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Diurnal Variation in Intraocular Pressure
DIURNAL VARIATION IN INTRAOCULAR PRESSURE CHARLES D. PHELPS, M.D.,
AND ROBERT F. WOOLSON, P H . D .
Iowa City, Iowa AND ALLAN
E.
KOLKER,
M.D.,
AND
St. Louis,
Diurnal fluctuations of intraocular pres sure pose a difficult problem for the ophthal mologist involved in the diagnosis and man agement of glaucoma.1"5 The diurnal intra ocular pressure variation is quite minimal in normal eyes, averaging 3 to 4 mm Hg, but is often much greater in eyes with glaucoma. A single measurement of intraocular pressure during office hours is unlikely to catch the peak of the diurnal variation.1 Since the peak of the diurnal intraocular pressure variation is presumably the signifi cant level for the pathogenesis of glaucomatous visual field loss, its detection is quite important. This detection obviously requires measurement of intraocular pressures at times that are inconvenient for ophthalmolo gist and patient alike. Although the peak of the diurnal variation is most frequently between 6:00 and 8:00 A.M., 4 - 5 it may occur at any time of the day or night. Furthermore, the timing and the mag nitude of the peak intraocular pressure may vary from day to day.6 Thus, it is obvious that any choice of times for measurement is arbitrary. We have no method to continually measure intraocu lar pressure. Even a large number of pres sure measurements dispersed through a 24From the Glaucoma Center, Washington Univer sity School of Medicine, St. Louis, Missouri (Drs. Kolker and Becker), and from the Division of Biostatistics, Department of Preventive Medicine (Dr. Woolson), and the Department of Ophthal mology (Dr. Phelps), University of Iowa College of Medicine, Iowa City, Iowa. This study was sup ported in part by National Eye Institute Glaucoma Center grant E Y 00336 and Special Fellowship grant 1-F03 E Y 51101 (Dr. Phelps). Reprint requests to Charles D. Phelps, M.D., De partment of Ophthalmology, University Hospitals, Iowa City, IA 52242. 367
BERNARD
BECKER,
M.D.
Missouri
hour period may miss the peak pressure for that day. The inconvenience of obtaining aroundthe-clock measurements of intraocular pres sure has led various investigators to search for some means of predicting the diurnal variation in intraocular pressure.T's In this paper we shall consider the potential for pre dictive usefulness of two measurements: outflow facility and intraocular pressure re sponse to corticosteroids. Theoretically, an eye with a low outflow facility, when compared to an eye with a high outflow facility, should undergo a much greater fluctuation in intraocular pressure for a given change in the rate of aqueous production.7 This formulation, of course, de pends on the validity of the commonly held assumption that most of the diurnal varia tion in intraocular pressure is caused by al terations in the rate of aqueous formation rather than by alterations in outflow fa cility.8'9 However, a few investigators10-12 de tect small diurnal fluctuations in outflow fa cility which, in some eyes, appear to recipro cate with diurnal variations in concomitantly measured intraocular pressure. Nevertheless, the fluctuations of outflow facility do not follow a consistent pattern,6'7'13'14 a recipro cal relationship with intraocular pressure is frequently not present, and the variations in outflow facility are usually of insufficient magnitude to account fully for the variations in intraocular pressure. Eyes with low outflow facility tend to have higher intraocular pressures, and eyes with higher intraocular pressures tend to have wider diurnal pressure fluctuations. Therefore, a significant negative correlation
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AMERICAN JOURNAL OF OPHTHALMOLOGY
between outflow facility and either peak di urnal intraocular pressure or range of diur nal intraocular pressure variation is to be ex pected and has been found in the past. What has not been demonstrated is whether mea surement of outflow facility provides predic tive information about peak diurnal intraoc ular pressure, which is additional to that gained from a simple daytime measurement of intraocular pressure. In other words, given two eyes with equal intraocular pres sures in the office but unequal outflow facili ties, can we expect the eye with the lower outflow facility to reach a higher peak intra ocular pressure when intraocular pressures are measured in each eye around the clock? Measurement of the intraocular pressure response to prolonged administration of top ical corticosteroids is another test that theo retically might provide predictive informa tion about the spontaneous diurnal fluctua tion of intraocular pressure. Both the change in intraocular pressure that occurs in some eyes after corticosteroids and the natural di urnal fluctuations of intraocular pressure re flect instability of intraocular pressure regu lation. The purpose of the present study was threefold: 1. To correlate the highest (peak) pres sure an eye would attain during a 24-hour series of measurements with daytime office measurements of intraocular pressure, out flow facility, and intraocular pressure re sponse to dexamethasone. 2. To assess the effectiveness of the above three tests, used either singly or in combina tion, in predicting the peak pressure of a di urnal series of measurements. 3. To correlate the amount (or range) of diurnal intraocular pressure variation with height of intraocular pressure, outflow facil ity, and intraocular pressure response to dexamethasone. METHODS
The study included 389 eyes of 204 patients of the Washington University
MARCH, 1974
