A he Langham OBF System12 is used to measure pul- satile ocular blood flow (POBF). Pulsatile flow repre- sents 75% to 85% of total flow,3"5 and thus it is a.
Age-Related Ocular Blood Flow Changes Giuseppe Ravalico, Giovanni Toffoli, Giulio Pastori, Maristella Croce, and Sergio Calderini
Purpose. Pulsatile ocular blood flow (POBF is influenced by well-known parameters, such as intraocular pressure (IOP), heart rate, scleral rigidity, blood pressure, and posture. Age is also likely to influence POBF strongly. The purpose of this study was to evaluate POBF in relation to age in normal subjects. Methods. Relevant data were collected from a sample of 105 normal subjects, ranging in age from 10 to 80 years. To measure the effect of age on POBF, the subjects were divided into seven groups of 15 subjects each; the age range of each group spanned one decade, beginning with age 10. POBF and pulse amplitude (PA) were measured in sitting and supine positions and after suction cup application. Results. Using linear regression analysis, there was a significant correlation between PA and age in the supine position (P = 0.012) and after suction cup application (P = 0.002); in the sitting position, there was a borderline level of statistical significance (P = 0.053). In the sitting position, POBF was 819 ±212 /xl/minute in the second decade and 630 ±194 \i\/ minute in the eighth decade. In the sitting position and after suction cup application, but not in the supine position, a statistically significant correlation between POBF decrease and age was found with linear regression analysis (P < 0.001 and P = 0.004, respectively). Using multiple regression analysis, POBF values revealed a significant correlation with age (P < 0.001), but not with systolic and diastolic brachial pressure. Considering all the subjects, analysis of variance for repeated measures highlighted a significant decrease of POBF from the sitting to the supine position and associated with an IOP increase {P < 0.001) without significant changes of PA. After suction cup application, there was a significant reduction of both PA and POBF (P < 0.001). Conclusions. The data revealed that as age increased, PA decreased in all three series of measurements. POBF decreased with age, and in subjects older than 50 years, the decrease was more evident. These findings are especially noticeable after IOP increase with suction cup. It must be considered that the age-related value of POBF is a fundamental parameter to evaluate correctly the hemodynamic aspects of the pathologies affecting the eye. Invest Ophthalmol Vis Sci. 1996; 37:2645-2650.
A he Langham OBF System12 is used to measure pulsatile ocular blood flow (POBF). Pulsatile flow represents 75% to 85% of total flow,3"5 and thus it is a reliable parameter for evaluating chorioretinal circulation that is constituted for the 95% by the choroidal component.34'6'7 Riva, using laser Doppler flowmetry, found that the pulsatile component of the choroidal
From the Istitulo di Clinica Oculistica, Universita di Trieste, Ospedale Maggiore, Trieste, Italy. Submitted for publication June 27, 1995; revised May 2, 1996; accepted July 26, 1996. Proprietary interest category: N. Rejmnt requests: Giuseppe Ravalico, Istiluto di Clinica Oculistica, Universita di Trieste, Ospedale Maggiore, Piazza Ospedale 1, 34129 Trieste, Italy.
Investigative Ophthalmology & Visual Science, December 1996, Vol. 37, No. 13 Copyright © Association for Research in Vision and Ophthalmology
blood flow was approximately 34% in the cat8 and less than 23% of totalflowin the foveal region of humans.9 As he assesses, however, this method measures blood flow only in the choriocapillaris, not in the large vessels behind it in which the pulsatile component of flow is more important. The POBF may be affected by certain ocular diseases, such as glaucoma, retinitis pigmentosa, diabetic retinopathy, and myopia, as well as by extraocular diseases, such as carotid stenosis.510"13 Furthermore, the POBF value will show an interpersonal variability arising from several parameters, such as scleral rigidity, intraocular pressure (IOP), arterial and venous pressure, heart rate, and, indirecdy, from the person's pos-
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2646
TABLE i.
Distribution in Decades of Age
Range (years)
Mean Age (years)
10 20 21-30 31-40 41-50 51-60 61-70 71-80
18.2 26.6 37.2 47.0 54.2 66.8 75.5
TABLE 2.
