17
Use of Adjuncts in Surgery for Age-Related Macular Degeneration
Lawrence P. Chong
Doheny Retina Institute of the Doheny Eye Institute, University of Southern California Keck School of Medicine, Los Angeles, California
I.INTRODUCTION
Adjuncts that have been used surgery for age-related macular degeneration (AMD) include tissue plasminogen activator, balance salt solution (BSS), and calcium-and-magnesium- free retinal detachment-enhancing solutions. The surgeries in which these solution have been used include submacular surgery to excise choroidal neovascular membranes, largescale macular translocation surgery, limited macular translocation surgery, evacuation, or displacement of submacular hemorrhages.
II.TISSUE PLASMINOGEN ACTIVATOR
Tissue plasminogen activator (tPA) is a polypeptide of 527 amino acids that cleaves the Arg560–Val561 bond of plasminogen. Because of its high affinity for fibrin, its enhancement of binding of plasminogen to fibrin clot, and potentiation of its activity in the presence of fibrin, fibrinolysis occurs almost exclusively in fibrin clots.
Commercial tPA (Activase, Genentech, Inc.; Actilyse, Boehringer Ingelheim International, GmbH) is a 70,000-MW, single-chain protein produced from a cloned human tPA gene using Chinese hamster ovary cells (1). Endogenous tPA is secreted in its single-chain form to be enzymatically converted by plasmin to its two chain form. Both forms of tPA are equally active. The vehicle consists of L-arginine phosphate, phosphoric acid, and polysorbate 80.
tPA has been used both intracamerally and subretinally. The utility of intracameral tPA was demonstrated in animal models of fibrin (2–4), hyphema (5), vitreous hemorrhage (6–8), and subretinal hemorrhage (9,10). The utility of subretinal injection of tPA was demonstrated in animal models of subretinal hemorrhage (11–13).
In the anterior chamber 0.05 mL containing up to 200 g and 0.10 mL containing up to 36 g have been injected without unusual inflammation or toxicity to the cornea or lens.
319
320 |
Chong |
In the vitreous cavity 0.10 mL containing up to 25 g has been injected without cornea or retinal toxicity. Repetitive injections (three times, separated by 7-day intervals) of 3 g tPA also did not show retinal toxicity (8). A single report suggested probable retinal toxicity of 0.1 mL containing 25 g (14). Dose-dependent retinal toxicity was seen with 0.10-mL injections of 50, 75, and 100 g into the vitreous cavity (15). Traction retinal detachments were seen following 100-mg (6) and 200- g (16) tPA injections.
In the subretinal space no retina toxicity was seen after subretinal injection of 25 and 50 g of tPA in 0.l mL of volume (11,12).
Lewis and colleagues demonstrated in rabbits that subretinal clots 30 min old cleared faster after a 0.1-mL subretinal injection of 25 g tPA as compared to an equivalent volume of BSS (11). However, the subretinal tPA could not completely prevent retinal damage. Both BSS and tPA decreased the toxic effect of blood partly on the basis of dilution of the subretinal blood. Johnson and colleagues showed a similar effect for lower doses of tPA (2.5 g in 0.05 mL) on clots that were 24 h old, but severe progressive retinal degeneration was still seen (12). An ultrasurgical approach using a microinfusion of 0.5–5 g of tPA facilitated lysis of 1- and 2-day-old clots and their removal through micropipettes under stereotactic control. Good preservation of the retinal architecture was seen compared to untreated controls (13).
The ability of intravitreal injections of tPA to lyse subretinal clots has been explored. Coll and colleagues found that 0.l mL 50 g of tPA facilitated the lysis and absorption of 1 day-old subretinal clots compared to equivalent volume injections of saline (9). Unfortunately, retinal damage was not prevented. Boone and colleagues injected 25 g of tPA into the vitreous space and found only partial clot lysis that was not enough to allow removal by aspiration alone (10). The inability of labeled tPA injected into the vitreous to penetrate the intact neural retina or a subretinal clot in rabbits was demonstrated by Kamei and colleagues (17). Some labeled tPA was able to penetrate into eyes with vitreous hemorrhage presumably from the microdefects through which blood escaped from the subretinal space into the vitreous.
The previous studies spurred simultaneous interest in the clinical use of tPA to assist in the removal of subretinal hemorrhage. These techniques involved the injection of 6.25–12.5 g of tPA in a volume of 0.05–0.05 mL into the subretinal space and then waiting 10–45 min before aspiration of the liquefied blood. Injections into the subretinal space were accomplished with a glass pipette (18), 33-gauge cannula (19), or bent-tipped 30gauge needle (20,21). Aspiration was performed with double-barrel subretinal-injector aspirator (19), soft-tipped cannula (18,22), tapered 20-gauge Charles flute needle (21), or 30gauge subretinal cannula (23). Liquefied subretinal blood was also manipulated with a small perfluorocarbon liquid bubble (20,24,25).
