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Topical timolol and the human retinal circulation (summary)
SURVEY OF OPHTHALMOLOGY
VOLUME 33 - SUPPLEMENT - APRIL 1989
Topical Timolol and the Human Retinal Circulation (Summary) JUAN
E. GRUNWALD,
M.D.
Scheie Eye Institute,
University of Pennsylvania,
Philadelphia,
Pennsylunnict
Key words. beta-adrenergic blocker fundus photography laser Doppler velocimetry retinal circulation retinal vascular occlusion l
l
Timolol is a nonspecific beta-adrenergic blocking agent that reduces intraocular pressure (IOP)“‘,” by lowering the rate of aqueous formation in the ciliary body. Since antiglaucomatous therapy has been advocated for use in patients with retinal vascular occlusion and elevated IOP,5 we investigated the effect of timolol on retinal circulation,’ using laser Doppler velocimetry in combination with monochromatic fundus photography.21fiB7 The laser Doppler measured the maximum velocity (V,,,,,) of red blood cells flowing in the main retinal veins, and fundus photography made it possible to gauge the diameter of a blood vessel. Blood flow was then calculated (V,,,, divided by 1.6 times vessel cross section). The study population consisted of 14 normal subjects aged 18 to 40 years; none had a history of systemic or intraocular disease. All eyes had a best refracted visual acuity of 6/6, an IOP < 19 mm Hg, and steady fixation. In a double-blind randomized study, blood flow in one major temporal retinal vein was measured in each eye before and after administration of two drops of timololO.5% in one eye and placebo drops in the other. Measurements were made at baseline and 90 minutes after instillation of the drops. The instrument used to measure retinal circulation was developed by Dr. Charles Riva. It is a fundus camera into which a very weak laser is incorporated. Light from the laser enters the eye and is reflected back to photo multipliers which record the Doppler shift due to red blood cell movement. Perfusion pressure was defined as two-thirds of the mean brachial blood pressure (diastolic blood pressure plus one-third of the pulse pressure) minus IOP. Following instillation of the drops, IOP decreased by 18%) in the eye receiving placebo and 35% in the eye receiving timolol. The significant IOP decrease in the placebo-treated eye probably
l
l
resulted from some of the active drug reaching it through circulation. Perfusion pressure increased by an average of 7% with placebo and 13% with timolol. The average percentage changes in the diameter of the veins, velocity of red blood cells, and in blood flow for placebo- and timolol-treated eyes are shown in Fig. 1. The bars correspond to the 95%’ confidence limits; those that do not cross the zero line represent statistically significant results (p < 0.0 1). No significant change occurred in the diameter of the retinal veins with either treatment. Blood flow velocity increased 3% in the eyes receiving placebo (not statistically significant) and I 1% in the eyes receiving timolol, a statistically significant difference. Blood flow was not significantly changed in the placebo-treated eyes (1.5%). A significant increase (13.2%) was observed, however, in the timololtreated eyes. Individual percentage changes in mean brachial artery pressure were plotted against the percentage changes in blood flow rate occurring with placebo and timolol. No significant linear correlations were observed in the eyes receiving placebo, whereas significant correlations were noted in the eyes treated with timolol (Fig. 2).
Comment The results of this study show a significant increase in average retinal blood flow of 13q fbllowing timolol instillation. This increase is produced mainly by an increase of 11% in blood velocity. The lack of correlation between changes in blood pressure and retinal blood flow in the eyes receiving placebo is not surprising, since the retina can autoregulate blood flow within a certain range to compensate for changes in perfusion pressure.“.‘.‘.!’ However, the correlation observed in the eyes treat-
416
Surv Ophthalmol
33 (Supplement)
GRUNWALD
April 1989
nm0lol
Placebo
Fig. I. Percentage changes in the diameter of the veins (D), velocity of red blood
cl .E 540-
0 .c 0 PM-
cells (V,,), and blood flow (Q) for placebo- and timolol-treated normal eyes. (Reprinted from Grunwald JE” with permission from Invest Oph~~~~l Vis &if
z
: l
l
I -10
<5
l
.
(, . l
.
E
20-
* 1
.
0
. I
5.
l%
I
10 change in BPm
I
, F-10
-5
0
l
5
10
% change in 8Pm
l
-2o-
-2O.
Fig. 2. Scattergrams relating volumetric blood flow rate (Q) and mean blood pressure (BP,) in placebo- and timolol-treated eyes. There is no significant correlation in the placebo-treated eyes and a significant correlation in the timolol-treated eyes (p < 0.01). (Reprinted from Grunwald JE2 with permission from Invest Op~~~~~ VzLs Sci)
25
r
” -
q q Timolol Plscabc
15 -
ed with timolol is surprising since it suggests that this drug may affect the capacity of the retina to autoregulate blood flow. It appears that retinal blood flow more passively follows blood pressure after timoiol treatment. In a preliminary study, we have used these methods to assess the effects of timolol on retinal blood flow in I1 patients with ocular hypertension. Just as in normals, there were no significant changes in the diameter of the blood vessels, but there were statistically significant increases in blood velocity and blood flow in the eyes that received timolol.
