this prospective study followed the principles of the declaration of helsinki and was approved by the hospital ethical committee , and all participants signed a standard informed consent form reporting the potential risks and benefits of the procedure and subsequent management .
all patients were confirmed by the ophthalmology department of beijing hospital for a detailed examination including best - corrected visual acuity ( bcva ) and iop , slit - lamp biomicroscopy , auto refractometry , gonioscopy , and dilated fundoscopic examinations of both eyes .
the study included 352 eyes from 352 patients ( 1 eye per patient ) diagnosed exudative amd , diabetic macular edema ( dme ) , retinal vein occlusion ( rvo ) , pathologic myopia ( pm ) , idiopathic choroidal neovascularization ( icnv ) , or cystoid macular edema ( cme ) who were treated with ranibizumab ( 0.5 mg/0.05 ml ) ivi between april 2013 and june 2014 .
exclusion criteria included younger than 18 old years , ocular hypertension before injection , family history or a prior diagnosis of glaucoma , prior vitrectomy or phacoemulsification surgery , use of iop - lowering agents , allergy to sulfur / sulphonamide - containing drugs .
all the patients were divided randomly into two groups . in control group , 203 patients ( mean  standard deviation [ sd ] , 64.21  14.10 years ) only received the ranibizumab ivi while in case group , 149 patients ( mean  sd , 61.54  14.60 years ) received one drop of prophylactic intraocular brinzolamide before ranibizumab ivi .
the iop was measured by noncontact topcon tonometry ( japan ) during the study . for the operation procedure ,
injection of ranibizumab was performed at the upper pars plana with a sharp 30-gauge needle after complete sterile draping and rinsing with topical povidone - iodine under topical anesthesia with bupivacaine hydrochloride 0.75% eye drops .
the injection site was located 3.5 mm posterior to the limbus . both before and after ivi
no eye received iop - lowering medications or anterior chamber paracentesis before or after ivi .
the iop were measured before injection , at 10 , 30 , 120 min and 1 day after injection in a sitting position .
one drop of brinzolamide was used after the baseline iop measurement approximately 2 h ( mean  sd , 112.05  26.61 min ) before injection .
statistical analysis was performed using spss ( version 17.0 ) software ( spss inc . ,
smirnov test of nonparametric analysis and chi - square test were used to analyze the data of two groups .
we set p < 0.05 ( two - sided ) with statistical significance in this study .
this prospective study followed the principles of the declaration of helsinki and was approved by the hospital ethical committee , and all participants signed a standard informed consent form reporting the potential risks and benefits of the procedure and subsequent management .
all patients were confirmed by the ophthalmology department of beijing hospital for a detailed examination including best - corrected visual acuity ( bcva ) and iop , slit - lamp biomicroscopy , auto refractometry , gonioscopy , and dilated fundoscopic examinations of both eyes .
the study included 352 eyes from 352 patients ( 1 eye per patient ) diagnosed exudative amd , diabetic macular edema ( dme ) , retinal vein occlusion ( rvo ) , pathologic myopia ( pm ) , idiopathic choroidal neovascularization ( icnv ) , or cystoid macular edema ( cme ) who were treated with ranibizumab ( 0.5 mg/0.05 ml ) ivi between april 2013 and june 2014 .
exclusion criteria included younger than 18 old years , ocular hypertension before injection , family history or a prior diagnosis of glaucoma , prior vitrectomy or phacoemulsification surgery , use of iop - lowering agents , allergy to sulfur / sulphonamide - containing drugs .
all the patients were divided randomly into two groups . in control group , 203 patients ( mean  standard deviation [ sd ] , 64.21  14.10 years ) only received the ranibizumab ivi while in case group , 149 patients ( mean  sd , 61.54  14.60 years ) received one drop of prophylactic intraocular brinzolamide before ranibizumab ivi .
the iop was measured by noncontact topcon tonometry ( japan ) during the study . for the operation procedure ,
injection of ranibizumab was performed at the upper pars plana with a sharp 30-gauge needle after complete sterile draping and rinsing with topical povidone - iodine under topical anesthesia with bupivacaine hydrochloride 0.75% eye drops .
