Article Text
Abstract
Purpose To investigate the effect of nicotine on choroidal thickness using optical coherence tomography (OCT).
Design Prospective, case–control study.
Methods Sixteen young, healthy subjects and 16 age and gender matched control cases were included in this study; 4 mg nicotine gum was given to the study group and placebo gum to the control group. All participants underwent OCT scanning with a high-speed and resolution spectral-domain OCT device (3D OCT 2000, Topcon, Japan) at baseline, and 1 h following nicotine or placebo administration. The measurements were taken in the morning (10:00–12:00 hours) to avoid diurnal fluctuation.
Results The median foveal choroidal thickness at baseline was 337.00 μm (IQR 84.50), which decreased to 311.00 μm (IQR 78.00) at 1 h following oral nicotine intake (p=0.001). The median choroidal thickness was also significantly decreased at five other extrafoveal points (p<0.05 for all). In the control group, the median baseline choroidal thickness at the fovea was 330.50 μm (IQR 104.25), and was 332.00 μm (IQR 103.75) at 1 h (p=0.271).
Conclusions Nicotine causes a significant decrease in choroidal thickness following oral intake. This acute decrease might be a result of reduced ocular blood flow due to the vasoconstrictive effect of nicotine.
- Retina
- Choroid
- Pharmacology
- Imaging
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Introduction
The association of cigarette smoking with macrovascular and peripheral vascular disease is well documented in the literature.1––3 The effects of cigarette smoking or nicotine on ocular circulation have also been reported in previous studies.4––7 Although the haemodynamic effects of nicotine are well known, the pathogenesis of smoking- related ocular blood flow changes is not fully understood.8 ,9
Ocular blood flow can be assessed by colour duplex imaging, the laser speckle method and Doppler flowmetry. Because the choroid receives approximately 95% of all ocular blood flow, changes in its structure would help to evaluate choroidal and thus ocular blood flow.10 Choroidal thickness measurement could be obtained by spectral domain optical coherence tomography (OCT) devices through enhanced depth imaging.11––13 Choroidal thickness has recently been reported to change with sildenafil14 and cigarette smoking.7
There are numerous additives (approximately 600)15 in cigarettes. Although it is reasonable to assume that the combination of chemicals from tobacco smoke affects the choroidal blood flow, it is all but impossible to isolate the effects of specific compounds. In this study we aimed to examine how nicotine in isolation, administered as gum, affects the choroidal thickness, thus choroidal blood flow using OCT measurements.
Methods
Sixteen young, healthy subjects and 16 age and gender-matched control cases were included in this study. The study and control groups had neither systemic nor ocular disease. The study protocol was approved by Izmir University Institutional Review Board and Ethics Committee. The research adhered to the tenets of the Declaration of Helsinki, and a detailed written informed consent was taken before each individual's participation in the study.
All patients underwent detailed ophthalmic examination, including visual acuity testing, biomicroscopy, intraocular pressure measurement with non-contact tonometry, fundus examination and choroidal thickness measurements by OCT. Subjects were given either 4 mg of nicotine gum (Nicorette; McNeil AB, Helsingborg, Sweden) or a placebo gum (Biotene; Laclede, Inc, Rancho Dominguez, California, USA). The placebo gum had a similar taste and appearance to the nicotine gum.
The participants in the study and control groups were asked not to consume any caffeine-containing beverages and chocolate for at least 24 h before the basal OCT measurement. Participants in the study were non-smokers. All basal OCT scans were performed at the same time of the day, in the morning (between 10:00 and 12:00 hours), to avoid diurnal fluctuations. This was immediately followed by chewing of nicotine gum in the study group and placebo gum in the control groups. The OCT measurements were repeated at 1 h following the baseline measurement in both groups.
The absorption of nicotine in gum form is slower and the increase in nicotine blood levels is more gradual than from smoking (time to maximum blood concentration, 5–8 min for smoking, 30 min for nicotine gum).16 This slow increase in blood and especially in brain levels results in a low abuse liability of nicotine gum, in other words, it makes this substance less addictive than smoking.17 However, comparable amounts of blood nicotine concentrations could be achieved by using different forms of administration (maximum blood concentration: 15–30 ng/mL for smoking, 10–19 ng/mL for gum). The bioavailibility of nicotine gum (55%) is also lower than smoking (80–90%) due to first-pass metabolism and the fact that some nicotine is retained in the gum.16 Based on these pharmacokinetic properties of nicotine and the findings of our previous study,7 we measured choroidal thickness at 1 h after consumption.