References GrunwaldJE: The effect of topicat timolol on human retinal circulation. Invest OphthuZmoEVis Sci 27: 17 13-17 19, 1986 Grunwald JE, Riva CE, Sinclair SH, et al: Laser Doppler velocimetry study of retinal circulation in diabetic mellitus. Arch Op~~rnol 104r991, 1986 Grunwald JE, Riva GE, Stone RA, et al: Retinal autoregulation in open angle glaucoma. Ophthalmology 91:1690, 1984 Grunwald JE, Sinclair SH, Riva CE: Autoregulation of reti-
’’
nal circulation in response to decrease in intraocular pressure. Znvest Ophthulmol Vi.s Sci 23:124, 1982 Kolker AE, Hetherington J: in Becker-Schaffer (ed): Diagnosis urzd Therms of the Gloom. St Louis, CV Mosby, 1983, p 245 Riva CE, Feke GT: Laser Doppler velocimetry in the measurement of retinal blood flow, in Goldman L (ed): The Biomedical ZJxer: Technology and Clinical Applications. New York, Springer-Verlag, 1981, pp 135-161 ~. _~~ Riva CE, Grunwald JE, Sinclair SH, et al: Blood velocity and volumetric flow rate in human retinal vessels. Invest Ophthul-
mol Vis Sci 26:1124, 1985 8. Riva CE, Loebl M: Autoregulation ofblood flow in the capillaries of the human macula. invest ~~~~~1 Vti Sci Z6:568, 1977 9. Riva CE, Sinclair SH, Grunwald JE: Autoregulation of retinal circulation in response to decrease of perfusion pressure. Invest Ophthalmol Vis Sci 21:34, 1981 10. Zimmerman TJ, Kaufman HE: Timolol, a beta adrenergic blocking agentfor the treatment of glaucoma. Arch ~~~-
naoE95:601, 1977 Il.
Zimmerman TJ, Kaufman HE: Timolol, dose response and duration of action. Arch O$hthulmol 95:605, 1977
Author’s address: Scheie Eye Institute, University of Pennsylvania, 51 North 39 Street, Philadelphia, PA 19104.
VOLUME 33 - SUPPLEMENT - APRIL 1989
Topical Timolol and the Human Retinal Circulation (Summary) JUAN
E. GRUNWALD,
M.D.
Scheie Eye Institute,
University of Pennsylvania,
Philadelphia,
Pennsylunnict
Key words. beta-adrenergic blocker fundus photography laser Doppler velocimetry retinal circulation retinal vascular occlusion l
l
Timolol is a nonspecific beta-adrenergic blocking agent that reduces intraocular pressure (IOP)“‘,” by lowering the rate of aqueous formation in the ciliary body. Since antiglaucomatous therapy has been advocated for use in patients with retinal vascular occlusion and elevated IOP,5 we investigated the effect of timolol on retinal circulation,’ using laser Doppler velocimetry in combination with monochromatic fundus photography.21fiB7 The laser Doppler measured the maximum velocity (V,,,,,) of red blood cells flowing in the main retinal veins, and fundus photography made it possible to gauge the diameter of a blood vessel. Blood flow was then calculated (V,,,, divided by 1.6 times vessel cross section). The study population consisted of 14 normal subjects aged 18 to 40 years; none had a history of systemic or intraocular disease. All eyes had a best refracted visual acuity of 6/6, an IOP < 19 mm Hg, and steady fixation. In a double-blind randomized study, blood flow in one major temporal retinal vein was measured in each eye before and after administration of two drops of timololO.5% in one eye and placebo drops in the other. Measurements were made at baseline and 90 minutes after instillation of the drops. The instrument used to measure retinal circulation was developed by Dr. Charles Riva. It is a fundus camera into which a very weak laser is incorporated. Light from the laser enters the eye and is reflected back to photo multipliers which record the Doppler shift due to red blood cell movement. Perfusion pressure was defined as two-thirds of the mean brachial blood pressure (diastolic blood pressure plus one-third of the pulse pressure) minus IOP. Following instillation of the drops, IOP decreased by 18%) in the eye receiving placebo and 35% in the eye receiving timolol. The significant IOP decrease in the placebo-treated eye probably
l
l
resulted from some of the active drug reaching it through circulation. Perfusion pressure increased by an average of 7% with placebo and 13% with timolol. The average percentage changes in the diameter of the veins, velocity of red blood cells, and in blood flow for placebo- and timolol-treated eyes are shown in Fig. 1. The bars correspond to the 95%’ confidence limits; those that do not cross the zero line represent statistically significant results (p < 0.0 1). No significant change occurred in the diameter of the retinal veins with either treatment. Blood flow velocity increased 3% in the eyes receiving placebo (not statistically significant) and I 1% in the eyes receiving timolol, a statistically significant difference. Blood flow was not significantly changed in the placebo-treated eyes (1.5%). A significant increase (13.2%) was observed, however, in the timololtreated eyes. Individual percentage changes in mean brachial artery pressure were plotted against the percentage changes in blood flow rate occurring with placebo and timolol. No significant linear correlations were observed in the eyes receiving placebo, whereas significant correlations were noted in the eyes treated with timolol (Fig. 2).
