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ORIGINAL ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 4  |  Page : 1436-1440

Intraocular pressure changes after repeated ranibizumab injection


1 Department of Ophthalmology, Faculty of Medicine, Menoufia University, Menoufia, Shebin El-Kom, Egypt
2 Department of Ophthalmology, Kalawon Hospital, Nasr City, Cairo, Egypt

Date of Submission28-Aug-2018
Date of Decision31-Oct-2018
Date of Acceptance02-Nov-2018
Date of Web Publication31-Dec-2019

Correspondence Address:
Ahmed S Elesawy
Nasr City, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_270_18

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  Abstract 


Objective
The aim was to evaluate early changes of intraocular pressure (IOP) after repeated ranibizumab (Lucentis) injection.
Background
Ranibizumab is widely used in the treatment of macular edema and choroidal neovascularization. Screening should be frequently done to avoid its adverse effect.
Materials and methods
A prospective noncomparative case series study was conducted at Menoufia and Kalawoon hospitals, where patients were subjected to intravitreal injection of ranibizumab (Lucentis) for early IOP changes. IOP was measured with a Goldman tonometer before injection, after 30 min, after 1 day, and after 1 week of injection.
Results
At every time of injection, there was a highly significant difference in IOP measured at 30 min after injection (P < 0.001). However, there was no significant difference measured after 1 day (P = 0.91) and after 1 week of injection (P = 0.56). In repeated intravitreal ranibizumab injection comparison of preoperative, 30 min, 1 day, and 1 week after injection correspondingly, we found no significant difference in IOP measured between first and second injection in preoperative, 30 min, 1 day, and 1 week after injection (P = 0.11, 0.36, 0.17, and 0.26, respectively). However, there was a significant difference in IOP measured between first and third injections regarding preoperative, 30 min, 1 day, and 1 week after injection (P = 0.3, 0.2, 0.1, and 0.3, respectively).
Conclusion
Ranibizumab injected intravitreally causes a significant transient rise of IOP. The rise is transient for 24 h and normalizes after that.

Keywords: choroidal neovascularization, intraocular pressure, intravitreal injections, ranibizumab, vascular endothelial growth factor


How to cite this article:
El-Mazar HM, Al Hagaa AA, Elesawy AS. Intraocular pressure changes after repeated ranibizumab injection. Menoufia Med J 2019;32:1436-40

How to cite this URL:
El-Mazar HM, Al Hagaa AA, Elesawy AS. Intraocular pressure changes after repeated ranibizumab injection. Menoufia Med J [serial online] 2019 [cited 2020 Feb 16];32:1436-40. Available from: http://www.mmj.eg.net/text.asp?2019/32/4/1436/274251




  Introduction Top


The vascular endothelial growth factor (VEGF) has been involved in the pathogenesis of various diseases in the posterior segment of the eye. The said factor is an important regulator of vascular genesis and angiogenesis and a powerful inducer of vascular permeability [1]. Intravitreal bevacizumab for the treatment of age-related macular degeneration (ARMD) was first reported in 2005, and since then, its use has grown exponentially [2]. The intravitreal injection of any substance involves the risk of an increased intraocular pressure (IOP) that could be potentially damaging for the eye. Various clinical trials have made in-depth studies of sodium pegaptanib sodico as well as ranibizumab. Both products do not exhibit long-term effects on IOP. However, transient IOP peaks are frequent after an injection, probably secondary to volume expansion [3],[4],[5].

In a variety of pathological conditions, such as hypoxia, ischemia, inflammation, infection, and trauma, the balance between angiogenic stimulators and angiogenic inhibitors is disturbed, leading to the formation of new vessels [6]. According to the Center of Medicare and Medicaid Services, intravitreal injections were the fastest growing ophthalmic procedure in 2006. Therefore, it is important to investigate ways to ensure patient safety while improving overall patient experience. One of the ways to determine the necessity of postinjection IOP is monitoring and then to identify patients at risk for delayed normalization of IOP after injection. Recent guidelines for intravitreal injections recommend 'monitoring of IOP after injection and providing therapy when elevated IOP warrants intervention' [7].

Previous reports reached the conclusion that one intravitreal injection of 1.25 mg (0.05 ml) of bevacizumab was safe regarding the IOP [8].

