degraded within the eye. HPMC cannot be completely degraded by any human enzymes. Chondroitin sulfate has induced epiretinal membranes when injected into the rabbit vitreous36 Although the purity of the chondroitin sulfate was carefully evaluated, the investigators did not use a commercially available, FDA-approved combined chondroitin sulfate and hyaluronate solution.
Surgical removal of viscoelastic solutions is recommended in anterior segment surgery because of high postoperative intraocular pressures that presumably result from occlusion of the trabecular meshwork by large molecules of the viscoelastic solution.37 High and sometimes uncontrollable pressure spikes occurring after the use of intraocular viscoelastic solutions are the most troublesome complication.38 The use of large amounts of hyaluronate in the posterior segment can cause very high intraocular pressure, requiring a second operation to remove the viscoelastic substance.39 Meticulous removal of hyaluronic acid at the end of most posterior segment applications is not usually done and, indeed, could be as challenging as the associated vitreoretinal surgery. High intraocular pressures are much less frequently noted with posterior injection of viscoelastic solutions in phakic rather than aphakic eyes. The chondroitin sulfate and hyaluronate solution is less likely to give increased intraocular pressures and may give more easily controlled pressure spikes than hyaluronic acid.40 The lowering of the pressure spike is most pronounced when the chondroitin and hyaluronate solution is aspirated at the end of surgery. This is due to the lower molecular weight of chondroitin sulfate and hyaluronate in Viscoat relative to the hyaluronic acid in Healon or Amvisc. When unacceptable pressure elevations occur, treatment with acetazolamide, β-blockers, and 4% pilocarpine gel have been shown to be effective in reducing postoperative intraocular pressure. If these efforts fail, aspiration or irrigation of the remaining viscoelastic solution is indicated. This is particularly relevant in posterior segment surgery, when large amounts of viscoelastic substance may remain in the eye for very long periods of time.
Viscous vitreous substitutes are used extensively by anterior segment surgeons in extracapsular cataract extraction, phacoemulsification, lens insertion and removal, and corneal transplantation.41 The most common use of viscoelastic agents by the vitreoretinal surgeon is as an optical-binding substance between the corneal contact lens and the corneal surface. All three major viscoelastic substances are effective for this use. Viscoelastic solutions placed on the corneal surface during a long retinal procedure slow down corneal epithelial desiccation and decrease the frequency of wetting required. This is especially helpful in the use of the noncontact binocular indirect ophthalmoscope in conjunction with the stereo diagonal inverter. Here, the objective lens of the system can be quite close to the cornea. Frequent wetting of the cornea may splash droplets onto the objective lens surface. Using a viscoelastic solution decreases the frequency of corneal wetting so visualization is less frequently compromised. HPMC solutions are preferable to hyaluronate solutions in this instance because they are less viscous and less elastic, and replicate the corneal curvature much more rapidly than concentrated hyaluronic acid solutions. This is important because the concentrated hyaluronic acid often develops its own contour, which results in irregular astigmatism, causing either a blurred image or a distorted image through the microscope.
Viscoelastic solutions are frequently used in the anterior chamber when an intraocular lens is removed or placed by the vitreoretinal surgeon. All of the viscoelastic solutions appear to give good protection of the corneal endothelium from potential lens touch during insertion or removal of an intraocular lens. In cases in which the iris has become adherent to the corneal epithelium over fairly wide areas, the use of concentrated hyaluronic acid solutions is perhaps the gentlest method of dissection and offers the best hope of retaining corneal endothelial function.
Viscoelastic solutions such as hyaluronic acid are valuable as viscous agents in repair of corneal lacerations during posterior segment surgery. Hyaluronic acid solutions are the most effective for maintaining a optically clear plug in the anterior chamber when oozing blood is trapped there by either an intraocular or a native lens. The surgeon should remove at least some of the viscous material from the anterior chamber at the end of the surgery to minimize the risk of a postoperative pressure spike. A similar technique is useful in vitrectomy for endophthalmitis, in which continued oozing and settling of white blood cells and fibrin trapped by an intraocular lens may prevent good visualization during vitrectomy.
Hyaluronic acid is frequently used on the posterior corneal surface as an aid to visualization after fluid–gas exchange.42 After a long procedure, the cornea may have multiple folds in Descemet's membrane. When fluid–gas exchange is performed, the folds in Descemet's membrane at the fluid–air interface can cause pronounced image degradation and may prevent further surgery. Coating the posterior surface of the cornea with a hyaluronic acid solution will improve the image so that surgery can be completed.43 Theoretically, HPMC and combined hyaluronate and chondroitin sulfate solutions could be superior to hyaluronate solutions alone because they would tend to form a smoother fluid viscoelastic substance interface more quickly than hyaluronate solution. There are, however, no reports in the literature of the use of these two solutions for such a purpose.
There has been some suggestion by anterior segment surgeons that viscoelastic solutions may protect the corneal endothelium from high flow and turbulence during phacoemulsification.44 Controlled animal experiments, however, have shown no benefit of hyaluronic acid or the hyaluronate–chondroitin sulfate mixtures over BSS Plus in protecting the corneal endothelium.45 There is no compelling reason for the vitreous surgeon to use such a solution during ultrasonic lensectomy at this time.
Hyaluronic acid solution has been used as a bulk vitreous substitute in the vitreous cavity and to replace volume as choroidal hemorrhagic detachments are drained. A single case is reported. There was no abnormal rise in intraocular pressure postoperatively.46 A good visual recovery was also achieved.
Concentrated hyaluronic acid solution has been injected in the suprachoroidal space to create a temporary scleral buckle.47 This was used to treat both recurrent detachments after scleral buckling and primary detachments. The hyaluronic acid formed an adequate buckle for approximately 1 week, then slowly reabsorbed over the second week. One case was complicated by development of spontaneous nonhemorrhagic choroidal detachments, but there was no report of hemorrhagic choroidal detachment. Fourteen retinas were reattached with at least 5 months of follow-up. Hyaluronate solution, 0.3 to 0.8 ml, was injected through a sclerotomy down to the level of the choroid. Subretinal fluid was drained before injection in 12 of the patients.
Healon has been used as a bulk vitreous substitute in retinal detachment surgery after drainage of subretinal fluid in the same way that BSS and intraocular air or gas are used to restore normal ocular tension.41, 49 This is usually done in conjunction with scleral buckling and cryopexy or laser treatment.50 Although the hyaluronic acid solution had excellent biocompatibility, Koster and Stilma51 found at least a transient pressure rise in 19 of 40 patients. Vatne39 found intraocular pressure rises of 60 to 70 mm Hg, which necessitated removal of concentrated hyaluronic acid solution to control the intraocular pressure. In this study, the hyaluronic acid actually passed through a retinal break into the subretinal space and was assessed to be mechanically preventing retinal reattachment because of a slow resorption of the viscous substance from the subretinal space. This study, however, dealt mainly with patients with PVR grades C and D. It was concluded that hyaluronic acid solutions are at best a limited addition to conventional scleral buckling surgery in PVR detachment. A relatively large amount of hyaluronic acid solution is required for bulk vitreous substitution, creating a fairly substantial expense. Hylangel, which is created by cross-linking hyaluronate molecules with vinylsulfone, has been used as a vitreous substitute.52
Hyaluronic acid solutions have been used to unfold giant tears, especially those with rolled-over flaps.53 This technique had been moderately popular but has been supplanted by the use of liquid perfluorocarbons (discussed further later).
Elevation and partial dissection of preretinal membranes with injection of viscoelastic substance with a small cannula have been advocated.54 Such surgery has been performed with both hyaluronic acid solutions and in one case with HPMC. The much higher viscosity of hyaluronate as well as its ability to be injected through a cannula as small as 30 gauge would seem to confer a significant advantage. Increasing the viscosity of Healon and tinting the Healon with fluorescein have facilitated the procedure.55,56 Experience with this technique has been that it dissects the membranes nicely where they are loosely adherent. Loosely adherent membranes, however, can be easily removed without the use of viscous dissection. In the more difficult and tightly adherent membranes, the viscous dissection does not work very well. Furthermore, the hyaluronic acid solution adheres to the tissues of interest. This lubricates them and makes them hard to grasp with instruments. The solution is difficult to remove and disrupts the local hydrodynamic flow with the vitrectomy device and aspirating suction. In vitrectomy for advanced cicatricial retinopathy of prematurity, hyaluronic acid has been advocated as a volume vitreous substitute to hold open the funnel extending posterior to the optic nerve during dissection.
The procoagulant affects of concentrated hyaluronic acid solutions after phakic diabetic vitrectomy have been investigated.57 In a prospective randomized study, rebleeding was significantly reduced with injection of 0.5 to 0.75 mm of hyaluronic acid at the end of phakic diabetic vitrectomies.58 At 2 weeks, the amount of time in which the hyaluronic solution concentration would be effectively reduced, the procoagulant effect disappeared. In a previous study, only one of four aphakic diabetic eyes with severely increased intraocular pressure could be controlled with timolol and acetazolamide. The pressures of these patients ran in the 40- to 50- mm Hg range for 3 to 6 weeks. Because all of these eyes were thought to have a very poor prognosis preoperatively, removal of hyaluronic acid was not performed. The authors were unable to find any anticoagulant effect and concluded that hyaluronic acid forms a barrier that actually encases small bleeding sites. Additionally, the increased viscosity caused by hyaluronic acid in the posterior segment could decrease turbulent flow over newly formed clots. The basis for this is noted in the previous discussion of the Reynolds number (Fig. 2).
|INTRAOCULAR GASES AS VITREOUS SUBSTITUTES|
The first use of intraocular air recorded in literature was in 1911 by Ohm. He and several subsequent investigators were unaware of the relationship of retinal holes and retinal detachments, but they were still able to reattach an occasional retina. Subsequent to Gonin's discovery that retinal holes were the cause of retinal detachment, Rosengren used intravitreal air injection with drainage of subretinal fluid and diathermy. He achieved a 77% reattachment rate, which was a tremendous advance at that time. In the 1950s, the use of air became less popular because of rapid advances in the scleral buckling technique. Intravitreal air was used for supplementation of buckling procedures throughout that period. In 1973, Norton used sulfur hexafluoride (SF6) gas for a longer tamponade than was provided by air injection for difficult retinal detachments, particularly giant tears.83 Vygantas and colleagues59 were the first to use perfluorocarbon gases to provide a longer intraocular tamponade than SF6. Lincoff and associates then developed several perfluorocarbon gases.65,72 Air, SF6, and perfluoropropane were used for many new vitrectomy procedures throughout the 1970s and 1980s. In 1984, Hilton reported a series of pneumatic retinopexy patients in which he advocated the use of intraocular gas tamponade as a primary treatment for selected retinal detachments.64
MODE OF ACTION AND PHYSICAL PROPERTIES
Surface tension between gas bubbles and surrounding fluids is the most important physical property of the gases in retinal reattachment. The gas bubble is positioned so that it occludes the retinal break either continuously or a substantial percentage of the time to prevent bulk flow of fluid through the hole. This allows the natural reabsorption of subretinal fluid to slowly reattach the retina. Surface tension arises from electrostatic attractive forces between fluid molecules. These van der Waals forces are both weaker and longer range than the electronic exchange forces of the chemical bond. Van der Waals forces are responsible for condensation of vapors into liquids. The most important attractive force is the dispersion or London-van der Waals force, which arises from neutral atoms because they are oscillating systems of negative electronic charges around a positive nuclear charge.60
Hydrogen bonding and dipolar interactions also can play a role in surface tension. Dipolar forces arise from uneven charge distribution around a molecule. Internal molecular attraction forces neutralize each other in the bulk of the fluid but are not neutralized at the surface. The surface tension arises from lateral extension of the surface caused by crowding of interior molecules being brought to the surface by the attractive forces that are not neutralized. The attractive intermolecular forces decrease as the seventh power of the intermolecular distance. Thus, the surface tension layer is only one to two molecules thick. The saline–gas interface produces the highest surface tension available to the ophthalmologist (measuring approximately 60 ergs/cm2), because the attractive forces in the saline are not neutralized by the overlying air at the air–fluid interface.
Another important property of gas is buoyancy, which is a result of the large difference in specific gravity between fluid and gas. A fresh, freely movable superior tear tamponaded with a large air bubble will usually displace fluid inferiorly and away from the tear, allowing it to flatten against the wall of the eye. Buoyancy directs the effectiveness of the tamponade, which for gases on earth must always be in the gravitational upward direction. Large bubbles and face-down positioning are required to tamponade inferior retinal breaks.
The solubility of a gas in the aqueous medium is the most important property determining the reabsorption rate of a gas bubble from the vitreous cavity.61 If the gas bubble is less soluble than nitrogen, expansion of the bubble can occur. Expansion can also occur with relatively soluble gases such as air when the patient is breathing nitrous oxide, which is more soluble than air in water.
The relationship between bubble volume and its arc of contact inside the eye is important. It determines how much gas is necessary to treat a tear or group of tears of a specific size and proximity. By using a glass model eye, it was determined that in an average eye with a diameter of 21 mm, approximately 0.28 ml of gas is required to give a 90-degree arc of contact.62,63 In a larger myopic eye of 24-mm diameter, 0.42 mL would be required. The respective volumes for an arc of contact of 120 degrees are 0.75 mL for the normal eye and 1.13 mL for the myopic eye. An arc of contact of 180 degrees requires respective bubble sizes of 2.4 mL and 3.62 mL. A later study using computed tomography of actual human eyes showed that for an arc of contact of 90 degrees, a somewhat greater volume of approximately 1.5 mL was required (Fig. 3).64
SF6 and the perfluorocarbon gases have a purity of 99.8% or better. Although they are frequently injected as mixtures with air, the pure gases are usually described as chemically nonreactive, colorless, odorless, and nontoxic. Earlier papers show haziness of the vitreous after SF6, perfluorocarbon, and air injection.65 Pathologic examination of the retina showed some changes in the outer layer of the retina, but these changes were no worse in eyes injected with long-acting gas than in the eyes injected with air.66 A study using SF6 and perfluoropropane monitored by the FDA under an investigational device exemption for pneumatic retinopexy showed no significant flare or cell with the biomicroscope.67 No significant vitreous inflammation measured by the National Eye Institute scale was noted for either SF6 or perfluoropropane. SF6 may contain up to 0.3 ppm of hydrogen fluoride. This is generally regarded as the most toxic contaminant found in SF6. There is an established threshold limit value for hydrogen fluoride in the workplace. Similarly, perfluoropropane may contain up to 10 ppm of perfluoropropalene. Perfluoropropalene is a toxic gas for which a threshold-limiting value has also been established. Because of the stricter FDA standards, modern gases may contain less of these contaminants than gases used by early investigators. Greater purity, smaller injection volumes, and more attention to conjunctival sterilization could explain why recent investigators have seen a quiet vitreous when earlier investigators observed the flare and cell or a hazy vitreous response. If the bubble is large enough to cover the back of the lens, a cataract will develop unless the patient is positioned so that a layer of fluid covers the posterior surface of the lens.68,69 This is thought to result from a drying or deprivation of nutrient effect rather than from a toxic effect of the gases.
Prolonged contact with the corneal endothelium has been shown to cause increased inflammation, seen to a greater extent with SF6 than perfluoropropane.70 Both gases caused persistent corneal edema and posterior corneal membrane formation. Posterior corneal membrane formation has been described in more than 20 disorders and is due to interference with nutrition of the endothelium rather than to a specific toxic effect.
|ABSORPTION AND KINETICS OF GASES|
|Intraocular gas bubbles are eventually reabsorbed. Inert gases such as
helium, neon, argon, krypton, and xenon are reabsorbed more rapidly than
air. Thus they are nonexpansile gases when breathing air. Nitrous oxide
is extremely soluble in blood and tissue, and can lead to significant
expansion of even an air bubble during the course of an operation. Breathing 100% oxygen and a volatile anesthetic, however, causes
little change in an intraocular gas bubble during anesthesia.|
The kinetics of the less water-soluble gases such as SF6 and perfluorocarbon are much more complex and have been studied in substantial detail.71–78 Injection of a bubble of 100% SF6 or perfluoropropane leads to expansion of the bubble. The volume continues to increase, reaching a maximum after 2 to 4 days for SF6 and 4 to 5 days for perfluoropropane. The main constituent gas that leads to expansion of the gas bubble is nitrogen. About 10% of the gas bubble concentration is carbon dioxide and oxygen, which remain at a fairly constant low concentration throughout the life of the gas bubble. Eventually, the partial pressure of nitrogen in the bubble equilibrates roughly with the nitrogen partial pressure in the capillary blood. The proportions of gases in the bubble then remain constant as the bubble volume gradually decreases and all the gases leave the eye at the same rate. Because the long-acting gas is the slowest to leave the eye, it essentially controls the rate of clearance of the bubble volume in the final stage.
This dynamic has been summarized as having three phases (Fig. 4). The first phase is bubble expansion caused by rapid diffusion of nitrogen into the bubble. The second phase lasts from maximum expansion of the bubble until the nitrogen concentration in the bubble is stable and roughly the same as its concentration in venous blood. The third phase is from the time of nitrogen equilibration until the bubble is reabsorbed.
The clearance of gas in the third stage is approximately described as a first-order exponential equation having the form V = V0ekt, where V0 is the volume at the time of equilibration of nitrogen concentration with that in the blood and V is the volume at any subsequent time, t. K is a constant for a particular gas. A half-life for the bubble determining the time it takes for V to equal one half of V0 can be calculated once k is determined. Perfluoromethane, perfluoroethane, and perfluoro-n-butane also have an exponential decay pattern. This description must be regarded as approximate because it would imply that small bubbles would just get smaller but never really disappear. This is contrary to observation because smaller bubbles are noted to disappear rather abruptly. The half-life of the disappearance phase of SF6 has been reported to be 2.4 to 2.8 days and that of perfluoropropane to be 4.5 to 6 days. The gases are removed from the eye more rapidly when the eye is either aphakic or pseudophakic. The bubble lasts much longer in the presence of severe hypotony. Many publications indicate the average time to disappearance of bubbles of various size and of various gas mixtures with air injected into the vitreous. From clinical and animal observations, the actual time of disappearance depends on concentration of the gas, the size of the gas bubble injected, whether the patient is aphakic or phakic, and whether there is a hypotony. The theoretical factors governing gas leaving the eye are the molecular weight of the gas, diffusion coefficient of tissues, water solubility of the gas, intraocular pressure, inflow rate of ciliary body secretion, phakic or aphakic status, hypotony, vitrectomy, stirring of vitreous fluid by ocular motion, bulk outflow of aqueous through trabecular meshwork, posterior choroid venous concentration of gases, and vascular perfusion rate of the choroid. In most models, the most important factors seem to be the water solubility of the gas, hypotony, aphakia, vitrectomy, and bulk flow of water from the eye. Theoretical models show reasonable approximate results but are too complex to accurately predict what will happen for an individual patient. Certainly, determining the optimal size and composition of a gas bubble injected into a specific patient in a specific circumstance is part of the art of vitreoretinal surgery at this time.79
One approach to gas injection is to estimate the maximum bubble size expected from the amount injected. Excessive volumes of pure expansile gases can lead to a maximum bubble size larger than the ocular volume. Extremely high pressures resulting in central retinal artery occlusion and loss of light perception then occur. One would also like to keep the maximum size of the gas bubble slightly less than vitreous volume to prevent cataract formation in phakic patients and corneal opacification in aphakic patients. Ratios of the maximum volume of the expanded gas bubble to the original volume of injected gas are for SF6, 2; for perfluoromethane, 2; for perfluoroethane, 3.25; for perfluoropropane, 4; and for perfluoro-n-butane, 5.