Glaucoma Center. The patient sample in cluded normal control subjects and patients referred for elevated intraocular pressures without visual field defects. Each eye was carefully examined to insure that there was no evidence of ocular disease other than pri mary open-angle ocular hypertension. The eyes studied had never been treated with local or systemic medication to lower intra ocular pressure. All patients were hospitalized and had intraocular pressures measured by Goldmann applanation tonometry at approxi mately 8:00 A.M., 11:00 A.M., 4:00 P.M., 11:00 P.M., and 8:00 A.M. Tonography was per formed in 104 eyes the day preceding the di urnal curve and in the remaining 284 eyes after one of the daytime pressure measure ments on the day of the diurnal curve. Re view of each tonogram verified the techni cian's interpretation and excluded subjects with unsatisfactory tracings. On a separate occasion, 175 of these pa tients instilled dexamethasone 0.1% eye drops into one eye four times daily for six weeks. Intraocular pressures were measured before and at completion of the dexametha sone test regimen. The following measurements were avail able for analysis: 1. For all 388 eyes, (a) "Peak" pressure: The highest of the five intraocular pressure measurements during the diurnal curve, (b) "Range" of intraocular pressure variation: The difference between the highest and the lowest of the five diurnal intraocular pres sure measurements, (c) "Index" pressure: The intraocular pressure measured just prior to tonography. This represents a mea surement which might be taken during nor mal office hours. In 284 of the eyes, it was one of the diurnal series of pressure mea surements. (d) Outflow facility. 2. In 175 of the 388 eyes, (a) "End" pressure: The intraocular pressure at the completion of the dexamethasone test regi men. (b) "Change": The change in intraocu lar pressure after dexamethasone. This
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DIURNAL VARIATION INTRAOCULAR PRESSURE TABLE 1
equals the difference between end pressure and pretest intraocular pressure.
DESCRIPTION OF SAMPLE: MEANS AND STANDARD DEVIATIONS
RESULTS
A preliminary analysis indicated no sig nificant differences in results between the 104 eyes in which index pressure and out flow facility were measured the day before and the 284 eyes in which they were mea sured the day of the diurnal curve. There fore, the two groups were pooled. The means and standard deviations for each of the measured parameters are listed in Table 1. These describe only this particu lar sample of selected patients and should not be interpreted as representing the population-at-large.
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Fig. 2 (Phelps, Woolson, Kolker, and Becker). Scattergram of peak intraocular pressure vs. outflow facility. Peak pressure—Figures 1-4 are scatter di agrams of peak pressure against index pres sure, outflow facility, end pressure after dexamethasone testing, and change in pres sure after dexamethasone testing. Inspection
of these graphs and the corresponding un weighted least square lines shows that index pressure is the parameter with the most pro nounced linear relationship to peak pressure. This result, of course, was anticipated since
TABLE 2 CORRELATION COEFFICIENTS OF VARIABLES STUDIED* Peak Peak Index Outflow End Change Range
.001 .001 .001 .003 .001
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* Correlations above diagonal and P-values below.
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Fig. 3 (Phelps, Woolson, Kolker, and Becker). Scattergram of peak intraocular pressure vs. intra ocular pressure at end of dexamethasone test. both are the same variable measured at dif ferent times during the day. The other three parameters also have an appreciable linear relationship with peak pressure; however, for each there is considerably more variation about the fitted lines. The visual impressions gained from inspec tion of these scatter diagrams are supported by the size of the association estimates found in the first row of Table 2, which lists the Pearson Product Moment Correlation Coeffi cients for all pairs of the six parameters studied. Index pressure is indeed the param eter most correlated with peak pressure (r — .84, P < .001), and change in pressure after dexamethasone is least correlated with peak pressure (r — .21, P < .001).
The figures below the diagonal in Table 2 are the corresponding P values for testing the hypothesis of no linear relationship be tween any pair of the six parameters. All correlation coefficients differ significantly from 0, even though some of the individual correlations are quite low. Part of the expla nation of this statistical significance is the large sample size. If a clinician wished to predict peak pres sure from only one of the four parameters (index pressure, outflow facility, end pres sure after dexamethasone, or change in pres sure after dexamethasone), he could do so using the equation of the least square line presented on the pertinent scatter diagram (Figs. 1-4). Table 3 lists the standard errors
372
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for the slope of these four lines. The stan dard error, of course, is used to place confi dence intervals on predictions of peak pres sure from the corresponding regression equation. Index pressure is clearly the best predictor of peak pressure. The question remained if any of the re maining parameters (outflow facility, end pressure after dexamethasone, or change in pressure after dexamethasone), or subsets of these three parameters, provided informa tion which was of additional usefulness in prediction of peak pressure when the index pressure was already known. To answer this question we performed a forward regression analysis.15 In this procedure, the variable most correlated with the peak pressure (that
is, index pressure) is introduced first into the predictive equation, followed by the in troduction of the one of the remaining vari ables which, as measured by partial correla tion, is next best correlated, and so forth. At each step, the additional contribution made by the last variable to be introduced is evalu ated by an F statistic for significance. The procedure is terminated when a step is reached at which the F value is not signifi cant at some predetermined level of signifi cance (such as .05). We used this procedure to analyze two models. In the first model we assumed that index pressure and outflow facility were the only measurements available. In the second we assumed that the end pressure after dex-
