INTRODUCTION

Perfluorocarbon liquids (PFCLs) were first developed in 1970s as possible substitutes to erythrocytes[1],[2] because of their capacity to dissolve relatively large amounts of oxygen. Initial trials with these compounds focused on their feasibility to be used as blood substitutes. These experiments proved the biocompatibility of these compounds. Based on their properties, they were then introduced for intraocular use, in what has become a milestone in vitreoretinal surgery.
After animal studies confirmed the safety of PFCL compounds as vitreous substitutes, Chang et al in 1987 first described the successful intraocular use of low viscosity liquid fluorocarbons (perfluorotributylamine and perfluorodecalin) in four patients with complicated retinal detachments.[3],[4] Long-term tamponade in animal models demonstrated retinal atrophy and retinal necrosis at the perfluorocarbon aqueous interface after 4 weeks even when highly purified PFCL compounds (perfluorodecalin) were used.[5] The current role of PFCL in vitreoretinal surgery is restricted to intraoperative use and occasionally as a short-term postoperative tamponade agent.

PHYSICAL PROPERTIES AND THEIR IMPLICATIONS FOR SURGICAL USE

Perfluorocarbon liquids are colorless and odorless organofluorine compounds and are made up of only carbon-fluorine bonds. The stability of the carbon-fluorine bonds makes these liquids biologically inert, and their ‘toxic’ effects are mainly due to their physical effect rather than chemical reactivity.
Due to their high molecular weight, PFCLs are highly dense liquids with a reported specific gravity of 1.3–2.1. Their viscosity is very low due to the presence of low intermolecular forces. They have a refractive index close to that of balanced salt solution (BSS). They have a slightly higher boiling point compared to water, low heat of vaporization and are immiscible with most inorganic and organic solvents. These physical and chemical properties make them highly useful intraoperative adjuncts in vitreoretinal surgery (Table 1).

The PFCLs tried out in ophthalmology include perfluoro-n-octane, perfluoroperhydrophenanthrene, perfluorodecalin, perfluorohexyloctane, perfluorotributylamine and perfluorooctylbromide.[6] Of these, perfluoro-n-octane is most commonly used because it is the most stable, and can be manufactured to a great level of purity (the chance of perfluorocarbon species other than perfluoro-n-octane being present is less than 0.1%). Purity plays a very important role because it makes the liquid more stable, thereby improving retinal tolerance.[7] Due to a low boiling point, it vaporizes from the retinal surface easily during fluid-air exchange. This property allows complete and easy removal of PFCL at the end of surgery.[8]

USE IN VITREORETINAL SURGERY

Though developed as a vitreous substitute, the long-term results of PFCL showed retinal damage. However, the other properties of these compounds made them ideal intraoperative adjuncts for hydrokinetic manipulation of the retina, floating up lens matter and dropped intraocular lenses (IOLs) and for various other applications.
Method of Injecting Perfluorocarbon Liquids
Before injecting the PFCL, care should be taken to induce a posterior vitreous detachment, if it is not already present. As the PFCL is a low viscosity liquid, it can easily be injected with small-bore cannulas. When injecting PFCL into the vitreous cavity, care should be taken to make sure that BSS exits out of the globe through the infusion cannula or a dual bore PFCL injector cannula.
During the process of injection, the flow should never be directed toward the fovea as the force of the fluid jet can produce iatrogenic macular holes. Directing the flow toward retinal breaks should also be avoided to prevent subretinal migration. The speed of injection should also be slow and continuous to avoid retinal injury and breaking up of the PFCL into multiple small bubbles, respectively. Bubble formation also can be avoided by keeping the cannula tip inside the PFCL bubble during the entire process of injection. When removing instruments (vitreous cutter, light pipe or forceps) out of the eye, the infusion flow increases drastically as fluid escapes the eye in large quantities. This turbulence may cause the PFCL bubble to break into multiple small bubbles in the vitreous cavity. This bubble formation can be avoided by plugging the ports immediately as instruments are removed, or by using valved cannulas during microinscisional vitrectomy surgery. Bubble formation should be avoided as these small bubbles can migrate subretinally through retinal breaks.
To avoid subretinal migration, PFCL should ideally be injected after relieving major tractional elements because a stiff retina or gaping break increases the chance of such eventuality. Small quantities of PFCL may be positioned over the posterior pole and the volume increased later as peripheral dissection proceeds to free the traction. The injected volume of the PFCL should be such that the level of the PFCL bubble should be posterior to the posterior edge of the retinal break. Alternatively, a larger volume of the PFCL can be injected such that the anterior edge of the retinal break is also totally submerged in the PFCL bubble preventing subretinal migration.

