Effect of Body Position On Intraocular Pressure and Aqueous Ow

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Effect of body position on intraocular pressure and aqueous flow

Article  in  Investigative Ophthalmology & Visual Science · September 1987


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Effect of Body Position on Introoculor Pressure
and Aqueous Flow
Keirh H. Carlson, Jay W. McLaren, Jane E. Topper, and Richard F. Brubaker

The relationship between intraocular pressure and the rate of aqueous humor formation was studied in
human subjects. Intraocular pressure was altered by changing the subject's gravity-dependent body
position. Aqueous humor flow was measured fluorophotometrically. An average change of intraocular
pressure of 2.4 ± 1.2 mmHg and 11.2 ± 2.7 mmHg was recorded in subjects whose body position was
alternated ±15° from horizontal and ±50° from horizontal. No change of the rate of fluorescein
clearance was observed for the milder change of position. A small change of fluorescein clearance was
noted in response to the steeper change of position. Changing intraocular pressure seems not to induce
compensatory changes in aqueous flow. Therefore we conclude that aqueous formation is relatively
pressure-insensitive, a conclusion one would draw from clinical instances of angle-closure glaucoma or
as in other systems of secretion, such as the toad bladder or the cerebrospinal fluid, where alterations
in pressure do not necessarily influence flow. If there is a regulator of aqueous flow it is not responsive
to the changes in intraocular pressure brought about in this study. If aqueous flow regulates intraocu-
lar pressure or compensates for changes in intraocular pressure, the signal is not small changes in
pressure. Invest Ophthalmol Vis Sci 28:1346-1352,1987

Goldmann's important work1 established that the property to the organism primarily by compensating
major determinants of intraocular pressure were flow for uncontrolled inputs (disturbances).3 Thus a regu-
of aqueous humor, resistance to outflow, and epis- lator creates a forcing function which can maintain
cleral venous pressure. An additional factor, uveo- the regulated variable within narrow limits around a
scleral flow, was established by the more recent work set point.
of Bill.2 These four factors maintain the steady-state In the experiment described below, the intraocular
intraocular pressure of the normal eye within fairly pressure of normal conscious humans was disturbed
narrow limits over the span of a lifetime. by changing the position of the body with respect to
This paper is concerned with one of the determi- gravity. The disturbance of intraocular pressure was
nants of intraocular pressure, namely the rate of flow measured by tonometry and the response of the rate
of aqueous humor through the anterior chamber. The of aqueous humor flow was measured by fluoropho-
research reported in this paper is an attempt to find if tometry.
the rate of aqueous humor flow through the anterior
chamber changes in response to disturbances of intra- Materials and Methods
ocular pressure, and if the direction and magnitude of
such change is sufficient to suggest that intraocular Healthy volunteers ranging in age from 14 to 47
pressure is regulated by feedback onto the rate of were studied. Each volunteer was interviewed and
aqueous flow. underwent an ophthalmic examination to confirm
Before describing the experiment, it is necessary to that both eyes were normal. Informed consent was
define exactly what is meant in this paper by the term obtained in accordance with federal guidelines. The
"regulator." We define a regulator as a control pro- experiment consisted of independent measurements
cessor which imparts a biologically advantageous of the intraocular pressure and the rate of flow of
aqueous humor of each eye while the intraocular
pressure was modulated. Modulation of intraocular
From the Department of Ophthalmology, Mayo Clinic, Roches- pressure was achieved by alternating the supine vol-
ter, Minnesota. unteer between two gravity-dependent body positions
Supported in part by NIH grant EY-00634, Research to Prevent on a tilt table.
Blindness, Inc., New York, New York and the Mayo Foundation, The experiment was divided into three parts. In
Rochester, Minnesota.
Submitted for publication: April 21, 1986.
Part 1, 11 volunteers remained for 6 hr in the 15°
Reprint requests: Richard F. Brubaker, MD, Mayo Clinic, De- head-up position one day and in the 15° head-down
partment of Ophthalmology, Rochester, MN 55905. position another day. In Part 2, 20 volunteers alter-