Another approach to the problem of an expanding gas bubble is to inject nonexpansile or a slightly expansile concentration of the gas. The nonexpansile concentration of SF6 was initially reported at 40%. Most surgeons err on the side of caution by using a 20% concentration of SF6 when attempting a total or near-total fluid–gas exchange at the conclusion of vitrectomy. A nonexpansile concentration of perfluoropropane is thought to be 12%.80 Surgeons frequently use concentrations between 10% and 16% perfluoropropane for large posterior segment tamponades.
In pneumatic retinopexy, in which relatively small volumes of gas are injected, pure gases can be safely used because they are unlikely to overfill the vitreous volume. An estimate has been made of the amount of time a therapeutic volume of gas is maintained by injection of 0.3 mL of gas. A therapeutic volume of gas for pneumatic retinopexy has a 90-degree arc of contact and will tamponade a break for approximately 1 clock hour. The amount of time estimated for the presence of therapeutic volume of gas is for air, less than 1 day; for SF6, 3 to 4 days; for perfluoromethane, 2 days; for perfluoropropane, 16 days; and for perfluoro-n-butane, 30 days.81 SF6 and perfluoropropane are the most common gases used in small volume injection for pneumatic retinopexy. There are reports of the effective use of air and octofluorocyclobutane.82 Volumes injected for pneumatic retinopexy usually vary between 0.3 and 0.6 ml (Table 5).
|INDICATIONS FOR INTRAOCULAR GASES|
|Interest in gases began when Norton and associates83 used intravitreal air to unfold giant retinal tears that had a poor success
rate with scleral buckling alone. Machemer and Allen84 used incarceration to anchor the retina anteriorly in some cases. This
technique occasionally resulted in vitreous hemorrhage. They were able
to reattach the retina in 12 of 13 cases with tears of 180 degrees or
less. Machemer and his associates then investigated SF6 with the aim of finding a longer tamponade than that given by air. They
sought a higher success rate for giant retinal tears of greater than 180 degrees
with the longer tamponade. When the longer acting gas was
used in conjunction with newly developed vitrectomy, Machemer and Allen
were able to reattach 12 of 14 cases with tears of 180 degrees or greater.84 At 6-month follow-up, however, only 6 of the 14 cases remained
attached because of the development of PVR. Lensectomy was a further
improvement in management of giant retinal tears with large tears
and PVR. Surgery on a special table with face-down positioning
of the patient was required to unfold the retina and minimize posterior
slippage of the retinal break. After air–fluid exchange, a thin
layer of fluid remaining under the retina usually resulted in the
retinal flap sliding posteriorly in the supine position. Using a cannulated
extrusion needle, Joondeph and colleagues85 removed subretinal fluid and brushed or held the retina anteriorly at
the completion of air–fluid exchange. Posterior slippage was controlled
with surgery in the supine position in 18 eyes. Perfluorocarbon
liquids are now the most common method used to unfold retinal tears
with the patient in the supine position. Silicone oil has been used as
a long-term tamponade in cases of giant retinal tears. Although
silicone oil gives superior results to SF6, in cases with PVR, no advantage over perfluoropropane has been proven. This
factor is discussed in more detail in the section on silicone oil.|
Treatment of detachments caused strictly by macular holes is successfully approached with intraocular gas bubbles.86,87 When the vitreous is separated from the posterior segment, vitrectomy is not required for lasting retinal reattachment. Strict face-down patient positioning is required. Because of the expansile properties of the perfluorocarbon gases, small volume injections are made without requiring drainage of subretinal fluid. Vitrectomy can be employed when vitreoretinal traction is present. The retina usually remains adherent after reattachment without use of laser treatment around the macular hole. In some difficult recurrent cases, laser treatment around the reattached retinal hole will maintain retinal reattachment. Face-down positioning was maintained for 8 to 11 days in tolerant patients. This was based on the notion that a firm adhesion between the neurosensory retina and the retinal pigment epithelium takes 8 to 11 days to form after treatment with laser or cryopexy.
The use of intraocular gases to tamponade the retina in PVR has become extremely important. There has been a suspicion that even SF6 did not provide a long enough tamponade to develop sufficient adhesion to counter the epiretinal, subretinal, and transvitreal traction forces of PVR.88 Perfluoropropane has been proven to give superior results in tamponading postvitrectomy PVR cases. Of 18 patients treated with vitrectomy and perfluoropropane, in the successfully reattached cases, there was an average bubble reabsorption time of 92 days, whereas those with failed cases had an average reabsorption time of 62.7 days.89 Surgeons generally seek nearly total fill with a long-acting gas bubble. Nonexpansile or only slightly expansile concentrations of the gas are used to avoid extremely high pressures that could cause central retinal artery occlusion. It is important to monitor these patients postoperatively so that some gas can be removed to relieve elevated pressure. Although applanation tonometry is the most accurate means of following intraocular pressure, visual acuity monitoring for the loss of light perception by the nurse or by the patient can be used as the earliest sign of excessively high pressure. In measuring intraocular pressure in patients with a gas bubble, large displacement tonometry such as Schiotz tonometry gives falsely low values. A correction factor based on the size of the gas bubble is necessary. Applanation technique such as Goldmann tonometry or the use of electronic penlike devices is much more accurate. With large bubbles used in PVR surgery, face-down positioning is important to prevent gas block glaucoma and to minimize the risk of peripheral anterior synechiae formation. The higher surface tension and higher buoyant forces of the intraocular gas bubbles relative to silicone oil result in better internal tamponade with a gas bubble. The volume of the gas bubble is constantly decreasing, however, a silicone oil bubble remains at constant volume. The gas bubble volume can be easily supplemented using an outpatient fluid–gas exchange if the bubble is too small or disappearing too rapidly. The most frequent complication of PVR surgery is recurrent PVR and retinal redetachment. In the cases that remain attached, macular pucker is the most frequent complication (seen in 30% of patients).90 These complications are not due to a toxic effect of the gas but seem to be due to the displacement of fluid, which may concentrate proliferative factors near the retinal surface.
The use of gas has been generalized to treatment of any retinal break at the end of vitrectomy.91 Although retinal breaks do not routinely require gas tamponade in a simple scleral buckling procedure, the situation is different after vitrectomy. The replacement of slightly viscous vitreous fluid and more viscous subretinal fluid with low viscosity BSS permits transitional and more turbulent flows with ocular motion. These flows create detachment forces around retinal breaks. Furthermore, these flows persist longer because of prolonged damping times in lower viscosity fluids. If small or even large amounts of subretinal fluid remain at the end of the vitrectomy, the retina can be flattened postoperatively by the gas bubble with appropriate prone or lateral positioning.
To illustrate the advantage of stabilization of retinal motion by leaving the viscous subretinal fluid in place until the end of vitrectomy but before fluid–gas exchange, visualize two jars with a tissue suspended in fluid in each. One jar has water in it, the other jar has honey in it. Twist both jars rapidly a few times, then wait for the fluid motion to stop. Obviously, the jar with honey in it will have the fluid motion come to rest much more quickly. The decay times are proportioned to the reciprocal of the square root of the Ekman number.92 The Ekman number is a measure of comparison of viscous forces to Coriolis forces in such a system. In a system with relatively fixed rotational and physical properties such as the eye, the damping time will be proportional to the reciprocal of the square root of the viscosity of the subretinal fluid. A viscous subretinal fluid may have a viscosity of around 100 cp while BSS has a viscosity of 0.7 cp. Thus the damping time would be 12 times shorter and stabilization of the retina would be 12 times greater with the subretinal fluid in place.
Pneumatic retinopexy is frequently substituted for scleral buckling for retinal detachments in which there is a small number of tears in the superior 8 clock hours. There are reports of reattachments with inferior tears and also with tears at multiple clock hours superiorly.93 These techniques require either face-down positioning for the inferior tears or sequential postural positions for two or more tears at significantly different clock hours. When pneumatic retinopexy is used for one or more tears all located within 1 clock hour in the upper 8 clock hours of the eye, the primary retinal reattachment rate is similar to that of scleral buckling.94 In failed pneumatic retinopexy cases, reoperation with scleral buckling or vitrectomy gives a final success rate comparable to the final success rate for patients initially treated with scleral buckling. In the subset of patients with recent macular detachment and a subtotal detachment, visual acuity results are superior to those with scleral buckling. This would suggest that pneumatic retinopexy may be the procedure of choice for this subset of patients. Pneumatic retinopexy is more successful at reattaching the retina on a single procedure basis with phakic patients than with aphakic patients.95 The gas is injected with a small-gauge needle through the pars plana. Production of a single bubble is desirable because multiple small bubbles may go through a larger retinal tear. If multiple small bubbles are obtained, a thump to the eye performed by flexing a cotton-tipped applicator and then releasing its tip to firmly strike the pars plana of the eye may coalesce the small bubbles. If this technique does not work, the patient is usually positioned with the bubbles in the direction opposite from the tear overnight so the bubbles will coalesce. This is especially important if the break is large enough to admit any of these small bubbles. Cryopexy can be performed before injection of the gas bubble or subsequent to flattening the retina. If laser treatment is used, it requires flattening of the retinal break and is usually performed on the second or third postoperative day. Relatively small amounts of gas, on the order of 0.3 to 0.6 L are injected. In patients suspected of having glaucoma, either the procedure should be avoided or intraocular pressure and volume should be lowered enough to accommodate the entire gas bubble before injection. In emergency situations, anterior paracentesis can be performed in phakic or capsule-intact pseudophakic patients. Paracentesis of the anterior chamber through the pars plana can be performed on aphakic patients. When the gas bubble is adequately coalesced, usually shortly after the time of injection, the patient is positioned for 16 hours a day such that the bubble lies directly beneath the retinal break. This position tamponades the tear and allows spontaneous reabsorption of the fluid by the choroid. A steamroller maneuver, in which the patient is placed face down and then slowly lifts his or her head, can be used to propel a substantial amount of subretinal fluid from under the retina in patients with larger breaks. This procedure can speed up retinal flattening, but it is not absolutely necessary for retinal reattachment. Delayed reabsorption of subretinal fluid has been noted in patients with subretinal precipitates and in cases with heavy cryotherapy.96 Sulfur hexafluoride gas is the most frequently used gas, but perfluoropropane may be used if a longer tamponades is desired. Air, perfluoroethane, and octofluorocyclobutane have also been successfully used in pneumatic retinopexy.
Intraocular gas injections, which are essentially modified pneumatic retinopexy procedures, are frequently used to rescue recurrent detachments from a new or previously undetected retinal break in scleral buckling and postvitrectomy cases. The gas is injected through the pars plana. The head is positioned so as to tamponade the tear. Either indirect or slit-lamp laser photocoagulation is preferred because cryopexy is often impossible because of an overlying silicone buckle. Because vitrectomy and a scleral buckle have already been performed, intraocular air may be sufficient in these cases. If recurrent PVR is suspected, longer acting gases are preferred.
A postvitrectomy fluid–gas exchange is frequently performed to remove persistent vitreous hemorrhage, especially in diabetic retinopathy. Because the vitreous fluid is now modified aqueous, the exchange can be performed at the bedside or in the office. A 10-mL syringe filled with 5 mL of sterile air or nonexpansile gas is used with a 25-gauge needle. The needle entry is through the limbus in aphakic patients or through the pars plana in phakic or pseudophakic patients (Fig. 5). The patient is positioned so that needle entry is from below. Fluid is aspirated and gas is injected alternately until most of the hemorrhagic liquid is replaced with gas. This procedure allows supplemental laser photocoagulation and temporary removal of proliferative factors in the hemorrhagic vitreous fluid.
Macular holes in undetached retina are treated with vitrectomy in combination with membrane dissection and fluid–gas exchange.97 Subsequent macular hole surgery experience demonstrates that successful surgery requires at least removal of the posterior hyaloid face over the disc and macular and tamponade with a large gas (usually 14% perfluoropropane) or silicone oil bubble. Epriretinal membranes are usually removed if present. Internal limiting membrane removal is usually performed in longstanding macular holes or reoperations. Various adjuvants such as transforming growth factor β, plasma, serum, and platelet concentrate have not been shown to confer a significant advantage.
Treatment of macular detachment secondary to optic nerve pits has been performed with intraocular gases. A pneumatic retinopexy treatment with prone positioning to flatten the retina in the papillomacular bundle region is performed initially. A barricade of laser is then placed across the papillomacular bundle region separating the optic nerve pit from the macula. If this is not successful, vitrectomy and a larger gas bubble with face-down positioning and repeat laser photocoagulation can be done. This procedure is warranted since a natural history study showed a very high percentage of visual loss with chronic macular detachment caused by optic pits.
|COMPLICATIONS OF INTRAOCULAR GASES|
|The complications of corneal opacity and cataract formation resulting from
drying by gas bubbles have been noted already. Face-down or
lateral positioning is necessary to prevent continuous contact of the
gas bubble with the cornea and lens and to minimize the risk of corneal
opacity and cataract formation.|
Glaucoma can develop from association with intraocular gas bubbles. Overfilling of the eye with expansile gas and consequent central retinal artery occlusion have led to permanent blindness.98 Medium size fills and inadequate attention to prone positioning can cause peripheral anterior synechiae with total angle closure. Sharp increases in intraocular pressure can occur if the patient remains supine, because fluid from the ciliary body continues to fill the posterior segment while the air bubble blocks fluid egress through the trabecular meshwork. Changes in atmospheric pressure, such as air travel or driving rapidly up a steep mountain, can lead to painful pressure increases and loss of vision. In order to avoid loss of vision in patients with a gas tamponade due to nitrous oxide anesthesia during an unanticipated emergency, a gas identification bracelet should be issued at the time of their vitreoretinal procedure.
Indirect and slit-lamp laser treatment can cause undesirable burns from reflections of internal fluid–air and air–fluid surfaces. To reduce this risk, one should avoid treatment through a gas–fluid or fluid–gas interface whenever possible.100 When treatment through such an interface is unavoidable, it should be done as perpendicular to the interface as possible, because the intensity of a reflected beam increases as the angle of incidence decreases. A divergent beam should be used. The location and the intensity of internally reflected beams should be evaluated with the aiming beam before photocoagulating the area of interest. Polarization of the laser beam could potentially reduce the problem of internal laser reflectance. Changes in beam intensity caused by reflectance and relative magnification encountered when switching from treating through a gas bubble to treating around it can lead to overintense burns and result in retinal and choroidal hemorrhages.
Some complications are particularly important to pneumatic retinopexy. Endophthalmitis has been encountered on two occasions. Undiluted povidone-iodine (Betadine) solution was not used in either case. The use of povidone-iodine is exceptionally important in pneumatic retinopexy or any transconjunctival injection into the vitreous because it kills bacteria on contact. Topical antibiotics are not adequate because they require a long time to act and may be merely bacteriostatic rather than bactericidal. The conjunctiva should be dried with a sterile cotton-tipped applicator just before injection through the site to avoid placing potentially contaminated and iodine-containing fluid into the vitreous cavity.
Endophthalmitis has been reported with the use of gases in vitrectomy surgery, but it is not clearly related to the use of the gas. Gas for intraocular injection is aspirated through a 0.22-μm filter for sterilization. Many surgeons use two such filters in series to reduce risk of contamination by failure of one filter membrane. If the injecting needle used during pneumatic retinopexy is not first inserted deep into the vitreous before pulling it back to approximately 2 mm, gas can be trapped in the anterior hyaloid. This produces a donut- or sausage-appearing gas pocket anteriorly (Fig. 6). The gas may break free into the vitreous after 1 or 2 days. Many surgeons prefer to aspirate the gas immediately and reinject it deeper into the vitreous. If multiple small bubbles are formed at injection and not eliminated before positioning them beneath the retinal tear, subretinal gas may be found. New tears occur in 7% to 23% of patients treated with pneumatic retinopexy. New tears are also found in approximately 13% of patients treated with scleral buckling. Iris-supported intraocular lenses may flatten against the cornea after posterior fluid–gas exchange. Several remedies have been proposed for this problem, including injection of hyaluronic acid into the anterior chamber, injection of air into the anterior chamber, and placement of anterior chamber sutures to prevent the implant from touching the corneal endothelium.101 Fortunately, the implantation of this kind of lens is now rare. The rigid angle-supported anterior chamber lens and the posterior chamber intraocular lens rarely touch the cornea with fluid–gas exchange of the posterior segment.
|AVAILABILITY OF GASES|
|Perfluoropropane and SF6 have been approved by the FDA for commercial distribution. Two surveys have shown that the use of SF6 and perfluoropropane have long been the standard of care in the United States.102,103 In one survey, several respondents indicated that they used perfluoroethane. Air was preferred over the longer acting gases for the treatment of retinal fish-mouthing during scleral buckle and to restore to intraocular volume during scleral buckling. The longer-acting gases were preferred over air for pneumatic retinopexy, treatment of posterior tears, and treatment of PVR. Use of air, SF6, and perfluoropropane for fluid–gas exchange to facilitate laser treatment after vitrectomy was evenly divided.|
|SILICONE OIL AS A VITREOUS SUBSTITUTE|
|Silicone oils, first available in about 1945, were developed as a replacement
for hydrocarbon lubricants and rubbers. They were used for breast
augmentation in the mid 1950s. Silicone oils were proposed as a vitreous
substitute in 1958 but were first used for ocular surgery by Cibis
and co-workers104 and Armaly105 in 1962. Although Cibis and co-workers were successful at reattaching
PVR detachments that were otherwise inoperable at the time, their
work predated the development of vitrectomy.|
Because of early clinical and laboratory reports of severe silicone oil retinopathy and because of the subsequent development and success of vitrectomy surgery for PVR, silicone oil was not used in the United States in the late 1960s and 1970s.106 Scott107 continued to use silicone oil with a viscodissection technique in Great Britain. He performed dissection of vitreous membranes with the indirect ophthalmoscope using needles and early vitrectomy scissors. Haut and associates,108 in France, were the first to use silicone oil as a modern tamponade after vitrectomy. In Holland, Zivojnovic and colleagues109 aggressively developed the full potential of silicone oil as an adjunct to vitrectomy surgery. Ando made a major contribution to the use of silicone oil with vitrectomy by noting that a 6 o'clock peripheral iridectomy substantially reduced the incidence of silicone keratopathy in aphakic patients. In 1992, a multi-institutional randomized study showed that silicone oil was superior to SF6 and equal to perfluoropropane in repairing PVR detachments in conjunction with vitrectomy.110
BASIC SCIENCE CONSIDERATION FOR SILICONE OILS
The chemistry of silicone oil begins when silicone dioxide (sand) is reacted with carbon at a high temperature, resulting in silicium.111 Silicium is reacted with methylchloride, whose product is then reacted with water. The result is dimethylsilanediol, which polymerizes into long chains of silicium oxygen molecules with two methyl groups on each silicium. The polymer chains continue to grow in length until a trimethyl group is placed at each end of the chain. The greater the length of the polymer, the greater the viscosity of the resulting silicone oil. During the synthesis of silicone oil, mixtures of different chemical substances can result. Therefore, the chemical composition of a particular silicone oil depends on the manufacturing process.
