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Introduction

The treatment of ocular neovascular diseases is being revolutionized by intravitreal injections targeting vascu-lar endothelial growth factor (VEGF) (1). Ranibizumab (Lucentis, Genentech) is an antibody fragment that inhibits all isoforms of VEGF (2) and clinical trials estab-lished the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD) (3,4). Thereby, the number of intravitreal ranibizumab injection (IRI) have been increasing exponentially.

Injection of ranibizumab into vitreous cavity is expected to increase vitreous volume and subsequently elevate intraocular pressure. Indeed, transient rise in intraocular

pressure (IOP) has been shown by various studies (5,6). In addition, the biometric changes of the human eye have been demonstrated in vivo as a response to mechanical elevation of IOP (7). Also, a small magnitude of elevation in IOP induced through mechanical means and imposed for a short period of time was associated with statistically significant axial elongation of the eye (8).

Based on these findings, we hypothesized that additional volume with injection of ranibizumab into vitreous cavity or subsequently elevated IOP after the injection may change ocular dimension. To the best of our knowledge, this issue has not been studied before. Moreover, knowing the AOD changes after IRI may be

ReseaRch aRtIcle

Short-term impact of intravitreal ranibizumab injection on axial ocular dimension and intraocular pressure

Altan Goktas1, Sertan Goktas2, Mustafa Atas1, Suleyman Demircan1, and Yusufcan Yurtsever1

1Department of Ophthalmology, Training and Research Hospital, Kayseri, Turkey and 2Eye Clinic, Tekden Hospital, Kayseri, Turkey

abstractObjective: To evaluate the short-term impact of intravitreal ranibizumab injection on axial ocular dimension (AOD) and intraocular pressure (IOP). Methods: A total of 31 patients who received 0.05 mL intravitreal ranibizumab injection (IRI) for age-related macular degeneration and 30 healthy volunteers were enrolled in the study. AODs i.e. anterior chamber depth and axial length were measured with IOL Master and IOP with noncontact tonometer before and 5 min, 30 min and 1 day after the injection. Results: Five minutes after the injection, mean IOP increased to 24.8 ± 9.5 (13–46) mmHg from 14.5 ± 2.3 (10–18) mmHg (p < 0.001). Thirty minutes after the injection, IOP decreased a mean level of 17.3 ± 4.1 (11–26) mmHg. The change in axial length and anterior chamber depth measurements did not reach a statistical significance across the time points (p > 0.05, for all values). There was no correlation between biometric measurements and IOP before (r = 0.016, p = 0.948 for axial length and r = −0.48 p = 0.075 for anterior chamber depth) and 5 min after IRI (r = 0.049, p = 0.835 for axial length and r = −0.219 p = 0.367 for anterior chamber depth). Measurements of control group taken across same time points did not reveal statistically significant differences (p > 0.05, for all measurements). Conclusion: Although IOP increases transiently after the intravitreal injection of 0.05 mL ranibizumab, axial length and anterior chamber depth are not affected by this amount of injection, and the increase in IOP after the injection seems to be irrelevant to AL and anterior chamber depth. Therefore, it is postulated that ranibizumab can be used safely in patients with age-related macular degeneration who have shallow anterior chamber and/or short axial length simultaneously.Keywords: Ranibizumab, intravitreal injection, intraocular pressure, biometry

Address for Correspondence: Altan Goktas, Department of Ophthalmology, Training and Research Hospital, Kayseri, Turkey. E-mail: altandr@hotmail.com

(Received 16 April 2012; revised 10 May 2012; accepted 21 May 2012)

Cutaneous and Ocular Toxicology, 2013; 32(1): 23–26© 2013 Informa Healthcare USA, Inc.ISSN 1556-9527 print/ISSN 1556-9535 onlineDOI: 10.3109/15569527.2012.696569

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IOP and biometry after ranibizumab injection

A. Goktas et al.

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24 A. Goktas et al.

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important in patients who have macular degenerations and shallow anterior chambers simultaneously.

In this study, the aim was to evaluate the short-term impact of intravitreal ranibizumab injection on axial ocular dimension (AOD) and to assess whether there is any correlation between AOD and IOP.

Materials and methods

A total of 31 eyes of 31 patients with active subfoveal/jux-tafoveal choroidal neovascular (CNV) membrane were recruited for this prospective study that was conducted at Ophthalmology Department, Kayseri Training and Research Hospital between October, 2011 and January, 2012. Written informed consent was obtained from all participants before the intervention. The study adhered to the tenets of the Declaration of Helsinki. The patients with a history of any ocular surgery, laser treatment, glau-coma, media opacity and previous intravitreal injection were excluded from the study. In addition, 30 healthy volunteers were included in the study as a control group.

