CLINICAL SCIENCES
`
`Effect of Brimonidine Tartrate on Ocular
`Hemodynamic Measurements
`
`Yves Lachkar, MD; Clive Migdal, MD; Surinda Dhanjil, MSc, RVT
`
`Objective: To study the effect of a selective ␣2-
`adrenoreceptor agonist, brimonidine tartrate, on ocular
`hemodynamics.
`
`Subjects and Methods: Eighteen patients with ocular hy-
`pertension were enrolled in a prospective, randomized,
`double-masked study in which 0.2% brimonidine tartrate,
`administered twice daily, was compared with its vehicle in
`a crossover fashion. The effect on the ocular circulation was
`assessedbycolorDopplerultrasound,whichmeasuredblood
`flow velocities (peak systolic and end diastolic velocities)
`in the central retinal, ophthalmic, nasal, and temporal cili-
`ary arteries. The following tests were performed at 2 weekly
`intervals on both treatments, 0.2% brimonidine tartrate and
`the placebo: intraocular pressure, heart rate, blood pressure,
`and color Doppler ultrasound.
`
`Results: Velocities and resistivity indices measured by
`color Doppler ultrasound in the ophthalmic artery, cen-
`tral retinal artery, nasal artery, and temporal ciliary
`arteries showed no statistically significant differences
`between the placebo and 0.2% brimonidine tartrate
`when compared with baseline values and between the
`groups. Intraocular pressure was decreased by 17.7% ±
`9.5% with 0.2% brimonidine tartrate (vs 9% ± 8% with
`placebo).
`
`Conclusion: The hemodynamics of the posterior seg-
`ment of the eye as measured by color Doppler ultra-
`sound do not appear to be altered by 2% brimonidine
`tartrate.
`
`Arch Ophthalmol. 1998;116:1591-1594
`
`W HILE INTRAOCULAR
`
`pressure is still con-
`sidered the main
`risk factor in the
`pathophysiology of
`optic nerve head damage in glaucoma, is-
`chemia of the optic nerve at the level of
`the lamina cribrosa is also relevant.1 Cur-
`rent therapy for primary open-angle glau-
`coma consists of lowering intraocular pres-
`sure to a level sufficient to prevent further
`functional loss.
`Brimonidine tartrate (Alphagan,
`Allergan Inc, Irvine, Calif), a selective ␣2-
`adrenoreceptor agonist, has been shown
`to decrease intraocular pressure both in
`the prevention of intraocular pressure
`elevation following argon laser trabecu-
`loplasty,2,3 and in the long-term control
`of intraocular pressure in patients with
`glaucoma and ocular hypertension.4
`Another ␣2-adrenoreceptor agonist, apra-
`clonidine hydrochloride, is known to
`cause vasoconstriction in anterior seg-
`ment tissues including the conjunctiva,
`ciliary body, and iris.5,6 This vasocon-
`strictive effect was considered beneficial
`in decreasing the incidence of postopera-
`
`tive bleeding after laser peripheral iri-
`dotomies.7 It is important, however, to
`exclude any adverse vascular effect of
`these compounds, particularly at the
`optic nerve head.
`This study was designed to evaluate
`whether short-term topical administra-
`tion of the ␣2-adrenoreceptor agonist 0.2%
`brimonidine tartrate produces any mea-
`surable vascular changes at the posterior
`pole of the eye.
`
`RESULTS
`
`INTRAOCULAR PRESSURE
`
`Mean intraocular pressure ± standard de-
`viation was 24.89 ± 2.76 mm Hg at base-
`line, 22.67 ± 3.46 mm Hg in the placebo
`group, and 20.47 ± 3.06 mm Hg in the
`0.2% brimonidine tartrate group. Intra-
`ocular pressure was significantly de-
`creased by 17.7% ± 9.5% with 0.2% bri-
`monidine tartrate (P = .003), vs 9% ± 8%
`with placebo (P = .1). This ocular hypo-
`tensive effect in the sequence 2 group
`(18.2%) was similar in percentage to the
`sequence 1 group (17.2%). There was no
`
`ARCH OPHTHALMOL/ VOL 116, DEC 1998
`1591
`
`©1998 American Medical Association. All rights reserved.