The most commonly used silicone oil clinically is methyl-3,3,3 polydimethylsiloxane. This is the familiar silicone oil that is lighter than water. The methyl groups, however, can be substituted with trifluoropropylmethyl or methylphenyl side chains, which result in heavier than water silicone oil.
The silicone oil chains form a helix with approximately six silicium units per turn. A pure 1,000-centistoke oil will have a helix of 63 turns and a 5,000-centistoke oil a helix of approximately 100 turns (Fig. 7).112 Interdigitation of the helix accounts for part of the viscosity, as does the increasing molecular weight of the larger molecules. Temperature dependence of the viscosity of silicone oil is shown by the fact that 1,000-centistoke dimethylsiloxane at room temperature has a viscosity of 800 centistokes at body temperature.
Because aqueous and silicone oils are immiscible, buoyancy occurs. The density of aqueous humor is 1.01 g/mL. The density of regular silicone oil at body temperature is 0.96 g/mL, and the density of the trifluoropropylmethylsiloxane at body temperature is 1.29 g/mL. The lighter silicone oil floats on the water, whereas the heavier silicone oil sink beneath the aqueous phase. The buoyant force of a regular silicone oil bubble with a volume of 5 mL is approximately 0.25 g. The downward force of the fluorinated silicone oil can be as much as 1.3 g. This downward force is distributed over the surface of the bubble and is greatest in the directly vertical axis. It tapers off to zero on the retinal surface parallel to the vertical axis. For regular silicone oil, the most important implication of buoyancy is that it directs the tamponade of the immiscible silicone oil upward. With the heavier-than-water silicone oils, the negative buoyancy is sufficiently great that it becomes a valuable intraoperative tool in expressing subretinal fluid from beneath the retina through peripheral tears. The heavier oils are also valuable in defining residual membranes on the retina by putting them on the stretch.
Surface tension is the most important means by which silicone oil assists in tamponading retinal tears for retinal reattachment. Surface tension between air and liquid was discussed earlier. The interface between silicone oil and water is somewhat more complex. The short range forces at the surface that give rise to surface tension are diminished between the water/oil interface relative to the water/air interface. This is because there is some attractiveness between the water and oil molecules that diminishes the dispersive forces and, therefore, the surface tension (Fig. 8). Strong polar forces give a further boost to surface tension at the water/hydrocarbon interface. Strong polar forces play a similar role in the silicone oil/water interface. Although in a successful retinal reattachment no fluid is seen in the area of successful tamponade, the retina itself and the choroid underlying the tamponaded retinal break may be thought of as being an aqueous phase material.
A rough theoretical calculation gives the surface tension between pure water and regular silicone oils as approximately 50 ergs/cm2,113 An actual measurement of pure water and silicone oil was 40 ergs/cm2. When physiologic saline was used, surface tension was found to be 33 ergs/cm2. If hyaluronic acid solution is used during the surgery and remains in the aqueous phase, surface tension may be reduced to 25 ergs/cm2.
The surface tension may be further decreased by surfactants or surface-active agents. Surfactants coat the interface between the oil and the aqueous phase vitreous fluid since they are partially soluble in both phases. This makes the transition between the two immiscible liquids less abrupt.114 The most important van der Waals' forces at the interface are of very short range (on the order of one molecular layer). Thus, a surfactant that is one molecular layer thick can substantially decrease the dispersive force at the surface of the liquids. Because the dispersive force is decreased, there is less crowding at the interface and less surface tension. In ocular surgery, proteins and phospholipids act as surface-active agents intraocularly. Proteins, however, are least effective at physiologic pH. Therefore, phospholipids are probably the best candidates for natural intraocular surfactants.115
The surface tension of silicone oil can be reduced to 12 to 14 ergs/cm2 by the absorption of lipoprotein. Albumin was found in high concentration in one patient's emulsified silicone oil.116 When 1,000-centistoke silicone oil or fluorosilicone oil was placed against liquified bovine vitreous, it had an interfacial tension of 14 ergs/cm2.117 After silicone oil has been in the eye, its surface tension may become so low that it can easily slip through a retinal break.
The concept of first flattening the retina with air, which has a much higher surface tension than silicone oil, is important. If the retina cannot be flattened by an air–fluid exchange because of residual traction, silicone oil cannot do so because its surface tension against the retina and choroid is less than that of air. According to Boyle's law, the pressure differential across the silicone aqueous interface is proportional to two times the surface tension divided by the radius of the bubble. As the pressure differential rises across the silicone oil/subretinal fluid interface in the plane of a break, a small hemispheric bubble is formed on the subretinal fluid side.118 The maximum pressure difference that the surface of the bubble can sustain is reached when the radius of curvature of the bubble is equal to the radius of the break (Fig. 9). Any further increase in pressure forces silicone oil under the retina. As a surgical rule, oil rarely goes under the retina if the retina is closer to the choroid than the diameter of a 20-gauge cannula.
A further problem with decreasing surface tension of silicone oils over a period of time is the development of emulsification.119 Spontaneous emulsification without physical motion occurs as the surface tension approaches zero. As a practical rule, emulsification occurs with surface tension in the range of 6 to 15 ergs/cm2. Surfactants alone probably do not lead to spontaneous emulsification of clinical silicone oils. Ocular motion can lead to emulsification, especially as surface tension decreases. Again, viscosity is important. Lower viscosity silicone oils emulsify more rapidly than higher viscosity silicone oils.120 Ocular fluid motion with instability at the interface leads to formation and separation of tiny droplets. Droplet formation decreases with increasing viscosity, because increasing viscosity dampens unstable motion at the interface. This notion was discussed under the topic of the Reynolds number in the section on viscous vitreous substitutes. Thus, a higher viscosity silicone oil emulsifies less easily than a lower viscosity oil even if the surface tension is the same.
It has been suggested that the reason fluorinated silicone oils develop droplets more easily than regular silicone oils is that a greater specific gravity difference exists between the fluorinated oil and the aqueous phase than for silicone oil and the aqueous phase. The theoretical description of this problem is called the Kelvin-Helmholtz instability.121 Because this theory states that the droplets are less likely to form as the difference between specific gravities of the two liquids increase as long as the heavier fluid is on the bottom, the greater specific gravity of fluorinated oils may not be the reason they emulsify more easily, or fluid motion in the eye may elevate the heavy liquid above the lighter liquid intermittently.
The index of refraction of silicone oil varies between 1.400 and 1.405. The fact that this refractive index is slightly higher than that of aqueous or vitreous, which has a refractive index of 1.34, causes refractive changes. When the lens is retained, a negative curvature between the posterior surface of the lens and silicone oil is formed (Fig. 10). This makes formerly emmetropic eyes hypermetropic by +6 to +7 diopters.122 Myopes with a lens present notice considerable improvement in sight and may become nearly emmetropic. Most eyes that have silicone oil in contact with the lens develop a cataract and thus become aphakic. Because aphakic eyes completely filled with silicone oil such that the oil touches the cornea develop opaque corneas, the most important case is that in which silicone oil fills the aphakic eye to the level of the iris diaphragm.123 The aphakic silicone oil meniscus has a positive curvature over the pupillary aperture and induces a hyperopia that may make the eye nearly emmetropic. Because the silicone oil–aqueous interface is liquid, the curvature of this refractive surface is subject to change with posture and can be highly variable. Patients who have relatively good vision with a silicone bubble in their eye often have much improved visual acuity after oil removal and adequate refraction. Theoretical calculations have shown that the meniscus-style intraocular lens is the preferred intraocular lens in the presence of a vitreous filled with silicone oil because the meniscus style minimizes the change in refractive power on removal of the silicone oil.124
Silicone oil is a poor conductor of electrical current and has a high volume resistivity. The volume resistivity depends on the amount of metallic catalyzer remnants used at the time of manufacture and varies between 2 × 1014 and 3 × 1015 ς-cm. Early reports indicated that the electroretinogram was extinguished when silicone oil was placed in the eye. This was initially interpreted as toxic effect of the silicone oil. When the silicone oil was removed, the normal electroretinogram could be recorded again.125 Subsequently, higher amplification of the electrical signals proportional to the increased resistance of silicone oil demonstrated a normal electroretinogram in the presence of a vitreous cavity filled with silicone oil.
The velocity of sound in silicone oil at ultrasonic frequencies of 7 to 10 MHz is approximately 976 m/s.126 It takes approximately 1.5 times as long for an ultrasound pulse to return through a vitreous cavity filled with silicone oil as it does through one filled with aqueous or vitreous. This makes images appear farther away in eyes treated with silicone oil than in normal eyes. Attenuation by silicone oil is approximately 10 times greater for a 5,000-centistoke oil than for normal vitreous. The attenuation is directly proportional to the viscosity of the silicone oil and is less important for 1,000-centistoke silicone oil. If the eye is partially filled with silicone oil, the silicone oil–water interface is highly reflective and easily visualized on both the A- and B-scan devices. In phakic cases, the lens transmits sounds faster in both aqueous fluids and silicone oil. The lens is more ultrasonically defocusing with silicone oil–filled eyes than with aqueous-filled eyes. The smoothness of the silicone oil–retina interface causes less scattering of the ultra-sound pulse. Because the ultrasound pulse is reflected away from the transducer, loss of signal from the peripheral retina results. These changes lead to an extremely distorted B-scan image that requires caution in interpretation. Similarly, the A-scan time intervals in distance measurements require adjustment for adequate interpretation.
Biocompatibility is one of the most important and most controversial issues for silicone oil. Because silicone oil is intended to remain in the eye for 3 months or longer, its effect on the eye becomes extremely important. The physical drying effect or deprivation of nutrients resulting from blockage of aqueous circulation is an accepted problem. The notion that emulsification of silicone oil leads to complications is well accepted. The degree of biologic versus physical mechanism in the development of emulsification is interpreted in several ways. Tissue toxicity of silicone oil has been a major area of controversy since silicone oil was first used in the vitreous. Whether silicone oil suppresses or stimulates PVR and perisilicone oil proliferation is controversial. When silicone oil is injected into the phakic postvitrectomy eye, the incidence of cataract is 62% with a follow-up of 1 month or more. If the silicone oil is left in the eye indefinitely, cataracts are even more likely to develop, depending on whether there is a protective layer of anterior vitreous between the silicone oil and the posterior surface of the lens. Because silicone oil is not found within the lens material proper, cataract formation is caused by deprivation of nutrients to the posterior capsule of the lens and possibly by a drying or dehydration effect.127 When the aphakic eye is filled with silicone oil, the corneal endothelium is destroyed, leading to eventual opacity of the cornea. Dehydration of the cornea by the waterproof quality of the silicone oil can maintain corneal clarity even in the absence of the corneal endothelium. However, when the silicone oil is removed, the cornea immediately opacifies as a result of stromal swelling.
We have already dealt with the physical origins of emulsification. Droplets develop with ocular motion. The reduction of the surface tension of silicone oil probably results from biologic surfactants absorbed from the vitreous. Once the smaller droplets and bubbles are formed, they may be imbibed by macrophages or physically invade tissue. Silicone oil-filled macrophages can block the trabecular meshwork, causing glaucoma. There is little doubt that silicone oil can be imbibed by macrophages and by retinal pigment epithelial cells that are not covered by the neurosensory retina. Many investigators find that if the retina is flat and covering the retinal pigment epithelium, it resists invasion by silicone oil.128 Other investigators find that silicone oil may be phagocytized by Müller cells of the retina. Certainly, this has been observed by some investigators, especially in animal models, with low viscosity silicone oils or silicone oils with low-molecular-weight components.129–132 Because there are numerous reports of relatively well-preserved vision in eyes filled with silicone oil for decades, it is safe to say that silicone oil does not always invade the attached retinal tissue, or that if it does, it does not cause rapid degradation of function.
Several investigators state that there is no direct toxic effect of medical-grade silicone oil on the retina or other tissues of the eye. Although silicone oils have caused increased permeability of the cornea to inulin and dextran, no such increased permeability is found with the retina. A similar evaluation of the blood–aqueous barrier with fluorescein showed no difference between vitrectomized rabbit eyes and vitrectomized rabbit eyes filled with silicone oil.133,134 This indicates that the blood–aqueous barrier disruption mainly resulted from the surgery. A more recent notion is that by purifying medical-grade silicone oil sufficiently, any toxicity of the oil can be minimized.135,136 In past clinical studies, silicone oils have frequently been poorly characterized, particularly regarding the percentage of low-molecular weight components, amount of residual catalyzers, and amount of reactive hydroxyl end groups present. Low-molecular-weight siloxanes, particularly cyclosiloxanes, have been specifically shown to be inflammatory in the eye. When octamethyl-cyclotetrasiloxane was injected into the anterior chamber of rabbits, corneal edema, corneal opacification, and marked fibrin formation were noted around the globule.137 These symptoms worsened and vascularization of the cornea developed. In the rabbit eye, the lowest molecular weight components of the silicone oil disappear faster than the larger low-molecular-weight components. Because of the increased volatility of low-molecular-weight components of the silicone oil, they may diffuse into the surrounding tissue and cause toxic and inflammatory reactions. Because the anterior segment is cooler than the posterior segment, the low-molecular-weight components could condense in the anterior chamber and account for the hyperoleon occasionally seen in phakic patients. The most toxic low-molecular-weight siloxanes have a molecular weight below 800 daltons. Higher purity silicone oils also seek to minimize or eliminate components of polydimethylsiloxane weights between 800 and 2000 daltons.
Removal of catalyst remnants left over from the manufacture of the polydimethylsiloxane is directed at reducing toxicity, although no specific toxic effects from catalysts have been demonstrated. The presence of metallic remnants can be measured by the volume resistivity of the silicone oil, which should be higher than 10 to the 14 ς-cm. Polydimethylsiloxane molecules with hydroxyl end groups lead to earlier and easier emulsification of the silicone oil. For this reason, better medical-grade silicone oils seek to minimize hydroxyl end groups. Carefully purified silicone oil with a viscosity of approximately 5,000 centistokes will have few if any of the toxic reactions described earlier. These oils should be specifically tested for cell toxicity by the lot using the growth inhibition method.
The recurrence of fibrous tissue in PVR detachment cases, particularly around the silicone oil bubble, has been attributed to silicone oil. Certainly the morphology of perisilicone oil proliferation around the bubble itself is due to the silicone oil acting as a liquid scaffold.138 The injection of 25,000 fibroblasts into the vitrectomized rabbit eye created retinal detachments at a rate that was the same for silicone oil and 50% SF6–air mixtures.139 A more recent experiment with rabbits using gas compression for vitrectomy and 15,000 pigment epithelial cells showed a significant increase in the formation of PVR detachments in rabbit eyes filled with silicone oil as opposed to perfluoropropane.140 Clinically, silicone oil does not appear to lead to greater recurrence of PVR than perfluoropropane. Both may equally foster proliferation through concentration of proliferative factors near the retinal surface, stimulation of increased proliferative factors, or a direct proliferative effect.141
No reports of primary allergy to any intraocular silicone oil compounds have been found.142 Patients sensitized to silicone can be detected by a sensitizing patch test. Antibodies to solid Silastic ventriculoperitoneal shunts have been detected in the blood of some children. Inflammation developed around these tubes and was initially thought to be infection.143 This reaction is unusual, and it is hoped that it will not lead to abandonment of all silicone-based medical devices. Connective tissue syndromes, notably scleroderma, have been reported to be related to breast augmentation with silicone prosthesis. These reactions are seen 2 to 21 years after silicone augmentation mammoplasty.144 Removal of the prosthesis resulted in improvement in some individuals.145 Similar reactions have not been reported for the ophthalmic use of liquid or solid silicone devices. The fluorinated silicone oils generally have all the problems of polydimethylsiloxane as well as a few more. Fluorinated silicone oils have a higher polarity than silicone oil, which may influence the absorption of emulsifiers on the oil surface. When fluorinated silicone oil is injected into the foot pad of rats, it creates a monocytic, leukocytic, and giant cell reaction similar to that of silicone oil. However, there is an additional eosinophilic reaction with the fluorinated silicone oil.146
Emulsification occurs much more frequently in fluorinated silicone oils than in polydimethylsiloxane despite high viscosity and removal of low-molecular-weight components.147 Animal experiments in which fluorinated silicone oil did not emulsify have shown no unusual damage to the retina for periods of up to 6 weeks.148 Damage does occur whenever emulsification is present. Fluorinated silicone oil emulsifies more rapidly and frequently in the eye than polydimethylsiloxane. It has been reported that the hydrolysis of fluorinated silicone oil occurs at room temperature, giving rise to linear and cyclic low-molecular-weight components. This may contribute to direct tissue toxicity and to the development of emulsification despite prior purification.149 Because of the frequent reports of emulsification, inflammation, and retinal destruction with fluorinated silicone oil, fluorinated silicone oil has never achieved wide acceptance or usage.