Removal of PFCL from the vitreous cavity at the end of surgery can be performed by either passive or active aspiration through a silicone-tipped cannula. This can be done in the presence of BSS or during a fluid-air exchange as desired by the surgeon. When removing under air, the BSS in the vitreous cavity should first be removed by keeping the tip of the aspiration cannula in the fluid meniscus at the edge of the PFCL bubble. This maneuver helps in the near-complete removal of vitreous cavity fluid. The PFCL can be removed finally by aspirating just above the optic disk.

Applications

Rhegmatogenous Retinal Detachment
Perfluorocarbon liquids can be used in routine rhegmatogenous retinal detachments to displace the subretinal fluid (SRF) to the anterior periphery so that it can be removed through pre-existing peripheral retinal breaks, obviating the need to create posterior retinotomies. PFCL is also used to also stabilize the peripheral retina. The retina tends to move less, thereby decreasing the risk of accidental retinal breaks while performing vitreous base shaving.

Complex Retinal Detachments
In the presence of extensive proliferative vitreoretinopathy (PVR), removal of offending membranes and performance of a complete vitrectomy becomes a daunting task. Chang et al. first described the successful use of PFCL in the management of complex retinal detachments with massive PVR.9 They showed that use of PFCL to displace posterior fluid anteriorly decreased the need for performing a posterior retinotomy for draining SRF and increased the ease with which epiretinal membranes could be removed by stabilizing the retina. Both anatomic and functional outcomes of surgery in eyes with massive PVR can improve considerably when PFCL was used.[10],[11]

Giant Retinal Tears
One field where the introduction of PFCL has made a substantial difference in vitreoretinal surgery is in the management of giant retinal tears (GRTs). Before the advent of PFCL, surgery had a low success rate and included various eccentric maneuvers that involved the famous GRT table and making the patient prone when air bubble was injected into the vitreous cavity to unfold the retina.[12],[13] Success rates were far from desired. Chang et al first reported the use of PFCL in these eyes with a success rate of 94%.[14] Later, other studies have confirmed the huge difference PFCL has made in the management of GRTs.[15]
The surgical procedure is now rather straightforward and can be done in the comfortable supine position. The PFCL bubble is slowly injected over the optic nerve head, unfolding the inverted retina and flattening the edges of the GRT. The PFCL bubble is increased till the GRT edge is flattened. Laser can then be applied to the edges of the tear followed by direct silicone oil-PFCL exchange.

Dislocated Lens Matter and Intraocular Lens
The removal of posteriorly dislocated crystalline lens matter or dropped IOLs has been simplified by the use of PFCL. The surgical technique involves first releasing the vitreous adhesions around the dropped lens matter and then injecting PFCL. The lens matter floats on the PFCL bubble. The surgeon has the option of either fragmenting the lens inside the vitreous cavity or removing it through a limbal section or scleral tunnel depending on the hardness of the nucleus. The volume of the PFCL injected will depend on the technique employed. If fragmentation within the vitreous cavity is contemplated, a small volume of PFCL just enough to cover the macula and protect it from injury can be injected. If floating the lens to the pupillary area to remove it through the limbal route is contemplated, then a large volume of PFCL may need to be injected.[16][17][18] Dropped IOLs may be removed in a similar manner by floating them to the pupillary plane. Scleral fixation of such IOLs using prolene sutures can then be done.

Macular Hole with Retinal Detachment

Macular holes can occur as a complication of rhegmatogenous retinal detachment or in high myopic eyes with posterior staphyloma and localized retinal detachment. Peeling of ILM may be difficult in these eyes due to the loss of countertraction. The dye used to stain the ILM can also enter the subretinal space through the macular hole causing damage to the RPE. A small volume of PFCL injected over the posterior pole can provide countertraction for easy peeling of the ILM and will also prevent subretinal migration, when the dye is injected under PFCL cover.

Proliferative Diabetic Retinopathy

In the presence of combined mechanism (tractional and rhegmatogenous) retinal detachments in eyes with proliferative diabetic retinopathy (PDR) or vein occlusions, PFCL can be used to stabilize retina providing countertraction during peeling of fibrovascular membranes. In some eyes with tractional retinal detachment, intraoperative retinal tears can occur due to the presence of atrophic retina. These breaks may extend or allow the retina to become bullous and behave like a combined mechanism retinal detachment. The mobile retina prevents easy removal of the fibrovascular membranes. PFCL can be used to provide counter traction in such an eventuality.[19]
Continuous PFCL infusion vitrectomy without BSS has also been tried in PDR with limited success. The logic behind this was the stabilization of the retina and preventing intraocular bleeding by PFCL tamponade.[20]