Participants in both groups were instructed not to eat, drink and take any medications until the end of the measurements. Each participant in both groups was instructed to chew the nicotine or placebo gum continuously at a normal chewing rate up to 1 h.
Choroidal thickness measurements were performed using a spectral-domain OCT device (λ=840 nm, 27 000A-scans/s, and 5 μm axial resolution), 3D OCT-2000 (Topcon; Topcon Corp., Tokyo, Japan). The protocol of the enhanced choroidal mode cross-scan was performed centring on the fovea. This protocol consisted of 6-mm cross-lines with 1024 A-scans/B-scans and overlapping four B-scans per image and direct B-scan observation was available. The B-scan scale was adjusted to 1:1 and approximately doubled the size of the original image. Then, the observer determined subfoveal choroidal thickness perpendicular from the outer edge of the hyperreflective retinal pigment epithelium to the inner sclera, centred on the fovea. All measurements were done using the ‘caliper function’, which is a built-in linear measuring tool of the device. Scans of low quality and blinks were not included and were repeated. Choroidal thickness was measured perpendicularly from the outer edge of the retinal pigment epithelium to the choroid–sclera boundary at the fovea and at five more points that are located at 500 μm nasal to the fovea, 1000 μm nasal to the fovea, 500 μm temporal to the fovea, 1000 μm temporal to the fovea and 1500 μm temporal to the fovea, respectively. Choroidal thickness measurements were made by two masked physicians (MOZ and CK). The average of the two measurements was taken; the differences between readings of the masked physicians were found to be within 10 μm of the mean. If the measurements did not agree within 10 μm, then they were repeated, and if the inconsistency persisted, a third masked reader (EC) took a measurement.
The statistical analysis was performed using SPSS for Windows 16.0. For each continuous variable, normality was checked by the Kolmogorov–Smirnov test. Continuous variables were demonstrated as medians and IQR for normally distributed data (because of the small sample size). Baseline choroidal thickness measurements of the groups were compared by the Mann–Whitney U test. Data were analysed by the Wilcoxon test for choroidal thickness measurements at baseline, and at 1 h following nicotine or placebo administration in both groups. The categorical variables between the groups were analysed by using the χ2 test. A p value less than 0.05 was considered statistically significant.
Results
The nicotine group consisted of nine women and seven men with a median age of 30 years (IQR 9.5), ranging between 22 and 42 years. The control group (nine women, seven men) were aged between 24 and 45 years (median 32.5 years; IQR 7.5). The groups showed no significant difference by means of age (p=0.345) and gender (p>0.05). Tne baseline choroidal thickness measurements of the study and control groups showed no significant difference (table 1).
The median choroidal thickness measurements of nicotine users at baseline, and at 1 h following nicotine gum are shown in table 2. At the fovea, choroidal thickness, which was 337.00 μm (IQR 84.50) (median (IQR)) at baseline, decreased to 311.00 μm (IQR 78.00) at 1 h following nicotine intake. (p=0.001). Nicotine caused a significant reduction in choroidal thickness, compared with baseline, at all six measurement points. However, the choroidal thicknesses of the control group revealed no significant difference at all points when comparing measurements at baseline with 1 h after placebo intake (table 3). Figures 1A,B and 2A,B illustrate the change in choroidal thickness at each study interval for an individual in the nicotine user and control groups, respectively.
Side effects of the nicotine gum such as throat irritation, mild dyspepsia, cough and a cold feeling were reported, in the study cases, but these were minor.