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PRESSURE
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TABLE 3 amethasone and the change in pressure after dexamethasone were also available. (For the STANDARD ERRORS OF THE SLOPE OF THE LEAST SQUARE LINES USED FOR PREDICTION second model we used only the 175 eyes in OF PEAK PRESSURE* which all five measurements were available.) In the first model, the question was whether Standard Error Variable Slope of Estimate, measurement of outflow facility made a sig mm Hg nificant contribution to the prediction of peak pressure over and above that contributed by Index pressure .91 3.33 -32.50 5.28 the measurement of index pressure. The pre Outflow facility diction equation, when both variables were End pressure after dexamethasone .25 4.33 entered, was: peak pressure = 7.35 + .87 Change in pressure after dexamethasone .12 4.91 index pressure — 4.98 outflow facility. An analysis of the variance in peak pres * See Figures 1-4. sure, which is accounted for by the contribu tions of index pressure and outflow facility, indicated an F statistic for the additional flow facilitv as a fourth independent variable contribution of outflow facility of 5.49. This did not add a substantial amount to the pre is significant at the .05 level, indicating that diction of peak pressure. The foregoing analyses indicate that out outflow facility does make a statistically sig nificant contribution to the prediction of flow facility in the first model, and end pres sure and change in pressure in the second peak pressure. model, made statistically significant contri In the second model, we first introduced in butions to the prediction of peak pressure dex pressure, followed by the end pressure above that offered by index pressure. Our after dexamethasone, then the change in pres sure after dexamethasone, and finally outflow next problem was to determine how much facility. The analysis of variance at step 2 of additional predictive information was con this regression procedure, i.e., after introduc tributed by each of these measurements. tion of index pressure and end pressure, re The criterion we examined was the coeffi sulted in an F statistic of 7.18 for testing the cient of determination. This quantity is the additional contribution of end pressure. This ration of the sum of squares due to the vari is significant at the .01 level of confidence. ables in the regression equation, divided by The prediction equation is: peak pressure = the sum of squares of the variable to be pre 5.37 + 0.80 index pressure + .07 end pres dicted, and multiplied by 100 for conversion sure. to a percentage. In the models considered Change in pressure after dexamethasone here, the coefficient of determination may be testing was then introduced as a third inde considered to indicate the percentage of the pendent variable; the analysis of variance in variation in peak pressure of the entire sam this case resulted in an F value of 10.8, which ple, which is explained by the independent is statistically significant at the .05 level of variables in the regression equations. Table 4 confidence, indicating that introducing this lists coefficients of determination for each of variable does add a statistically significant the two models. These values indicate that amount of predictive information. The pre even though in the first model outflow facil dictive equation for the three variables is: ity does make a statistically significant con peak pressure = 4.50 + .72 index + .20 end tribution to the prediction of peak pressure beyond that contributed by the measurement — .16 change. The only remaining variable in our second of index pressure, the clinical significance of model was outflow facility. An analysis of this contribution is slight. The same state variance indicated that introduction of out- ment can be made for the second model
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AMERICAN JOURNAL OF OPHTHALMOLOGY TABLE 4 COEFFICIENTS OF DETERMINATION FOR THE REGRESSIONS IN EACH MODEL
Coefficient of Determination,
%
Model 1 (388 eyes) Index pressure Index pressure +outflow facility
70.02 70.47
Model 2 (175 eyes) Index pressure Index pressure+end pressure Index pressure+end pressure +change
65.76 67.13 69.08
about the additional contribution made by measuring an eye's intraocular pressure re sponse to corticosteroids.
M A R C H , 1974
Range of pressure—Table 2 shows that the range of intraocular pressure variation during a diurnal curve correlates highly with the peak pressure attained during the curve (Fig. 5) ; it also correlates fairly well with the index pressure. It has a smaller and in verse correlation with outflow facility (Fig. 6) and a weak (although still statistically significant) correlation with the change in intraocular pressure after dexamethasone testing (Fig. 7). DISCUSSION
The results of this study indicate that a single office-hour measurement of intraocu lar pressure, measurement of outflow facility during office hours, and measurement of the intraocular pressure response to corticoste-
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DIURNAL VARIATION INTRAOCULAR PRESSURE
roids (using either the final pressure or the change in pressure as a criterion of re sponse) all correlate with the peak intraocu lar pressure measured during a diurnal pres sure curve, and all have some predictive value. However, if one makes the most sim ple measurement first, i.e., a single measure ment of intraocular pressure, the additional predictive contribution made by either of the other two tests is clinically minimal even though statistically significant. This apparent paradox is the result of the large sample size; in samples as large as one reported here, tests of statistical significance are very sensitive to even small departures from the null hypothesis.