Exudative Retinal Detachments
Occasionally, PFCL has also been used to aid external drainage of SRF in eyes with exudative retinal detachments (e.g. atypical central serous chorioretinopathy). Chen et al. described performing a pars plana vitrectomy followed by PFCL injection which facilitated external drainage of SRF. External drainage avoided creating an iatrogenic retinal break and consequently the need for silicone oil or gas tamponade.[21]

Other Applications
Perfluorocarbon liquids may facilitate the drainage of hemorrhagic choroidal detachment by pushing suprachoroidal blood anteriorly, which can then be removed by performing a sclerotomy. In cases of intraoperative complications that lead to subretinal hemorrhage (e.g. globe perforation, external drainage, choroidal bleed), PFCL may be used to evacuate subretinal blood from under the macula or prevent blood from reaching the submacular area. PFCL may also prove very useful in the management of ocular trauma where multiple pathologies are involved. It may help in removing traumatically dislocated lens or IOL, aid removal of subretinal and suprachoroidal blood and also help in the management of traumatic retinal detachment.[22][23][24]

Complications

Perfluorocarbon liquids are primarily used as intraoperative adjuncts and removed completely at the end of surgery. Therefore, retinal complications from PFCL are minimal and most result from their unintended retention in the eye. The reported rates of retained PFCL vary with the molecule, with lower rates with perfluoro-n-octane than perfluoroperhydrophenanthrene or vitreon (7.8% versus 38.3%).[25],[26] Perfluorodecalin retention rates were similar to perfluoro-n-octane.[27]
Retained subretinal PFCL has shown photoreceptor damage in animal models [28] and can cause central scotoma when subfoveal.[29] Risk factors for retained subretinal PFCL include larger peripheral retinotomies and incomplete saline rinse after PFCL removal.[27] The most common sites of retained subretinal PFCL are the fovea and the peripapillary area. If significant in quantity or location, the subretinal PFCL may be evacuated by mobilizing it toward a peripheral retinotomy with a silicone brush or Tano’s scrapper. PFCL has not been found to mechanically cause retinal damage in animal models,[30] but this remains controversial.
Retained PFCL in the vitreous cavity may gain access to the anterior chamber. This is more frequent in patients positioned prone after surgery. Stromal inflammation, loss of endothelial cells, and corneal vascularization have been demonstrated after PFCL injection into the anterior chambers of aphakic rabbits.[31] Corneal complications, uveitis, and increased intraocular pressure have also been reported in patients with rates depending upon the molecule used during surgery.[25],[32]

CONCLUSION

In the last 20 years since their introduction into the armamentarium of the vitreoretinal surgeon, perfluorocarbons have revolutionized vitreoretinal surgery. They have not only made surgery easier, safer, and more successful in several situations but have also helped decrease surgical time. In the forthcoming years, the quest for newer molecules will continue with ever-expanding applications for the same.