In addition to intravitreal injection of tPA during the pars plana vitrectomy procedure, the injection of 0.1 mL of 25 g of tPA into the subretinal clot by passing a 30-gauge needle through the pars plana under indirect ophthalmoscopy the day before pars plana vitrectomy has also been described (26).
An intravitreal injection consisting of 6 g of tPA in 0.1 mL was injected into the midvitreous cavity to liquefy subretinal clots 12–36 h prior to vitrectomy and removal of blood through a retinotomy using perfluorocarbon liquid manipulation (27). Intravitreal injections of 0.1–0.2 mL containing 25–100 g of tPA into the vitreous cavity have been given either the day before (28) or immediately before (29,30) injection of intravitreal gas to displace submacular hemorrhage. Exudative retinal detachments seen after 100- g injections were attributed to tPA toxicity (29).
Use of Adjuncts in Surgery for AMD |
321 |
A number of investigators have injected 25–50 g tPA into the subretinal space following pars plana vitrectomy (31–33). An air fluid exchange was performed and the patient was kept erect to pneumatically displace the liquefied blood from the fovea.
Lewis injected tPA into the subretinal space before excision of the choroidal neovascular membrane but found no improvement compared with injection of BSS into the subretinal space in a randomized
III.CALCIUMAND MAGNESIUM-FREE RETINAL DETACHMENT–ENHANCING SOLUTIONS
Marmor had discovered that removing calcium and magnesium from a solution that bathed eye wall sections in vitro weakened retinal adhesive force (35). Wiedemann described a “detachment infusion” for macular translocation surgery that was calcium and magnesium free (36). Substituted for conventional vitrectomy infusion fluid, this solution enabled the immediate detachment of the retina from its peripheral, diathermy-induced perforation site to the center of the macula or macular area. He described its use in retinal organ culture and creation of experimental retinal detachment in rabbits and in human surgery.
We hypothesized that BSS Part A might be an ideal retinal detachment-enhancing solution and studied its safety and efficacy in rabbits before using it clinically in humans. BSS was developed as an improvement over normal saline, lactated Ringer’s, and Plasma-lyte 148 as a physiologically compatible solution to be used in the eye during surgery (37,38). To further improve the physiological compatibility of BSS, glutathione, glucose, and bicarbonate buffer system were added (39–41) resulting in BSS Plus. BSS Plus consists of two parts, which are reconstituted just prior to use in surgery. These two parts consist of Part B, a sterile 480-mL solution in a 500-mL single-dose bottle to which Part A, a sterile concentrate in a 20-mL single-dose vial, is added. Compared to BSS, BSS Part A lacks magnesium and calcium, and the citrate and acetate buffers of BSS have been replaced with bicarbonate buffer. BSS Part B contains the calcium and magnesium as well as the dextrose and the glutathione, which are unique to BSS Plus. We hypothesized that BSS Part A alone could be used safely in the human eye since it contained almost all the ingredients of BSS except for the calcium and magnesium with a different buffering system and a pH of 7.4. A tremendous advantage to the vitreous surgeons is the commercial availability of BSS. We felt that all these qualities plus the historical use of the solution in the operating room (albeit reconstituted with Part B) could make it an ideal solution to enhance retinal detachment during macular translocation surgery. We showed the safety and efficacy of a calciumand magnesium-free macular translocation solution by comparing the results of injecting BSS Part A or BSS solution into the subretinal space of rabbit eyes using a 39-gauge cannula (41). No difference was seen in fundus appearance, fluorescein angiography, ERG, or light or electron microscopy in rabbit retinas that had been detached using retinal detachment solution compared to commercially available solution. Using a manual infusion system no more than 100 g of BSS compared to a much larger volume of retinal detachment solution could be infused into the subretinal space. The diameter of BSS retinal detachments was always less than that of BSS Part A retinal detachments after injection of 100- g of subretinal fluid.
Aaberg et al. have similarly shown the safety of subretinal BSS Part A in the subretinal space of the rabbit using transscleral infusion (42).
322 |
Chong |
We have used a 39-gauge cannula to atraumatically infuse BSS Part A underneath the retina in macular translocation surgery and to displace submacular hemorrhage.
Clinically, we have found that macular translocation surgery requires only one or two penetrations through the retina with a 39-gauge cannula to detach the posterior retina sufficiently. We have used BSS Part A to displace submacular hemorrhages by performing pars plana vitrectomy, injecting the solution to detach the posterior pole of the retina, performing partial gas-fluid exchange, and then positioning the patient in an erect position for 24 h to displace blood away from the fovea.