Systolic and Diastolic
Brachial Pressure* Males
Females
10
5 5 7 2 4 7 8
10 8 13 11 8 7
14-17
ture. Several authors have reported an average value of the POBF between 648 /^1/minute and 740 /7,1/minute in normal subjects. 10121819 Thus, it is likely that another salient variable in explaining the POBF value may be age. To determine the relevance of this factor, the authors quantified the POBF value in normal subjects and then examined the data statistically to deduce differences in the POBF value explainable by age.
METHODS One hundred five subjects, 67 males and 38 females, ranging in age from 10 to 80 years, were examined. The subjects were divided into seven groups of 15 subjects each, and the age range of each group spanned one decade beginning with age 10 (Table 1). Subjects were prescreened, and they were excluded from the study if they had heart disease, arrhythmia, hypertension, hemopathy, diabetes, or other systemic vascular pathologies or if they were taking vasoactive drugs, such as alpha-adrenergic blocking agents, nicotinic acid and its derivatives, calcium-channel blockers, ergot alkaloids, and purine derivatives. Subjects with ammetropia, cataract, retinal vascular illness, glaucoma, or ocular hypertension, and those who had undergone ophthalmologic surgery, also were excluded from the study. All subjects included in the study were informed of the purpose of the research and the procedures to be used in collecting the data. The study was performed according to the tenets of the Declaration of Helsinki. Brachial arterial pressure and heart rate were measured with subjects in the sitting position. Ocular blood flow was evaluated with the Langham OBF System, first in the sitting position, then, after a 5-minute adjustment period, in the supine position, and finally with application of the suction cup to achieve an average increase in the IOP of approximately 10 mm Hg. Data were collected for the IOP, pulse amplitude (PA), and POBF for each subject with a mean and a standard deviation calculated for each of the seven decades.
Age (years)
10-20 21-30 31-40 41-50 51-60 61-70 71-80
Diastolic BP (mm Hg)
Systolic BP (mm Hg)
122 123 119 124 132 152 147
± ± ± ± ± ± ±
76 80 78 82 82 85 80
9 16 11 5 18 18 25
± ± ± ± ± ± ±
7 7 5 3 10 5 12
Heart Rate (beats/min) 82 76 77 70 75 81 79
± ± ± ± ± ± ±
14 10 15 9 9 11 7
BP = brachial pressure. * Values are mean ± standard deviation. The measurements were taken in the sitting position.
Linear regression analysis was used to determine correlations among PA, POBF, and age in all three series of measurements. In addition, linear regression analysis was used to determine correlations among cardiocirculatory parameters (systolic and diastolic brachial pressure, heart rate) and age in the sitting position. Further multiple regression analysis was performed to determine correlations among POBF, systolic and diastolic brachial pressure, and age for the sitting position. Analysis of variance for repeated measures was used to allow statistical inferences concerning IOP, PA, and POBF values between the sitting and the supine positions and—restricted to PA and POBF—between the supine position and after suction cup application. RESULTS Average values of systolic and diastolic brachial pressures and of heart rates for each decade are summaTABLE 3.
Mean Intraocular Pressure Values in the Sitting and the Supine Positions and After Application of the Suction Cup ( + 1 0 mm Hg)* Intraocular Pressure (mm Hg) Age (years)
10-20 21-30 31-40 41-50 51-60 61-70 71-80 All
Sitting
16 17 16 16 17 16 16 16
± ± ± ± ± ± ± ±
2.4 2.4 2.4 2.5 3.1 2.0 2.4 2.4
Supine
17 ± 17 ± 17 ± 17 ± 18 ± 17 ± 17 ± 17 ±
2.3 3.4 2.4 2.3 2.9 2.8 2.9 2.5
Cup
28 27 30 27 28 27 27 28
± ± ± ± ± ± ± ±
4.3 1.8 2.1 1.9 4.3 2.7 1.4 2.6
Values are mean ± standard deviation. * Analysis of variance for repeated measures shows a statistically significant increase in the intraocular pressure from sitting to supine position (P < 0.001).