`
`From the Glaucoma
`Department, The Western Eye
`Hospital (Drs Lachkar and
`Migdal), and the Vascular
`Surgery Department, St Mary’s
`Hospital (Mr Dhanjil),
`London, England.
`
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`SUBJECTS AND METHODS
`
`In this randomized crossover study, we investigated the ef-
`fect of 0.2% brimonidine tartrate on the ocular hemodynam-
`ics by color Doppler ultrasound (HTI 3000, Advanced Tech-
`nology Laboratory, Seattle, Wash), measuring blood flow
`velocity (peak systolic and end diastolic velocities) in the cen-
`tral retinal artery, ophthalmic artery, and nasal and tempo-
`ral ciliary arteries.
`Eighteen patients with ocular hypertension were en-
`rolled in a prospective, randomized, double-masked cross-
`over study. Following ethical committee approval, in-
`formed consent was obtained from all participants. Ocular
`hypertension was defined as the presence of raised intra-
`ocular pressure (⬎21 mm Hg) without demonstrable vi-
`sual field defects (program 24-2, Humphrey Visual Field
`Analyzer 640, Humphrey Instruments, San Leandro, Calif).
`Exclusion criteria included systemic hypertension, high
`myopia, diabetes mellitus, vasculopathy (including periph-
`eral vascular disease such as Raynaud syndrome, mi-
`graine, and giant cell arteritis), and patients taking oral va-
`soactive medications including systemic ␤-blockers or
`calcium channel blockers. Patients receiving medications
`that altered blood viscosity or coagulation were also ex-
`cluded, as were those with a history of previous laser treat-
`ment or eye surgery. The mean age of the patients was 55
`years (range, 38-66 years). The mean refraction was +0.15
`diopters (range, −3 to +3.25 diopters).
`Patients were randomized to receive either 0.2% bri-
`monidine tartrate (twice daily) initially for 2 weeks fol-
`lowed by the placebo treatment or vice versa. Ten patients
`received the placebo followed by brimonidine tartrate (se-
`quence 1) and 8 patients were treated with the reverse se-
`quence (sequence 2). The following tests were performed
`on 1 eye selected randomly at baseline and at 2 weekly in-
`tervals while using each treatment: intraocular pressure
`(Goldmann applanation tonometry), baseline heart rate (bra-
`chial pulse), blood pressure, and color Doppler measure-
`ments. All measurements were obtained between 2 and 4 PM.
`
`Tests were performed at 2 weekly intervals because
`the plasma elimination half-life of brimonidine tartrate is
`approximately 2 to 5 hours.
`Color Doppler measurements were carried out using
`a color Doppler ultrasound machine (model ADT 3000, Ad-
`vanced Data Technology, Seattle, Wash). A linear array high-
`resolution 10-MHz probe was used for imaging of the globe.