REMOVAL OF SILICONE OIL
In the patients in Cibis and colleagues' original study,104 continued progression of complications was shown for up to 15 years after surgery. In this series, vitrectomy was not used and removal was not considered as an option. Because silicone oil is a foreign substance and because it is not reabsorbed by the eye, the surgeon would ideally remove it in all cases. Unfortunately, even in carefully selected cases retinal redetachment occurs immediately or shortly after removal of silicone oil in 3% to 33% of cases. The actual number of patients from whom silicone oil has been removed varies from 21% (in patients who had retinal detachments combined with diabetic retinopathy) to 57% (in a series of mainly PVR detachments). The silicone oil is removed because complications associated with prolonged retention of an intraocular foreign substance are anticipated. On the other hand, 40% or more of the patients retain the silicone oil because of fear of redetachment.
Patients in the nonremoval group include those who have a peripheral traction detachment or rhegmatogenous detachment that the surgeon suspects will lead to immediate redetachment on removal of the silicone oil. The surgeon is in the position of offering the patient more surgery with retention of silicone oil so that the silicone oil can be removed at a later date. Because many of these patients have already had several operations before stabilization of the retina with silicone oil, they are often reluctant to undergo further surgery. Also in the nonremoval group are patients who will experience phthisis caused by hypotony if the silicone oil is removed. There may be some sight even in the hypotonus eye because the retina is attached behind the silicone oil. Although surgery to remove the fibrous tissue over the ciliary process may be successful in restoring pressure in some instances, in many cases, it is not. Another category of the nonremoval group are patients who have a hopelessly detached and atrophic retina, in which case further surgery to restore vision is not warranted. In such an eye, removal of silicone oil often leads to immediate phthisis and a rather severe cosmetic problem. Finally, some patients are potential candidates for removal of silicone oil but will simply decline further surgery until there are signs of complications from the silicone oil. In a series of 58 eyes undergoing tamponade for complicated retinal detachment, there was no significant difference in the redetachment rate and the postoperative visual acuity for patients having oil removal before 6 months versus those having removal more than 6 months after silicone oil injection.150
One indication for removal of silicone oil is glaucoma, which appears to be associated with emulsification. If the emulsified oil is removed, the glaucoma is manageable with medical therapy in 70% of cases.151,152 If the silicone oil is in contact with the cornea, a corneal graft will not survive for very long unless the oil is removed.
Silicone oil should be removed if there is a reasonable chance that the retina will stay reattached after the oil is removed. This decision should be made carefully because even a short period of vision is better than immediate redetachment.153 If the retina stays attached in the period immediately after silicone oil removal (approximately 2 months), it will probably remain attached. The safest way to remove silicone oil is to insert an infusion cannula connected to BSS through the pars plana: make an incision in the limbus or, in phakic cases, through the pars plana; and allow passive egress of the silicone oil while infusing BSS. One refinement of this technique is to do an air–fluid exchange after completion of the silicone oil–fluid exchange. This allows small bubbles of silicone oil trapped behind the iris to fall backward. Silicone oil can then be aspirated from the fluid surface or washed out of the eye through the limbal or pars plana incision. This technique, however, does not reduce the incidence of complaints of floaters from residual silicone oil.154 Silicone oil can also be actively aspirated with a 20-gauge needle or stiff cannula. This aspiration can be done using a syringe suction or an automated suction unit. During this procedure, hypotony and additional manipulations of the globe, such as cryotherapy or buckling, should be performed after the sclerotomies are closed to avoid or limit expulsive choroidal hemorrhage.
If the retina should detach after removal of silicone oil, it can often be reattached with additional procedures including reinjection of silicone oil, gas injection, vitrectomy, and scleral buckle.127
INDICATIONS AND TECHNIQUES
Historic Techniques and Retinopiesis
Since the first intravitreal use of silicone oil by Cibis and colleagues, silicone oil has been reserved for cases judged hopeless for other procedures, especially patients in whom repeated attempts at surgical repair have failed.104 Cibis and colleagues also included in their original series eyes with multiple nonmagnetic and toxic foreign bodies and eyes with severe intravitreal hemorrhage. On analyzing their patients further, they found that they fell into three categories: (1) retinal detachments and giant breaks with rolled-over retina, (2) retinal detachment with PVR, and (3) retinal detachment with advanced atrophy and multiple breaks. Using a technique of injection behind preretinal membranes, Cibis and colleagues obtained remarkable results for those days, with return of useful vision in several patients who otherwise would have been abandoned to blindness. This procedure was later named silicone retinopiesis by Watzke,155 who used a similar procedure. Cibis and colleagues noted that vitreous strands needed to be severed before silicone oil injection in PVR cases.
Watzke's later development of this procedure was less encouraging. He believed that only nine of 33 cases could be considered initially successful, and only five of them were able to maintain an attached macula for 3 years or more. He used fluorinated silicone oil as well as regular silicone oil and encountered a great deal of emulsification. He did not describe worse complications with the fluorinated silicone oil at this time. He noted that in most cases only the macula was reattached.
Scott156 continued using nonfluorinated silicone oil in a retinopiesis-type procedure in Great Britain. He used 2,000-centistoke silicone oil and attributed the lower complication rates to the higher viscosity. He operated with the indirect ophthalmoscope, although he was able to use intraocular scissors to cut membranes in some PVR cases.
Constable and colleagues157 used even more viscous silicone oil viscosity of 12,500 centistokes. Their indications included macular hole, giant tear, PVR, trauma, branch vein occlusion with traction, diabetic traction, and stage 5 cicatricial retinopathy of prematurity in one case. They had a 72% reattachment rate, and 92% of the patients had visual acuity of finger-counting or better. They saw no cases of emulsification with this highly viscous silicone oil. The follow-up period ranged from only 3 months to 2 years. A blunt needle with a wide bore ranging from 6 to 18 gauge was required for injection. A regular syringe could be used provided that the liquid silicone oil was preheated to body temperature, otherwise a screw syringe was required. Constable and colleagues believed that viscodissection gave superior results to vitrectomy with preretinal membrane dissection in 1982.
Manschot,158 in Rotterdam, and Alexandridis and Daniel,159 in Heidelberg, stressed results and complications with the use of this procedure. Manschot cites a complicated case requiring enucleation in which there was an inferior oil emulsification level. This implies that fluorinated silicone oils were used. The literature at this time did not emphasize the much poorer tolerance by the eye of the fluorinated silicone oils as opposed to the better tolerance of polydimethylsiloxane.
Vitrectomy and Silicone Oil
The modern era of silicone oil with vitrectomy began in 1979 when Haut in France first combined vitrectomy and silicone oil for tamponade in difficult PVR cases. He stated, “Je pense que la toxicité n'existe pas.” The concept of low toxicity of polydimethylsiloxane and use of vitrectomy signal the beginning of the present era of use of silicone oil. Scott160 commented at this time that pars plana vitrectomy in combination with silicone oil appeared to be a rational method for treating giant breaks, especially those with rolled-over flaps, PVR detachments, and diabetic eyes with detachment even with rubeosis and neovascular glaucoma. In 1982, Zivojnovic and associates109 reported 280 cases with the use of silicone oil in which 80% were done with vitrectomy, whereas the balance were done by the older retinopiesis type procedure.
Retinal detachment with severe PVR has been the most frequent modern indication for the use of silicone oil.110,161 The most authoritative study of silicone oil for PVR is by the Silicone Study Group, which published its results in 1992. This study group published two reports demonstrating the efficacy of silicone oil tamponade.. The first report randomized patients to either vitrectomy with silicone oil or vitrectomy with SF6. The second report randomized to either perfluoropropane or silicone oil. The technique was a modern one. Preretinal membranes were peeled or segmented, and subretinal membranes were divided or removed through a retinotomy or pre-existing break. Scleral buckling was combined with cryotherapy or endolaser to treat the tears. Relaxing retinotomies were used where necessary. Dow Corning Corporation provided 1,000-centistoke oil, but the grade and purity are not cited in this report. Macular attachment was achieved with silicone oil in 80% of the patients versus 60% with SF6. This was found to be a significant difference (p value less than 0.05).
In the second report, in which perfluoropropane gas was randomized against silicone oil, the study was divided into two groups. One group included primary cases not having previous vitrectomy. The other group included those having undergone previous vitrectomy with intraocular gas tamponade. In the primary surgery group, they found no significant difference between perfluoropropane gas and silicone oil in achieving visual acuity better than or equal to 5/200 (1.5/60).* They also achieved macular attachment in 73% of the patients treated with perfluoropropane versus 64% in group 1 and 61% in group 2 for silicone oil. In group 1 eyes followed for at least 16 months, there was a borderline advantage for complete posterior retinal reattachment with the perfluoropropane. It was stated that a longer tamponade of perfluoropropane was the reason for the higher success rate than with SF6. The SF6 study was structured similarly to group 1 in the perfluoropropane study. Looking at this comparison, it is interesting to note that in the perfluoropropane study, only 45% of the patients treated with silicone oil had better than 5/200 vision, whereas in the SF6 study approximately 55% of the patients treated with silicone oil had better than 5/200 vision. Similarly, in the SF6 study, 80% of the patients with silicone oil had macular attachment, whereas in the perfluoropropane study, only 60% of the patients treated with silicone oil had macular attachment at approximately 2 years.
* Metric equivalent given in parentheses after Snellen notation. Subsequent reports have shown valid results with longer follow-up times.162
A randomized prospective trial of silicone oil versus SF6 was reported by Hammer.163 Seventeen patients were randomized to a group treated with silicone oil, and another 17 patients to a group treated with SF6. The mean follow-up time for the patients treated with SF6 was 27 months and for the patients treated with silicone oil, 24 months. These were patients with severe PVR in whom previous vitrectomy and treatment with gas had failed at least one time. Only four of the patients treated with SF6 had macular reattachment. With the silicone oil, in seven patients, the macula remained attached after the silicone oil was removal. An additional four eyes had the macula attached with oil remaining in the eye. Ten patients treated with silicone oil and four of those treated with SF6 had visual acuity of 20/400 (6/120) or better. Purified 5,000-centistoke Adatomed silicone oil was used in all patients in the group treated with silicone oil.
In earlier studies of advanced proliferative retinopathy, Cox and colleagues164 noted in 51 patients that retinal reattachment was achieved in 65% and ambulatory or better vision was restored in 74% of the reattached cases, or 50% of the total cases. They used similar surgical techniques to the silicone oil study group and 1,000-centistoke silicone oil from Holland or other European sources. Follow up varied from 6 to 36 months and averaged 16 months.
Using a purified 5,000-centistoke silicone oil, Kampik and colleagues165 in 1984 reported a series of 49 patients in whom useful vision was achieved in 76% with PVR. The mean follow-up time is unclear. Lean and associates166 reported macular reattachment in 68% of eyes with PVR and visual improvement in 53% with 49 eyes in the study. They noted that more than half of the successful cases showed some residual traction or combined traction and rhegmatogenous component. Follow-up time was a minimum of 6 months. In a study by Lucke and co-workers167 of 210 uncomplicated PVR cases there was 75% macular reattachment at 6 months and 66% at 24 months. At 6 months, 68% had vision greater than or equal to 5/200, and at 24 months, 65% had this visual acuity. This was a very large study and included some patients who had been operated on with the old retinopiesis-type procedure. Twenty-nine of the 210 patients had grade C1 and C2 PVR, giving the impression that silicone oil may have been used more liberally than in other studies.
Responding to the concept that the use of silicone oil tamponade requires balancing long-term complications against the benefit of long-term tamponade, Gonvers168,169 performed a study in which temporary silicone oil tamponade of 4 to 6 weeks' duration was performed in 146 eyes. He achieved retinal reattachment and recovery of useful vision for 6 months after removal of silicone oil in 62% of his patients. However, only 82 patients (56%) were known to have between grade C3 and D3 PVR. Forty-two (29%) were known to have grade C1 and C2 PVR, again suggesting a more liberal indication for silicone oil tamponade than in many of the other studies.
The use of silicone oil in PVR has stimulated the development of some newer approaches. Federman and Eagle170 reported a 360-degree posterior retinotomy in a series of 18 patients. Visual acuity of 20/400 or better was achieved in 22% of the patients. In all instances, the patients had at least two previous pars plana vitrectomies. The median follow up after retinal resection was 31 months. The cases represented nondissectable membranes, intraretinal fibrosis, incarcerated retina, or malpositioned chorioretinal scars preventing reattachment by ordinary techniques. Retinotomy was performed with scissors after full-thickness diathermy and 1,000-centistoke silicone oil was used. Direct silicone oil–fluid exchange was performed without intermediate air exchange. Two circumferential rows of endolaser were placed around the edge of the posterior 360-degree retinotomy.
Peyman describes a technique in which cataract extraction with preservation of the anterior lens capsule is used in conjunction with vitrectomy and silicone oil injection for PVR. Charles171 reports the use of silicone oil for retinopexy avoidance at the time of surgery so that laser can be placed in stages at a later date.
Giant Retinal Tears
The use of silicone oil in surgery for giant tears is reported in the European literature to be highly successful. Lucke167 reports an 84% reattachment at 6 months and an 81% reattachment at 24 months. In one series of 50 uncomplicated giant tears, visual acuity is better than or equal to 5/200 for 78% at 6 months and for 67% at 24 months. Lean166 reports a series of 42 eyes with giant tears greater than 90 degrees of circumferential extent in which retinal reattachment was achieved in 88% and vision improved in 71%. Leaver and colleagues172,173 report a series of 64 giant tears treated with vitrectomy and fluid–silicone oil exchange with a 5-year follow-up. The anatomic success rate was 73%, and 66% achieved visual acuities of 20/200 (6/60) or better. Silicone oil was removed in 73% of the cases. In 10 patients (21%), there was redetachment after silicone oil removal, but they were able to achieve reattachment in seven of these percent with further procedures. In all of these series, fluid–silicone oil exchange was used. Preretinal and subretinal fluid was slowly drained as silicone oil was infused by means of a cannula to prevent posterior slippage of the flap of the giant tear, which can occur during fluid–air exchange.
Severe ocular trauma is another category in which silicone oil is often advocated. Antoszyk and associates174 reported 42 cases of traumatic retinal detachment failing previous vitreous surgery treated with subsequent vitrectomy and silicone oil injection using 1,000-centistoke oil. Posterior retinal reattachment was achieved in 50%, and 28% had visual acuity of 5/200 or better at 6-month follow-up. A final visual acuity of 5/200 or better was obtained in only 12% of the eyes at the last follow-up examination. The average follow-up time was 20 months. Fluid–air exchange was performed before silicone oil injection. Lemmen and Heimann175 reported 11 primary trauma cases in which early vitrectomy with silicone tamponade was performed. The severely injured eyes included those with large multiple intraocular foreign bodies, double perforations, and ruptures. All had vitreous hemorrhage and retinal detachment. Primary retinal reattachment was achieved in seven cases, or 64% of the eyes. Traction detachment caused by PVR developed in three eyes 6 to 9 months postoperatively. Six eyes had visual acuity between 1/25 (6/150) and 0.6 (6/10). Lucke167 reported 39 cases of perforating injury with a 71% reattachment rate at 6 months and 53% at 24 months. Visual acuities of 5/200 or greater were obtained in 56% at both 6 and 24 months. Silicone oil was removed in 49% of these patients.
Proliferative Diabetic Retinopathy
Proliferative diabetic retinopathy, particularly with retinal detachment, has been another area in which silicone oil has been used extensively. Rinkoff and co-workers176 report 10 eyes with rhegmatogenous retinal detachment and advanced PVR after vitrectomy for proliferative diabetic retinopathy. With a minimum follow-up of 1 year, only three patients achieved total retinal reattachment. Only two patients achieved 5/200 or better vision. Although the prognosis was poor, it was believed that the patients would have no chance of retinal reattachment by any other method. McLeod177 reported 42 diabetic retinal detachments treated with vitrectomy and silicone oil tamponade using 1,000-centistoke silicone oil. The indication in this series was rhegmatogenous retinal detachment associated with residual or reparative epiretinal fibrosis. Anatomic reattachment was achieved in 22 eyes for a total of 52%, and 16 eyes showed a significant visual improvement over the preoperative visual acuity for a total of 38%. Minimum follow up was 6 months, although patients were recruited over a 4-year period. The decision to inject silicone oil was made during surgery depending on the conditions of surgery. In 35 of the 42 cases, the injection was made at the initial surgery for diabetic retinopathy. McLeod's study did not show a clear-cut influence of vitreal silicone oil on postoperative rubeosis irides.
A series of 37 diabetic retinal detachments in 34 patients was reported by Brourman and associates.178 These patients had either severe neovascular glaucoma or recurrent retinal detachment from surgery for proliferative diabetic retinopathy that failed to respond to conventional vitrectomy, membrane peeling, gas tamponade, and photocoagulation. They divided their patients into group 1, which included 15 eyes with severe traction or combined rhegmatogenous and traction detachment without rubeosis, and group 2, which included 22 eyes with detachment and preoperative rubeosis. In group 1, reattachment was maintained in 87% of the eyes and ambulatory vision in 27% of the eyes. In group 2, anatomic reattachment was maintained in only 59% and ambulatory vision in 23%. In group 2, the mean follow-up time was 13 months and ranged from 6 to 36 months. One thousand-centistoke silicone oil was injected in all eyes. Anterior loop traction was invariably present and surgically treated. A peripheral relaxing retinotomy was performed in seven eyes with intractable retinal traction. Fourteen reoperations were performed on 11 eyes after silicone oil injection. Regression of iris neovascularization was demonstrated in 8 of 22 eyes for a total of 36%. Visual success, however, was only reported in three of the eight eyes with regression of iris neovascularization.
Gonvers179 reported a series of 132 eyes with retinal detachment from advanced proliferative diabetic retinopathy treated with vitrectomy and 1,000-centistoke silicone oil tamponade. The membranes were dissected with vitrectomy technique. Silicone oil was removed in 64 or 49% of the eyes that achieved a vision of 5/200 or better. An additional 17 (13%) of the eyes had improved vision, but the oil could not be removed. Fifty-one (38%) of the eyes were judged to be surgical and visual failures. The final goal was to remove the silicone oil a few weeks after vitrectomy to avoid long-term complications of intraocular silicone oil. One hundred twenty-nine of the eyes had a follow up of more than 6 months. Gonvers noted that rubeosis was prevented in all eyes that had both successful reattachment and visual improvement. It was thought that the prevalence of rubeosis and neovascular glaucoma was decreased by silicone oil even when anatomic failure occurred. The silicone oil procedure was used mainly as a primary procedure in this study. The 132 eyes represent approximately 50% of the total diabetic vitrectomies performed during this period. This would indicate a much more liberal use of silicone oil than in previous study by Brourman and co-workers.178
Karel and Kalvodova180 from Czechoslovakia reported vitrectomy and silicone oil tamponade in 110 eyes of 98 diabetic patients. Seventy percent of the cases performed were during primary diabetic vitrectomy and 30% as a secondary operation. The mean follow-up time was 53 months, with a range of 24 to 72 months. Anatomic success was achieved at the end of surgery in 95 (86%) of the eyes and at the end of the follow-up period in 63 (53%) of the eyes. Visual acuity of finger-counting or better was reported in 32% of the eyes. Although 67% of the operations were judged successful at 6 months, by 24 months, the success rate had fallen to 46%, and by 72 months, to 50%. Failure of the operation was due to neovascular glaucoma in 10 eyes (9%). The authors believed that their successful results were long lasting and improved the quality of life of many diabetic patients.