The purpose of this study is to describe the early effects on the IOP after repeated intravitreal injection of 2.5 mg (0.1 ml) of ranibizumab.


  Materials and Methods Top


A prospective noncomparative case series study was conduct at Menoufia and Kalawoon hospitals, where 50 patients were subjected to intravitreal injection of ranibizumab (Lucentis) for early IOP changes. It was done between May 2017 and May 2018. The study was conducted on 50 patients. All patients knew that their participation was voluntary, and they could leave at any time, without giving any reason. If any patient left the study, he/she was told that it would not affect our relationship or receiving medical treatment. General patient sheet recording and detailed systemic examination were done while also asking about history of ocular disorders. Evaluation of the case was carried out in all patients immediately or 1 day before injection.

IOP was measured with a Goldman tonometer before the injection, immediately, after 30 min, after 1 day, and after 1 week.

After preparing the eye following a standardized protocol with 5% povidone/iodine, a blepharostat was used for stabilization before injecting 2.5 mg (0.1 ml) of ranibizumab at a point located between 3.5 and 4 mm posteriorly to the limbus, through the inferotemporal pars plana with a 30-G needle under topical anaesthesia. Immediately after the injection, the profusion of the central retinal artery was checked. It was not necessary to perform paracentesis in any eye.

A total of 50 patients repeated injected with ranibizumab. Injection was administered for any patients with new vascular ARMD), clinically significant macular edema (CSMO), proliferative diabetic retinopathy, retinal vein occlusion, cystoid macular edema, and choroidal neovascularization. We exclude any pathient with history of intravitreal triamcinolone, glaucoma or ocular hypertension.


  Results Top


A total of 50 eyes were included in our study. They received 0.1 ml (2.5 mg) of intravitreal ranibizumab. There were 24 male and 26 female patients. The patients' age ranged from 24 to 86 years, with a mean age of 60.78 ± 13.2 years.

Of 50 patients, 21 patients had choroidal neovascularization, 10 patient had cystoid macular edema, nine patients had DME (diabetic macular edema), seven patients had CSMO, two patients had central retinal vein occlusion, and one patients had branch retinal vein occlusion [Figure 1].
Figure 1: Pie chart showing diagnosis distribution among studied cases.

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At the first time of injection, mean IOP before injection was 16.82 ± 2.97 mmHg, and after 30 min of injection, the mean IOP was 19.50 ± 2.98 mmHg. There was a highly significant difference in IOP measured at 30 min after injection (P < 0.001)., and after 1 day of injection, the mean IOP was 16.84 ± 2.89 mmHg. There was no significant difference in IOP measured 1 day after injection (P = 0.91, >0.05). We followed up the patients at 1 week after injection, and we checked the IOP. The mean IOP after 1 week was 16.80 ± 2.92 mmHg. There was no significant difference in IOP measured 1 week after injection in comparison with preoperative injection (P = 0.56) [Table 1] and [Figure 2].
Table 1: Comparison of intraocular pressure changes between preoperative and postoperative values during first injection of ranibizumab

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Figure 2: Bar chart showing mean intraocular pressure change at first injection.

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At the second time of injection, mean IOP before injection was 16.36 ± 3.2 mmHg, and after 30 min of injection, the mean IOP was 19.2 ± 3.4 mmHg. There was a highly significant difference in IOP measured at 30 min after injection (P < 0.001). After 1 day of injection, the mean IOP was 16.40 ± 3.2 mmHg. There was no significant difference in IOP measured 1 day after injection (P = 0.86, >0.05). We followed up the patients to 1 week after injection and we checked the IOP. The mean IOP after 1 week was 16.48 ± 3.2 mmHg. There was no significant difference in IOP measured 1 week after injection in comparison with preoperative injection (P = 0.52).

At the third time of injection, mean IOP before injection was 15.89 ± 2.62 mmHg, and after 30 min of injection, the mean IOP was 18.50 ± 2.87 mmHg. There was a highly significant difference in IOP measured at 30 min after injection (P < 0.001). After 1 day of injection, the mean IOP was 15.75 ± 2.89 mmHg. There was no significant difference in IOP measured 1 day after injection (P = 0.18). We followed up the patients to 1 week after injection and we checked the IOP. The mean IOP after 1 week was 15.91 ± 2.60 mmHg. There was no significant difference in IOP measured 1 week after injection in comparison with preoperative injection (P = 0.32).