All patients underwent a complete ophthalmic exami-nation including best-corrected visual acuity evaluation, slit-lamp examination, fundus biomicroscopy fluores-cein angiography (FA), optical coherence tomography (OCT, Spectralis, Heidelberg, Germany) imaging for diagnosis and follow-up of AMD. IOP was measured with noncontact tonometer (NT-510, Nidek Co, Tokyo, Japan) and axial biometry with IOL Master optical biometer (Carl Zeiss Meditec, Jena, Germany) by an experienced technician. IOL Master is a partial coherence laser inter-ferometry and is capable of noncontact high-resolution axial length measurement (9).

All patients underwent intravitreal injection with 0.5 mg (0.05 mL) of ranibizumab (Lucentis; Genentech, Inc, South San Francisco, CA). Patients were uniformly sterilely prepped, which included instillation of topical antibiotic and anesthetic drops, insertion of a lid speculum, and a 5% povidone iodine flush, followed by a rinse with balanced salt solution. Using a cotton-tipped applicator soaked with a topical anesthetic, the inferotemporal area of sclera to be injected was anesthetized. After marking the injec-tion site on the sclera with a caliper measuring 3–3.5 mm from the limbus, the conjunctiva was displaced slightly with a sterile cotton-tipped applicator just before entering the eye with a needle. All the injections were performed using tunneled injection without a reflux by same surgeon (AG), that is, all the injected volume of ranibizumab was kept in the vitreous. After injection, the injection site was occluded temporarily and was massaged with a sterile

cotton-tipped applicator as the needle was withdrawn from the eye. IOP and axial biometry were measured before and 5 min, 30 min and 1 day after IRI. Also, IOP and axial biometry measurements were taken from randomly selected eye of healthy volunteers across the same time points likewise the study group to test repeatability of measurements taken with the devices.

The distributions of all variables determined with Kolmogorov–Smirnov test were normal. The parameters were presented as mean ± standard deviation. The analy-sis of variance (one-way ANOVA) was used to evaluate the statistical significance over IOP and biometry changes. All comparisons between different time points were applied using Tukey post-hoc correction. A simple linear regression test was performed between IOP and axial biometric mea-surements to reveal linear relationships before and 5 min after IRI. All statistical analyses were performed using SPSS Version 13.0 statistical analysis software and p values less than 0.05 were considered statistically significant.

Results

All the patients completed the study. The mean age of patients was 72 ± 7.8 years (range, 57–84 years), with 13 men and 18 women. The patients had wet-type subfo-veal/juxtafoveal CNV confirmed by FA and OCT. Eighty percent of the patients had occult or minimally classic type CNV and the remaining patients had classic type. Mean best-corrected visual acuity was 1/10 ranged 3 meter finger counting to 3/10 before IRI. The mean age of the control group was 67 ± 12 years (54–73 years) with 14 men and 16 women.

Mean IOP, axial length (AL) and anterior chamber depth (ACD) before and 5 min, 30 min and 1 day after the injection were shown in Table 1 and Figure 1A–1C.

Five minutes after the injection, mean IOP increased to 24.8 ± 9.5 mmHg (range, 13–46) from 14.5 ± 2.3 mmHg (range, 10–18) and the difference was statistically sig-nificant (p < 0.001). Thirty minutes after the injection, IOP decreased a mean level of 17.3 ± 4.1 mmHg (range, 11–26). In other words, compared with baseline, the mean increase in IOP was statistically significant at 5 min (p < 0.001) the differences, however, were not significant after 30 min and 1 day (p > 0.05). The mean difference between preoperative IOP and 5 min after IRI was 10.3 ± 8.3(0–30) mmHg. The eye with AL of 24.48 mm (largest AL in the study) developed 6 mmHg increase in IOP and the eye with AL of 21.23 mm (smallest AL in the study) showed 7 mmHg increase in IOP. The eye without any IOP change had AL of 24.05 mm (second largest AL in the study).