375
that, if one studies an entire population in cluding eyes with all levels of intraocular pressure, the eyes with low outflow facilities tend to have higher peaks in their diurnal intraocular pressure variation than do eyes with high outflow facilities. However, if one looks only at eyes with a specified level of intraocular pressure, for instance 20 mm Hg, as measured during routine daytime office hours, the additional measurement of outflow facility offers minimal information to aid the ophthalmologist in distinguishing eyes at the peak of their diurnal intraocular pressure variation from eyes destined to in crease in pressure later in the day. Similar remarks can be made about the additional in formation gained by measuring the intraocu-
To be more explicit, this study indicates 24 22
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lar pressure response to corticosteroids. To illustrate this point further, we se lected from our entire sample a subsample of 89 eyes that have index pressures of 20, 21, or 22 mm Hg. (Eyes with borderline pres sures were purposefully selected, because it is in these eyes that the ophthalmologist fre quently wants more information about the diurnal change in intraocular pressure.) The subsample was divided into three groups, ac cording to level of outflow facility, and each group was analyzed to determine the per centage of eyes in which the peak pressure exceeded 25 mm Hg. The results, listed in Table 5, indicate that outflow facility was of no value in the prediction of peak pressure for this particular subsample. It is of some conceptual interest to note
the weakness of the correlation between the range of variation of intraocular pressure over a 24-hour period and either outflow fa cility or corticosteroid response. It was the hypothesis that these correlations woukl be much higher that underlay our rationale for TABLE 5 PREDICTION OF PEAK PRESSURE FROM OUTFLOW FACILITY*
Outflow Facility, m l / m m / m m Hg <0.18 0.18-0.23 >0.23 All eyes
> 2 5
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(35.5) (28.9) (40.0) (34.7)
In eyes with an index pressure of 20 to 22 mm Hg.
VOL. 77, NO. 3
DIURNAL VARIATION INTRAOCULAR
this study. The strong correlations between range of diurnal variation and either peak pressure or index pressure confirm previous investigators' findings that eyes with high intraocular pressures tend to have greater di urnal variations in intraocular presssure. A significant limitation of this study is that we have attempted to detect the peak of the daily variation of intraocular pressure from only five measurements obtained dur ing a single 24-hour period. There is no question that measurement of intraocular pressure at more frequent intervals, over a period of several days, would have provided a more accurate representation of the diurnal intraocular pressure variation. Such an ex acting study, however desirable, was clearly impractical. Thus, our conclusions are to some extent limited. Nevertheless, the implication of this study is clear. Until a better predictive tool be comes available, the most likely way to detect the highest intraocular pressure during the diurnal variation will remain the laborious, time-consuming, and inconvenient method of frequently measuring intraocular pressure around the clock. The limitations of measur ing intraocular pressure an arbitrary number of times over a limited time span make the development of a practical telemetric device for the continuous measurement of intraocu lar pressure a most desirable future research goal. SUMMARY
The diurnal variation in intraocular pres sure was studied in 388 nonoglaucomatous eyes. Outflow facility was measured in all eyes and the intraocular pressure response to prolonged topical applications of dexameth asone was measured in 175 eyes. The peak intraocular pressure in the diur nal variation could best be predicted from a
PRESSURE
377
single office-hour measurement of intraocu lar pressure. Measurements of outflow facil ity or of intraocular pressure response to dexamethasone did not provide additional predictive information of clinical signifi cance. REFERENCES 1. Drance, S. M.: The significance of the diurnal tension variations in normal and glaucomatous eyes. Arch. Ophthalmol. 64:494, 1960. 2. : Diurnal variation of intraocular pres sure in treated glaucoma. Arch. Ophthalmol. 70: 302, 1963. 3. Duke-Elder, S.: The phasic variation in the ocular tension in primary glaucoma. Am. J. Oph thalmol. 35:1, 1952. 4. Langley, D., and Swanljung, H . : Ocular ten sion in glaucoma simplex. Br. J. Ophthalmol. 35: 445, 1951. 5. deVenecia, G., and Davis, M. D . : Diurnal var iation of intraocular pressure in the normal eye. Arch. Ophthalmol. 69:752, 1963. 6. Newell, F. W., and Krill, A. E . : Diurnal tonographv in normal and glaucomatous eyes. Am. J. Ophthalmol. 59 :840, 1965. 7. Grant, \V. M . : Clinical aspects of the outflow of the aqueous humor. 2. Tonography. In Duke-El der, S. (ed.) : Glaucoma. A Symposium. Spring field, Charles C Thomas, 1955, p. 141. 8. Miller, D . : The relationship between diurnal tension variation and the water-drinking test. Am. J. Ophthalmol. 58 :243, 1964. 9. Ericson, L. A.: Twenty-four hourly variations of the aqueous flow. Acta Ophthalmol. Suppl. 50, 1958. 10. Boyd, T. A. S.: Relationship of the diurnal rhythms of intraocular pressure with aqueous out flow facility. Can. Med. Assoc. J. 90:467, 1964. 11. Horwich, H., and Breinin, G. M.: Phasic variations in tonographv. Arch. Ophthalmol. 51 : 687, 1954. 12. Stepanik, J.: Diurnal tonographic varia tions and their relation to visible aqueous outflow. Am. J. Ophthalmol. 38:629, 1954. 13. Spencer, R. W., Helmick, E. D., and Scheie, H. G.: Tonography, technical difficulties and con trol studies. Arch. Ophthalmol. 54:515, 1955. 14. DeRoetth, A., J r . : Relation of tonography to phasic variations of intraocular pressure. Arch. Ophthalmol. 51 :740, 1954. 15. Draper, N., and Smith, H . : Applied regres sion analysis. New York, Tohn Wylie and Sons, 1966.