1346
No. 8 EFFECT OF DODY POSITION ON IOP AND AQUEOUS FLOW / Corlson er ol. 1347

nated every hour between 15° head-up and 15°


head-down for three complete cycles. In Part 3, 10
volunteers alternated every 30 min between 50°
head-up and 50° head-down for two complete
cycles.4
Intraocular pressure was measured without mov-
ing the subject. The Bigliano-Webb tonometer was
employed (Pneumatonograph, Alcon Laboratories,
Inc., Fort Worth, TX). The axis of the tonometer was
held at approximately 45° from vertical for all mea-
surements because of the gravity dependency of this
instrument5 (Fig. 1 and 2).
Intraocular pressure was measured after instillation
of 1/2% proparacaine hydrochloride. Each eye was
measured twice, alternating between the two eyes.
The pressure was recorded on a strip chart recorder.
The tonometer was allowed to rest against the cornea
for approximately 3 sec. This procedure permitted Fig. 1. Subject in 50° head-up position. Pressure recorded with
the examiner to be sure that the tonometer was prop- Bigliano-Webb tonometer (Pneumatonometer) held at 45° from
erly coupled to the eye. Intraocular pressure was vertical.
measured from the tracing. The average of the two
readings for each eye was used to calculate the pres- total fluorescence. The mass of fluorescein in the cor-
sure for that eye. neal stroma (mc) was calculated as the product of the
The procedure for measuring the intraocular pres- mean concentration of fluorescein in the stroma (cc)
sure of both eyes could be accomplished in approxi- and the geometric volume of the stroma (vc) (as-
mately 1 min. Intraocular pressure was measured at sumed to be 70 /A for all eyes). The mass of fluores-
the end of each half-cycle of modulation and 7 min cein in the anterior chamber (ma) was calculated as
after the beginning of each half-cycle. (A 7-min delay the product of the mean concentration of fluorescein
is sufficient to permit the unregulated eye to return in the anterior chamber (ca) and the geometric vol-
almost completely to a steady-state pressure after a ume of the anterior chamber (va), measured for each
change of body position, as calculated by Gold- eye photogrammetrically.10
mann's1 and Friedenwald's models of the eye6; regu- The rate of clearance of fluorescein from the ante-
lation would hasten the return to a steady-state pres- rior chamber by diffusion and flow was calculated for
sure.) each temporally-spaced pair of measurements of flu-
The rate of flow of aqueous humor through the orescence in the eye employing equation 14, page 211
anterior chamber was measured by observing the rate of Jones and Maurice7:
of clearance of topically applied fluorescein according
to the method described by Jones and Maurice.7 Flu-
orescein was applied to the conjunctival cul-de-sac by
the subject 6 hr prior to the beginning of testing ac-
cording to the method of Yablonski et al.8 The con-
centration of fluorescein in the cornea and in the
anterior chamber was measured at the beginning and
end of each half-cycle of modulation of intraocular
pressure. In all three experiments measurements of
fluorescence were made half-hourly or hourly. This
procedure made it necessary that the subject step
down from the tilt table and sit in front of a fluoro-
photometer for approximately 4 min before return-
ing to the position required by the protocol (Fig. 3).
The concentration of fluorescein in the mid-hori-
zontal plane of the anterior segment was measured
with a two-dimensional scanning fluorophotometer.9 Fig. 2. Subject in 50° head-down position. Pressure recorded
The autofluorescence of the stroma, measured before with Bigliano-Webb tonometer (Pneumatonometer) held at 45°
application of fluorescein, was subtracted from the from vertical.
1348 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / August 1987 Vol. 28