Azzolini and associates181 used silicone oil during primary vitrectomy for traction detachment in diabetic retinopathy in 20 eyes. They used 1,000-centistoke silicone oil and endophotocoagulation in conjunction with vitrectomy. They studied the iris with fluorescein angiography. Breakdown of the blood–iris barrier and iris neovascularization improved or stabilized in 40% and worsened in 60% of all eyes, including aphakic eyes. Aphakia and postoperative inflammation were significantly correlated with worsening iris microangiopathy. There was no significant correlation with recurrent detachment. Neovascular glaucoma occurred in only one case (5%), suggesting a lower incidence in silicone eyes, than in other series in which silicone oil was not used.
MACULAR HOLE, CHOROIDAL COLOBOMA, AND UVEITIS WITH HYPOTONY
Silicone oil in conjunction with vitrectomy has been used to treat patients with macular hole. Haut and colleagues182 report a series of 35 mainly myopic patients. Fluid–silicone oil exchange was performed while fluid was aspirated through the macular hole with a fine needle if the hole was large enough. If vision was better than 1/20 (6/120), the silicone oil was left in place. If visual acuity was worse than 1/50 (6/300), the edges of the macular hole were photocoagulated and silicone oil was removed 4 to 5 weeks later. Silicone oil has also been used as a substitute for a gas bubble to treat nonmyopic macular holes. The advantage is that face-down positioning is not required. However, the surgeon must remove the silicone and manage complications of silicone oil tamponade.183
Gopal and co-workers184 reported a series of 17 eyes with retinal detachment associated with choroidal coloboma treated with vitrectomy and 1,000-centistoke silicone oil tamponade. At the 2-month follow-up visit, there was 100% anatomic success, and 71% of the patients recovered visual acuity of 10/200 (6/120) or better. Of 11 eyes with more than 6 months follow up, 81% remained anatomically attached and 55% had a visual acuity of 10/200 or better. The mean follow-up time was 10.76 months. These patients were all diagnosed as having a retinal detachment caused by a retinal break over the coloboma. Vitrectomy was performed with membrane peeling when necessary. Internal drainage was done through the break in the colobomatous area. Fluid–air exchange was performed before silicone oil injection. Endolaser was performed in two or three rows of overlapping burns along the entire margin of the coloboma and around associated peripheral breaks. When the coloboma involved the optic disc, the functional border of the disc was left untreated. The retinal break was usually located in the center of the colobomatous area, although some breaks were found on the slope of the colobomatous area. A 33% recurrence of detachment was noted after removal of silicone oil.
Morse and McCuen185 reported use of silicone oil in uveitis with hypotony in five patients. At the 6-month follow-up visit, visual acuity was improved in all five eyes and intraocular pressure increased in four of the five eyes. At the last follow-up examination, which averaged 19 months, the intraocular pressure improved in four eyes but the visual acuity improved in only three. The diagnoses included toxoplasmosis, psoriatic arthritis, Vogt-Koyanagi-Harada disease, and undetermined (1 eye). A 360-degree retinotomy was required in two cases, and retinal tacks and cyanoacrylate tissue adhesive were used in one case. Although the authors believed that this technique was beneficial, they also noted that it was of limited benefit and mostly palliative.
Cytomegalovirus Retinitis and Acute Retinal Necrosis
Vitrectomy and silicone oil have been found to be helpful in the treatment of retinal detachments caused by cytomegalovirus (CMV) chorioretinitis in patients with acquired immune deficiency syndrome (AIDS) and with acute retinal necrosis. Sidikaro and associates186 reported that in 68 patients with AIDS or retinal necrosis infections, 27 eyes in 16 patients developed rhegmatogenous retinal detachment. CMV retinopathy was present in 75%, whereas 19% had presumed herpes simplex retinopathy and 6.2% had toxoplasmic retinochoroiditis. Retinal detachment was bilateral in 69%. The retina was reattached successfully in 91% of operated eyes. The authors used various techniques including pneumatic reattachment, scleral buckling, vitrectomy, and silicone oil injection. Only three of the 11 eyes with CMV retinitis were treated with vitrectomy and silicone oil injection. In retinal necrosis, multiple atrophic holes, large areas of marked retinal thinning, preretinal fibrosis, and broad areas of vitreous traction presented a considerable surgical challenge. Three patients with detachment resulting from herpes simplex retinopathy had their retinas successfully reattached with vitrectomy and silicone oil. Vitrectomy with silicone oil was the most appropriate treatment for these patients because of the complexity of the detachments and the tenuous medical status of the patients. Laser demarcation or scleral buckling might still be appropriate in simpler cases. The median interval between rhegmatogenous retinal detachment and death was 17 weeks. Visual acuity results were poor, mainly because of involvement of the macula by retinitis. More than half of the eyes maintained 5/200 vision or better up to the time of the patient's death.
Orellana and co-workers187 reported a series of 31 patients with retinal detachments caused by CMV retinitis. The patients were treated with laser demarcation, scleral buckle, pars plana vitrectomy, or no therapy. Photocoagulation and scleral buckling were successful when there was no active retinitis. If the patient had extensive active disease in the posterior pole and total detachment, pars plana vitrectomy and silicone oil were used. This was done in two of the 39 eyes and was successful in both cases. Orellana and co-workers noted that the median time for diagnosis of retinal detachment after AIDS diagnosis was 420 days and that the median time from diagnosis of CMV retinitis to retinal detachment was 150 days. Median survival from the time of detachment diagnosis was 3 months. They also noted that the most important benefit of silicone oil is that it ensures anatomic reattachment despite continuing active disease.
Jabs and colleagues188 reported a series of 38 patients with CMV retinitis who developed retinal detachment. Vitrectomy with 5,000-centistoke silicone oil was performed as the initial procedure and was thought to be the most effective approach. Anatomic reattachment was achieved in 70% of the patients, but visual acuity of 5/200 or better was achieved in only 20% of the patients. The surgery was technically difficult because of incomplete posterior vitreous detachment. Intraocular air tamponade was performed, and laser photocoagulation was placed around all the breaks. In some cases, laser treatment was used to demarcate the inferior peripheral retina in several confluent rows, anticipating the level of the postoperative inferior silicone oil meniscus. The median survival time of the patient after the diagnosis of retinal detachment was 9 months. Six vitrectomies performed without the use of silicone oil failed. Use of silicone oil was substantially more likely to reattach the retina (p = 0.01). The reasons for poor visual results were thought to be extensive retinal damage from CMV retinitis, previous detachment of the macula, refractive properties of silicone oil, and in only one case, cataract. The patient with cataract underwent cataract surgery and still had limited visual acuity because of retinal disease. The crystalline lens was left to maximize visual rehabilitation and minimize corneal injury. Patients treated with anti-CMV therapy appeared to have significantly fewer detachments than those untreated. Jabs and colleagues suggested a clinical trial using laser photocoagulation to prevent detachment in high-risk patients. Better therapy for HIV and CMV retinitis has allowed much longer survival times after the diagnosis of HIV. Removal of silicone oil due to long-term complications of the silicone oil and minimization of the use of oil in these patients is a direct result of the improved antiviral therapies since the time of the above-mentioned reports.
COMPLICATIONS IN THE USE OF SILICONE OIL
Accepted complications of silicone oil consist of cataract, glaucoma, keratopathy, absorption of silicone oil by silicone intraocular lenses, migration of silicone oil into the optic nerve and rarely into the brain, and emulsification. Retinopathy has been shown in some cases, but in other long-standing cases, it appears not to be present. Recurrent retinal detachments are the most frequent cause of failure in vitrectomy with silicone oil, but whether proliferation leading to redetachment is directly attributable to silicone oil is controversial.
Cataract is an inevitable consequence of silicone oil coming into contact with the posterior lens capsule if the silicone oil is in the eye long enough. If the silicone oil is withdrawn after a few weeks, often the cataract will continue to develop. In the retinopiesis procedure, a layer of vitreous was more likely to prevent direct contact between the silicone oil and the lens. Chan and Okun189 identified a group of retinopiesis patients who had an average cataract formation time of 5.8 years. They reported one patient who had ambulatory vision for 15 years until a dense cataract formed. In postvitrectomy cases, the lens may occasionally remain clear for a period of time.
Direct contact with the silicone oil covering the posterior lens and depriving it of nutrients is thought to be the cause of the cataract.190 If the oil is going to be removed during cataract extraction, a straightforward extracapsular extraction with intraocular lens implantation is performed. If oil is retained in the eye, either an extracapsular or intracapsular cataract extraction can be performed.191 As noted earlier, biometry to calculate the power of the intraocular lens in silicone-filled eyes can cause errors of deviation of refraction, especially in highly myopic eyes.192 Silicone intraocular lenses should be avoided, especially if silicone oil is retained or if reinjection with silicone at a later date is a possibility. Silicone intraocular lenses develop condensation on the posterior surface after air–fluid exchange, leading to poor visualization.193 Silicone intraocular lenses during silcone oil vitreous tamponade absorb silicone oil, which results in reduced clarity and altered refractive properties of the intraocular lens.194 Glaucoma can arise in several different ways from the use of silicone oil.195,196 In aphakic patients, it is necessary to do a peripheral iridectomy at the 6 o'clock position to prevent silicone oil from being forced into the anterior chamber, causing pupillary block glaucoma.197 If there are lens remnants or if the eye is inflamed, a peripheral iridectomy at the 6 o'clock position may close, precipitating pupillary block glaucoma. Yttrium-aluminum-garnet (YAG) laser treatment will usually open the 6 o'clock peripheral iridectomy, but occasionally, a surgical procedure may be required to open it. Despite high intraocular pressures, the cornea may remain clear because silicone oil is preventing edema fluid from entering the posterior cornea.
Even the earliest form of emulsification, evidenced by microdroplets in the anterior chamber fluid or by small creamy areas of emulsification seen in the superior equatorial retina, may be associated with silicone oil–induced glaucoma. There is a high correlation between the quantity of silicone oil in the anterior chamber and high pressure in vitrectomized eye with retained silicone oil tamponade.198 As noted previously, histopathologic examination has shown macrophages filled with silicone oil blocking the trabecular meshwork channels. In such a case, the silicone oil should be removed. If it is necessary, fresh high-purity silicone oil may be reinjected. Frequently, the glaucoma will resolve or be manageable with medical therapy after the silicone oil is removed.
Peripheral anterior synechiae may also be encountered in aphakic patients who tend to sleep on their backs. In this case, the oil floats upward, pushing the peripheral iris against the trabecular meshwork. The angle forms peripheral anterior synechiae, slowly “zipping up” the entire angle. If the condition is detected early enough, the patient is reminded to lie face down and to avoid the face-up position as much as possible. In severe cases, a filtering procedure requiring removal of silicone oil or a glaucoma valve procedure may be required.
Neovascular glaucoma is encountered in diabetics with residual peripheral detachment. Reattachment of the retina and additional laser or cryopexy coagulation of the avascular retina may help. Medical therapy may control residual glaucoma, but filtering procedures or glaucoma valve procedures may be required. Silicone can drain form the vitreous cavity to the subconjunctival space through the glaucoma valve, resulting in loss of oil tamponade and elevated intraocular pressure.199 In cases in which silicone oil must remain in the eye, cyclocryotherapy may be required to control the intraocular pressure. In a series of 43 patients requiring incisional surgery for glaucoma patients who had removal of oil alone were more likely to require further glaucoma surgery, whereas those that had combined oil removal and glaucoma surgery were more likely to have hypotony. 200
Corneal endothelial keratopathy in the form of severe corneal edema and corneal decompensation occurs whenever silicone oil fills most of the anterior chamber for more than a few weeks. One experimental study showed a 40% reduction of endothelial density in the area of silicone oil contact within 6 days in rabbits and cats.201,202 Keratopathy in the form of striate keratopathy, areas of translucency, corneal vascularization, and band keratopathy may be seen. Band keratopathy is frequently seen, even in phakic eyes with no silicone oil in the anterior chamber. Corneal decompensation has been reported in 4% to 10% of patients having silicone oil and vitrectomy. Penetrating keratoplasty may be required in severe cases. In one series of 14 corneal transplantation patients, the frequency of graft failure was 25% when silicone oil was removed at the time of keratoplasty and 67% when silicone oil was retained in the eye.203 There was a mean graft survival of 25 months, with a range from 2 to 61 months. If silicone oil remains in contact with a corneal transplant, the corneal transplant will fail because of contact with the oil. Graft failure is almost inevitable in corneas that have preoperative corneal neovascularization and in hypotonous eyes. Iris neovascularization also is a significant risk factor for graft rejection.
Emulsification of the silicone oil probably depends on the relative purity of silicone oils. With a 20-centistoke viscosity, emulsification occurs within a few weeks to months. If 1,000-centistoke silicone oil is used, even if it is highly purified, tiny oil droplets that are the precursors of gross emulsification are present in 100% of cases at 1 year. With 12,500-centistoke silicone oil, one investigator found no emulsification, with a follow-up time ranging from 3 months to 2 years. Because of the potential development of glaucoma and retinopathy, if emulsification occurs, it should either be dealt with immediately or, if the initial complications are not too severe, one should begin thinking about a time when the silicone oil will have to be removed or replaced.
Hypotony is a complication that frequently results in failure of silicone oil procedures. It can be associated with keratopathy and graft failure because it brings silicone oil into contact with the cornea in aphakic cases. Hypotony is equally frequent with long-acting gases and silicone oil, as noted in the second report of the silicone oil study. Hypotony is probably not due primarily to silicone oil but is secondary to confining proliferative factors to the area of the ciliary body, physically flattening the ciliary processes against the ciliary body through buoyancy, or in allowing PVR to develop to an extreme that would not otherwise be noticed without successful tamponade of silicone oil.
Retinopathy occurs at a microscopic level in some cases. It is more prevalent with low-molecular-weight silicone oils and with fluorinated silicone oils. Imbibition of silicone oil by bare retinal pigment epithelium, retinal macrophages, and fibrous tissue on the retinal surface is observed. The use of higher viscosity and pure silicone oils can maintain retinal function over several years, which implies that retinopathy may not be present, or if it is present, it is not functionally impairing when the retina covers the retinal pigment epithelium.
Recurrent retinal detachment is the most common cause of failure of silicone oil procedures. Recurrent retinal detachment is usually caused by reproliferation of fibrous tissue on the surface, in the subretinal space, and around the silicone oil bubble itself. If the macula remains reattached and the fibrous tissue stops contracting, no action is required. If removal of silicone oil is required or if the macula becomes detached, reoperation to remove the fibrous tissue is required. When perisilicone oil proliferation occurs around the silicone oil bubble, several months should elapse before reoperation so that the fibrous membranes can mature and be easily dissected.204 A substantial amount of work has been done using pharmacologic mechanisms, either within the silicone oil or at the time of surgery, to inhibit the proliferation of fibrous tissue. Uncontrolled series of patients with 5-fluorouracil and daunomycin indicate some promise. Sustained release devices show promise of minimizing toxicity of the inhibitors.205,206 A randomized study on the effectiveness of daunomycin to inhibit reproliferation conducted in Germany showed that the use of daunomycin decreased the number of reoperations but did not improve visual acuity results.207 A randomized study conducted in Great Britain showed that a combined infusion during vitrectomy of 5-fluorouracil and low-molecular-weight heparin decreased the rate of occurrence of PVR in primary detachment cases, but did not improve results in established cases of PVR.208
Silicone oil can migrate into the retrolaminar optic nerve in 24 % of eyes enucleated after silicone tamponade.209 Rarely, intraocular silicone can migrate into the brain.210 Intraconjunctival silicone oil inclusions have been reported in one case. The oil was thought to have migrated through the sclera or trabecular meshwork.211
FDA STATUS AND COST
In the United States, silicone oil usage was surveyed by mail questionnaire to the two largest retinal and vitreous associations or societies in the United States.212 The results were as follows: 287 (53%) of the questionnaires were returned. Sixty-one percent of those who performed vitreous surgery stated that they used silicone oil. Ninety-six percent of the respondents believed that silicone oil was an acceptable standard of care. Eighty-five percent of the respondents who used silicone oil used it for PVR. Seventy-eight percent used it for proliferative diabetic retinopathy with PVR. Forty-seven percent used it for primary repair of giant tears. Twelve percent used it for CMV-related detachments. (Because CMV-related detachment was a write-in response, the survey may underestimate the actual usage of silicone oil for CMV retinal detachments.) Forty-five percent of the respondents preferred 1,000-centistoke silicone oil. Thirty-two percent preferred 5,000-centistoke silicone oil. Twenty-three percent chose viscosity based on the surgical indication. The FDA has approved both 1000 centistoke and 5000 centistoke silicone oil for retinal tamponade. The chemical stability of the 5000 centistoke silicone oil has been shown to be stable after prolonged clinical use in the human eye.213
|PERFLUOROCARBON LIQUIDS AS VITREOUS SUBSTITUTES|
|Interest in biologic applications of perfluorocarbon liquid for oxygen-carrying
ability and as a blood substitute was demonstrated by
Clark and Gollan in 1966.214 The first use of liquid perfluorocarbon as a vitreous substitute was reported
by Haidt and co-workers in 1982.215 In 1984, Clark216 received a patent for the use of liquid perfluorocarbons in the eye, which
included vitreous replacement with perfluorocarbon liquids. Zimmerman
and Faris217 published an abstract on the use of a mixture of N-perfluorocarbon
liquids as a vitreous substitute in 1984. Since 1987, Chang218 has published numerous papers advocating the use of perfluorocarbon liquids, especially
perfluoro-n-octane, as an intraoperative
tool to be removed at the end of surgery. Nabih and colleagues219 have developed the more viscous perfluorophenanthrene liquid as a short-term
The perfluorocarbon liquids are immiscible and have a surface tension of approximately 14 to 16 dynes/cm measured against air (Table 6). Perfluorotributylamine has a surface tension of 56 dynes/cm measured against water.218 This is roughly comparable to the surface tension of silicone oil against water. Perfluorocarbon liquids are also immiscible with silicone oil.