`All measurements were performed by 1 experienced sono-
`grapher (S.D.) who was unaware of the subject’s clinical
`status. All examinations were carried out with the pa-
`tients in a supine position and maintaining fixation. Us-
`ing the color flow as a map, the central retinal artery was
`first identified, followed by the ophthalmic artery, and tem-
`poral and nasal ciliary arteries. Peak systolic velocities and
`end diastolic velocities were calculated from the Doppler
`shifts. At the baseline visit the angle of calculation and the
`exact site of measurement in a vessel were noted for each
`vessel of each patient to improve the reproducibility of mea-
`surements. On subsequent evaluation, the same angle in
`each patient was used to calculate the velocities, thus mini-
`mizing error. The resistive index was calculated by the
`method of Pourcelot: resistive indices = (peak systolic ve-
`locity − end diastolic velocities)/peak systolic velocity.8
`Because of the double-masked crossover design of
`the study, we first analyzed the sequence effect bias by
`measuring the differences between results calculated for
`sequence 1 and sequence 2. A t test for period effect was
`then calculated.9 A paired t test for normally distributed
`data, the Student t test, was used to compare the intraocu-
`lar pressures in the 2 groups. As the distribution of the
`results was not gaussian, a nonparametric test (the Wil-
`coxon rank sum test) was used to compare velocity indi-
`ces and resistive indices. P⬍.05 was considered statisti-
`cally significant. Bonferroni correction for multiple
`comparison was used. A sample size of 18 was chosen to
`provide 90% power to detect a 10% change in flow veloc-
`ity or resistance in the ophthalmic artery.10 The sample
`size provides 90% power to detect a 15% change in the
`central retinal artery and a 20% change in the posterior
`ciliary arteries.
`
`significant evidence of a period effect between the 2 se-
`quences (t = 3.25; P⬎.01).
`
`CARDIOVASCULAR FACTORS
`
`Mean systolic blood pressure ± standard deviation was
`135 ± 15.04 mm Hg at baseline, 137 ± 16.1 mm Hg
`with placebo (P = .38), and 135.3 ± 15.94 mm Hg with
`0.2% brimonidine tartrate (P = .87 vs baseline and
`P = .48 vs placebo). Mean diastolic blood pressure ± SD
`was 79.44 ± 14.64 mm Hg at baseline, 83.9 ± 9.3 mm
`Hg with placebo (P = .19), and 83.06 ± 12.38 mm Hg
`with 0.2% brimonidine tartrate (P = .23 vs baseline and
`P = .61 vs placebo). Pulse rate ± SD was 85.44/min ±
`7.05/min at baseline, 86.44/min ± 7.56/min with
`placebo (P = .58), and 83.33/min ± 5.48/min with 0.2%
`brimonidine tartrate (P = .15 vs baseline and P = .43 vs
`placebo). There was no significant difference between
`the 0.2% brimonidine tartrate and the placebo groups
`for the cardiovascular factors.
`
`COLOR DOPPLER IMAGING
`
`The Table shows the mean peak systolic and end dias-
`tolic velocities and the mean resistive indices in the cen-
`tral retinal artery, ophthalmic artery, nasal, and tempo-
`ral ciliary arteries, calculated for baseline, placebo, and
`0.2% brimonidine tartrate. There was no significant modi-
`fication (P⬎.05) between the baseline values and those
`following drug administration in the central retinal, oph-
`thalmic, nasal, and temporal ciliary arteries for the mean
`peak systolic and end diastolic velocities and the mean
`resistive index.
`
`COMMENT
`
`This study found that 0.2% brimonidine tartrate low-
`ered intraocular pressure without significantly modify-
`ing measurements of the blood circulation at the poste-
`rior segment of the eye. This could be explained by the
`
`ARCH OPHTHALMOL/ VOL 116, DEC 1998
`1592
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`©1998 American Medical Association. All rights reserved.