A detailed explanation of this method is given else-


where."
In one volunteer, measurements of the axial depth
of the anterior chamber were made ultrasonometri-
Fluorophotometer cally before, during, and after prolonged exposure to
the 50° head-down position.
The reproducibility of the technique for measuring
hourly flows was determined by comparing the rate
of clearance of fluorescein during adjacent hourly pe-
riods in subjects who were studied in Part 1. We also
calculated the reproducibility of hourly flow mea-
surements by comparing the flow measured at the
same time of day on two different days. In addition,
we compared hourly and half-hourly measurements
of flows made simultaneously in fellow-eyes. These
measurements permitted us to determine the statisti-
cal power of the experimental procedures. Signifi-
Fig. 3. Concentration of fluorescein in anterior chamber and cance was determined by the single-sided t test for
cornea measured with fluorophotometer in sitting position. paired samples, a <. 0.5. The same procedure was
carried out to determine the reproducibility of to-
nometry.
rate of clearance = (Amc + Ama)/(ca X At)
Results
Ten percent of the clearance of fluorescein was as-
sumed to be due to diffusional losses and 90% due to In Part 1 of the experiment the subjects lay in the
the flow of aqueous humor through the anterior supine position (± 15°) for 6 hr. On one day the head
chamber: was elevated and on another day the head was low-
ered. At the beginning of the experiment, the mean
rate of flow of aqueous humor intraocular pressure was 14.5 ± 1.24 (mean ± SD) in
= (rate of clearance) X 0.9 the head-up position and 16.8 ± 1.44 in the head-
down position. The intraocular pressure difference
remained approximately 2 mmHg (higher in the
head-down position) during the early part of the ex-
CONSTANT POSITION 15 periment and gradually diminished to approximately
1 mmHg. The difference was statistically significant
(P < .05) for all 6 hr.
The mean flow of the eleven subjects in the 15°
head-up position for 6 hr was 3.00 ± 0.78 jil/min. On
a separate day when the head was down 15° for 6 hr
the mean flow was almost identical, 2.99 ± 0.57 MV
min (P > .05). In both positions there was a gradual
and significant decrease in the rate of flow, which
began at 3.1 /tl/min and diminished over the 6 hr to
2.9 /xl/min (see Fig. 4). The gravity-dependent posi-
tion had no effect on this gradual decline.
The reproducibilities of the measurements of pres-
sure and flow were determined by comparing paired
hourly measurements (Table 1). The coefficient of
variation of the measurement of either the mean
pressure of two eyes or the mean flow of two eyes of a
single subject over 1 hr was found to be 9%. When the
comparison of flow was made on two different days
the coefficient of variation was 20% for hourly mea-
Fig. 4. Aqueous flow is same in both body positions. Intraocular surements and 18% for 6-hr measurements. The sta-
pressure is significantly higher in head down position (P < .05). tistical power of the flow measurement of Part 1 of
No. 8 EFFECT OF BODY POSITION ON D P AND AQUEOUS FLOW / Corlson er ol. 1349

Table 1. Reproducibility of measurements


Standard deviation
Number of of differences Coefficient
paired between paired of
Parameter measurements measurements variation

Intraocular pressure
Mean pressure of two fellow eyes measured at two times 1 hr apart 132 1.4 mmHg 9.0%
Pressure of right eye versus left eye measured at same time 153 1.3 mmHg 8.3%
Aqueous humor flow
Mean flow during 1 hr of two fellow eyes measured at two times 1
hr apart 110 0.27 Ml/min 9.0%
Mean flow during 1 hr of two fellow eyes measured at two times
at same time of day on different days 66 0.60 Ml/min 20%
Mean flow during 6 hr of two fellow eyes measured at two times
on different days 11 0.53 M'/min 18%
Flow of right eye versus left eye measured during the same hour 131 0.54 Ml/min 18%
*Flow of right eye versus left eye measured during the same 4 hr 71 0.41 M'/min 16%
*Flow of right eye versus left eye measured during the same 8 hr 71 0.34 Ml/min 13%
1
Different group of 71 subjects.