Table 1. Mean IOP, AL and ACD before and at different time points after injection.Before

Mean ± SD (range)5 min after

Mean ± SD (range)30 min after

Mean ± SD (range)1 day after

Mean ± SD (range)IOP (mmHg) 14.5 ± 2.3 (10–18) 24.8 ± 9.5 (13–46) 17.3 ± 4.1 (11–26) 13.3 ± 2.4 (9–19)AL (mm) 22.81 ± 0.92 (21.23–24.42) 22.84 ± 0.88 (21.22–24.48) 22.82 ± 0.90 (21.25–24.44) 22.80 ± 0.89 (21.23–24.40)ACD (mm) 3.21 ± 0.65 (2.53–4.91) 3.18 ± 0.49 (2.46–4.61) 3.12 ± 0.50 (2.49–4.64) 3.11 ± 0.52 (2.49–4.75)ACD, Anterior chamber depth; AL, Axial length; IOP, Intraocular pressure.

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IOP and biometry after ranibizumab injection 25

© 2013 Informa Healthcare USA, Inc.

The change in axial length and anterior chamber depth measurements did not reach a statistical significance across the time points i.e. before and after 5 min, 30 min and 1 day (p > 0.05, for all values).

There was no correlation between biometric measure-ments and IOP before (r = 0.016, p = 0.948 for axial length and r = −0.48 p = 0.075 for anterior chamber depth) and 5 min after IRI (r = 0.049, p = 0.835 for axial length and r = −0.219 p = 0.367 for anterior chamber depth). The mean IOP in different axial length and anterior chamber depth values was shown in Tables 2 and 3, respectively.

Measurements of control group taken across same time points did not reveal a statistically significant differ-ence (Table 4) (p > 0.05 for all measurements).

Any of the patients did not develop serious adverse events such as retinal tear or detachment, vitreous hem-orrhage and endophthalmitis after IRI. We observed sub-conjunctival hemorrhage that resolved spontaneously in four patients and mild anterior chamber reaction that responded to topical mild steroid therapy in two patients.

Discussion

In the current study, we showed immediate increase in IOP 5 min after IRI. We also found that IOP normalized

over 30 min. This is in agreement with previous studies (5,6,10). Höhn and Mirshahi (10) showed strong decrease in IOP in patients receiving a tunneled ranibizumab injection during the first 10 postoperative minutes. In contrast, Gismondi et al. (6) reported that the mean IOP values were significantly different from baseline 30 min after the injection and dropped to baseline values 60 min after. They thought that the study population and/or IOP measurement techniques in their study could be reasons for longer lasting IOP values. As a result, increase in IOP has been shown after intravitreal injection of 0.05 mL ranibizumab. However, this elevation of IOP was tran-sient, and a rapid and spontaneous decline was observed in the majority of the cases (5,6,10). Intravitreously administered ranibizumab is thought to exit the vitre-ous cavity via one of two pathways: posteriorly via retinal penetration and then drainage into the choroidal vascu-lature or anteriorly through the aqueous drainage route (11). Therefore, one of the pathways may be responsible for drop in IOP after the injection.

On the other hand, 5 min after the injection, the IOP increased to a level of 24.8 ± 9.5 mmHg in our study and the mean increase in IOP was found to be 10.3 ± 8.3 mmHg. However, Höhn and Mirshahi (8) reported that

Figure 1.  Error bars show the distribution of IOP measurement (A), axial length (B) and anterior chamber depth (C) before, 5 min, 30 min, 1 day after intravitreal injection of 0.05 mL ranibizumab.

Table 4. Mean IOP, AL and ACD before and at different time points after injection for control group.Before

Mean ± SD (range)5 min after

Mean ± SD (range)30 min after

Mean ± SD (range)1 day after

Mean ± SD (range)

IOP (mmHg) 15.9 ± 2.8 (11–17) 16.1 ± 3.2 (12–19) 16.3 ± 2.9 (12–18) 16.0 ± 2.7 (9–19)AL (mm) 22.86 ± 0.92 (21.61–24.58) 22.88 ± 0.87 (21.60–24.59) 22.87 ± 0.91 (21.60–24.60) 22.86 ± 0.89 (21.61–24.59)ACD (mm) 3.24 ± 0.63 (2.64–4.98) 3.23 ± 0.51 (2.63–4.97) 3.24 ± 0.53 (2.63–4.99) 3.25 ± 0.47 (2.63–4.99)ACD, Anterior chamber depth; IOP, Intraocular pressure.

Table 2. Mean IOP values with respect to different axial length measurements before and 5 min after injection.