IV. SUMMARY
Adjuncts are used primarily in the subretinal space during surgery for AMD. Tissue plasminogen activator can be infused into the subretinal space to liquefy subretinal blood. Tissue plasminogen activator may penetrate human retina after injection into the vitreous cavity through microperforations to liquify subretinal blood. Calciumand magnesium-free solutions enhance retinal detachment. BSS Plus Part A is a safe and readily available retinal detachment solution. Calciumand magnesium-free solutions can aid macular translocation surgery and the displacement of submacular hemorrhage.
REFERENCES
1.Pennica D, Holmes WE, Kohr WJ, Harkins RN, Vehar GA, Ward CA, Bennett WF, Yelverton E, Seeburg PH, Heyneker HL, Goeddel DV, Collen D. Cloning and expression of human tissue type plasminogen activator with DNA in E coli. Nature 1983; 301:214–221.
2.Johnson RN, Olsen K, Hernandez E. Tissue plasminogen activator treatment of postoperative intraocular fibrin. Ophthalmology 1988; 95:592–596.
3.Lambrou FH, Snyder RW, Williams GA, Lewandowski M. Treatment of experimental intravitreal fibrin with tissue plasminogen activator. Am J Ophthalmol 1987; 104:619–623.
4.Snyder RW, Lambrou FH, Williams GA. Intraocular fibrinolysis with recombinant human tissue plasminogen activator. Arch Ophthalmol 1987; 105:1277–1280.
5.Lambrou FH, Snyder RW, Williams GA. Use of tissue plasminogen activator in experimental hyphema. Arch Ophthalmol 1987; 105:995–997.
6.Johnson RN, Olsen DR, Hernandez E. Intravitreal tissue plasminogen activator treatment of experimental vitreous hemorrhage. Arch Ophthalmol 1989; 107:891–894.
7.Min WK, Kim YB, Lee KM. Treatment of experimental vitreous hemorrhage with tissue plasminogen activator. Korean J Ophthalmol 1990; 4:12–15.
8.Min WK, Kim YB, Ahn BH, Seong GH. Repetitive low-dose tissue plasminogen activator for the clearance of experimental vitreous hemorrhage. Korean J Ophthalmol 1994; 8:45–48.
9.Coll GE, Sparrow JR, Marinovic A, Chang S. Effect of intravitreal tissue plasminogen activator on experimental subretinal hemorrhage. Retina 1995; 15:319–326.
10.Boone DE, Boldt HC, Ross RD, Folk JC, Kimura AE. The use of intravitreal tissue plasminogen activator in the treatment of experimental subretinal hemorrhage in the pig model. Retina 1996; 16:518–524.
11.Lewis H, Resnick SC, Flannery JG, Straatsma BR. Tissue plasminogen activator treatment of experimental subretinal hemorrhage. Am J Ophthalmol 1991; 111:197–204.
12.Johnson MW, Olsen DR, Hernandez E. Tissue plasminogen activator treatment of experimental subretinal hemorrhage. Retina 1991;11:250–258.
13.Toth CA, Benner JD, Hjelmeland LM, Landers III M.B., Morse LS. Ultramicrosurgical removal of subretinal hemorrhage in cats. Am J Ophthalmol 1992; 113:175–182.
Use of Adjuncts in Surgery for AMD |
323 |
14.Min WK, Kim YB. Resolution of experimental intravitreal fibrin by tissue plasminogen activator. Korean J Ophthalmol 1990; 4:58.
15.Johnson MW, Olsen KR, Hernandez E, Irvine WD, Johnson RJ. Retinal toxicity of recombinant tissue plasminogen activator in the retina. Arch Ophthalmol 1990; 108:259–263.
16.Min WK, Kim YB, Lee KM. Treatment of experimental vitreous hemorrhage with tissue plasminogen activator. Korean J Ophthalmol 1990; 4:12–15.
17.Kamei M, Misono K, Lewis H. Study of the ability of tissue plasminogen activator to diffuse into the subretinal space after intravitreal injection in rabbits. Am J Ophthalmol 1999; 128:739–746.
18.Peyman GA, Nelson NC, Alturki W, FlinderKJ, Paris CL, Desai UR, Harper, III CA. Tissue plasminogen activating factor assisted removal of subretinal hemorrhage. Ophthalm Surg 1991; 22:575–582.
19.Lewis H. Intraoperative fibrinolysis of submacular hemorrhage with tissue plasminogen activator and surgical drainage. Am J Ophthalmol 1994; 118:559–568.
20.Vander JF. Tissue plasminogen activator irrigation to facilitate removal of subretinal hemorrhage during vitrectomy. Ophthalmic Surg 1992; 23:361–363.