Age-Related Ocular Blood Flow Changes
2647
TABLE 4.
Mean Ocular Pulse Amplitudes in the Sitting and the Supine Positions and After Suction Cup Application ( + 1 0 mm Hg)* Pulse Amplitude (mm Hg) Age (years)
10-20 21-30 31-40 41-50 51-60 61-70 71-80 All
Sitting
2.1 2.6 2.4 2.5 2.1 2.0 1.9 2.2
± ± ± ± ± ± ± ±
0.6 1.1 0.9 0.7 0.7 0.6 0.5 0.8
Supine
2.3 2.4 2.3 2.1 2.2 2.0 1.8 2.1
± ± ± ± ± ± ± ±
0.6 1.0 0.7 0.7 0.5 0.9 0.3 0.7
Cup
2.1 1.8 2.1 1.9 1.6 1.6 1.4 1.8
± ± ± ± ± ± ± ±
0.7 0.9 1.1 0.6 0.3 0.6 0.2 0.6
Values are mean ± standard deviation. * A significant decrease in pulse amplitude can be noted only between the supine posture and after suction cup application (P < 0.001; analysis of variance for repeated measures).
rized in Table 2. The value of systolic brachial pressure did not vary considerably through the first four decades (10 to 50 years). An increment of approximately 20% was observed in the eighth decade compared to the second decade. Linear regression analysis evidenced a significant correlation between systolic brachial pressure and diastolic brachial pressure increase and age (r = 0.563, P < 0.001, and r = 0.264, P = 0.006, respectively). On the other hand, heart rate variations were not correlated with age. Using linear regression analysis, no statistically significant changes in sitting and supine IOP were found with age. Nevertheless, the mean of the IOP in the supine position was higher than that in the sitting position; considering all subjects, the repeated measures analysis of variance showed a statistically significant mean increase of 1 mm Hg (P < 0.001) (Table 3). Mean PA values for each decade are summarized in Table 4. By comparing the values of the PA obtained in the three different conditions of measurement, it can be seen that PA does not vary significantly (P =
10
l. Correlation between pulse amplitude (mm Hg) and age (years) in the supine position.
30
60
70
80 years
2. Correlation between pulse amplitude (mm Hg) and age (years) in the supine position after suction cup application.
FIGURE
0.122) from the sitting to the supine position. On the other hand, the decrease in PA between the supine position and after a 10 mm Hg raise in the IOP is statistically significant (P < 0.001) and was more evident in the third and sixth decades. Using linear regression analysis, there was a significant correlation between PA and age in the supine position (r = -0.0244; P = 0.012) (Fig. 1) and after suction cup application ( r = -0.305; P= 0.002) (Fig. 2); in the sitting position, there was a borderline level of statistical significance (r = 0.189; P = 0.053) (Fig. 3). Table 5 shows the mean values of the POBF for each decade. The mean POBF value for the sitting position in the second decade was 819 /zl/minute. Although for the third decade values were similar to those for the second decade, mean POBF began to decline with age. Examining POBF values in the supine position, the mean was 654 //1/minute in the second decade, and then it declined to 560 ^I/minute in the eighth decade. After suction cup application, the POBF declined from a value of 384 /ul/minute in the second decade to 297 /Ltl/minute in the eighth decade. Only the seventh decade showed a different behavior: In all subjects, POBF values were slightly higher than the earlier one. Linear regression analysis shows a highly signifi-
80 years
FIGURE
20
50
80 years
3. Correlation between pulse amplitude (mm Hg) and age (years) in the sitting position.
FIGURE
Investigative Ophthalmology & Visual Science, December 1996, Vol. 37, No. 13
2648
TABLE 5.