AL (mm)

n (eyes) IOP (mmHg) Mean ± SD (range)

Before5 min after Before

5 min after

21–22 6 7 14.0 ± 2.6 (11–18) 22.1 ± 4.8 (15–28)22–23 9 8 15.8 ± 1.9 (13–18) 22.3 ± 3.8 (19–26)23–24 11 12 13.6 ± 2.6 (10–18) 29.5 ± 12.9 (13–46)24–25 5 4 15.0 ± 1.4 (14–16) 21.2 ± 2.8 (16–24)AL, Axial length; IOP, Intraocular pressure.

Table 3. Mean IOP values with respect to different anterior chamber measurements before and 5 min after injection.

ACD (mm)

N (eyes) IOP (mmHg) Mean ± SD (range)

Before5 min after Before

5 min after

2.5–3 11 12 15.8 ± 21.9 (13–18) 25.2 ± 9.4 (16–42)

3.0–3.5 13 14 14.3 ± 2.1 (12–18) 27.7 ± 10.3 (18–46)3.5–5.0 7 5 12.5 ± 2.4 (10–15) 17.8 ± 4.6 (13–23)ACD, Anterior chamber depth; IOP, Intraocular pressure.

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the IOP was 43.4 ± 8.3 mmHg 3 min after the injection and the mean increase from the baseline was 34.8 ± 7.3. The higher IOP levels in that study may be explained by the measurement technique. Because, IOP measurements in the supine position with Schiötz tonometry revealed higher IOP values than those in the upright position with pneumatic tonometer (5,12).

The increase in IOP after intravitreal injection is gen-erally attributed to the injected volume (13). Moreover, Leydolt (7) et al. showed biometric changes of the human eye in vivo as a response to IOP changes of short duration. They found a significant increase of AL with short-term elevation of IOP. The IOP reduction resulted in a signifi-cant decrease in AL and a deepening of ACD compared to baseline values. These biometric changes correlated well with the IOP reductions. Even, a brief period of ele-vated IOP was found to be associated with a statistically significant axial elongation of the eye (8). On the basis of these findings, we speculate that intravitreal injection of 0.05 mL ranibizumab may expand ocular structure that results in change in axial ocular dimension. To investi-gate this, axial length and anterior chamber depth were measured across the different time points after the injec-tion. Contrary to our hypothesis, we did not observe any significant change in these parameters throughout the measurements. In other words, ocular dimensions seem to be stationary after the injection. This result could be related to three factors. Firstly, IOP elevation was medi-ated by mechanical pressure in previous studies (7,8) but by intravitreal injection in our study. Secondly, the injected volume (0.05 mL) may not be enough to make such changes in axial measurements and thirdly, the study population (mean age 72 ± 7.8 years) was older compared to those in previous studies (mean age 21.8 and 25 years, respectively). As is well known, scleral elas-ticity decreases as age increases. We need further studies to understand the relation between intravitreal injection and ocular dimensions. Finally, our study showed that, at least, this amount of intravitreal injections did not seem to change the axial ocular dimensions.

Theoretically, eyes with shorter AL would be expected to have higher IOP immediately postinjection. Gismondi et al. (6) and Leydolt et al. (7) showed that eyes with shorter AL had higher IOP immediately postinjection. On the contrary, such inverse correlation between axial length and IOP after the injection was not found in our study. The reason may be the differences in range of AL measurements. Mean AL was 22.81 ± 0.92 (range, 21.23–24.42) mm in our study. It was 23.3 ± 1.3 (22.0–25.6) and 23.0 ± 1.0 (20.5–24.5) in studies by Gismondi et al. (6) and Leydolt et al. (7) respectively. A limited number of sub-jects in our study may be another reason for this statis-tical insignificance. Moreover, we observed that the eye with AL of 24.48 mm (largest AL in the study) developed 6 mmHg increase in IOP but it was 7 mmHg in the eye with AL of 21.23 mm. So, data from our study suggests that IOP appears to be irrelevant to AL within this range of AL measurements.

To test the repeatability of the measurements taken with devices, IOP and axial biometry were taken from randomly selected eye of healthy volunteers across the same time points likewise the study group. We did not observe any statistically significant change in these parameters. Thus, the devices that were used in our study were considered to take repeatable measurements.

In conclusion, the current study shows that IOP increases transiently after the intravitreal injection of 0.05 mL ranibizumab, confirming the previous studies. However, axial length and anterior chamber depth are not affected by this amount of injection, and the increase in IOP after the injection seems to be irrelevant to AL and anterior chamber depth. Therefore, it is postulated that ranibizumab can be used safely in patients with age-related macular degeneration who have shallow anterior chamber and/or short axial length simultaneously.

Declaration of interest

The authors declare no conflicts of interest.

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