Clinically, the most remarkable property of the perfluorocarbon liquids is the specific gravity, which is higher than that of water. Typically the specific gravities range from 1.7 to 2.03. The intraoperative uses of perfluorocarbon liquids depend on their higher specific gravity, because it enables the fluid to settle posteriorly, opening folds in the retina while expressing subretinal fluid anteriorly through pre-existing retinal breaks.
A tamponade pressure on the inferior retina can be calculated by subtracting the specific gravity of the aqueous liquid from that of the perfluorocarbon liquid and multiplying by the height of the overlying perfluorocarbon liquid column. The tamponade pressure in the downward direction for the perfluorocarbon liquids is thus 12 to 14 times greater than that for silicone oil in the upward direction for equivalent size bubbles.
The viscosity of the perfluorocarbon liquids ranges from 0.8 to 8.0 centistokes. Some related perfluoropolyethers have viscosities up to 500 centistokes but are not well tolerated clinically. The lower viscosities of the perfluorocarbon liquids used clinically allow them to be injected and removed easily from the eye with low-pressure gradients.
Vapor pressure varies from less than 1 mm Hg for perfluorophenanthrene to 57 mm Hg for perfluoro-n-octane at 37°C. The high vapor pressure of perfluoro-n-octane and perfluoroethylcyclohexane allows rapid evaporation of small remnants of the liquid if fluid–air exchange is performed after flattening the retina with perfluoro-n-octane.220
The refractive index of perfluorocarbon liquids varies from 1.33 for perfluorophenanthrene to 1.27 for perfluoro-n-octane. Because the refractive index of the aqueous liquids is 1.33, the difference in refractive index between perfluoro-n-octane and aqueous is significant enough to allow easy visualization of a water–perfluoro-n-octane interface. The refractive index for perfluorophenanthrene is the same as water; therefore, the interface is difficult to visualize. The refractive indexes of perfluorotributylamine (1.29), perfluoroethylcyclohexane (1.29), and perfluorodecalin (1.31) are intermediate between perfluoro-n-octane and perfluorophenanthrene.
The velocity of sound for perfluoro-n-octane was found to be 556.5 m/s.221 Retained perfluorocarbon droplets seen postoperatively give reverberation artifacts similar to those seen with BBs.
Perfluorodecalin and perfluorophenanthrene have been shown to have high transparency to light in the visible spectrum. They present no obstacle to laser photocoagulation in the visible and infrared spectrum. Initial laser power settings should be kept low because the transmission of the perfluorocarbon liquids is superior to that of Ringer's solution, which is a model for the aqueous- or vitreous-filled eye.222 Excitation of fluorescence occurs in the 200- to 275-nm range, which is not important for visible or infrared lasers. These ultraviolet frequencies are filtered from external ambient light by the cornea.
Perfluorooctylbromide is radiopaque, and it has potential application as a contrast agent.223
Perfluorocarbon liquids generally have a high oxygen-carrying capacity. Mice immersed in an oxygenated bath of low viscosity perfluorocarbon liquids can survive by breathing this liquid. Perfluorocarbon liquids have potential application as an oxygen reservoir in the vitreous cavity.224
Perfluorocarbon liquids are manufactured by fluorination of hydrocarbons. Hydrofluoric acid, perfluoroisobutylene, and similarly toxic hydrogen-containing compounds remain in the unprocessed product.225,226 Because of the extreme toxicity of hydrofluoric acid, perfluoroisobutylene, and other hydrogen-containing compounds, they must be completely removed before the perfluorocarbon liquid is used in the eye. Potassium hydroxide and alumina can be used to remove these contaminants.227,228 Magnetic resonance spectroscopy can be used to measure hydrogen impurity in the sample. Purified perfluoro-n-octane has essentially no contaminating hydrogen-containing perfluorocarbons, with the only hydrogen-containing compound found to be water.229
Perfluorocarbon liquids containing only fluorine and carbon atoms are the most biologically inert in the eye219 Fomblin-H, the fluorinated polyether, contains oxygen and is very poorly tolerated in the vitreous.230 Similarly, perfluorotributylamine contains nitrogen. Perfluoro chemicals having an oxygen or nitrogen atom tend to be retained longer in the body. Clark and co-workers231 have postulated that this occurs because of a stronger reaction between body tissue and fluorocarbon atoms containing nitrogen or oxygen. This makes them more biologically reactive and less likely to be good vitreous substitutes.
In general, short-term exposure of the anterior chamber and vitreous cavity to purified perfluorocarbon liquids is well tolerated.232 After a week to several weeks, profound changes can occur.233,234In the anterior chamber all of the perfluorocarbon liquids lead to inferior corneal endothelial loss with subsequent corneal opacity and thickening in the inferior half of the cornea when the anterior chamber is half filled with the heavy perfluorocarbon liquid. This effect has been documented even with the most highly purified products. Inflammation with fibrin exudation can occur in the first 1 to 2 weeks. Inflammation and fibrin are more prominent with less purified products.235 This suggests a toxicity effect that can be controlled or eliminated by adequate purification. If the perfluorocarbon liquid is retained in the anterior chamber for more than a few weeks, dispersion and droplet formation will develop. If the droplet formation persists long enough, a macrophage response to the droplets can develop. In contrast, extremely short exposures of the cornea to perfluorocarbon liquids (on the order of an hour to several hours) show minimal if any permanent damage.
Injection of perfluorocarbon liquids into the posterior segment has been characterized electroretinographically, histologically, and clinically. The electroretinographic changes in rabbits show no difference from saline controls for up to 19 days of perfluorotributylamine substitution.236 The electroretinographic changes returned to normal in rabbits after the removal of intravitreal perfluorotri-n-propylamine, which had been retained for 2 weeks.237 The electroretinographic changes in pigs injected with intravitreal perfluorooctylbromide showed reversion to normal with a 2-hour exposure and were interpreted as showing only an insulator effect in eyes retaining the injection for up to 6 months, although dispersion and macrophages were noted histologically starting at around 2 weeks in the long-term retention eyes.238 Perfluorophenanthrene shows no significant electroretinographic abnormalities in rabbits for up to 6 weeks.219 Highly purified perfluoro-n-octane liquid shows no difference in scotopic A-wave, scotopic D-wave, and B-wave implicit times for up to 2 months relative to controls. This assumes, however, that the perfluoro-n-octane is removed 48 hours after initial placement. A slight decline in A-wave detected for both control and perfluoro-n-octane–injected eyes merely indicates the electroretinographic effect of surgical injury. The rise in electroretinographic amplitude immediately after removal of perfluoro-n-octane suggests a possibly insulating effect of perfluorocarbon liquids.
The histologic effects of short-term injection of intravitreal perfluorocarbon liquids are relatively minor; however, after a few weeks to months relatively severe changes can occur. Fomblin-H, a perfluoropolyether, has been noted to cause glial cell proliferation and retinal disorganization at 1 month. At 3 months, preretinal membranes, gliosis, and retinal disorganization were noted. By 6 months, retinal detachments were noted. The histopathologic changes with Fomblin-H were much more severe than the relatively minor changes in silicone oil controls over the same period of time.
Perfluorotributylamine was noted to cause a “moth-eaten appearance,” which refers to irregularly shaped defects in the outer segment discs in both the superior and the inferior retina after 2 days.239 The moth-eaten effect was reversible if the fluid was removed after 2 days. Three to 4 weeks after perfluorotributylamine injection in rabbits, macrophages containing perfluoro chemical droplets were regularly found on the inner retinal surface. At 3 to 4 months after surgery, there were changes in the inferior retina that included large clusters of monocytes, a decreased number of photoreceptor nuclei in the outer nuclear layer, and occasional dropdown of photoreceptor nuclei from the outer nuclear layer into the rod and cone layer. At 3 months after mechanical vitrectomy and injection of perfluorotributylamine, preretinal glial proliferation, proliferation of Müller cells through the internal limiting membrane and fluorochemical droplets in the glial cells were noted in both the superior and the inferior retina. In one study, both perfluorotributylamine and perfluorodecalin showed total emulsification with macrophage ingestion of the perfluorocarbon liquids.233 Moderate to severe cataract was noted in both of these studies. The perfluorocarbon liquids used in this study, however, were provided by Green-Cross Company (Osaka, Japan) and were probably considerably less purified than subsequently used perfluorodecalin, perfluoro-n-octane, and perfluorophenanthrene, which were specifically purified for intraocular use.
Velikay and co-workers240 reported that perfluorodecalin and perfluorooctylbromide had greater intraocular inflammation and fibrin exudation in the first 2 postoperative weeks in rabbit eyes for industrial grade products versus highly purified products. After 2 weeks, however, changes such as hypertrophy of the Müller cells, macrophage formation, and dropdown of photoreceptor nuclei had occurred in both groups. After 4 to 8 weeks, there were only minor histologic and electron microscopic differences between the eyes receiving industrial and highly purified perfluorodecalin and perfluorooctylbromide. Conway and colleagues241 noted that emulsification with perfluorooctylbromide began 1 week after injection and progressively worsened for up to 3 weeks. Histologic evaluation showed no toxic effect. These researchers stated that perfluorooctylbromide was more suitable for intraoperative rather than long-term postoperative tamponade because of visual impairment resulting from rapid emulsification.
Highly purified perfluoro-n-octane was studied by Chang and associates229 for injection periods of up to 2 days in pigs and rabbits. Very minor changes (occasional photoreceptor dropdown and a few macrophages containing oil-like vacuoles near the retinal surface) were noted. In extended-term placement of perfluoro-n-octane in rabbit eyes, occasional macrophages containing oil-like vacuoles were noted on the retinal surface inferiorly in all eyes after approximately 1 week. After 2 weeks, the outer plexiform layer of the inferior retina narrowed and was absent in all eyes by the end of 2 months. Abnormally increased photoreceptor dropdown was noted after 2 months, as were the moth-eaten phenomenon in the inferior retina and the occasional phagocytic cells in the subretinal space in these regions.
Eckardt and associates242 investigated perfluoro-n-octane as well as two perfluoropolyethers, Hostinert-130 and Hostinert-245, in the vitreous cavity. From 6 days to 2 months, they noticed increasing hypertrophy of Müller cells, development of bumplike and droplike Müller cell protrusions, macrophages in the inner photoreceptor cell layer, and a loss of inner and outer segments. After 1 and 2 months, there was progressive folding of the outer retinal layers except the retinal pigment epithelium, increasing rarefaction of nuclei in the nuclear layers, dropdown of photoreceptor nuclei, increasing hypertrophy of the retinal pigment epithelium with drusen extending toward the Müller cell protrusions, and increasing amounts of vesicles in the inner photoreceptor space. Amorphous precipitates not composed of inflammatory cells were seen. These precipitates, which were thought to represent vitreous proteins, were also noted by Chang. The highly purified perfluoro-n-octane and the two perfluorinated polyethers Hostinert-130 and Hostinert-245 were tolerated equally well in the vitreous cavity. All three were well tolerated for 8 hours but produced similar retinal damage with long-term vitreous replacement.
Nabih and associates219 showed that after 6 weeks of perfluorophenanthrene intravitreal injection in rabbit vitreous, light microscopy demonstrated vacuoles containing perfluorophenanthrene in localized areas on the retinal surface. Electron microscopy showed essentially normal architecture in all retinal layers. Peyman did a histologic study in the monkey vitreous of Vitreon (Vitreophage, Inc, Lyons, IL), a purified medical-grade brand of perfluorophenanthrene.243 There was no cellular infiltration of the vitreous and no preretinal membrane formation or uptake of Vitreon by retinal cells, and there was a normal ganglion cell layer, retinal pigment epithelium, and photoreceptor outer segment layer for up to 162 days, as shown by light and electron microscopy.
The major clinical signs of biocompatibility problems are cataract formation; dispersion, emulsification, or both; and in less purified products used for longer periods of time, retinal detachment. Cataract formation develops slowly over a few weeks and with the use of intravitreal Fomblin-H as well as with less pure grades of perfluorotributylamine and perfluorodecalin.230,235 With purified perfluoro-n-octane, minimal lens opacities developed after 2 months and involved less than 10% of the lens, with no limitation of viewing with the indirect ophthalmoscope in rabbit eyes. No significant lens changes were noted with Hostinert-130 and Hostinert-245 for up to 2 months. No note of lens changes was made with the use of intravitreal perfluorophenanthrene by Nabih and associates.219
Dispersion and macrophage ingestion of the smaller bubbles appears to occur within 1 to 2 months for both relatively impure and pure grades of low-viscosity perfluorocarbon liquids. In the second week, all eyes with perfluorotributylamine were noted to have some degree of dispersion.239 By 3 to 4 weeks, cells were noted in the vitreous, and by 3 to 4 months, the fundus was difficult to visualize. Perfluorooctylbromide shows rapid dispersion, and even purified perfluoro-n-octane showed subtotal dispersion by the end of 2 months. With purified perfluoro-n-octane, however, more than two thirds of the vitreous was filled with a single large bubble. The fish-egg appearance was judged not to be as severe as with perfluorotributylamine. It was found that droplet division or fish-egging formed with perfluoro-n-octane after the first week. By the end of the fourth week, the perfluoropolyethers Hostinert-245 and Hostinert-130 had similar fish-egg and bubble division. Nabih and associates219 noted the formation of small droplets around the surface of the main globule of perfluorophenanthrene in rabbit eyes followed for 6 weeks.
The combined use of silicone oil and perfluoropolyether has shown a tendency to reduce the emulsification of the perfluoropolyether.244,245 Peyman and colleagues243 also noted that silicone oil retarded the onset of emulsification of Vitreon when the two were combined in the vitrectomized monkey eye.
Retinal detachments were noted in eyes injected with perfluorotributylamine and with Fomblin-H, especially after several months. Some of these detachments may be due to the difficulties with animal surgery. However, the severe inflammatory and fibrotic changes noted with Fomblin-H probably show that detachment is caused by Fomblin-H itself. Rises in intraocular pressure after the use of perfluorocarbon liquids are generally not a problem unless the anterior chamber has been completely filled with the perfluorocarbon liquid. Acute iritis, uveitis, and inflammatory reactions have been noted immediately postoperatively, especially with Fomblin-H and less purified perfluorocarbon liquids. When the fluid is left in the eye, these reactions generally subside within 1 to 2 weeks. This has not been a noticeable problem when the perfluorocarbon liquids are removed within a few hours to few days after their placement.
REMOVAL OF PERFLUOROCARBON LIQUIDS
The overwhelming majority of researchers at this time recommend use of perfluorocarbon liquids only as an intraoperative tool. Thus, the exposure of the retina to the perfluorocarbon liquid is on the order of an hour. Bottoni and co-workers,246 however, have used perfluorodecalin and perfluorophenanthrene for 5 days of supine positioning in 19 patients. Perfluorocarbon liquid–silicone oil exchange or air exchange was performed after approximately 5 days. They had an anatomic success rate of 84% and believed that the materials were safe for short-term postoperative internal tamponade. Soike and colleagues247 reported no toxic effects of Vitreon for up to 133 days in vitreous cavity in African green monkeys247. The Vitreon Study Group studied 60 patients in whom Vitreon (perfluorophenanthrene) was well tolerated as an intravitreal tamponade for 5 days to 4 weeks.248 The Vitreon Study Group did report a recurrent detachment rate of 11% and moderate to severe fibrinous reaction in 4%. Individual reports of pain, loss of vision, inflammation, and glaucoma with emulsification of retained Vitreon have led some to recommend that Vitreon is unsuitable for postoperative retinal tamponade.249, 250 These adverse reactions were noted at 75 days in one case and at 8 weeks in a second case. Bubble division, fish-egging, or emulsification are concerns in addition to that of toxicity during long-term vitreous tamponade. Because emulsification does not occur immediately, it has been at least theoretically attributed to decreasing interfacial tension of the perfluorocarbon liquids as they adsorb substances in the vitreous fluid. An analogous change has been demonstrated in the surface tension of silicone oils with time. The droplet formation begins in the first 7 to 10 days for perfluorotributylamine, perfluoro-n-octane, perfluorooctylbromide, and perfluorodecalin. The onset of droplet formation appears to occur approximately 2 weeks later in Hostinert-130, Hostinert-245, and perfluorophenanthrene. The greater viscosity of these three agents, or perhaps superior surface tension characteristics, may account for delay in the formation of droplets with subsequent fish-egging, dispersion, and emulsification.
Removal of subretinal perfluorocarbon liquids, at least in larger amounts, is believed to be particularly important. DeQueiroz and co-workers251 reported industrial quality perfluoro-n-octane droplets in phagocytized photoreceptor outer segments in the retinal pigment epithelium 3 hours after injection in one eye.251 Foam cells or macrophages containing perfluorocarbon droplets in the retinal pigment epithelium were noted in two experimental eyes 3 days after injection. Fourteen days after injection, the outer segments of the rods and cones were missing in the areas where there had been direct contact with the subretinal droplets. Berglin and associates252,253 reported loss of outer and inner segments of the photoreceptors as early as 24 hours after injection of subretinal perfluorodecalin. Progressive retinal detachment in the inferior quadrants, large retinal breaks, and emulsification were regularly found with perfluorodecalin. Based on their experience Berglin and associates thought that all perfluorodecalin should be completely removed from the eye at the end of surgery. Chang and co-workers254 have followed some patients with tiny droplets of subretinal perfluoro-n-octane for several months. Because of the high vapor pressure of perfluoro-n-octane, these droplets have slowly been absorbed, leaving a tiny and localized area of retinal abnormality. Retention of more than 0.5 to l mL of perfluoro-n-octane can lead to severe inflammatory response, which can be relieved by vitrectomy to remove the retained perfluoro-n-octane.255
INDICATIONS AND TECHNIQUES
The five main indications being advocated for intraocular use of perfluorocarbon liquids clinically are detachments with giant retinal tears, detachments with complicated PVR, traumatic retinal detachments, removal of posterior lens fragments and posteriorly dislocated intraocular lenses, and macular rotation with a 360-degree retinotomy. Additional uses have been developed to a lesser extent. These additional uses are diabetic traction retinal detachment; nonexpulsive hemorrhagic detachment after glaucoma filtration surgery; retinal detachment with dialysis; release of a retina incarcerated in the pars plana sclerotomy site; retinal detachment after prosthokeratoplasty; extrusion of subretinal hemorrhage after retinotomy and tissue plasminogen activator injection; and control of intraoperative hemorrhage.