Mean Pulsatile Ocular Blood Flows in the Sitting and the Supine Positions and After Application of the Suction Cup ( + 1 0 mm Hg)*
pl/min iOO -i
600- A
A
A
Sitting
Cup
Supine
*
A
i
A*A
*—rA^
300-
Age (years)
A
A
500400-
POBF (fil/min)
r = -0.281 P = 0.004
A
700-
iiA
A
A
819 821 790 704 643 659 630 724
All
± ± ± ± ± ± ± ±
654 673 666 595 587 636 560 624
212 243 156 175 148 132 194 195
± ± ± ± ± ± ± ±
384 356 349 364 275 321 297 335
176 218 182 145 139 235 147 180
± ± ± ± ± ± ± ±
104 137 98 87 93 92 51 101
Values are mean ± standard deviation. POBF = pulsatile ocular blood flow. * Analysis of variance for repeated measures highlights a significant reduction both between sitting and supine positions (P < 0.001) and between supine position and after suction cup application (P < 0.001).
cant correlation between the decrease in POBF in the sitting position and age (r = -0.360; P< 0.001) (Fig. 4). Similarly, a significant correlation was found between POBF and age after suction cup application (r = -0.281; P = 0.004) (Fig. 5), but there was no significant correlation between POBF in the supine position and age (r = -0.166; P = 0.09) (Fig. 6). Pulsatile ocular blood flow decreased significantly from the sitting to the supine position and from the supine position to suction cup application (P< 0.001) (Table 5). In particular, from the sitting to the supine position, flow declined more rapidly from the second to the fifth decade (approximately 18%) than from the sixth to the eighth decade (approximately 7%). On the contrary, after IOP increase, it declined similarly in all decades, with fluctuations between 38.8%, in the fifth decade and 53% in the sixth. Using multiple regression analysis, POBF values showed a significant correlation with age (P < 0.001), but not with systolic and diastolic brachial pressure (Table 6). r = -0.360 p < 0.001
A A
1200-
0-
1
1 20
H
1—
H 60
30
' A
1
1 80 years
FIGURE 5. Correlation between pulsatile ocular blood flow (//1/minute) and age (years) in the supine position after suction cup application.
DISCUSSION Tissues responsive to hypoxia, such as those of the nerve retinal fibers and the optic nerve head, require a constant, adequate supply of blood. In several diseases, a decrease in ocular flow is found through the involvement of the vascular ocular or systemic network. In this study, it was found that ocular flow declines with age, something not found in a previous study using fluorescein videoangiography.20 In a study performed by Langham5 on a group of healthy subjects not age selected but with a mean age of 65 years, the mean pulsatile ocular blood flow value was 724 //1/minute. Data in this study were similar to those we found for the seventh decade, in which the mean age was 66.8 years. Here, the POBF was found to be 659 /xl/minute (SD = 132.3 /nl/minute). Another study12 found a POBF of 648 ^1/minute (SD = 42 /il/minute) and a PA of 2.3 mm Hg (SD = 0.1 mm Hg) in a group of 19 healthy subjects with a mean age of 55 years (SD = 6 years); these values are similar to those found for the sixth decade in our study. In another study19 on ocular flow based on 25 normal subjects with an average age of 50.9 years (SD = 7.1 years), the authors found a POBF of 740.1 /zl/minute (SD = 58.83 /A/ minute). Compared to decade five (mean age, 47 years) in this study, the values again were consistent. However, the data in this study highlight a decline
ft
P=
A
A
^
A ft A
*
*
A
A
1000-
A
A
4t ft
A
A
A
A
A_ A
A
VA
A
A A
A -.
A
iA
A
lr
A i*l* ~?*
A
600 •
A
A A
400-
A
A
A
\ 1
A
A. A . . A
A
AA^
800-
A A
i A **
A A
A
* A
A A A
A
(
—H—
—1
1
1
1 80 years
FIGURE 4. Correlation between pulsatile ocular blood flow (//1/minute) and age (years) in the sitting position.
0-
A
A*
A A A
A
A AA
A AA
i
A
—frx *
AA
A
*
A A
' A
A A
.
A
A A
A
200
200 1
-0.166 0.09
1200-
A
A A A A
r=
1400-
A
A 4
400-
0
ft 1 A
A
A
AA A ^
800600-
A
A
pl/min
pl/min 1400n
1000-
A
—ft—^-A, A A J
*^ A4
A
100-
10-20 21-30 31-40 41-50 51-60 61-70 71-80
A
A
A
AA ft ^
A
200-
A
A
••
1
-H—
—1
1
H
80 years
6. Correlation between pulsatile ocular blood flow (/il/minute) and age (years) in the supine position.
FIGURE
Age-Related Ocular Blood Flow Changes
2649
TABLE 6.