Discussion
As a highly vascular ocular structure, the choroid is directly influenced by intraocular and perfusion pressure; therefore, real time high-definition images of the choroid are more likely to demonstrate the real time vascular status of this tissue in vivo.18 It is suggested that even histology cannot demonstrate the thickness of the living choroid. Moreover, OCT is shown to be superior to histology to reflect accurate choroidal thickness.19 However, there is still debate on the relationship of choroidal thickness with choroidal blood flow. Many recent studies have reported ocular disorders associated with altered abnormal choroidal thickness.20––23 Also, there are recent data on the haemodynamic effect of chemicals—sildenafil and cigarettes—on the choroid, obtained by OCT.7 ,14
It has been reported that sildenafil citrate increases choroidal thickness due to a vasodilatory effect of sildenafil citrate on the choroidal circulation.14 This relationship was further investigated by Kim et al24 using swept-scan high-frequency digital ultrasound to measure the ocular blood flow. Moreover, in a recent study by Ulaş et al,25 significant choroidal thinning was reported in chronic renal failure patients after haemodialysis. In another recent study on this topic by Rishi et al,26 the choroidal thickness in eyes with polypoidal choroidal vasculopathy was found to be higher than normal. The authors hypothesised that the high mean ocular perfusion pressure could possibly play a role in the aetiology of the disease. All of the above-mentioned studies give strong evidence that choroidal thickness reflects choroidal blood flow.
According to the results of our study, chewing 4 mg of nicotine gum decreased choroidal thickness compared with placebo. Rojanapongpun and Drance6 studied the effect of nicotine on the ophthalmic artery flow velocity using transcranial Doppler ultrasound. They observed that small doses of nicotine (nicotine gum) increased blood flow velocities in the ophthalmic artery while finger blood flow was significantly decreased when comparing the nicotine-tested glaucoma group with the placebo-tested group. Steigerwalt et al9 found a reduction in blood flow velocity in the posterior ciliary artery following smoking, which the authors suggested was a good indicator of peripapillary choroidal blood flow, with colour duplex scanning. They proposed that this decrease was due to the increase in the vascular resistance of the vessels. In another study using the laser speckle method, Tamaki et al27 reported a decrease in choroidal blood flow 30 min after smoking. Although choroidal blood flow was not measured directly in the current study, when previous reports about nicotine and ocular blood flow changes are considered, our results support the hypothesis of the relationship between choroidal thickness and ocular blood flow. Moreover, cigarette smoking has been shown to be related to choroidal thickness decrease in otherwise healthy subjects.7 In our opinion, our study findings give further evidence that choroidal thickness correlates directly with choroidal blood flow.
There are several limitations to our study. One is that we have no quantification of nicotine levels for our subjects. Ideally, we would be able to measure blood serum nicotine levels to quantify the amount of nicotine being absorbed through the gum. Without this information, we cannot definitively identify when nicotine concentrations reached their maximum. However, based on the investigation reported by Russell and colleagues28 on blood nicotine levels after cigarette smoking and nicotine gum, we can estimate when nicotine might reach the maximum level. Their study revealed maximum blood plasma nicotine levels 1 h after the consumption of 4 mg nicotine gum, which was comparable to that of smoking one cigarette.28 In addition, the study by Sizmaz et al,7 which showed significant choroidal thickness reduction at 1 h after smoking, supports these findings.
Other limitations of the current study are the limited number of cases and the potential interobserver and intraobserver bias while measuring choroidal thickness manually. However, this bias is an issue to be solved in all studies regarding choroidal thickness measurements. To include more than one measurement point and to use two independent observer may partly overcome this problem. The relatively small sample size may also result in type 1 error; however, the design of the study with age and sex-matched control groups makes the results more valuable.
Besides these limitations, to the best of our knowledge this is the first study to investigate the isolated effects of nicotine on choroidal thickness. As there is growing evidence in the literature on the relationship between choroidal thickness and choroidal blood flow, the findings of this preliminary study may be of clinical importance. We believe that the results of this preliminary study will be useful in future studies about this topic.
References
Footnotes
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Contributors Conception and design: MOZ and CK; acquisition of data: MOZ; analysis and interpretation of data: MOZ, CK and EC; article drafting and revising: CK; final approval: CK.
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Competing interests None.
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Patient consent Obtained.
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Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
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Ethics approval The study protocol was approved by Izmir University Institutional Review Board and Ethics Committee, and the research adhered to the tenets of the Declaration of Helsinki.
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Provenance and peer review Not commissioned; externally peer reviewed.