Comment The results of this study show a significant increase in average retinal blood flow of 13q fbllowing timolol instillation. This increase is produced mainly by an increase of 11% in blood velocity. The lack of correlation between changes in blood pressure and retinal blood flow in the eyes receiving placebo is not surprising, since the retina can autoregulate blood flow within a certain range to compensate for changes in perfusion pressure.“.‘.‘.!’ However, the correlation observed in the eyes treat-
416
Surv Ophthalmol
33 (Supplement)
GRUNWALD
April 1989
nm0lol
Placebo
Fig. I. Percentage changes in the diameter of the veins (D), velocity of red blood
cl .E 540-
0 .c 0 PM-
cells (V,,), and blood flow (Q) for placebo- and timolol-treated normal eyes. (Reprinted from Grunwald JE” with permission from Invest Oph~~~~l Vis &if
z
: l
l
I -10
<5
l
.
(, . l
.
E
20-
* 1
.
0
. I
5.
l%
I
10 change in BPm
I
, F-10
-5
0
l
5
10
% change in 8Pm
l
-2o-
-2O.
Fig. 2. Scattergrams relating volumetric blood flow rate (Q) and mean blood pressure (BP,) in placebo- and timolol-treated eyes. There is no significant correlation in the placebo-treated eyes and a significant correlation in the timolol-treated eyes (p < 0.01). (Reprinted from Grunwald JE2 with permission from Invest Op~~~~~ VzLs Sci)
25
r
” -
q q Timolol Plscabc
15 -
ed with timolol is surprising since it suggests that this drug may affect the capacity of the retina to autoregulate blood flow. It appears that retinal blood flow more passively follows blood pressure after timoiol treatment. In a preliminary study, we have used these methods to assess the effects of timolol on retinal blood flow in I1 patients with ocular hypertension. Just as in normals, there were no significant changes in the diameter of the blood vessels, but there were statistically significant increases in blood velocity and blood flow in the eyes that received timolol.
References GrunwaldJE: The effect of topicat timolol on human retinal circulation. Invest OphthuZmoEVis Sci 27: 17 13-17 19, 1986 Grunwald JE, Riva CE, Sinclair SH, et al: Laser Doppler velocimetry study of retinal circulation in diabetic mellitus. Arch Op~~rnol 104r991, 1986 Grunwald JE, Riva GE, Stone RA, et al: Retinal autoregulation in open angle glaucoma. Ophthalmology 91:1690, 1984 Grunwald JE, Sinclair SH, Riva CE: Autoregulation of reti-
’’
nal circulation in response to decrease in intraocular pressure. Znvest Ophthulmol Vi.s Sci 23:124, 1982 Kolker AE, Hetherington J: in Becker-Schaffer (ed): Diagnosis urzd Therms of the Gloom. St Louis, CV Mosby, 1983, p 245 Riva CE, Feke GT: Laser Doppler velocimetry in the measurement of retinal blood flow, in Goldman L (ed): The Biomedical ZJxer: Technology and Clinical Applications. New York, Springer-Verlag, 1981, pp 135-161 ~. _~~ Riva CE, Grunwald JE, Sinclair SH, et al: Blood velocity and volumetric flow rate in human retinal vessels. Invest Ophthul-
mol Vis Sci 26:1124, 1985 8. Riva CE, Loebl M: Autoregulation ofblood flow in the capillaries of the human macula. invest ~~~~~1 Vti Sci Z6:568, 1977 9. Riva CE, Sinclair SH, Grunwald JE: Autoregulation of retinal circulation in response to decrease of perfusion pressure. Invest Ophthalmol Vis Sci 21:34, 1981 10. Zimmerman TJ, Kaufman HE: Timolol, a beta adrenergic blocking agentfor the treatment of glaucoma. Arch ~~~-
naoE95:601, 1977 Il.
Zimmerman TJ, Kaufman HE: Timolol, dose response and duration of action. Arch O$hthulmol 95:605, 1977
Author’s address: Scheie Eye Institute, University of Pennsylvania, 51 North 39 Street, Philadelphia, PA 19104.