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`Peak Systolic and End Diastolic Velocities and
`Resistive Indices for All Vessels Studied*
`
`Baseline
`
`P,
`Baseline/
`Placebo Brimonidine
`Placebo
`Ophthalmic Artery
`PSV 37.4 ± 9.15 37.57 ± 12.63
`. . ./.94
`EDV 7.82 ± 2.41
`7.70 ± 3.00
`. . ./.83
`RI
`0.78 ± 0.05
`0.78 ± 0.08
`. . ./.54
`
`36.11 ± 7.30
`8.47 ± 2.14
`0.76 ± 0.06
`
`P,
`Baseline/
`Placebo
`
`.54/.52
`.16/.38
`.04/.25
`
`PSV 10.2 ± 2.64
`EDV 2.53 ± 0.89
`RI
`0.75 ± 0.08
`
`PSV 8.70 ± 2.70
`EDV 2.13 ± 1.01
`RI
`0.76 ± 0.09
`
`PSV 9.30 ± 4.00
`EDV 2.55 ± 1.43
`RI
`0.72 ± 0.00
`
`Central Retinal Artery
`8.82 ± 3.20
`. . ./.08
`2.32 ± 1.45
`. . ./.52
`0.74 ± 0.11
`. . ./.42
`
`Nasal Ciliary Artery
`7.68 ± 1.77
`. . ./.15
`2.23 ± 0.39
`. . ./.50
`0.72 ± 0.11
`. . ./.08
`
`Temporal Ciliary Artery
`8.37 ± 2.40
`. . ./.48
`2.49 ± 1.23
`. . ./.75
`0.71 ± 0.12
`. . ./.60
`
`9.24 ± 3.13
`2.55 ± 1.22
`0.73 ± 0.09
`
`.19/.21
`.93/.30
`.23/.49
`
`8.40 ± 2.60
`2.54 ± 0.95
`0.69 ± 0.10
`
`.72/.36
`.08/.18
`.02/.36
`
`9.18 ± 3.12
`2.68 ± 1.30
`0.71 ± 0.11
`
`.75/.43
`.77/.26
`.55/.95
`
`*PSVindicatespeaksystolicvelocity;EDV,enddiastolicvelocity;
`RI,resistiveindices.P valuesnotapplicable.
`
`high specificity of brimonidine tartrate for ␣ 2-
`adrenergic receptors.11,12
`Many different methods have been used to mea-
`sure the dynamics of ocular circulation in vivo.13-20 For
`technical reasons, wide variations between individuals
`can occur due to problems related to patient coopera-
`tion and posture, as well as a technician’s expertise. Fur-
`thermore, in glaucoma, it is the blood supply to the ret-
`rolaminar portion of the optic nerve head that is relevant,
`ie, small vessels that are difficult to visualize and have
`wide anatomic variability.
`With color Doppler imaging, good reproducibility
`of measurements of blood velocities for the ophthalmic
`artery and the central retinal artery can be obtained (ranges
`of variability, 6.5%-12.2%).21 However, the reproduc-
`ibility of velocities from the posterior ciliary vessels, which
`are difficult to scan, is poorer than the other vessels (19%-
`38.8%).11 In this study, to improve accuracy, we used a
`10-MHz probe and documented the image on video to
`ensure the measurement of the flow at the same loca-
`tion and at the same angle on each successive scanning.
`This fact is of practical importance, as the angle of the
`ultrasound beam and the location of the measurements
`influence the calculations when imaging each artery. A
`significant velocity gradient exists in the central retinal
`artery, with the maximum velocity achieved approxi-
`mately 2 mm from the optic disc in normal subjects.22
`Moreover, as the angle of measurement shifts perpen-
`dicular to the direction of flow, the velocity measure-
`ment is increasingly underestimated.
`The presence of vasoactive ␣2 receptors on the or-
`bital vessels is doubtful.23,24 Yu et al24 studied the re-
`sponse of isolated human ciliary artery to 9 agonists, con-
`cluding that functional histamine, ␣1-adrenergic, and
`serotonin receptors were present on these arteries, but
`that no ␣2-adrenergic receptors were present. A previ-
`
`ous animal study was also unable to demonstrate ob-
`servable optic nerve vasomotor effects with the ␣2-
`adrenoreceptor agonist apraclonidine hydrochloride.25
`Brimonidine tartrate was also applied topically to
`retinal tissue transplanted into the hamster cheek
`pouch membrane.26 In this model, the arteriolar calibre
`in the retinal xenografts was measured by intravital
`microscopy. Brimonidine tartrate did not cause signifi-
`cant arteriolar vasoconstriction of the human arteriole
`tissue over a dose range of 10−9 to 10−4 MAJ evaluated 5
`minutes after topical suffusion. Moreover, pharmacoki-
`netic studies in rabbits and monkeys showed that vitre-
`ous humor concentrations following administration of
`0.2% brimonidine tartrate twice daily for 2 weeks was
`10−7 MAJ.2,27,28
`Another animal study investigated the effect of bri-
`monidine tartrate on the optic nerve blood flow in rab-
`bits eyes.29 Either 0.2% brimonidine tartrate or placebo
`was applied once daily for 4 weeks. Ocular blood flow
`was assessed by colored microspheres and vascular cor-
`rosion casting. As measured with colored microspheres,
`optic nerve blood flow was 0.17 ± 0.04 µg/mg per minute
`in brimonidine tartrate–treated eyes and 0.18 ± 0.06 µg/mg
`per minute in the placebo-treated eyes. Corrosion cast-
`ing showed that the average constriction was 16.7% ± 3.7%
`in brimonidine tartrate–treated eyes, and 16.1% ± 5.3%
`in the placebo-treated eyes.