AND ROBERT F. WOOLSON, P H . D .
Iowa City, Iowa AND ALLAN
E.
KOLKER,
M.D.,
AND
St. Louis,
Diurnal fluctuations of intraocular pres sure pose a difficult problem for the ophthal mologist involved in the diagnosis and man agement of glaucoma.1"5 The diurnal intra ocular pressure variation is quite minimal in normal eyes, averaging 3 to 4 mm Hg, but is often much greater in eyes with glaucoma. A single measurement of intraocular pressure during office hours is unlikely to catch the peak of the diurnal variation.1 Since the peak of the diurnal intraocular pressure variation is presumably the signifi cant level for the pathogenesis of glaucomatous visual field loss, its detection is quite important. This detection obviously requires measurement of intraocular pressures at times that are inconvenient for ophthalmolo gist and patient alike. Although the peak of the diurnal variation is most frequently between 6:00 and 8:00 A.M., 4 - 5 it may occur at any time of the day or night. Furthermore, the timing and the mag nitude of the peak intraocular pressure may vary from day to day.6 Thus, it is obvious that any choice of times for measurement is arbitrary. We have no method to continually measure intraocu lar pressure. Even a large number of pres sure measurements dispersed through a 24From the Glaucoma Center, Washington Univer sity School of Medicine, St. Louis, Missouri (Drs. Kolker and Becker), and from the Division of Biostatistics, Department of Preventive Medicine (Dr. Woolson), and the Department of Ophthal mology (Dr. Phelps), University of Iowa College of Medicine, Iowa City, Iowa. This study was sup ported in part by National Eye Institute Glaucoma Center grant E Y 00336 and Special Fellowship grant 1-F03 E Y 51101 (Dr. Phelps). Reprint requests to Charles D. Phelps, M.D., De partment of Ophthalmology, University Hospitals, Iowa City, IA 52242. 367
BERNARD
BECKER,
M.D.
Missouri
hour period may miss the peak pressure for that day. The inconvenience of obtaining aroundthe-clock measurements of intraocular pres sure has led various investigators to search for some means of predicting the diurnal variation in intraocular pressure.T's In this paper we shall consider the potential for pre dictive usefulness of two measurements: outflow facility and intraocular pressure re sponse to corticosteroids. Theoretically, an eye with a low outflow facility, when compared to an eye with a high outflow facility, should undergo a much greater fluctuation in intraocular pressure for a given change in the rate of aqueous production.7 This formulation, of course, de pends on the validity of the commonly held assumption that most of the diurnal varia tion in intraocular pressure is caused by al terations in the rate of aqueous formation rather than by alterations in outflow fa cility.8'9 However, a few investigators10-12 de tect small diurnal fluctuations in outflow fa cility which, in some eyes, appear to recipro cate with diurnal variations in concomitantly measured intraocular pressure. Nevertheless, the fluctuations of outflow facility do not follow a consistent pattern,6'7'13'14 a recipro cal relationship with intraocular pressure is frequently not present, and the variations in outflow facility are usually of insufficient magnitude to account fully for the variations in intraocular pressure. Eyes with low outflow facility tend to have higher intraocular pressures, and eyes with higher intraocular pressures tend to have wider diurnal pressure fluctuations. Therefore, a significant negative correlation
368
AMERICAN JOURNAL OF OPHTHALMOLOGY
between outflow facility and either peak di urnal intraocular pressure or range of diur nal intraocular pressure variation is to be ex pected and has been found in the past. What has not been demonstrated is whether mea surement of outflow facility provides predic tive information about peak diurnal intraoc ular pressure, which is additional to that gained from a simple daytime measurement of intraocular pressure. In other words, given two eyes with equal intraocular pres sures in the office but unequal outflow facili ties, can we expect the eye with the lower outflow facility to reach a higher peak intra ocular pressure when intraocular pressures are measured in each eye around the clock? Measurement of the intraocular pressure response to prolonged administration of top ical corticosteroids is another test that theo retically might provide predictive informa tion about the spontaneous diurnal fluctua tion of intraocular pressure. Both the change in intraocular pressure that occurs in some eyes after corticosteroids and the natural di urnal fluctuations of intraocular pressure re flect instability of intraocular pressure regu lation. The purpose of the present study was threefold: 1. To correlate the highest (peak) pres sure an eye would attain during a 24-hour series of measurements with daytime office measurements of intraocular pressure, out flow facility, and intraocular pressure re sponse to dexamethasone. 2. To assess the effectiveness of the above three tests, used either singly or in combina tion, in predicting the peak pressure of a di urnal series of measurements. 3. To correlate the amount (or range) of diurnal intraocular pressure variation with height of intraocular pressure, outflow facil ity, and intraocular pressure response to dexamethasone. METHODS
The study included 389 eyes of 204 patients of the Washington University
MARCH, 1974
