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Phenylephrine 5% added to Tropicamide 0.5% eye drops does not influence retinal oxygen saturation values or retinal vessel diameter in glaucoma patients

2012; Wiley; Volume: 91; Issue: 8 Linguagem: Inglês

10.1111/j.1755-3768.2012.02545.x

1755-3768

Evelien Vandewalle, Luís Abegão Pinto, Ólöf Birna Ólafsdóttir, Ingeborg Stalmans,

Retinal Diseases and Treatments

Purpose: To test whether adding topical phenylephrine 5% to tropicamide 0.5% eye drops in the protocol for pupil dilation affects the retinal vessel oximeter measurements in patients with glaucoma. To test whether phenylephrine 5% has an influence as a vasoconstrictor on the retinal vessel width and can improve the proportion of high-quality retinal images in patients with glaucoma. Methods: Retinal images of 66 patients with chronic open-angle glaucoma were obtained before and after the administration of phenylephrine 5% eye drops to patients already dilated with tropicamide 0.5% with the Oxymap Retinal Oximeter (Oxymap ehf, Reykjavik, Iceland). Specialized software, Oxymap Analyzer, analysed the images and measured the oxygen saturation and vessel diameter. Oxygen saturation was measured in first- and second-degree vessels. A Mann–Whitney U-test was used to compare both groups. Quality of the images was assessed, and a Fisher's exact test was used to compare the proportion of high- and poor-quality images. Results: There was no significant difference in arterial and venous oxygen saturation in patients with glaucoma whether dilated by tropicamide alone or a combination of tropicamide and phenylephrine (97 ± 6% versus 96 ± 5%, p = 0.88 for arterial saturation and 66 ± 6% versus 67 ± 6%, p = 0.78 for venous saturation, n = 27). There was no significant difference in vessel diameter between both conditions for the different vessels (p = 0.61 for arterial saturation and p = 0.51 for venous saturation, n = 27). The proportion of high-quality images was significantly higher after the combination regimen compared with tropicamide only (p = 0.0001). Conclusion: The addition of topical phenylephrine 5% after tropicamide 0.5% improved the proportion of high-quality retinal oximetry images without influencing the retinal oxygen saturation values or the retinal vessel diameter in patients with glaucoma. Good pupil dilation is essential to obtain high-quality retinal fundus photographs. In previous retinal oximetry reports, different protocols for pupil dilation were used: dilation with tropicamide 1% supplemented with phenylephrine hydrochloride 10% when needed (Hardarson et al. 2009b; Hardarson & Stefánsson 2010; Hardarson & Stefánsson 2011a,b; Olafsdottir et al. 2011), tropicamide 1% alone (Hardarson et al. 2009a) or the combination of tropicamide and phenylephrine (Blondal et al. 2011). In the older reports for retinal oximetry, the methods of dilation were not mentioned (Hardarson et al. 2006; Siesky et al. 2008, 2010; Traustason et al. 2009). The magnitude of dilation depends on the sphincter muscle of the pupil controlled by the parasympathetic nerves and on the dilator muscle of the pupil controlled by sympathetic nerves. The parasympathetic antagonist tropicamide and the sympathetic agonist phenylephrine are frequently used to achieve dilation in the clinical setting. The parasympathetic regulation dominates over the sympathetic effect in control of the pupil (Trinavarat & Pituksung 2009). Not only specific alpha adrenergic agonists can mediate dilation, also the nonspecific beta receptor agonists can enhance the mydriatic effect of intracameral phenylephrine in a porcine eye model (Janbaz et al. 2011). As phenylephrine is an alpha 1 adrenergic agonist, it has the potential for vasoconstrictive activity in peri-pheral vessels. Different authors reported that topical instillation of phenylephrine caused substantial localized constriction of the arterioles in the optic nerve head in rabbits (Sugiyama et al. 1992), in monkeys (Takayama et al. 2004; Mayama et al. 2010) as well as in young human volunteers (Takayama et al. 2009). However, little influence was found on the optic nerve head circulation of aged human subjects (Takayama et al. 2004). Mayama et al. (2010) reported that the reactivity of the optic nerve head vasculature to an alpha agonist was diminished in an experimental glaucomatous monkey eye (Mayama et al. 2010). There was a drop in PO2 in the anterior chamber after topical or intracameral administration of epinephrine in cats. This drop in PO2 in the anterior chamber was not simply because of mydriasis, as atropine administered in a similar fashion did not cause a drop in PO2 (Stefansson et al. 1983). The aim of this study was to evaluate whether the addition of phenylephrine 5% to tropicamide 0.5% in the protocol for dilation affected the retinal vessel oximeter measurements and to test whether phenylephrine 5% had an influence as a vasoconstrictor on the retinal vessel width and could improve the proportion of high quality of retinal images in patients with glaucoma. This prospective, non-randomized clinical trial was approved by the Institutional Review Board of the University Hospitals Leuven and adhered to the tenets of the Declaration of Helsinki. All