The general technique for use of perfluorocarbon liquids is as follows. Usually, it is advisable to filter the liquid through a 0.22-μm fluid filter into a 5- or 10-mL syringe using a 20-gauge needle.256 This provides sterility and removal of any particles in the fluid. The 20-gauge needle is then exchanged for a blunt 23-gauge cannula. Complete peripheral vitrectomy and at least initial removal of posterior retinal membranes are performed. The perfluorocarbon liquid is injected over the optic nerve head, flattening the posterior retina. If a large posterior hole is present, perfluorocarbon liquid should not be used because there is a high probability of it going into the subretinal space. The fluid is slowly injected, being careful to keep the tip of the injection cannula within the initial perfluorocarbon liquid bubble to prevent fish-egging at the time of injection257. The fluid is injected up to the level of the most posterior break. If all of the posterior subretinal fluid or blood is not displaced anteriorly at this time, it is probably due to residual posterior membranes, which should be removed. Membrane dissection and relief of traction by whatever method necessary are performed. Fluid–air exchange is performed to allow residual subretinal fluid trapped anteriorly to drain through the break.258 The posterior edge of the break is held in place by the heavy perfluorocarbon liquid. As the air–fluid exchange continues, the blunt needle is allowed to passively aspirate perfluorocarbon liquids. With more viscous perfluorocarbon liquids, a 19-gauge extrusion needle may be helpful. A thin layer of perfluorocarbon liquid will remain on the retina. From 0.5 to 1 mL of BSS is injected into the eye. The perfluorocarbon liquid develops small droplets in the saline phase and can be identified and removed easily. BSS is then removed, leaving the retina flattened under air. Laser or cryopexy is administered. Final vitreous substitution is performed with air, gas, or silicone oil injection. A device preventing backflow of perfluorocarbon liquid into the syringe when the plunger is released and preventing injection of too much perfluorocarbon liquid has been described by Chang and co-workers.259
Giant Retinal Tears
The use of perfluorocarbon liquids has allowed a rational method of reattaching giant retinal tears in the supine position. The high specific gravity of the perfluorocarbon liquids tamponades the posterior edge of the break, allowing laser treatment before fluid–air exchange or fluid–silicone oil exchange. This reduces the rate of posterior slippage enormously. Chang and associates254 reported a 94% success rate in a series of 17 patients undergoing vitrectomy and reattachment with the use of perfluorocarbon liquids. Many of the patients, however, required additional laser photocoagulation, fluid–gas exchange, or revision of vitrectomy and scleral buckle. Posterior slippage of the tear occasionally occurred to the level of the equator during fluid–air exchange. Injection of air with saline solution followed by an expanding gas concentration and turning the patient to the appropriate position was used to remedy this.
A series of 25 patients with giant retinal tears treated with vitrectomy and perfluoro-n-octane was reported by Glaser and associates.260 Although these patients with retinal tears had grade D1 PVR or worse, 9 of the 10 retinas remained attached after 6 months of follow-up. Injection with a needle larger than 25-gauge allowed perfluoro-n-octane to drip into the eye without exertion of pressure on the syringe plunger. A short infusion cannula is used to prevent BSS injected through it from coming in contact with the perfluoro-n-octane. Jets of fluid from a longer infusion cannula would result in formation of numerous small bubbles of perfluoro-n-octane. To prevent posterior slippage, a slow and deliberate fluid–air exchange with frequent stops to allow drying was performed. Scott reported 212 eyes with retinal tears greater than 90 degrees treated with perfluoro-n-octane intraoperatively.261 Visual acuity improved in 59% and was at least 20/200 in 47% at 6 months. Reoperation for recurrent retinal detachment was required in 30% of the eyes. At 6 months, the retina was attached in 76% of the eyes.
Use of perfluoro-n-octane in conjunction with radical dissection of the vitreous base but without scleral buckling was reported by Kreiger and Lewis262 in 11 eyes with giant tears without PVR. The lens was removed by ultrasonic fragmentation in 5 of 6 phakic eyes. Endophotocoagulation was applied to the anterior and posterior edges of the tear as well as at the basal retina for 360 degrees. All 11 were reattached with a final visual acuity of 20/200 or better in 9 eyes. All patients had a follow-up of at least 7 months. Two eyes developed hypotony, both in children with 360 degree tears. Verstraeten used perfluorocarbon liquids to perform lens-sparing primary treatment of 24 phakic eyes with giant retinal tears.263 Use of perfluorodecalin in conjunction with postoperative silicone oil tamponade and intraoperative perfusion with daunomycin has been reported by Mathis and associates.264 Pars plana vitrectomy, unfolding of the giant retinal tears with perfluorodecalin, perfluorodecalin–silicone oil exchange, and endophotocoagulation were performed on 24 patients. Twenty-three of the 24 retinas remained successfully attached for a minimum of 6 months' follow-up. Daunomycin at a concentration of 7.5 mg/ml in Ringer's solution was infused and left in the vitreous cavity for 10 minutes during the surgery. The silicone oil was removed in 23 cases after a minimum of 1 month and a maximum of 5 months. Visual acuity was 20/200 or better in nine cases and 20/40 or better in three cases.
Use of perfluorodecalin as a tamponade for 5 days with supine positioning to treat 11 eyes with giant retinal tears was reported by Bottoni and associates.265 After 5 days, the perfluorodecalin was exchanged for silicone oil for extended tamponade. Severe flare and fibrinous reaction was noted in three patients in the first 5 days. Reattachment was maintained in 9 eyes, and 8 eyes had visual acuity of 20/60 or better.
Perfluorocarbon liquids confer the advantage of being able to express subretinal fluid posteriorly without the creation of a posterior retinotomy. It also assists in removal of epiretinal membranes by defining areas of residual vitreoretinal traction. Chang and co-workers266 report 23 patients with PVR grade D. In 21 of the 23 eyes the retina could be flattened without posterior retinotomy. Fifteen (65.2%) of the eyes maintained retinal reattachment for 6 months or more follow-up time. Perfluorotributylamine was used in 10 patients, perfluoro-n-octane in seven patients, and perfluorodecalin in six patients. Tamponade consisted of 17% to 20% perfluoropropane in 21 eyes, 20% to 25% perfluoroethane in one eye, and 1,000-centistoke silicone oil in one eye. Perfluorocarbon liquid was under the subretinal space in five eyes during epiretinal membrane dissection but was easily aspirated with a flute needle. In three patients, a small amount of postoperative perfluorocarbon was seen in the vitreous space. In two patients, the droplets of perfluorocarbon liquids were removed on reoperation. Patients were followed for 8 months with no evidence of inflammatory reaction. The fluid interface with perfluorodecalin was harder to visualize. Also, perfluorodecalin seemed to disperse more easily during injection.
In a larger series of 223 patients with proliferative vitreoretinopathy, Coll and associates used perfluoro-n-octane and tamponade with silicone oil in 9% and with gas in 91%.267 Grade D proliferative vitreoretinopathy was present in 92%. Initial retina reattachment rate was 78%, and the final rate was 96%. The postoperative visual acuity was at least 20/100 in 37% and at least 5/200 in 84%.
Perfluorocarbon liquids were used in 81 patients for the surgical treatment of PVR by Corcostegui and colleagues in Barcelona.268 Patients with PVR secondary to giant tear, macular hole, trauma, or other kinds of proliferative vasculopathy were not included in this group. Postoperative tamponade with silicone oil was used in 19 eyes. The retina was successfully reattached in 70 (86%) of the eyes, although four eyes had inferior subretinal fluid not involving the macula. The retina remained detached in 11 (14%) of the eyes. Corcostegui and colleagues268 noted that perfluorocarbon liquids were useful in displacing subretinal fluid, avoiding retinotomy, assisting in removal of epiretinal membranes, testing the elastic stretch of the retina, evaluating the importance of subretinal membranes, determining the necessity and size of relaxing retinotomies, and finding the position of retinal tears.
Perfluorodecalin and perfluorophenanthrene were used by Bottoni and co-workers of Monza, Italy, in 19 eyes with PVR.246 Of the 19 eyes, none had had previous vitrectomy and three had failed conventional scleral buckling. All had grade D1 or greater PVR, with seven of the eyes having previous ocular trauma and three having had giant tears. Lens removal, vitrectomy, membrane dissection, relaxing retinotomies in nine eyes, fluid perfluorocarbon exchange, and retinopexy were performed. Perfluorocarbon liquid was left in postoperatively with supine positioning for an average of 5 days, at most 6 weeks. One patient received perfluorodecalin–air exchange, whereas the other 19 underwent perfluorocarbon liquid–silicone oil exchange. A mean follow-up time of 4.5 months of anatomic reattachment was achieved in 16 (84%) of the eyes. With additional surgery, two more of the eyes (5%) had retinas reattached. Five eyes underwent silicone oil removal without redetachment. A final visual acuity greater than 5/200 was present in 13 (72%) of the 18 reattached retinas. Bottoni and associates stated that perfluorodecalin and perfluorophenanthrene appeared safe for short-term postoperative internal tamponade.
Perfluoro-n-octane is an effective method of managing large relaxing retinotomies, which are frequently encountered in the management of severe proliferative vitreoretinopathy. Han and his associates used perfluoro-n-octane to reattach the retina after creating relaxing retonotomies varying from 90 to 360 degrees.269 They treated 19 patients with 11 having proliferative vitreoretinopathy, five with trauma, and three with proliferative vitreoretinopathy. At 6 months, 68% of the retinas were attached and 42% had at least 5/200 vision. Direct perfluoro-n-octane to silicone oil exchange was performed in nine eyes, the others had perfluoro-n-octane to air exchange followed by injection of perfluoropropane gas or silicone oil.
Detachment arising from penetrating ocular trauma in 14 patients was treated with the use of perfluorocarbon liquids by Chang and co-workers.257 Eight patients sustained penetrating injury from a sharp object, three suffered rupture after blunt trauma, and three had detachment after removal of an intraocular foreign body. Thirteen of the eyes had previous surgery. Cyclitic membranes were present in two eyes and hypotony in six. Twelve of the eyes had at least grade D PVR. Anterior PVR tended to be more severe than in nontraumatized eyes. A broad encircling buckle was placed if not previously present. Bullous detachments were flattened by injection of perfluorotributylamine, perfluoro-n-octane, or perfluorodecalin. Pooled subretinal blood was displaced peripherally, where it could be internally aspirated through a peripheral retinal break. Displacing blood from the macular area was thought to increase the potential for central vision. Relaxing retinotomies were required either peripherally or at penetrating sites, where incarceration was present. Partial fluid–air exchange was performed and photocoagulation delivered through the air. Fluid–air exchange was completed, and perfluorocarbon liquids were removed. From 20% to 25% perfluoroethane was used in three eyes and 17% to 20% perfluoropropane in 10 eyes. In one eye, silicone oil was directly infused as the perfluorocarbon liquid was removed. Intraoperatively, all 14 retinas were flattened. No posterior retinotomy was required. Small amounts of clotted blood remained in the subretinal space. Recurrent retinal detachment with PVR developed later in 6 patients. In three of them, recurrences were managed with revision of vitrectomy and gas or silicone oil tamponade. Eleven patients had follow-up of 6 months or more, and eight of these patients had anatomic reattachment of the retina. Visual acuity of 5/200 or better was achieved in seven of the eight eyes with successfully reattached retinas. Six of these eyes had best corrected visual acuity to 20/400 or better. Factors associated with a lower long-term success rate were patients younger than 20 years of age, patients with previous vitrectomy, patients with a posterior retinal injury site, and patients with subretinal hemorrhage for more than 2 weeks. Perfluorocarbon liquid was found in the subretinal space in three patients, but it was removed intraoperatively. In one patient, a small droplet of perfluoro-n-octane was observed at the ora serrata inferiorly, but this disappeared 6 months postoperatively. In five eyes, heavy fibroblastic growth around the site of traumatic penetration required peripheral retinotomy or retinectomy as the only method of relieving traction on the retina. Chang and co-workers, however, preferred to avoid dissection under perfluorocarbon liquids because of the risk of subretinal passage of the perfluorocarbon liquid.
Desai and co-workers270,271 reported the use of Vitreon for the removal of massive vitreous hemorrhage after surgery of trauma. Three patients in this report underwent limited anterior vitrectomy with injection of Vitreon through a 20-gauge cannula just posterior to the hyaloid face. Desai and co-workers believed that the barrier between the retina and the posterior hyaloid allowed the residual hemorrhage to be safely removed with the vitrectomy instrument. At the completion of the case, Vitreon–air exchange was followed by tamponade. All three retinas remained attached at a 3-month follow-up.
Removal of Crystalline Lens Fragments and Posteriorly Dislocated Intraocular Lenses
Perfluorocarbon liquids have been used to remove a dislocated crystalline lens in the presence of retinal detachment. Lewis and associates272 report a series of four cases in which perfluoro-n-octane was used in three eyes and perfluorophenanthrene in one eye. In all four cases, the retina was reattached, the vision improved, and there were no complications. Pars plana vitrectomy was performed with as much removal of basal gel as possible. Perfluorocarbon liquid was then injected over the optic nerve head to float the dislocated lens off the retina and into the anterior vitreous cavity. This resulted in displacement of the posterior subretinal fluid out through the anterior break. Three of the four lenses were fragmented in the anterior vitreous cavity while floating on the perfluorocarbon liquids. One lens was cryoextracted through a limbal incision. In two of the cases undergoing fragmentation, small fragments of nucleus dropped into the perfluorocarbon liquid but were removed by aspiration or fragmentation. Chang found that perfluorocarbon liquids also protect the retina during phacofragmentation.273 Photocoagulation of the retinal breaks was performed through the perfluorocarbon liquid, followed by a perfluorocarbon liquid–air exchange. A scleral buckle was also used in all four cases. The retina remained reattached for at least 6 months in all four cases.Wallace reported the use of Vitreon in nine cases of removal of posteriorly dislocated lenses and lens fragments due to cataract extraction (eight eyes) and trauma (one eye).274 The lenses were floated on the Vitreon, then fragmented and aspirated through the pars plana. Final visual acuity ranged from 20/30 (6/9) to 20/80 (6/24), with six of nine patients having 20/50 (6/21) or better. No residual Vitreon was noted, and no complications were attributed to the use of Vitreon. A larger series of 28 patients using Vitreon to float lenses and lens material into the midvitreous cavity was reported by Greve and associates.275 Visual acuity results were: at least 20/40 in 32% of patients, 20/40 to 20/100 in 36%, 20/100 to 20/400 in 18%, and less than 20/400 in 14%.
Lewis and Sanchez276 have successfully used perfluorocarbon liquid in the management of dislocated lenses. Perfluoro-n-octane was used to float the lens into the iris plane, where it was anchored with pars plana sutures in eight eyes. Lewis and Sanchez believed that there was decreased potential for retinal damage because of the flotation effect of the liquid perfluorocarbons, the viscosity cushioning the lens, and the flattening effect of the specific gravity in eyes with concurrent retinal detachment. Liu and colleagues277 have used Vitreon in a similar fashion.
Perfluorodecalin has been used to treat complicated proliferative diabetic retinopathy in conjunction with pars plana vitrectomy. Mathis and associates278 report 27 eyes treated in 27 patients by this method.278 Fourteen eyes developed rhegmatogenous retinal detachment, 10 had vitrectomy for traction retinal detachment, while three had progressive fibroblastic proliferation. Thirteen eyes developed iatrogenic retinal holes with surrounding retinal detachment. Perfluorodecalin was used intraoperatively, followed by endophotocoagulation. Postoperative tamponade with silicone oil was used in 12 cases and long-acting gas in 15 eyes. Twenty-one of the 27 cases were reattached with a minimum of 6 months' follow-up and a mean follow-up time of 10.9 months. In two cases, residual droplets of perfluorodecalin were removed during reoperation, whereas in one case, a small subretinal droplet was observed postoperatively without apparent toxicity for up to 22 months. Eleven eyes had improved vision, eight had the same vision, and eight had decreased vision. The main advantage was flattening of the retina, which allowed effective endophotocoagulation under good viewing conditions.
Macular Rotation with a 360-Degree Retinotomy
Macular rotation with a 360-degree retinotomy depends on perfluorcarbon liquid, followed by perfluorocarbon to silicone oil exchange to attach the retina. Macular rotation is a surgical procedure to treat macular degeneration with subfoveolar involvement by detaching the entire retina so as to move the fovea to a position with underlying retinal pigmented epithelium that is not involved by exudative or atrophic macular degeneration. If the macular rotation is successful, counter-rotation of the globe with muscle surgery is required to avoid diplopia and cyclotropia. The initial macular rotation surgery can be combined with the torsional muscle surgery.279 Complete freedom from diplopia was reported by Eckardt in 24 of 25 patients who had the muscle surgery. In this series, 60% of the eyes had 20/50 vision for reading newsprint. Retinal detachment was the most serious complication and occurred in three of 30 patients. The retina was reattached with one additional procedure in two of the three patients.
Macular rotation surgery is complex and continues to evolve.280 Retinal detachments were reported in five of Toth's first 26 patients, but in a more recent series of 15 patients, no retinal detachments were reported with a more refined procedure.281 The procedure consists of removal of the crystalline lens with or with out insertion of a posterior chamber intraocular lens, vitrectomy with posterior vitreous detachment and shaving of the vitreous base, injection of balanced salt solution through one or more retinotomies to detach the retina, injection of perfluorooctane to stabilize the posterior retina, 360-degree retinotomy with scissors or vitrector, removal of the perfluorooctane and elevation of the detached retina, removal of the submacular membrane and control of any consequent hemorrhage, placement of a small amount of perflourooctane to flatten the macula, rotation of the macula 45 to 60 degrees superiorly, addition of perfluorooctane to flatten the retina completely while being vigilant to avoid retinal folds and pleats, trimming of any retina covering the ciliary body, placement of multiple rows of laser to the edge of the retinotomy and around any posterior breaks, a posterior chamber lens may be inserted at this stage if not inserted earlier, and perfluorooctane to silicone oil exchange. Silicone oil is removed at 1 to 3 months after the rotation surgery. Muscle rotation and intraocular lens implantation can be done at the time of silicone oil removal.