our experiment can be calculated from this last fig- ments in sequence on the same day is better than
ure.12 The experiment has a 90% chance of detecting comparable measurements on different days (see
a 26% reduction in the rate of flow in the head down Table 1). Second, twice as many subjects were stud-
position (a = 0.05, single-sided test). A smaller ied. Third, several comparisons of the two positions
change might have gone undetected, but a larger were possible in each subject. A power calculation
change probably would not. We conclude that the based on the number of subjects and the coefficient of
gravity-induced change of intraocular pressure did variation of this method suggests that experiment 2
not induce a biologically significant compensatory has a 90% chance of detecting a change of 10% or
change of flow (Fig. 4). greater in flow. Since no change was detected, we
In Part 2 the 15° head-up and the 15° head-down conclude that a modest increase in intraocular pres-
positions were alternated hourly. This procedure per- sure due to a change in the gravity-dependent posi-
mitted observation of the response of flow to a change tion for 1 hr causes no significant change in the rate of
of pressure without concern for drifts in the rate of aqueous humor formation.
flow over the 6 hr and without the need to compare In Part 3, 10 subjects underwent a procedure simi-
the pressures and flows on different days. lar to the procedure in Part 2. In Part 3 the angle of
Figure 5 summarizes the results of a single subject. tilt was 50° in order to produce a larger disturbance
In this subject, the higher intraocular pressure in the of intraocular pressure. The duration of a half cycle
head-down position is obvious. However, no changes
of flow were observed.
Half of the subjects of Part 2 (n = 10) began the SINGLE SUBJECT, ALTERNATING POSITION 15°
experiment in the head-up position. Figure 6 is a i s (sit)
55 Up
graphical representation of the results of these 10 ,?o Down
subjects. Figure 7 is a graphical representation of the • Right eye
results of the other 10 subjects of Part 2 who began o Left eye
. 21
the experiment in the head-down position. Neither 18
5J
group showed any significant changes except for the ; 15
gravity dependency of intraocular pressure. The Q.

12
change of pressure induced by the change of position
was 2.4 ± 1.2 mmHg (mean ± SD), which was statis-
tically significant. The mean change of the rate of
flow associated with the change of body position was
-0.05 ± 0.5 Ail/min (mean ± SD) which was neither
3
physiologically nor statistically significant. Hours
The statistical power of Part 2 to detect changes in Fig. 5. One subject changing body positions every hour. Intraoc-
flow is considerably greater than Part 1 for three rea- ular pressure is higher while head-down and lower while head-up.
sons. First, the reproducibility of hourly measure- Flow remains stable.
1350 INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / Augusr 1987 Vol. 28

ALTERNATING POSITION 15 flow was slower when the intraocular pressure was
higher. Thus, larger changes of intraocular pressure
were accompanied by small but consistent changes of
I f I f the rate of flow in the opposite direction (Fig. 8).
In one subject the depth of the central portion of
the anterior chamber was measured by ultrasonogra-
phy in each gravity-dependent position. The depth of
the anterior chamber during inversion to 50° was
stable and was the same as in the sitting position both
before and after inversion.

Discussion
Measurement of intraocular pressure was made in
such a way that the change in body position could
have had no direct effect on the tonometer; the to-
nometer was held at the same angle for all measure-
ments in order that its gravity-dependency not be a
factor. Intraocular pressure was measured near the
Fig. 6. Ten subjects beginning Part 2 in head-up position. beginning and at the end of each period. The results
suggest that intraocular pressure rises in a few min-
utes, remains elevated in the inverted position, and
was shortened to 30 min. Longer exposures to the returns in a few minutes to normal when the head is
head-down position caused numbness of the feet of elevated. The rate of rise or fall during the first 7 min
the subjects, due in part to tightness of a restraining was not measured.
ring clamped around the ankles (Gravity Inversion When the pressure changes, the volume of the con-
Boots®, Gravity Guidance, Inc., Duarte, CA). tents of the globe also change. The relation between
In this group, the gravity-dependent change of in- pressure and volume of the human eye has been
traocular pressure was 11.2 ± 2.7 mmHg (mean carefully worked out by Friedenwald6 and serve as
± SD), statistically significant. The gravity-depen- the basis for Schiotz tonometry. The largest pressure
dent change of flow was -0.4 ± 0 . 5 (mean ± SD) change observed in our experiment would have been
Ml/min. This change was also statistically significant associated with a 12 ^1 change in volume of the globe.
(P < .05). The negative sign indicates that the rate of This volume is 7% of the volume of the average ante-
rior chamber of our subjects and approximately 0.2%
the volume of the posterior segment of the eye.
ALTERNATING POSITION 15° Twelve microliters is also 15% of the measured clear-
ance of fluorescein in 30 min. In longer experiments
with smaller changes of intraocular pressure, the
change of volume is trivial compared to the volume
of aqueous humor passing through the anterior
chamber, and no allowance need be made for it.
It is likely that most of the change of volume occur-
ring with changes in pressure took place behind the
plane of the iris, away from the compartments con-
taining fluorescein. This point of view is supported by
the observation that the depth of the anterior
chamber of the subject who was measured by ultraso-
nography at 50° head-down did not change. The vol-
ume of expansion in the 50° experiment could have
come from either a 12 /A expansion of blood volume,
from 12 A*l of newly formed aqueous humor, or some
combination of the two. If the expansion had come
from any source other than newly formed aqueous
humor, the fluorophotometric measurement would
Fig. 7. Ten subjects beginning Part 2 in head-down position. accurately measure any change in the rate of aqueous
No. 8 EFFECT OF BODY POSITION ON IOP AND AQUEOUS FLOW / Carlson er ol. 1351