In repeated intravitreal ranibizumab injection comparison in preoperative, 30 min after injection, 1 day after injection, and 1 week after injection correspondingly, we found that there was no significant difference in IOP measured between first and second injections in preoperative, 30 min after injection, 1 day after injection, and 1 week after injection in all. However, there was a significant difference in IOP measured between first and third injection in preoperative, 30 min after injection, 1 day after injection, and 1 week after injection in all [Table 2] and [Figure 3].
Table 2: Comparison of intraocular pressure changes after repeated ranibizumab (Lucentis) injection

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Figure 3: Intraocular pressure change between preoperative and postoperative injection periods.

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  Discussion Top


VEGF and its receptors play an important role in many pathologic ocular processes. VEGF binding initiates an intracellular cascade that leads to proliferation and migration of vascular endothelial and eventually to neovascular angiogenesis. In addition to its role in neovascularization, VEGF increases vascular permeability and contributes to local inflammation. Selective blockade of this pathway was first employed clinically for the treatment of systemic oncologic processes. Ranibizumab is a specifically designed recombinant humanized antibody that binds and inhibits all biologically active VEGF isoforms. It has a decreased systemic half-life and a higher binding affinity than bevacizumab [9].

As intravitreal injections become an increasingly common method of treatment, investigating the need for monitoring IOP after injection is important for patient safety, increased patient satisfaction despite need for repeated injections, and enhancement of office flow. In addition, this study aimed to determine factors that affect IOP immediately after injection. We found that elevations in IOP after intravitreal injections were common, can be quite high, and can occur with all currently used intravitreal injections. However, these IOP spikes were transient, and AC paracentesis was not required. This is in agreement with previous studies [10].

Consistent with our findings, Tseng et al. [11] reported that transient, short-term IOP elevation after intravitreal anti-VEGF therapy has been well described. The introduction of additional fluid into the vitreous cavity by intravitreal therapy would be expected to cause an immediate rise in the IOP. However, anti-VEGF therapy may also cause long term, sustained IOP elevation.

Our study was conducted on 50 eyes of 50 patients. The age of the patients ranged from 24 to 86 years, with a mean age of 60.78 ± 13.2 years.

The indication for injection in 21 patients was CVN, 10 patients was CMO, nine patients was DME, seven patients was CSMO, two patients was central retinal vein occlusion, and one patient was branch retinal vein occlusion.

Most of our results were comparable to the most recent studies. The first one was done to report course of IOP after intravitreal injection of 0.05-ml ranibizumab (Lucentis). A total of 45 eyes (45 patients, 16 male and 29 female, with mean age: 78 years) received intravitreal ranibizumab injections for treatment of wet AMD (0.05 ml = 0.5 mg). The IOP was measured by Schiotz tonometry immediately preoperatively and postoperatively, and also after 3 and 10 min in a supine position. No history of glaucoma was present. The mean preoperative IOP was 22.4 ± 5.5 mmHg in supine position. Immediately after the injection, IOP increased to 47.9 ± 15.1 (range: 23–82, P < 0.001), with 32 (71.1%) eyes greater than 40 and 19 (42.2%) eyes greater than 50 mmHg. The mean difference between preoperative IOP and immediately after the injection was +25.5 ± 13.6 mmHg. IOP decreased spontaneously by the first 3 min after operation by 12.6 ± 6.0 mmHg and after 10 min by 21 ± 9.4 mmHg. The mean difference between preoperative IOP and 10 min postoperatively was +4.6 ± 7.0 mmHg (range: –9.3 to +25.9 mmHg, P < 0.001). Eyes without a subconjunctival reflux had a higher increase in IOP than eyes with any reflux (P < 0.001) [12].