`Vasoconstriction is mediated mainly via ␣1-
`adrenergic receptors, although ␣2-adrenergic receptors
`may play a part30 and thereby have a role in the auto-
`regulation of capillary pressure and tissue oxygen deliv-
`ery. On the other hand, brimonidine tartrate may also
`produce vasodilatation via the ␣2-adrenergic receptors on
`endothelial cells, which release endothelial-derived re-
`laxing factor.31,32
`Our results confirmed the beneficial effect of 0.2%
`brimonidine tartrate on the intraocular pressure. No
`effect was demonstrated on the pulse rate or systolic
`and diastolic blood pressure after 15 days of treatment.
`A previous study in healthy volunteers on the cardio-
`vascular, pulmonary, and ocular hypotensive effects of
`0.2% brimonidine tartrate showed a slight reduction in
`systolic blood pressure during recovery from exercise 4
`hours after instillation.33 In the same study, the ocular
`hypotensive effect of brimonidine tartrate was compa-
`rable with that of timolol and greater than that of
`betaxolol suspension.
`In summary, the lack of effect of brimonidine tar-
`trate on the dynamics of the ocular circulation could be
`explained by any one or a combination of the following
`factors: the concentration of the drug at the posterior pole
`at a level insufficient to affect vasoconstrictive recep-
`tors, the release of endothelial-derived relaxing factor,
`and the absence of ␣2-adrenergic receptors on the pos-
`terior ciliary arteries.
`
`CONCLUSION
`
`Topically applied 0.2% brimonidine tartrate reduces in-
`traocular pressure, but does not appear to alter the he-
`modynamics of the posterior segment of the eye as mea-
`sured by color Doppler ultrasound.
`
`ARCH OPHTHALMOL/ VOL 116, DEC 1998
`1593
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`©1998 American Medical Association. All rights reserved.
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`Accepted for publication August 14, 1998.
`This study was supported by a research grant from Al-
`lergan Inc, Irvine, Calif.
`Presented at the Association of Vision Research in Oph-
`thalmology meeting, Fort Lauderdale, Fla, May 15, 1997.
`Corresponding author: Clive Migdal, The Western Eye
`Hospital, Marylebone Road, London NW1 5YE, England.
`
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`
`A look at the past . . .
`
`100 Years Ago in the ARCHIVES
`
`P uccioni describes a cases of bilateral luxation of the lens in a young peasant girl. The lens was dislocated upward and
`
`inward in one eye and upward and outward in the other. Since she was much disturbed by asthenopia both lenses
`were extracted by means of s small flap operation. There having been no trauma and the eyes being otherwise healthy,
`the author thought the condition to have been brought about by the patient’s habit of carrying heavy objects on her head.
`The straining of the muscles of the neck might so increase the intraocular tension that a weak zonula would be ruptured.
`
`Reference: Arch Ophthalmol. 1898;2:320-321.
`
`ARCH OPHTHALMOL/ VOL 116, DEC 1998
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