Glaucoma Center. The patient sample in cluded normal control subjects and patients referred for elevated intraocular pressures without visual field defects. Each eye was carefully examined to insure that there was no evidence of ocular disease other than pri mary open-angle ocular hypertension. The eyes studied had never been treated with local or systemic medication to lower intra ocular pressure. All patients were hospitalized and had intraocular pressures measured by Goldmann applanation tonometry at approxi mately 8:00 A.M., 11:00 A.M., 4:00 P.M., 11:00 P.M., and 8:00 A.M. Tonography was per formed in 104 eyes the day preceding the di urnal curve and in the remaining 284 eyes after one of the daytime pressure measure ments on the day of the diurnal curve. Re view of each tonogram verified the techni cian's interpretation and excluded subjects with unsatisfactory tracings. On a separate occasion, 175 of these pa tients instilled dexamethasone 0.1% eye drops into one eye four times daily for six weeks. Intraocular pressures were measured before and at completion of the dexametha sone test regimen. The following measurements were avail able for analysis: 1. For all 388 eyes, (a) "Peak" pressure: The highest of the five intraocular pressure measurements during the diurnal curve, (b) "Range" of intraocular pressure variation: The difference between the highest and the lowest of the five diurnal intraocular pres sure measurements, (c) "Index" pressure: The intraocular pressure measured just prior to tonography. This represents a mea surement which might be taken during nor mal office hours. In 284 of the eyes, it was one of the diurnal series of pressure mea surements. (d) Outflow facility. 2. In 175 of the 388 eyes, (a) "End" pressure: The intraocular pressure at the completion of the dexamethasone test regi men. (b) "Change": The change in intraocu lar pressure after dexamethasone. This
VOL. 77, NO. 3
369
DIURNAL VARIATION INTRAOCULAR PRESSURE TABLE 1
equals the difference between end pressure and pretest intraocular pressure.
DESCRIPTION OF SAMPLE: MEANS AND STANDARD DEVIATIONS
RESULTS
A preliminary analysis indicated no sig nificant differences in results between the 104 eyes in which index pressure and out flow facility were measured the day before and the 284 eyes in which they were mea sured the day of the diurnal curve. There fore, the two groups were pooled. The means and standard deviations for each of the measured parameters are listed in Table 1. These describe only this particu lar sample of selected patients and should not be interpreted as representing the population-at-large.
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of these graphs and the corresponding un weighted least square lines shows that index pressure is the parameter with the most pro nounced linear relationship to peak pressure. This result, of course, was anticipated since
TABLE 2 CORRELATION COEFFICIENTS OF VARIABLES STUDIED* Peak Peak Index Outflow End Change Range
.001 .001 .001 .003 .001
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Fig. 3 (Phelps, Woolson, Kolker, and Becker). Scattergram of peak intraocular pressure vs. intra ocular pressure at end of dexamethasone test. both are the same variable measured at dif ferent times during the day. The other three parameters also have an appreciable linear relationship with peak pressure; however, for each there is considerably more variation about the fitted lines. The visual impressions gained from inspec tion of these scatter diagrams are supported by the size of the association estimates found in the first row of Table 2, which lists the Pearson Product Moment Correlation Coeffi cients for all pairs of the six parameters studied. Index pressure is indeed the param eter most correlated with peak pressure (r — .84, P < .001), and change in pressure after dexamethasone is least correlated with peak pressure (r — .21, P < .001).
The figures below the diagonal in Table 2 are the corresponding P values for testing the hypothesis of no linear relationship be tween any pair of the six parameters. All correlation coefficients differ significantly from 0, even though some of the individual correlations are quite low. Part of the expla nation of this statistical significance is the large sample size. If a clinician wished to predict peak pres sure from only one of the four parameters (index pressure, outflow facility, end pres sure after dexamethasone, or change in pres sure after dexamethasone), he could do so using the equation of the least square line presented on the pertinent scatter diagram (Figs. 1-4). Table 3 lists the standard errors
372
AMERICAN JOURNAL OF OPHTHALMOLOGY
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for the slope of these four lines. The stan dard error, of course, is used to place confi dence intervals on predictions of peak pres sure from the corresponding regression equation. Index pressure is clearly the best predictor of peak pressure. The question remained if any of the re maining parameters (outflow facility, end pressure after dexamethasone, or change in pressure after dexamethasone), or subsets of these three parameters, provided informa tion which was of additional usefulness in prediction of peak pressure when the index pressure was already known. To answer this question we performed a forward regression analysis.15 In this procedure, the variable most correlated with the peak pressure (that
is, index pressure) is introduced first into the predictive equation, followed by the in troduction of the one of the remaining vari ables which, as measured by partial correla tion, is next best correlated, and so forth. At each step, the additional contribution made by the last variable to be introduced is evalu ated by an F statistic for significance. The procedure is terminated when a step is reached at which the F value is not signifi cant at some predetermined level of signifi cance (such as .05). We used this procedure to analyze two models. In the first model we assumed that index pressure and outflow facility were the only measurements available. In the second we assumed that the end pressure after dex-