REFERENCES

1. Sloviter HA. Perfluoro compounds as artificial erythrocytes. Fed Proc. 1975;34(6):1484-7.
2. Geyer RP. “Bloodless” rats through the use of artificial blood substitutes. Fed Proc. 1975;34(6):1499-505.
3. Chang S, Zimmerman NJ, Iwamoto T, et al. Experimental vitreous replacement with perfluorotributylamine. Am J Ophthalmol. 1987;103(1):29-37.
4. Chang S. Low viscosity liquid fluorochemicals in vitreous surgery. Am J Ophthalmol. 1987;103(1):38-43.
5. Velikay M, Wedrich A, Stolba U, et al. Experimental long-term vitreous replacement with purified and nonpurified perfluorodecalin. Am J Ophthalmol. 1993;116(5):565-70.
6. Nabib M, Peyman GA, Clark LC. Experimental evaluation of perfluorophenanthrene as a high specific gravity vitreous substitute. A preliminary report. Ophthalmic Surg. 1989;20(4):286-93.
7. Velikay M, Stolba U, Wedrich A, et al. The effect of chemical stability and purification of perfluorocarbon liquids in experimental extended-term vitreous substitution. Graefes Arch Clin Exp Ophthalmol. 1995;233(1):26-30.
8. Crafoord S, Larsson J, Hansson LJ, et al. The use of perfluorocarbon liquids in vitreoretinal surgery. Acta Ophthalmol Scand. 1995;73(5):442-5.
9. Chang S, Ozmert E, Zimmerman NJ, et al. Intraoperative perfluorocarbon liquids in the management of proliferative vitreoretinopathy. Am J Ophthalmol. 1988;106(6):668-74.
10. Scott IU, Flynn HW, Murray TG, et al. Perfluoron study group. Outcomes of surgery for retinal detachment associated with proliferative vitreoretinopathy using perfluoro-n-octane: A multicenter study. Am J Ophthalmol. 2003;136(3):454-63.
11. Comaratta MR, Chang S. Perfluorocarbon liquids in the management of complicated retinal detachments. Curr Opin Ophthalmol. 1991;2(3):291-8.
12. Michels RG, Rice TA, Blankenship G. Surgical techniques for selected giant retinal tears. Retina. 1983;3(3):139-53.
13. Vidaurri-Leal J, de Bustros S, Michels RG. Surgical treatment of giant retinal tears with inverted posterior retinal flaps. Am J Ophthalmol. 1984;98(4):463-6.
14. Chang S, Lincoff H, Zimmerman NJ, et al. Giant retinal tears. Surgical techniques and results using perfluorocarbon liquids. Arch Ophthalmol. 1989;107(5):761-6.
15. Scott IU, Murray TG, Flynn HW, et al. Perfluoron Study Group. Outcomes and complications associated with giant retinal tear management using perfluoro-n-octane. Ophthalmology. 2002;109(10):1828-33.
16. Korobelnik JF, Nabet L, Frau E, Elmaleh C, et al. [Use of perfluorocarbon solutions in the surgical treatment of posterior luxation of the lens]. J Fr Ophtalmol. 1992;15(4):235-42.
17. Omulecki W, Stolarska K, Synder A. Phacofragmentation with perfluorocarbon liquid and anterior chamber or scleral-fixated intraocular lens implantation for the management of luxated crystalline lenses. J Cataract Refract Surg. 2005;31(11):2147-52.
18. Liu KR, Peyman GA, Chen MS. Use of high-density vitreous substitutes in the removal of posteriorly dislocated lenses or intraocular lenses. Ophthalmic Surg. 1991;22(9):503-7.
19. Corcostegui B. Use of perfluorocarbon liquid in vitrectomy for diabetic rhegmatogenous retinal detachment. J Retina. 1992;1:30.
20. Velez-Montoya R, Guerrero-Naranjo JL, Garcia-Aguirre G, et al. Perfluorocarbon-perfused 23 gauge three-dimensional vitrectomy for complicated diabetic tractional retinal detachment. Clin Ophthalmol. 2011;5:1709-15.
21. Chen HC, Ho JD, Chen SN. Perfluorocarbon liquid-assisted external drainage in the management of central serous chorioretinopathy with bullous serous retinal detachment. Chang Gung Med J. 2003;26(10):777-81.
22. Chang S, Reppucci V, Zimmerman NJ, et al. Perfluorocarbon liquids in the management of traumatic retinal detachments. Ophthalmology. 1989;96(6):785-91.
23. Desai UR, Peyman GA, Harper III. Perfluorocarbon liquids in traumatic vitreous hemorrhage and retinal detachment. Ophthalmic Surg. 1993;24(8):537-41.
24. Desai UR, Peyman GA, Chen CJ, et al. Use of Perfluoro perhydrophenanthrene in the management of suprachoroidal hemorrhage. Ophthalmology. 1992;99(10):1542-7
25. Scott IU, Murray TG, Flynn HW, et al. Outcomes and complications associated with perfluoro-n-octane and perfluoroperhydrophenanthrene in complex retinal detachment repair. Ophthalmology. 2000;107(5):860-5.
26. Loewenstein A, Humayun MS, de Juan E, et al. Perfluoroperhydrophenanthrene versus perfluoro-n-octane in vitreoretinal surgery. Ophthalmology. 2000;107(6):1078-82.
27. Garcia-Valenzuela E, Ito Y, Abrams GW. Risk factors for retention of subretinal perfluorocarbon liquid in vitreoretinal surgery. Retina. 2004;24(5):746-52.
28. de Queiroz JM, Blanks JC, Ozler SA, et al. Subretinal perfluorocarbon liquids. An experimental study. Retina. 1992; 12(3 Suppl):S33-9.
29. Lesnoni G, Rossi T, Gelso A. Subfoveal liquid perfluorocarbon. Retina. 2004;24(1):172-6.
30. Osterholz J, Winter M, Winkler J, et al. [Retinal damage by perfluorocarbon liquids—a question of specific gravity? Intraocular pressure peaks and shearing forces]. Klin Monbl Augenheilkd. 2009;226(1):38-47.
31. Moreira H, de Queiroz JM, Liggett PE, et al. Corneal toxicity study of two perfluorocarbon liquids in rabbit eyes. Cornea. 1992;11(5):376-9.
32. Foster RE, Smiddy WS, Alfonso EC, et al. Secondary glaucoma associated with retained perfluorophenanthrene. Am J Ophthalmol. 1994;118(2):253-5.