the injection site was located 3.5 mm posterior to the limbus . both before and after ivi
no eye received iop - lowering medications or anterior chamber paracentesis before or after ivi .
the iop were measured before injection , at 10 , 30 , 120 min and 1 day after injection in a sitting position .
one drop of brinzolamide was used after the baseline iop measurement approximately 2 h ( mean  sd , 112.05  26.61 min ) before injection .
statistical analysis was performed using spss ( version 17.0 ) software ( spss inc . ,
smirnov test of nonparametric analysis and chi - square test were used to analyze the data of two groups .
we set p < 0.05 ( two - sided ) with statistical significance in this study .
the diagnoses of patients were as follows : exudative amd , dme , rvo , pm , icnv , and cme .
none of the study patients has significant intraoperative or shorter - term postoperative complications of operation or drugs such as endophthalmitis , hypersensitive to brinzolamide , or ranibizumab except high iop .
the baseline characteristics presented in table 1 shows that the differences were not significant in gender , age , study eye , bcva , and number of ivis ( p > 0.05 ) between two groups .
baseline characteristics outcome data collected included iop measurements of baseline and immediately at 10 , 30 , 120 min and 1 day after ivis .
the mean iop measured before injection , at 10 , 30 , 120 min and 1 day after injection individually were 15.79  2.21 mmhg , 19.33  4.86 mmhg , 16.64  2.93 mmhg , 16.17  3.13 mmhg , and 15.07  2.55 mmhg in case group and were 15.82  2.57 mmhg , 21.34  5.88 mmhg , 18.17  4.06 mmhg , 17.59  4.42 mmhg , and 15.48  2.92 mmhg in control group .
the tendency in both curves is a sharp increase on iop a few minutes after injection , with a gradual decline over the next hours .
maximum iop elevation occurred at the time point of 10 min after injection in both groups . at time
points of 10 , 30 , and 120 min postinjection , mean iop was significantly higher in control group when compared with the case group ( p < 0.05 ) ; however , the differences were not significant at baseline and after 1 day ( p = 0.463 ) .
the mean postinjection iop for control group at the time points of 10 , 30 , and 120 min was statistically different when compared with baseline iop ( p < 0.05 ) . on the contrary , in case group , this difference was observed only for the time point of 10 min ( p < 0.05 ) . mean intraocular pressure ( mmhg ) at before intravitreal and after intravitreal injection comparing two groups by chi - square test , it indicated that the ratio of iop 21 mmhg and the elevation of iop 5 mmhg within 2 h after injection had significant difference as tables 3 and 4 showed ( p < 0.05 ) .
comparison of intraocular pressure 21 mmhg after injection comparison of elevation of intraocular pressure 5 mmhg after injection
the diagnoses of patients were as follows : exudative amd , dme , rvo , pm , icnv , and cme .
none of the study patients has significant intraoperative or shorter - term postoperative complications of operation or drugs such as endophthalmitis , hypersensitive to brinzolamide , or ranibizumab except high iop .
the baseline characteristics presented in table 1 shows that the differences were not significant in gender , age , study eye , bcva , and number of ivis ( p > 0.05 ) between two groups .
outcome data collected included iop measurements of baseline and immediately at 10 , 30 , 120 min and 1 day after ivis .
the mean iop measured before injection , at 10 , 30 , 120 min and 1 day after injection individually were 15.79  2.21 mmhg , 19.33  4.86 mmhg , 16.64  2.93 mmhg , 16.17  3.13 mmhg , and 15.07  2.55 mmhg in case group and were 15.82  2.57 mmhg , 21.34  5.88 mmhg , 18.17  4.06 mmhg , 17.59  4.42 mmhg , and 15.48  2.92 mmhg in control group .
the tendency in both curves is a sharp increase on iop a few minutes after injection , with a gradual decline over the next hours .
maximum iop elevation occurred at the time point of 10 min after injection in both groups . at time
points of 10 , 30 , and 120 min postinjection , mean iop was significantly higher in control group when compared with the case group ( p < 0.05 ) ; however , the differences were not significant at baseline and after 1 day ( p = 0.463 ) .