Multiple Regression Analysis Between Pulsatile Ocular Blood Flow, Age, Systolic Brachial Pressure, and Diastolic Brachial Pressure for the Sitting Position* SEofp
N= 105 Intercept Age SBP DBP
-0.467592 0.221282 -0.140765
0.109936 0.130821 0.112628
SEofp 183.1641 1.0830 1.2956 2.7903
92.3548 -4.6064 2.1916 -3.4874
P Level
5.04659 -4.25331 1.69149 -1.24983
0.000002 0.000047 0.093827 0.214251
SE = standard error. * N = 105. Regression summary for dependent variable, pulsatile ocular blood flow: R = 0.41344342, R2 = 0.17093546, adjusted R* = 0.14630978, F(3.101) = 6.9413, P < 0.00027, SE of estimate, 180.10.
in ocular pulse amplitude with age, a result found also by Perkins,21 particularly in the supine position and after suction cup application. In elderly subjects, ocular pulse is more reduced, perhaps because choroidal net is less capacious and less stretchy from degenerative phenomena in microcirculation, particularly in the choriocapillaris, such as hyalinosis of the arteriolae and reduction of their diameters. Therefore, reduced pulsatility results in a lower pulsatile volume and, thus, a lower pulsatile flow. In addition, mechanical factors such as scleral rigidity modification may cause changes in ocular flow: A reduction in scleral rigidity may influence the measurement of ocular pulse amplitude, causing a mistake in the flow calculation.21 However, no significant changes in scleral rigidity have been found in subjects older than 60 years.22 The systemic increase of vascular resistance that arises with age may be involved in the reduction of ocular flow. A significant increase in the systolic and diastolic systemic pressure was more evident in subjects older than 50, probably because of an increase in peripheral vascular resistance. From the data, it appears that the POBF in the supine position does not vary much until 50 years of age; after that, it declines, and this decline becomes more evident when flow is measured after an IOP increase of 10 mm Hg. As several other studies have shown, an appreciable decrease in ocular flow can be seen from the sitting to the supine position 1523 that does not vary significantly with age.24 In contrast, the data show that in changing position, the flow declines more in younger subjects (on average, approximately 20%) than in older ones (approximately 7%). Considering the supine position, several factors could bring about modification in the ocular flow, such as an increase in IOP secondary to higher episcleral venous pressure and intraocular volume, an extension of the length of the diastolic phase of the ocular pulse caused by a decrease in heart rate, or a change of perfusion pressure in the ophthalmic artery.17 It could be assumed that young people are better able to adjust to the abrupt increase in ophthalmic artery perfusion pressure when passing to the supine
position. This may be explained by the better responsiveness of carotid baroceptors that set the postural modifications of the arterial systemic pressure. Because no other parameter changes significantly with age, the increase in vascular resistance could be considered the main factor influencing ocular flow. In fact, in those subjects older than 50, we observed a more evident increase in systemic arterial pressure. It cannot be excluded that in elderly subjects, the autoregulation mechanisms of the circulatory system are less efficacious. In normal subjects, POBF changes related to age are important. We must consider that the age-related value of POBF is a fundamental parameter to evaluate hemodynamic aspects of the pathologies affecting the eye. Key Words age, normal subject, pulsatile ocular blood flow, pulse amplitude References 1. Langham ME, To'Mey KF. A clinical procedure for the measurements of the ocular pulse-pressure relationshi P and the ophthalmic arterial pressure. Exp Eye Res. 1978;27:7-25. 2. Silver DM, Farrell RA, Langham ME, O'Brien V, Schilder P. Estimation of pulsatile ocular blood flow from intraocular pressure. Ada Ophthalmol. 1989; 67(suppl 191):25-29. 3. Langham ME, Farrell RA, O'Brien V, Silver DM, Schilder P. Blood flow in the human eye. Ada Ophthalmol. 1989;67(suppl 191):9-13. 4. Langham ME, Farrell RA, O'Brien V, Silver DM, Schilder P. Noninvasive measurement of pulsatile blood flow in the human eye. Lambrou GN, Greve EL, eds. Ocular Blood Floiu in Glaucoma. 1989:93-99. 5. Langham ME. Ocular blood flow in the diagnosis and treatment of open angle glaucoma. In: Cordelia M, Baratta G, Macaluso C, eds. Retinite pigmentosa, movivienti oculari e ambliopia, glaucoma. Fidenza: Mattioli; 1991:201-213. In Italian. 6. Riva CE, Grunwald JE, Sinclair SH, Petrig BL. Blood velocity and volumetric flow rate in human retinal vessels. Invest Ophthalmol Vis Sci. 1985;26:1124-1132.