humor formation; if the expansion were produced ALTERNATING POSITION 50


entirely from newly formed aqueous humor, a correc-
tion based on Friedenwald's formula of ocular rigid-
ity must be applied. If we apply a full correction to
the results, we can conclude that aqueous flow was
not suppressed at all in the head-down position; if we
apply no correction, the suppression was only 16%
when intraocular pressure was almost doubled.
In an eye with normal outflow resistance, a change
of aqueous flow of 16% would result in a change of
pressure of less than 1 mmHg, hardly sufficient to
overcome a disturbance of nearly 12 mmHg. If one
assumes that intraocular pressure is regulated by neg-
ative feedback, onto the rate of flow,3 the loop gain of
such a regulator can be calculated from the results of
this experiment. The calculated gain with or without
the Friedenwald correction is too low to be of any
biological significance.
The change of body position cannot be regarded as
an isolated perturbation of intraocular pressure. Fig. 8. Ten subjects alternated 50° every half-hour. Larger
Venous pressure around the eye will certainly have changes of intraocular pressure are observed as compared to Part 2.
changed and arterial pressure can have changed as Small, gravity-dependent changes in flow are observed.
well. Undoubtedly other autonomic changes occur in
order to regulate the vascular system; we have made
no attempt to block these changes with exogenously tary glaucoma share the common feature that the
applied pharmacologic agents. Is it possible that these resistance to aqueous humor outflow is abnormally
complex changes, some of which could have tended high. In neither disease does it seem likely that the
to increased aqueous flow and some of which could ciliary body would be unable to respond to the com-
have tended to decrease it can have overpowered the mands of a pressure regulator. Also, it has been
function of any putative regulator? If the answer to shown that improvement of outflow facility by laser
this question is "yes," then the biological advantage trabeculoplasty with subsequent lowering of intraoc-
of the eye's being equipped with such a regulator is ular pressure is not accompanied by a change in the
drawn into question, and the regulator does not meet rate of aqueous humor flow through the anterior
its functional expectations. chamber.1516 We conclude from these measurements
Aside from loop gain, feedback regulators differ in and from commonplace clinical observations of pa-
their response time. The possibility exists that a regu- tients affected with glaucoma of many causes that
lator exists which cannot respond to a disturbance as chronically elevated intraocular pressure does not
brief as 30 min to 6 hr. This experiment does not alter the rate of aqueous humor flow.
exclude the possibility of the existence of a regulator In 1963 Barany wrote a theoretical paper in which
with a slow response time. However, as cited in the he formulated the relation between intraocular pres-
next paragraph, data from other sources make it seem sure and aqueous formation, taking into account
unlikely that chronic disturbances of intraocular Starling's law of fluid exchange 17 and the anatomical
pressure due to increased outflow resistance induce arrangement of vessels inside the pressurized eye. He
important compensatory changes of the rate of predicted, in the absence of vasoregulatory influ-
aqueous flow. ences, aqueous formation would be suppressed by
Anselmi, Bron, and Maurice13 have compared the elevation of intraocular pressure, an effect he called
rate of flow in steroid responders whose intraocular pseudofacility. Subsequently, several investigators
pressure was raised an average of 18.8 mmHg in one measured pseudofacility in anesthetized primates
18 20
eye by the topical application of 0.1% dexamethasone ~ and in unanesthetized humans.21 The results of
for 1 month. The rate of flow was the same in the eye these studies indicate that the rate of aqueous humor
with the higher pressure as in the fellow eye. Brubaker flow slows as intraocular pressure rises.
et al14 have studied several patients with pigment dis- How do the results of this study compare to pre-
persion syndrome and have not found that such per- viously reported studies of pseudofacility? The results
sons have a chronically depressed rate of aqueous are similar. The experiment of Kupfer and Ross 21
humor flow. Steroid-induced glaucoma and pigmen- demonstrates that an elevation of intraocular pres-
1352 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / Augusr 1987 Vol. 28