21.Moriarty AP, McAllister IL, Constable IJ. Initial clinical experience with tissue plasminogen activator (tPA) assisted removal of submacular haemorrhage. Eye 1995; 9:582–588.
22.Manning LM, Contrad DK. Tissue plasminogen activator in the surgical management of subretinal haemorrhage. Aust NZ J Ophthalmol 1994; 22:59–63
23.Ibanez HE, Williams DF, Thomas MA, Ruby AJ, Meredith TA, Boniuk I, Grand MG. Surgical management of submacular hemorrhage: a series of 47 consecutive cases. Arch Ophthalmol 1995; 113:62–69.
24.Lim JI, Drews-Botsch C, Sternberg, Jr P, Capone, Jr A, Aaberg, Sr TM. Submacular hemorrhage removal. Ophthalmology 1995; 102:1393–1399.
25.Kamei M, Tano Y, Maeno T, Ikuno Y, Mitsuda H, Yuasa T. Surgical removal of submacular hemorrhage using tissue plasminogen activator and perfluorocarbon liquid. Am J Ophthalmol 1996; 121:267–275.
26.Chaudhry NA, Mieler WF, Han DP, Alfaro, III VD, Liggett PE. Preoperative use of tissue plasminogen activator for large submacular hemorrhage. Ophthalmic Surg Lasers 1999; 30:176–180.
27.Kimura AE, Reddy CV, Folk JC, Farmer SG. Removal of subretinal hemorrhage facilitated by preoperative intravitreal tissue plasminogen activator. Retina 1994; 14:83–84.
28.Heriot W. Intravitreal gas and tPA: an outpatient procedure for subretinal hemorrhage. Vail Vitrectomy Meeting, March 10–15, 1996, Vail, Co.
29.Hesse L, Schmidt J, Kroll P. Management of acute submacular hemorrhage using recombinant tissue plasminogen activator and gas. Graefe’s Arch Clin Exp Ophthalmol 1999; 202:273–277.
30.Hassan AS, Johnson MW, Schneiderman TE, Regillo CD, Tornambe PE, Poliner LS, Blodi BA, Elner SG. Managment of submacular hemorrhage with intravitreous tissue plasminogen activator injection and pneumatic displacement. Ophthalmology 1999; 106:1900–1907.
31.Connor TB. Surgical displacement of submaclar hemorrhage Vail Vitrectomy Meeting, March 15, 2000, Vail, CO.
32.Federman JL. Variation in surgical management of sub-macular hemorrhage. Vail Vitrectomy Meeting, March 15, 2000,Vail, CO.
33.McCuen BW. A new concept in the treatment of submacular hemorrhage in AMD. Vail Vitrectomy Meeting, March 14, 2000 Vail, CO.
34.Lewis H. VanderBrug Medendorp S. Tissue plasminogen activator-assisted surgical excision of subfoveal choroidal neovascularization in age-related macular degeneration: a randomized, double-masked trial [Clinical Trial. Journal Article. Randomized Controlled Trial]. Ophthalmology 1997; 104(11):1847–1851; discussion 1852.
35.Yao Xiao-Ying, Endo Eric G and Marmor Michael F. Reversibility of retinal adhesion in the rabbit. Invest Ophthalmol Vis Sci 1989; 30:220–224.
324 |
Chong |
36.Faude F, Reichenbach A, Wiedemann P. A detachment infusion for macular translocation surgery. Retina 1999; 19(2):173–174.
37.Edelhauser HF, Van Horn DL, Hyndiuk RA, Schultz RO. Intraocular irrigating solutions: their effect on the corneal endothelium. Arch Ophthalmol 1975; 93:648–657.
38.Waltman SR, Carroll D, Schinimelpfenning W, Okun E. Intraocular irrigating solutions for clinical vitrectomy. Ophthalmic Surg 1975; 6(4):90–94.
39.Benson WE, Diamond JG, Tasman W. Intraocular irrigating solutions for pars plana Vitrectomy: a prospective, randomized, double-blind study. Arch Ophthalmol 1981; 99:1013–1015.
40.Glasser DB, Matsuda M, Ellis JG, Edelhauser HF. Effect of intraocular irrigating solutions on the corneal endothelium after in vivo anterior chamber irrigation. Am J Ophthalmol 1985; 99:321–328.
41.Makoto, Araie MD. Barrier function of corneal endothelium and the intraocular irrigating solutions. Arch Ophthalmol 1986; 104:435–438.
42.Aaberg TM, Sharara NA, Edelhauser HF, and Grossniklaus HE. Hydroseparation of the neurosensory retina with calcium free BSS Plus. September 3, 2000. XXIInd Meeting of the Club Jules Gonin, Taormina, Italy, September 2–6, 2000.