Another study was reported with Wu et al. [13], where the immediate changes of IOP after an intravitreal injection of 2.5 mg (0.1 ml) of bevacizumab were assessed. They recruited 45 patients who had a variety of retinal disorders. They measured the IOP with a Goldmann tonometer at baseline, immediately after, 30 min, and 1 day after injection. At baseline, the mean IOP was 16.6 ± 2.8 mmHg (range: 10–24 mmHg, median: 16 mmHg, 25th percentile: 14 mmHg and 75th percentile: 18 mmHg). IOP rose to 53.9 ± 18.2 mmHg (range: 16–78 mmHg, median: 54 mmHg, 25th percentile: 40 mmHg and 75th percentile: 70 mmHg, P < 0.001) immediately after the injection. After 30 min, the IOP normalized but was still higher than baseline with a mean of 19.8 ± 5.2 mmHg (range: 10–36 mmHg, median: 18 mmHg, 25th percentile: 16 mmHg and 75th percentile: 24 mmHg, P < 0.01). At 24 h, the IOP was 15.7 ± 3.1 mmHg (range: 10–24 mmHg, median: 16 mmHg, 25th percentile: 14 mmHg and 75th percentile: 18 mmHg, P > 0.05) (P = 0.66).

Another study was reported with Chan and Cheng [14]. Two hundred and nine eyes in 173 patients were included in this study. In total, 2132 injections of anti-VEGF were performed, including 2071 injections of bevacizumab and 61 injections of ranibizumab. Overall, 180 eyes received intravitreal injections of bevacizumab monotherapy, and 29 eyes received both intravitreal injections of bevacizumab and ranibizumab sequentially. The mean age of the patients was 65.3 years (range: 58–82 years), and 73 (34.9%) were men. Overall, 70.3% of eyes were in patients with hypertension and 26.8% were in patients with diabetes mellitus. The mean number of injections was 10.1 (range: 3–23). There was no significant change in IOP (P = 0.41, paired t-test), and none of the patients experienced delayed ocular hypertension during the treatment course. There was no correlation between the difference in IOP and the number of injections.

Our study was similar to those in the literature that showed normalization of IOP in the first 24 h after intravitreal injection. Only a study by Segal et al. in 2013 showed rise of IOP beyond 24 h in 3.6% of 528 eyes that was normalized without antiglaucoma medication for short term. The difference between our study and the previous studies is that they included patients with single injection, measuring IOP after 30 min and after 1 day, and they had a large number of patients. However, in our study, the number was relatively small, with only 50 eyes, and it was with repeated injections for the patients, and we measured IOP after 30 min, after 1 day, and after 1 week.


  Conclusion Top


Our study revealed that IOP tends to increase after intravitreal injection of ranibizumab. We studied the effect of repeated injection of ranibizumab, 0.1 ml (2.5 mg), and we concluded that they all cause a transient immediate increase in IOP which tends to normalize after 1 day. This acute elevation of IOP after intravitreal ranibizumab is related to acute increase in volume inside the eye, and it takes 24 h for this IOP to decrease to a normal level.

Our study has several limitations in terms of the small number of eyes studied and short period of follow-up (only 1 week). A prospective, controlled study with a large number of patients and a long-term period of follow up of the patients is needed to further evaluate the effect of repeated intravitreal ranibizumab on IOP.

So we conclude that ranibizumab injected intravitreally causes a significant transient rise of IOP especially with 0.1 ml (2.5 mg) dose. The rise is transient for 24 h and normalizes after that. Care should be taken for cases with multiple injections and predisposing risk factors like glaucomatous patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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2.
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Kim YJ, Sung KR, Lee KS. Long-term effects of multiple intravitreal antivascular endothelial growth factor injections on intraocular pressure. Am J Ophthalmol 2014; 157:1266–1271.  Back to cited text no. 8
    
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Sharei V, Hohn F, Kohler T, Hattenbach L, Mirshahi A. Course of intraocular pressure after intravitreal injection of 0.05 mL ranibizumab (Lucentis®). Eur J Ophthalmol 2010; 20:174–179.  Back to cited text no. 12
    
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Wu L, Martinez-Castellanos MA, Quiroz-Mercado H. Twelve-month) Avastin): results of the Panerican Collaborative Retina safety of intravitreal injections of bevacizumab Study Group (PACOS). Graees Arch Clin Exp Ophthalmol 2008; 246:8187.  Back to cited text no. 13
    
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Chan T-Y, Cheng C-K. Intraocular pressure changes after repeated intravitreal antivascular endothelial growth factor injections in patients with neovascular age-related macular degeneration with or without glaucoma. Taiwan J Ophthalmol 2014; 4:28–32.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

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