eligible patients who agreed to participate in the study signed an informed consent before enrolment. This trial was registered on clinicaltrials.gov with the number NCT01391247. Eligible patients were recruited at the glaucoma division of the Department of Ophthalmology at the University Hospitals Leuven, Belgium. All study patients had been diagnosed with glaucoma by a senior glaucoma specialist (IS). Glaucoma was defined as having characteristic optic disc damage (based on cup/disc ratio, thinning of neuroretinal rim, notching, disc haemorrhages, etc.) and visual field defects. For the diagnosis of primary open-angle glaucoma (POAG), at least one measurement of intraocular pressure of >21 mmHg was required, whereas patients with IOPs consistently ≤21 mmHg were classified as having normal tension glaucoma (NTG). The eye with the worst glaucoma damage of each patient was studied. Non-invasive spectrophotometric retinal oximetry was performed on the same day as the ophthalmological evaluations. The retinal oximeter (Oxymap ehf, Reykjavik, Iceland) consists of a fundus camera (Topcon TRC-50DX/EX; Topcon Corporation, Tokyo, Japan) with an attached beam splitter and a digital camera. The instrument is described in detail elsewhere. Of note, this is a previous version of the oximeter, which is based on similar principles (Hardarson et al. 2006). It provides two images at two different wavelengths (600 nm, which is sensitive to oxygen saturation, and 570 nm, which is not sensitive to oxygen saturation). The optical density (OD) of retinal vessels from two acquired images is automatically calculated by software algorithm according the equation OD = log (I0/I), where I0 is light reflected by the background to the side of the vessel and I is the light reflected from the vessel. The ratio of the OD at 600nm and OD at 570 nm is inversely related to haemoglobin oxygen saturation (Beach et al. 1999; Harris et al. 2003). The vessel diameter measurements with the oximeter are consistent and repeatable (Blondal et al. 2011). Pupils were dilated with tropicamide 0.5% (Tropicol®; Théa Pharma, Wetteren, Belgium). After 20 min, a first session of oximetry was performed. Then phenylephrine 5% (Neosynephrin-POS®; Ursapharm, Saarbrücken, Germany) was added topically, and patients were instructed to wait for another 20 min before a second session of oximetry was repeated. All measurements were performed in darkness. Each subject spent two minutes in darkness before oximetry. The time on between images (flashes) was about 1 min on average. Retinal oxygen saturation was measured in the first-degree vessels, or second-degree vessels if the length of the first degree was <50 pixels. Both retinal arterioles and venules inferior and superior to the optic nerve head were measured. Only retinal vessels with a width of more than six pixels and a length between 50 and 200 pixels were analysed. Around the optic disc, an area of 15 pixels as well as branching vessels and their origin were excluded. The arteriovenous difference was calculated by oxygen saturation in arterioles minus oxygen saturation in venules. The quality of the retinal fundus photographs obtained after dilation with tropicamide alone and the combination of tropicamide and phenylephrine was assessed on four criteria: focus, contrast, glare and shadow. A pass/fail system was used. If the picture did not pass one of the four criteria (focus, contrast, glare and shadow), then the picture failed to have a high quality. IOP was measured using a Goldmann applanation tonometry mounted on a Haag-Streit slit lamp (Haag-Streit BQ 900; Haag-Streit International, Köniz, Switzerland). The eyes were anesthetized with oxybuprocaine 0.4% (Unicaïne 0.4%®, Théa Pharma). Systolic and diastolic blood pressure was measured using an automatic sphygmomanometer (Omron HEM-7001-E; Omron, Kyoto, Japan) after a 5-min rest. The number of ocular hypotensive medications was also recorded. The fixed combinations were documented according to the number of active ingredients. Systemic carbonic anhydrase inhibitors were counted as one medication. Statistical analysis was performed with Prism, version 5 (Graphpad Software Inc., La Jolla, CA, USA). A Mann–Whitney U-test was used to compare both groups. A Fisher's exact test was used to compare the quality of the obtained images. For both analyses, p < 0.05 was considered statistically significant. The baseline characteristics are described in Table 1. Retinal oxygen saturations are stated as mean ± standard deviation. Retinal oxygen saturation values after dilation with tropicamide alone were 97 ± 6% for arterial and 66 ± 6% for venous saturation in high-quality images (Table 2; n = 27). The corresponding values after additional dilation with phenylephrine were 96 ± 5% for arterial and 67 ± 6% for venous saturation (Table 2; n = 27). There was no significant difference in arterial (p = 0.88) or venous saturation (p = 0.78) between dilation with tropicamide only and tropicamide followed by phenylephrine (Table 2; n = 27). There was no significant difference in retinal vessel diameter between both dilation regimens for the different vessels (p = 0.61 for arterial diameter and p = 0.51 for venous diameter (Table 2; n = 27)). In Table 