VOL. 77, N O . 3
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PRESSURE
373
TABLE 3 amethasone and the change in pressure after dexamethasone were also available. (For the STANDARD ERRORS OF THE SLOPE OF THE LEAST SQUARE LINES USED FOR PREDICTION second model we used only the 175 eyes in OF PEAK PRESSURE* which all five measurements were available.) In the first model, the question was whether Standard Error Variable Slope of Estimate, measurement of outflow facility made a sig mm Hg nificant contribution to the prediction of peak pressure over and above that contributed by Index pressure .91 3.33 -32.50 5.28 the measurement of index pressure. The pre Outflow facility diction equation, when both variables were End pressure after dexamethasone .25 4.33 entered, was: peak pressure = 7.35 + .87 Change in pressure after dexamethasone .12 4.91 index pressure — 4.98 outflow facility. An analysis of the variance in peak pres * See Figures 1-4. sure, which is accounted for by the contribu tions of index pressure and outflow facility, indicated an F statistic for the additional flow facilitv as a fourth independent variable contribution of outflow facility of 5.49. This did not add a substantial amount to the pre is significant at the .05 level, indicating that diction of peak pressure. The foregoing analyses indicate that out outflow facility does make a statistically sig nificant contribution to the prediction of flow facility in the first model, and end pres sure and change in pressure in the second peak pressure. model, made statistically significant contri In the second model, we first introduced in butions to the prediction of peak pressure dex pressure, followed by the end pressure above that offered by index pressure. Our after dexamethasone, then the change in pres sure after dexamethasone, and finally outflow next problem was to determine how much facility. The analysis of variance at step 2 of additional predictive information was con this regression procedure, i.e., after introduc tributed by each of these measurements. tion of index pressure and end pressure, re The criterion we examined was the coeffi sulted in an F statistic of 7.18 for testing the cient of determination. This quantity is the additional contribution of end pressure. This ration of the sum of squares due to the vari is significant at the .01 level of confidence. ables in the regression equation, divided by The prediction equation is: peak pressure = the sum of squares of the variable to be pre 5.37 + 0.80 index pressure + .07 end pres dicted, and multiplied by 100 for conversion sure. to a percentage. In the models considered Change in pressure after dexamethasone here, the coefficient of determination may be testing was then introduced as a third inde considered to indicate the percentage of the pendent variable; the analysis of variance in variation in peak pressure of the entire sam this case resulted in an F value of 10.8, which ple, which is explained by the independent is statistically significant at the .05 level of variables in the regression equations. Table 4 confidence, indicating that introducing this lists coefficients of determination for each of variable does add a statistically significant the two models. These values indicate that amount of predictive information. The pre even though in the first model outflow facil dictive equation for the three variables is: ity does make a statistically significant con peak pressure = 4.50 + .72 index + .20 end tribution to the prediction of peak pressure beyond that contributed by the measurement — .16 change. The only remaining variable in our second of index pressure, the clinical significance of model was outflow facility. An analysis of this contribution is slight. The same state variance indicated that introduction of out- ment can be made for the second model
374
AMERICAN JOURNAL OF OPHTHALMOLOGY TABLE 4 COEFFICIENTS OF DETERMINATION FOR THE REGRESSIONS IN EACH MODEL
Coefficient of Determination,
%
Model 1 (388 eyes) Index pressure Index pressure +outflow facility
70.02 70.47
Model 2 (175 eyes) Index pressure Index pressure+end pressure Index pressure+end pressure +change
65.76 67.13 69.08
about the additional contribution made by measuring an eye's intraocular pressure re sponse to corticosteroids.
M A R C H , 1974
Range of pressure—Table 2 shows that the range of intraocular pressure variation during a diurnal curve correlates highly with the peak pressure attained during the curve (Fig. 5) ; it also correlates fairly well with the index pressure. It has a smaller and in verse correlation with outflow facility (Fig. 6) and a weak (although still statistically significant) correlation with the change in intraocular pressure after dexamethasone testing (Fig. 7). DISCUSSION
The results of this study indicate that a single office-hour measurement of intraocu lar pressure, measurement of outflow facility during office hours, and measurement of the intraocular pressure response to corticoste-
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VOL. 77, NO. 3
DIURNAL VARIATION INTRAOCULAR PRESSURE
roids (using either the final pressure or the change in pressure as a criterion of re sponse) all correlate with the peak intraocu lar pressure measured during a diurnal pres sure curve, and all have some predictive value. However, if one makes the most sim ple measurement first, i.e., a single measure ment of intraocular pressure, the additional predictive contribution made by either of the other two tests is clinically minimal even though statistically significant. This apparent paradox is the result of the large sample size; in samples as large as one reported here, tests of statistical significance are very sensitive to even small departures from the null hypothesis.