In a series of 50 consecutive eyes with subfoveal neovascularization due to macular degeneration treated with macular rotation Pertile and associates reported that 32% of the eyes saw at least 20/50 and only 16% saw worse than 20/200.282 The complications were reported as proliferative vitreoretinopathy in nine eyes, recurrent choroidal neovascularization in five eyes, diplopia in three eyes, choroidal hemorrhage in two eyes, macular hole in one eye, and temporary hypotony in one eye.
MISCELLANEOUS INDICATIONS AND TECHNIQUES.
Perfluorophenanthrene was used to treat a retinal detachment after a Cardona prosthokeratoplasty.283 Skin incisions down to sclera are required because of the nature of the Cardona implantation procedure. Vitrectomy is performed by direct visualization through the keratoprosthesis with an indirect ophthalmoscope. A partial fluid–air exchange is performed initially, and then perfluorophenanthrene is injected to flatten the retina. Endophotocoagulation is applied prophylactically, encircling the entire posterior pole. Because the peripheral location of the break could not be visualized, a 360-degree peripheral retinocryopexy was applied. A number 20 encircling element was placed around the globe. The perfluorophenanthrene was left in place for 3 weeks, at which time it is removed through a 20-gauge needle with balanced saline irrigation. Sequential air–fluid exchange was performed to ensure complete removal. In this single patient. visual acuity 8 months after perfluorophenanthrene stabilized to 20/200 and there was no evidence of recurrent detachment.
Vitreon has been used by Peyman and co-workers284 to release an incarcerated retina from a pars plana sclerotomy site. This condition occurs only with a detached retina that is mobile enough to reach the sclerotomy site. Using the 27-gauge needle, he injected Vitreon into the vitreous cavity. As the liquid filled the vitreous cavity, the detached retina was flattened, stabilizing the posterior retina. If needed, vitrectomy to cut the remaining traction was performed with subsequent endophotocoagulation of the peripheral retina combined with an encircling element. Long-acting gas or silicone oil as a postoperative tamponade is suggested.
Perfluoro-n-octane has been used to express subretinal fluid and hemorrhage through a posterior retinotomy performed for removal of subretinal hemorrhage associated with macular degeneration. In a single case report, Vander reported relatively good results after injecting tissue plasminogen activator through a small cannula into the subretinal space.285 After allowing incubation time of 15 minutes, he expressed the fluid and subretinal hemorrhage through a 20-gauge posterior retinotomy using perfluoro-n-octane on the overlying retina. He repeated the procedure to satisfactorily remove clots and free hemorrhage. He placed a laser retinopexy around the retinotomy site and used a postoperative tamponade of gas.
Heimann286 has used perfluorocarbon liquid in combination with silicone oil in a “sandwich technique” to control peripheral retinal bleeding. The weighty perfluorocarbon liquids prevent blood from entering the subretinal space and confine the flow of blood posteriorly in the vitreous cavity. The silicone oil confines the blood anteriorly and allows a clear view for clot extraction and endodiathermy.
COMPLICATIONS IN THE USE OF PERFLUOROCARBON LIQUIDS
Actual clinical complications encountered in human trials of perfluorocarbon liquids are fairly minor. They consist of small droplets of retained subretinal and intravitreal perfluorocarbon liquid and dispersion or fish-egg formation of the perfluorocarbon liquids, which prevents a clear view intraoperatively. In animal studies, especially where prolonged exposure of relatively impure grades of perfluorocarbon liquids are used, anterior chamber inflammation and fibrin formation, retinal degeneration, progressive retinal detachment with subretinal tears, emulsification with foam cell formation, and macrophage ingestion of the perfluorocarbon liquids are seen. Human trials have been conducted with pure grades of perfluorocarbon liquids and limited time exposures to avoid potential complications.
Subretinal migration of perfluorocarbon liquids is probably the most ominous complication. Glaser reported that subretinal perfluorocarbon liquids can usually be removed with a suction cannula from behind the retinal flap.260 Chang has noted that perfluorocarbon liquids should not be used if there is a large posterior retinal tear, because the development of subretinal perfluorocarbon liquids would be almost inevitable in such a situation.257 If a moderate amount of subretinal perfluorocarbon liquid should extend all the way back to the posterior pole, it could be necessary to perform either a large peripheral retinotomy or a small posterior retinotomy to remove it. Small droplets of retained subretinal perfluoro-n-octane and perfluorodecalin have been reported. They are slowly reabsorbed and leave a small localized retinal scotoma. It would therefore seem excessively risky to attempt to remove small droplets of subretinal perfluorocarbon liquids as long as they are not directly beneath the central macula.
Small droplets of intravitreal perfluorocarbon liquids have been noted and do not appear to cause either retinal degeneration or intraocular inflammation. They have often been removed at later or subsequent operations without any obvious adverse affects.
Dispersion, droplet formation, or fish-egg formation of the perfluorocarbon liquids can occur during instillation of the fluids. Every effort should be made to keep the injection needle within the original bubble so that multiple small droplets are not formed during injection. Glaser noted that a short BSS infusion cannula should be used to minimize exposure of the perfluorocarbon liquid body to turbulent jets from the infusion cannula. He noted that turbulent jets can cause droplet formation in the perfluorocarbon liquid. Droplet formation diminishes the clarity of the view. Also, smaller droplets can fit through a retinal break into the subretinal space more easily than a single large bubble of perfluorocarbon liquid within the vitreous cavity.
Neither Bottoni and co-workers246 nor Paris and associates283 commented as to whether dispersion of the perfluorocarbon liquid occurred during their studies in which extended tamponade of the retina with perfluorocarbon liquids was used in humans. Nevertheless, dispersion is likely to be noted if the perfluorocarbon liquid remains in the eye for more than a few days or weeks, based on animal studies.
Chronically elevated intraocular pressure was noted in 12 % and hypotony in 18% of 234 patients treated by Adile and associates with Vitreon as an intraoperative hydrokinetic manipulator.287 Vitreon was also used as a tamponade in 28 of the 234 patients. The incidence of elevated intraocular pressure and postoperative hypotony was not significantly different for tamponades with Vitreon, silicone oil, sulfurhexafluoride, and perfluoropropane.
In a retrospective study of 78 patients with Vitreon and 84 patients with Perfluoron (perfluoro-n-octane) used intraoperatively Scott and associates found no difference between the two groups in retinal reattachment rates.288 Perfluoron was associated with a small but significant of better 6-month visual acuity, a lower rate of corneal abnormality, and a lower rate of elevated intraocular pressure compared with Vitreon.
In a retrospective study of 142 patients with Vitreon and 125 patients with perfluorooctane used intraoperatively, Loewenstein and associates found no difference between the two groups in retinal reattachment rates and visual acuity at 6 and 12 months postoperatively.289 There was tendency at 12 months (P=.01) for the cornea to be clearer in the Vitreon group. Perfluorooctane was easier to visualize and remove completely from within the eye at surgery.
AVAILABILITY AND FDA STATUS
Perfluorocarbon liquids have been approved for us by the FDA. In the United States, perfluoro-n-octane is available as Perflouron and perfluorophenanthrene is available as Vitreon. In Europe there are many brands of perflourodecaline as well as perfluoro-n-octane marketed for intraocular surgery.
|SEMIFLOURONINATED ALKANE LIQUIDS AS A VITREOUS SUBSTITUTE|
|Meinert patented the semifluoinated alkanes for ophthalmic use in 1996. They
are heavier than water but are not as heavy as the perfluorocarbon
liquids. Initial animal experiments and a patient trial suggested that
they are somewhat better tolerated as a long-term tamponade
than the perfluorocarbon liquids. However, subsequent reports suggest
that for many patients, they are not well tolerated as a postoperative
tamponade. Semifluorinated alkanes are reported to be well tolerated
for intraoperative use. They are especially valuable in macular rotation
surgery because they press down on the retina less than the perflourocarbon
liquids, allowing rotation of the unfolded macular without damaging
it mechanically. They are also a solvent for silicone oil and
are useful in the removal of silicone oil adherent to silicone intraocular
lenses after silicone oil tamponade.|
The best-characterized semifluorinated alkane for clinical use is perfluorohexyloctane, which is C14H17F13 and has the structural formula CF3(CF2)5(CH2)7CH3. Perfluorohexyloctane is abbreviated F6H8 with the implication that there are 14 carbon atoms, six of which are saturated with fluorine and eight of which are saturated with hydrogen. Perflurohexyl hexane is abbreviated F6H6. Perfluorohexylethane is abbreviated F6H2 or alternatively O62. Perflourobutylbutane is abbreviated F4H4 or alternatively O44. In order to increase viscosity of the semiflourinated alkanes oligamers OL62 LV and Ol62 HV have been developed (Table 7).
The semifluorinated alkanes are immiscible with water but are miscible to a variable extent with silicone oil and perfluorocarbon liquids, because they are amphiphilic.290 They are amphiphilic because the CH groups are soluble in silicone oil, and the CF groups are soluble in the perfluorocarbon liquids. If silicone oil, semifluorinated alkanes, and perfluorcarbon liquids are combined in the wrong order and amounts, an opaque liquid that is hard to remove can be formed.291 Based on laboratory titrations Hoerauf and associates292 recommend that if semiflourinated alkanes are to be used intraoperatively, perfluorocarbon liquids should be added so that the resulting mixture is 90% perfluorcarbon liquid before silicone oil exchange is performed. The specific gravity of semifluorinated alkanes is around 1.35 which makes them heavier than water, but lighter than perfluorocarbon liquids. They have low viscosities around 2.5 mPa, similar to the perfluorcarbon liquids, except for the oligamers, which have viscosities ranging from 90 to 2000. They have an index of refraction of 1.3 to 1.33, which makes the interface with aqueous media difficult to visualize. The interfacial tension with aqueous media or tissue ranges from 22 to 50 mN/m and for the oligamers is 35, which is less than the perfluorcarbon liquids but about the same as silicone oil. The oxygen diffusion coefficient for the simple semiflourinated alkanes is high and similar to the that of the pefluorocarbon liquids but is low for the oligamers.
The most extensive testing has been with F6H8. The rabbit cornea developed edema with long-term filling of the anterior chamber with F6H8, but the rabbit corneas recovered after removal of the F6H8. When the rabbit vitreous was filled with F6H8, Zeana and associates293 noted that dispersion began at 2 to 3 weeks after injection. A narrowing of the medullary rays was noted at 2 to 4 weeks, and avascular areas were noted in the medullary rays at 14 weeks. White precipitates in vitreous cavity and behind the lens were noted in eyes with droplet dispersion of the F6H8. Retinal structure was normal in all eyes up to 6 weeks. Nuclear drop down was noted in the inferior retina at 14 weeks, where F6H8 was in contact with the retina in some eyes. ERG was normal at 9 weeks, with a slight decrease at 14 weeks. The rabbit data was interpreted to show excellent tolerance of tamponade with F6H8 for about 2 months and possibly up to 3 months.
The oligamers OL62 LV with a viscosity of 90 mPas and OL62 HV with a viscosity of 1750 mPAS was tested in rabbit eyes by Kobuch and associates.291 Both oligamers showed no dispersion or droplet formation for up to 3 months in the vitreous cavity. This factor suggests that viscosity plays an important role in droplet formation in the rabbit vitreous because the monomer form, O62, began droplet formation after about 7 days in the vitreous cavity. The retinal blood vessels were well preserved at 3 months. The ERG returned to normal within 10 days of removing the F6H8. Histologically the inferior retina showed hypertrophy of the Müller cells, occasional foam cells, and vacuolization of the inner retina surface.
REMOVAL OF SEMIFLOURINATED ALKANES
At this time, most investigators are using semiflourinated alkanes strictly as an intraoperative tool except in experimental protocols in Europe. They are not FDA approved for any use in the United States. Epiretinal and retrolental membranes developed during prolonged vitreous tamponade with F6H8 in a human trial. Eight epiretinal membranes and three opaque posterior capsules were evaluated by Hiscott and associates.294 Six of the membranes were avascular and two had capillaries. All the membranes had glial and RPE cells. Scattered lymphocytes and occasional plasma cells were observed. Vacuolated macrophages were seen frequently and multinucleated giant cells occasionally. These findings were thought to indicate biological reaction to F6H8 that exceeded that of PVR alone. They speculated that the additional response was due to the emulsification of F6H8 with prolonged tamponade.
In a shorter term study, F6H8 and OL62 HV were used as a vitreous tamponade for 6 weeks. In the five patients receiving F6H8, Roider and associates295 reported that two patients had soft epiretinal membranes between the retina and the tamponade inferiorly. Light microscopy of the two membranes showed cystic cells and amorphous material. One eye required cylophotocoagulation to control high intraocular pressure. In the four patients treated with OL62 HV, two patients had a severe recurrent PVR reaction inferiorly and all four had unusual precipitates. One patient had a reaction covering the entire surface of the implant. The eye was no light perception after 5 weeks. The retina was necrotic. The retinal blood vessels were constricted. There was optic atrophy. Based on these finding Roider stated that further investigation was required before the semifluorinated alkanes were used clinically for vitreous tamponade.
INDICATIONS AND TECHNIQUES
The most accepted clinical application for the semiflourinated alkanes is for intraoperative use during the rotation step of macular rotation surgery. Successful removal of silicone oil from the surface of intraocular lenses with F6H8 irrigation has been reported. Studies using F6H8 and OL62 HV as a long-term tamponade have both reported complications suggesting that this use needs more study before further clinical usage. Other potential uses of the semifluorinated alkanes are to create optically clear mixtures with silicone oil that have densities between 1.0 and 1.3 g/cm3, and as a solvent or solubilizer for intravitreal medications.
Macular Translocation Surgery With a 360-Degree Retinotomy
The procedure for macular translocation has been described earlier in the section on the perfluorocarbon liquids. Unfolding of the peripheral retina using F6H8 is described in a series of 90 consecutive patients by Aisenbrey and associates.296 After detaching the retina, performing the 360-degree retinotomy, and removing the macular membrane and hemorrhage, the retina over the macular region is unfolded with F6H8 (Fig. 11).
The macula is then easily rotated under the F6H8. Perfluorooctane is then injected to completely flatten the retina. The final fill is estimated to be 1/3 F6H8 and 2/3 perfluorooctane. Silicone oil exchange and the subsequent steps are then performed in the usual fashion. They reported no complications specifically associated with the use of F6H8. Visual acuity improved 15 or more letters in 24 patients, remained stable in 37 patients, and deteriorated 15 or more letters in 29 patients at 12 months of follow-up. Retinal detachment occurred in 19% of patients, but the final attachment rate was 100%.
Silicone Oil Removal from Silicone Intraocular Lenses
Successful removal of silicone oil from a silicone intraocular lens was reported by Zeana and associates.297 The patient had 20/25 vision preoperatively but suffered form monocular diplopia and blurred vision due to adherent silicone oil droplets form a previous tamponade. A jet application of F6H8 using a 20-gauge needle was performed. This was repeated several months later when another silicone oil droplet that had been behind the iris was removed in the same fashion. The vision remained 20/25, and the monocular diplopia and blurred vision had resolved. Another similar removal of silicone oil droplets from a silicone intraocular lens was reported briefly in the macular rotation paper by Aisenbrey.
Long Term Tamponade in Complicated Retinal Detachment Surgery
Vitreous tamponade with F6H8 lasting from 35 to 202 days was reported in a series of 23 patients by Kirchoff and associates.298 Total reattachement was reported in 19 of the 23 eyes 4 weeks after removal of the F6H8. The mean postoperative visual acuity was 4/14 which was slightly better than the mean preoperative visual acuity but there was no statistically significant difference. Dispersion of the tamponade fluid occurred in at least 12 of the patients. Cataract formation was noted in 9 of the 10 phakic eyes. There was no sign of optic atrophy, retinal necrosis, or retinal vascular occlusion.
As noted earlier, Roider reported cellular soft epiretinal membranes inferiorly after 5 weeks of tamponade with F6H8. A much more severe reaction was noted with OL62 HV tamponade leading to NLP vision after 5 weeks in 1 of four cases. They recommended further investigation before further clinical use.
COMPLICATIONS IN THE USE OF SEMIFLUORINATED ALKANE LIQUIDS
Although the semifluorinated alkanes are as well tolerated as or better tolerated than the perfluorocarbon liquids, the development of dispersion and of excessive PVR membranes containing foam cells, plasma cells and multinucleated giant cells with prolonged tamponade with F6H8 suggest that an acceptable agent for long-term inferior tamponade has not yet been found. An even more sever reaction was noted in the single small trial using OL62 HV for prolonged tamponade.
Pupillary block glaucoma with F6H8 tamponade can be relieved temporarily by supine positioning of the patient. Superior peripheral iridectomy will prevent the development of papillary block glaucoma. Glaucoma after removal of F6H8 can be controlled with topical medication. One case of severe glaucoma after the removal of OL62 HV required cyclophotoablation to control the intraocular pressure.
Cataract progression was noted in nine of 10 phakic eyes after prolonged tamponade with F6H8. Feathery posterior capsular changes and increasing nuclear sclerosis were noted.
Subretinal droplets of F6H8 were tolerated well. The reaction was similar to that of the perfluorcarbon liquids.
Dispersion of F6H8 can be begin as early as 3 days after injection and occurs more frequently as the duration of tamponade increases. Typically at the time of removal the upper 10% of the fluid will exhibit dispersion while the lower 90% remains clear. Droplets are more easily visible in the anterior chamber.
Opacification of the perfluorooctane mixture with F6H8 can theoretically occur when the mixture contains greater than 10% F6H8 at the time it is exchanged with silicone oil, but there was no reported problem with opacification in the 90 patients who had macular rotation using mixture with approximately 33% F6H8 in perfluorooctane. The opacified mixtures created in the laboratory would be difficult to remove from the eye.
There is potential problem of the semifluorinated alkane component of the mixture with perfluorooctane, dissolving in the silicone oil during the silicone exchange at the end of macular rotation surgery. The dissolved semifluorinated alkane could then lead to the complications seen with prolonged tamponade with the semifluorinated alkanes. The was, however, no reported excess of PVR response in the series of 90 patients who had macular rotation surgery by this method.
AVAILABILITY AND FDA STATUS
No semifluorinated alkanes are approved by the FDA. Thus the semifluorinated alkanes are not available in the United States.
Geuder AG in Heidelberg, Germany, markets F6H8, F6H6, a mixture of 90% perfluorodecalin and 10% F6H8, and a mixture of 90% perfluorooctane and 10% F6H8. The ultrapure F6H8 has received the CE mark, which means that it is ISO certified by the European Common Market Government. The CE mark, however, is not equivalent to FDA approval. The CE mark indicates that the level of purity is certified to be as high as the manufacture claims it to be, but there is no assurance of safety or efficacy.
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