sure of 10 mmHg should suppress aqueous flow by rate of aqueous flow in man with fluorescein. Exp Eye Res
0.6 Ail/min, close to our uncorrected figure of 0.4 ix\/ 5:208, 1966.
8. Yablonski ME, Zimmerman TJ, Waltman SR, and Becker B:
min for an 11 mmHg change. Earlier work was con- A fluorophotometric study of the effect of topical timolol on
ducted in anesthetized monkeys by Bill and Barany 18 aqueous humor dynamics. Exp Eye Res 27:135, 1978.
and by Brubaker and Kupfer.19 The results of this 9. McLaren J and Brubaker R: A two-dimensional scanning ocu-
work would suggest that elevation of intraocular lar fluorophotometer. Invest Ophthalmol Vis Sci 26:144,1985.
pressure by 10 mmHg would suppress aqueous for- 10. Johnson S, Coakes RL, and Brubaker RF: A simple photo-
grammetric method of measuring anterior chamber volume.
mation by 1.3-1.4 Atl/min, several times greater than Am J Ophthalmol 85:469, 1978.
later results would suggest. The pressure disturbances 11. Brubaker RF: Clinical evaluation of the circulation of aqueous
in the earlier work were short, 4-10 min. humor. In Clinical Ophthalmology, vol 3, Duane TD and
More recently, Bill conducted experiments in anes- Jaeger EA, editors. Philadelphia, JB Lippincott Co, 1986, pp.
thetized monkeys where pressure elevations were 1-11.
12. Beyer WH: Handbook of Tables for Probability and Statistics
maintained for several hours.22 His results suggest a (2nd ed.). Cleveland, Chemical Rubber Company, 1968, p.
long-standing rise in pressure has less effect on the 287.
rate of aqueous flow. The results of the present ex- 13. Anselmi P, Bron A, and Maurice D: Action of drugs on the
periment are in very good agreement with Bill's more aqueous flow in man measured by fluorophotometry. Exp Eye
recent study, despite differences in species and Res 7:487, 1968.
14. Brubaker RF, Bourne WM, and Nagataki S: Effect of chroni-
methods. Both experiments demonstrate that cally administered timolol on aqueous humor flow in patients
aqueous flow is rather insensitive to changes of intra- with glaucoma. Ophthalmology 89:280, 1982.
ocular pressure. 15. Brubaker RF and Liesegang TJ: Effect of trabecular photoco-
agulation on the aqueous humor dynamics of the human eye.
Key words: bioregulation, intraocular pressure, aqueous Am J Ophthalmol 96:139, 1983.
flow, human eye, body position 16. Yablonski ME, Cook DJ, and Gray J: A fluorophotometric
study of the effect of argon laser trabeculoplasty on aqueous
humor dynamics. Am J Ophthalmology 99:579, 1985.
References 17. Barany EH: A mathematical formulation of intraocular pres-
sure as dependent on secretion, ultrafiltration, bulk outflow,
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