3, poor-quality images (n = 24) were compared with high-quality images (n = 27) after dilation with tropicamide 0.5% alone. There was a significant difference in venous saturation (p = 0.01) and a trend of difference in arterioles saturation (p = 0.06) between high- and poor-quality images. The proportion of high-quality images significantly improved after the addition of phenylephrine (p = 0.0001, Table 4) compared with tropicamide alone. From the 66 patients with chronic open-angle glaucoma, a high-quality image was achieved in 77% after combination therapy compared with only 41% after pupil dilation with tropicamide alone. The criteria for failure are reported in Table 3. An example of an image of satisfactory quality and an image of insufficient quality is shown in 1, 2. Images of high quality. A. Tropicamide 0.5% B. Tropicamide 0.5% and phenylephrine 5% In both images, a high quality is achieved. An improvement in quality after addition of phenylephrine A. Tropicamide 0.5% B. Tropicamide 0.5% and phenylephrine 5% The image obtained after tropicamide 0.5% alone has insufficient quality because of shadows inferiorly owing to the eye lashes or the iris when there is incomplete dilation. Because of incomplete dilation, the vessels are inhomogeneous coloured. The image obtained after the addition of phenylephrine 5% to tropicamide 0.5% showed no shadows. The vessels are also more homogeneous coloured. There was no difference in retinal oxygen saturation between POAG and NTG patients. The addition of topical phenylephrine 5% to tropicamide 0.5% dilated eyes had no influence on the retinal oxygen saturation values and on the retinal vessel width in patients with glaucoma. Insufficient quality of the images had an influence on the venous oxygen saturation measurements, but also showed a trend to influence the arterial oxygen saturation measurements. Mayama et al. (2010) found that in a unilateral experimental glaucomatous monkey model, the reactivity of the optic nerve head vasculature to an alpha agonist (phenylephrine 5%) was diminished. The fellow non-treated eye from the same animal presented with a significant decrease in optic nerve head blood flow after a single phenylephrine instillation (Mayama et al. 2010). This study illustrated that the effect of topical phenylephrine on the optic nerve head circulation disappeared when experimental glaucoma was induced. The authors hypothesized that the difference in reactivity of the optic nerve head between both eyes should be attributed to the glaucomatous changes in the optic nerve head. Takayama et al. (2004) found that the instillation of topical phenylephrine 5% did not change the optic nerve circulation in aged human subjects. In this study, no significant differences in retinal vessel width or oxygen saturation were observed after instillation of phenylephrine 5% in a group of patients with glaucoma. Different concentrations of phenylephrine are available on the market. Because of the possibility of toxic effects of 10% phenylephrine (e.g. cardiac arrhythmias, acute hypertension, pallor, tremor, tachycardia and occipital headaches), this dose was not used (Fraunfelder & Scafidi 1978; Leopold et al. 1990). The quality of the images was significantly better after the combined regimen for pupil dilation compared with tropicamide 0.5% alone. Incomplete dilation after tropicamide 0.5% alone made it difficult to obtain sufficiently focused pictures, and frequently, shadows of the eye lashes or iris when there is incomplete dilation were seen on the pictures. From the literature, it was known that parasympatholytic agents alone may not provide sufficient pupil dilation (Trinavarat & Pituksung 2009). Indeed, the combination of tropicamide and phenylephrine eye drops has been shown to be more effective to obtain full pupil dilation than single eye drops of tropicamide or phenylephrine alone (Eyeson-Annan et al. 1998; Krumholz et al. 2006; Park et al. 2009). Most protocols for pupil dilation in previous studies already mentioned, if dilation with tropicamide 1% alone was not enough, it was supplemented with phenylephrine hydrochloride 10% (Hardarson et al. 2009b; Hardarson & Stefánsson 2010, 2011a,b; Olafsdottir et al. 2011) or the combination of tropicamide and phenylephrine was used systematically (Blondal et al. 2011). Not only dilation can negatively influence the quality images, also eye lashes or cataract formation can influence the quality of the obtained images. In 77% of the patients who received the combined dilation regimen, a high-quality image was obtained, compared with 41% in the patients who only received tropicamide, illustrating the influence of full dilation on the imaging quality. In 23% of the patients who received the combined dilation regimen, the image was discarded because of insufficient focus, a lack of good contrast, glare or shadows. It is therefore recommended to obtain good dilation prior to the acquisition of retinal oximetry pictures, to avoid insufficient quality of the obtained fundus photographs. The authors would like to thank Sien Boons and Veerle Vanbellinghen for their technical support. EV was supported with a grant from the FWO 'Fonds Wetenschappelijk Onderzoek – Vlaanderen'. No conflict of interest.