the mean postinjection iop for control group at the time points of 10 , 30 , and 120 min was statistically different when compared with baseline iop ( p < 0.05 ) . on the contrary , in case group , this difference was observed only for the time point of 10 min ( p < 0.05 ) .
mean intraocular pressure ( mmhg ) at before intravitreal and after intravitreal injection comparing two groups by chi - square test , it indicated that the ratio of iop 21 mmhg and the elevation of iop 5 mmhg within 2 h after injection had significant difference as tables 3 and 4 showed ( p < 0.05 ) .
comparison of intraocular pressure 21 mmhg after injection comparison of elevation of intraocular pressure 5 mmhg after injection
we found that the iop increase after ivi in the control group of our study persisted for short period . until 2 h after ivi ,
similarly , gismondi et al . reported that transient iop increases within 30 min after ivi , however , there were no significant differences after half an hour .
other published studies regarding ivi have reported transient iop increases after 3060 min , and stabilizing at baseline values after 1 day .
the little differences could be related to differences in the population race studied and/or iop measurement techniques . about the reasons of acute elevation of iop after ivis
, the volume change of the vitreous cavity may be the main reason of immediate iop increasing after ranibizumab ivis .
the volume of the vitreous cavity in human eye is 4 ml approximately , and the volume of ranibizumab injected into the vitreous is 0.05 ml .
therefore , the increase in fluid volume of the vitreous cavity is 1.25% approximately , which may cause immediate iop elevation .
the block hypothesis for the potential mechanisms inducing an iop elevation after ivi is that medications may block the immediate aqueous humor cycle channels , including the trabecular meshwork or schlemm 's canal outflow pathways by an unclear mechanism for several weeks or months .
although these hypotheses are related to the sustained increased iop , they may indicated that the ocular structure of patients with ivi have changed and are sensitive to the changes of the volume of the vitreous cavity .
in addition , the daily fluctuation of the iop may also play a role in the elevation of the iop .
we also found that in case group of our study , patients use prophylactic iop - lowering medication ( brinzolamide ) before injection have statistically significance only at 10 min after ivi .
when comparing with the control group , the significant difference was observed up to 2 h. no matter the ratio of iop 21 mmhg or elevation of iop 5 mmhg , the results are similar within 2 h. frenkel et al . reported that the iop reduced to < 30 mmhg in all patients within 20 min . by contrast , hariprasad et al . suggested that 13% of eyes with 30 mmhg or greater 30 min after injection .
however , they all indicated that prophylactic medication may not be necessary to prevent postinjection iop spikes . however , theoulakis et al . reported that brimonidine / timolol - fixed combination may be effective to prevent the short - term iop increase after ivi .
kim et al . also indicated that the prophylactic administration of antiglaucomatic drugs before intravitreal anti - vegf injection effectively reduced the early iop elevation .
similarly , in our study , under prophylactically using brinzolamide , the significant difference of iop after injection between two groups is obvious within 2 h which may indicate that brinzolamide can successfully suspend the iop rise . considering the contrast to the previous studies , the time interval of using the prophylactic iop - lowering medication before injection may an explanation . in this study ,
the time is approximately 2 h which is also the peak of iop - lowering medication ( brinzolamide ) effectiveness ; however , in frenkel 's study , the time interval was 5 min before injection which may be ineffective to decrease immediate iop postoperation .
furthermore , another explanation as kim et al . demonstrated that a lower iop elevation with 27-gauge needles than with 30- or 32-gauge needles which may suggested that iop rise may was more related to the needle diameter than to the volume injected .
supposed that a vitreous reflux occurs higher with a larger needle bore size which led to underestimate the probability of iop rise .
giving topical pressure - lowering medications can reduce iop , brinzolamide was used in this study to suppress the produce of aqueous humor mildly because of little side effects clinically comparing to other pressure - lowering medications .
as is known that prostaglandin analogs are major pressure - lowering medications with great effect , but it is not suitable for patients after ivis .