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7. Hill DW. Ocular and retinal blood flow. Ada Ophthalmol. 1989;67(suppl 191):5-17. 8. Riva CE, Cranstoun SD, Mann RM, Barnes GE. Local choroidal blood flow in the cat by laser Doppler flowmetry. Invest Ophthalmol Vis Sci. 1994;35:608-618. 9. Riva CE, Cranstoun SD, Grunwald JE, Petrig BL. Choroidal blood flow in the foveal region of the human ocular fundus. Invest Ophthalmol Vis Sci. 1994; 35:42734281. 10. Langham ME, Farrell R, Krakau T, Silver D. Ocular pulsatile blood flow, hypotensive drugs and differential light sensitivity in glaucoma. Krieglstein GM, ed. Glaucoma Update IV. 1991:162-172. 11. Langham ME, Kramer T. Decreased choroidal blood flow associated with retinitis pigmentosa. Eye. 1990; 4:374-381. 12. Langham ME, Grebe R, Hopkins S, Marcus S, Sebag M. Choroidal blood flow in diabetic retinopathy. Exp Eye Res. 1991;52:167-173. 13. Shilder P. Ocular blood flow responses to pathology of carotid and cerebral circulation. Surv Ophthalmol. 1994;38(suppl):52-58. 14. Kothe AC, Vachon N, Woo S. Factors affecting the pulsatile ocular blood flow: Axial length and ocular rigidity. Optom Vis Sci. 1992;69(suppl):74. 15. Trew DR, Smith SE. Postural studies in pulsatile ocular blood flow: Ocular hypertension and normotension. BrJ Ophthalmol. 1991;75:65-70.
16. Trew DR, James CB, Thomas SHL, et al. Factors influencing the ocular pulse: The heart rate. Graefe's Arch ClinExp Ophthalmol. 1991;229:553-556. 17. Kothe AC. The effect of posture on IOP and the pulsatile ocular blood flow in normal and glaucomatous eyes. Surv Ophthalmol. 1994;38(suppl):191-197. 18. Ravalico G, Pastori G, Toffoli G, Croce M. Visual and blood flow responses in low tension glaucoma. Surv Ophthalmol. 1994; 38 (suppl): 173 -176. 19. Quaranta L, Manni G, Donato F, Bucci M. The effect of increased intraocular pressure on pulsatile ocular blood flow in low tension glaucoma. Surv Ophthalmol. 1994;38(suppl):l77-182. 20. Prunte C, Niesel P. Quantification of choroidal blood flow paramethers using indocyanine green videoflourescens angiography and statistical picture analysis. Graefe's Arch ClinExp Ophthalmol. 1988; 226:55-58. 21. Perkins ES. The ocular pulse. CurrEyeRes. 1981; 1:1923. 22. Friedman E, Moshe I, Ebert E, et al. Increased scleral rigidity and age-related macular degeneration. Ophthalmology. 1989;96:104-108. 23. James CB, Smith SE. The effect of posture on the intraocular pressure and pulsatile ocular blood flow in patients with non arteritic anterior ischemic optic neuropathy. Eye. 1991;5:309-314. 24. Kothe AC, Lovasik JV, Kergoat H. Postural effects on ocular hemodynamics as a function of age. ARVO Abstracts. Invest Ophthalmol Vis Sci. 1992; 33:808.