375
that, if one studies an entire population in cluding eyes with all levels of intraocular pressure, the eyes with low outflow facilities tend to have higher peaks in their diurnal intraocular pressure variation than do eyes with high outflow facilities. However, if one looks only at eyes with a specified level of intraocular pressure, for instance 20 mm Hg, as measured during routine daytime office hours, the additional measurement of outflow facility offers minimal information to aid the ophthalmologist in distinguishing eyes at the peak of their diurnal intraocular pressure variation from eyes destined to in crease in pressure later in the day. Similar remarks can be made about the additional in formation gained by measuring the intraocu-
To be more explicit, this study indicates 24 22
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lar pressure response to corticosteroids. To illustrate this point further, we se lected from our entire sample a subsample of 89 eyes that have index pressures of 20, 21, or 22 mm Hg. (Eyes with borderline pres sures were purposefully selected, because it is in these eyes that the ophthalmologist fre quently wants more information about the diurnal change in intraocular pressure.) The subsample was divided into three groups, ac cording to level of outflow facility, and each group was analyzed to determine the per centage of eyes in which the peak pressure exceeded 25 mm Hg. The results, listed in Table 5, indicate that outflow facility was of no value in the prediction of peak pressure for this particular subsample. It is of some conceptual interest to note
the weakness of the correlation between the range of variation of intraocular pressure over a 24-hour period and either outflow fa cility or corticosteroid response. It was the hypothesis that these correlations woukl be much higher that underlay our rationale for TABLE 5 PREDICTION OF PEAK PRESSURE FROM OUTFLOW FACILITY*
Outflow Facility, m l / m m / m m Hg <0.18 0.18-0.23 >0.23 All eyes
> 2 5
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VOL. 77, NO. 3
DIURNAL VARIATION INTRAOCULAR
this study. The strong correlations between range of diurnal variation and either peak pressure or index pressure confirm previous investigators' findings that eyes with high intraocular pressures tend to have greater di urnal variations in intraocular presssure. A significant limitation of this study is that we have attempted to detect the peak of the daily variation of intraocular pressure from only five measurements obtained dur ing a single 24-hour period. There is no question that measurement of intraocular pressure at more frequent intervals, over a period of several days, would have provided a more accurate representation of the diurnal intraocular pressure variation. Such an ex acting study, however desirable, was clearly impractical. Thus, our conclusions are to some extent limited. Nevertheless, the implication of this study is clear. Until a better predictive tool be comes available, the most likely way to detect the highest intraocular pressure during the diurnal variation will remain the laborious, time-consuming, and inconvenient method of frequently measuring intraocular pressure around the clock. The limitations of measur ing intraocular pressure an arbitrary number of times over a limited time span make the development of a practical telemetric device for the continuous measurement of intraocu lar pressure a most desirable future research goal. SUMMARY
The diurnal variation in intraocular pres sure was studied in 388 nonoglaucomatous eyes. Outflow facility was measured in all eyes and the intraocular pressure response to prolonged topical applications of dexameth asone was measured in 175 eyes. The peak intraocular pressure in the diur nal variation could best be predicted from a
PRESSURE
377
single office-hour measurement of intraocu lar pressure. Measurements of outflow facil ity or of intraocular pressure response to dexamethasone did not provide additional predictive information of clinical signifi cance. REFERENCES 1. Drance, S. M.: The significance of the diurnal tension variations in normal and glaucomatous eyes. Arch. Ophthalmol. 64:494, 1960. 2. : Diurnal variation of intraocular pres sure in treated glaucoma. Arch. Ophthalmol. 70: 302, 1963. 3. Duke-Elder, S.: The phasic variation in the ocular tension in primary glaucoma. Am. J. Oph thalmol. 35:1, 1952. 4. Langley, D., and Swanljung, H . : Ocular ten sion in glaucoma simplex. Br. J. Ophthalmol. 35: 445, 1951. 5. deVenecia, G., and Davis, M. D . : Diurnal var iation of intraocular pressure in the normal eye. Arch. Ophthalmol. 69:752, 1963. 6. Newell, F. W., and Krill, A. E . : Diurnal tonographv in normal and glaucomatous eyes. Am. J. Ophthalmol. 59 :840, 1965. 7. Grant, \V. M . : Clinical aspects of the outflow of the aqueous humor. 2. Tonography. In Duke-El der, S. (ed.) : Glaucoma. A Symposium. Spring field, Charles C Thomas, 1955, p. 141. 8. Miller, D . : The relationship between diurnal tension variation and the water-drinking test. Am. J. Ophthalmol. 58 :243, 1964. 9. Ericson, L. A.: Twenty-four hourly variations of the aqueous flow. Acta Ophthalmol. Suppl. 50, 1958. 10. Boyd, T. A. S.: Relationship of the diurnal rhythms of intraocular pressure with aqueous out flow facility. Can. Med. Assoc. J. 90:467, 1964. 11. Horwich, H., and Breinin, G. M.: Phasic variations in tonographv. Arch. Ophthalmol. 51 : 687, 1954. 12. Stepanik, J.: Diurnal tonographic varia tions and their relation to visible aqueous outflow. Am. J. Ophthalmol. 38:629, 1954. 13. Spencer, R. W., Helmick, E. D., and Scheie, H. G.: Tonography, technical difficulties and con trol studies. Arch. Ophthalmol. 54:515, 1955. 14. DeRoetth, A., J r . : Relation of tonography to phasic variations of intraocular pressure. Arch. Ophthalmol. 51 :740, 1954. 15. Draper, N., and Smith, H . : Applied regres sion analysis. New York, Tohn Wylie and Sons, 1966.