in addition ,  blocker drugs have side effect for patients with some heart diseases .
because the explanation of how high of ocular hypertension and how long high iop lasting will damage the vision is unclear , we also can not conclude that whether prophylactic iop - lowering medication on iop after ranibizumab ivis is necessary . while as is known that patients should receive more injections to delay the loss of vision , every iop rises even short
iop fluctuations in glaucoma or high - iop patients , even at lower amplitudes , are a recognized risk factor for injury of optic nerve .
asrani et al . indicated that a diurnal variation of 5.4 mmhg in iop was associated with a 5.7-fold increase in the progression of visual field loss .
addition , murray et al . suggested that prophylactic treatment may be considered as an option to minimize neuroretinal rim damage in high - risk glaucoma patients who are most vulnerable to iop spikes and undergoing repeated ivis of ranibizumab .
therefore , this iop elevation may be harmless in normal patients but should be taken into account on patients with ocular hypertension or glaucoma .
first , the most important limitation is that the noncontact tonometer is not golden standard tool like goldmann tonometer though we had rectified it before measurement every time . because we thought goldmann tonometer may increase the risk of inflammation for the contact measure method and we focused on the changes of iop and it may affect little relatively .
second , iop elevation is much important to ocular hypertension or glaucoma patients ; we did not investigate these patients which are another limitation of our study and we will make found research about this in further study .
third , the central corneal thickness and axial length as important factors for volume changes of ocular were not measured in this study , and the effect would be investigated in advanced study .
in addition , this study just focused on short - term effect , but the long - term effect may affect optic nerve seriously which would be investigated in the further study . although these limitations including population race , small sample size , ocular disease distribution , iop measurement tool , unmeasured axial lengths , and operation procedure in this study may impact the result , we still insist that this study may help to illustrate the effect of prophylactic iop - lowering medication on iop after ranibizumab ivis and whether the iop - lowering therapy is necessary after ivis .
ivi of ranibizumab causes a considerable short - term transient rise on iop in most patients .
the effect of prophylactic iop - lowering medication ( brinzolamide ) on iop after ivis can be statistically significant from 10 min to 2 h after ivis .
this work was supported by beijing natural science foundation , bnsf grant 7152123 and beijing municipal science and technology commission , the capital characteristic clinic project z151100004015147 .
this work was supported by beijing natural science foundation , bnsf grant 7152123 and beijing municipal science and technology commission , the capital characteristic clinic project z151100004015147 .
 purpose : to observe the effect of prophylactic intraocular pressure ( iop)-lowering medication ( brinzolamide ) on iop after ranibizumab intravitreal injections ( ivis).materials and methods : this prospective case  
 control study included 352 eyes from 352 patients ( 1 eye per patient ) who were treated with ranibizumab intravitreal injection and divided randomly into two groups . 
 two hundred and three patients in control group only received the ranibizumab ivi , but 149 patients in case group received one drop of prophylactic intraocular brinzolamide preinjection . 
 the iop was measured by noncontact tonometer before injection , at 10 , 30 , 120 min and 1 day after injection in a sitting position.results:the mean iop measured before injection , at 10 , 30 , 120 min and 1 day after injection individually were 15.79  2.21 mmhg , 19.33  4.86 mmhg , 16.64  2.93 mmhg , 16.17  3.13 mmhg , and 15.07  2.55 mmhg in case group and were 15.82  2.57 mmhg , 21.34  5.88 mmhg , 18.17  4.06 mmhg , 17.59  4.42 mmhg , and15.48  2.92 mmhg in control group . comparing two groups , the mean increase on iop was statistically significant at 10 , 30 , 120 min postinjection ( p < 0.05).conclusions : ivi of ranibizumab causes a considerable short - term transient rise on iop in most patients . 
 the effect of prophylactic iop - lowering medication on iop after ivis can be statistically significant from 10 min to 2 h after ivis . 
Materials and Methods
Subjects
Statistical analysis
Results
Baseline characteristics
The changes of intraocular pressure after intravitreal injections
Discussion
Conclusions
Financial support and sponsorship
Conflicts of interest