Critical analysis of techniques and materials used in devices,syringes, and needles used for intravitreal injections

Intravitreal injections have become the most commonly performed intraocular treatments worldwide. Because intravitreal injections may induce severe adverse events, such as infectious and noninfectious endophthalmitis, cataract, ocular hypertension, vitreous hemorrhage, or retinal detachment, appropriate awareness of the materials and techniques used are essential to reduce these sight-threatening complications. This review provides insights into the needles, syringes, silicone oil coating, sterilization methods, devices to assist intravitreal injections, scleral piercing techniques using needles, syringe handling, anesthesia, and safety issues related to materials and techniques. It is paramount that physicians be aware of every step involved in intravitreal injections and consider the roles and implications of all materials and techniques used. The ability to understand the theoretical and practical circumstances may definitely lead to state-of-the-art treatments delivered to patients. The most important practical recommendations are: choosing syringes with as little silicone oil as possible, or, preferably, none; avoiding agitation of syringes; awareness that most biologics (e.g., antiangiogenic proteins) are susceptible to changes in molecular properties under some conditions, such as agitation and temperature variation; understanding that improper materials and techniques may lead to complications after intravitreal injections, e.g., inflammation; and recognizing that some devices may contribute to an enhanced, safer, and faster intravitreal injection technique.     

Incidence of rhegmatogenous retinal detachments after intravitreal antivascular endothelial factor injections

Acta Ophthalmol. 2011: 89: 70–75

Abstract.

Purpose: To determine the incidence of rhegmatogenous retinal detachments (RD) after intravitreal injection in six high‐volume centres. Methods: A consecutive, interventional, multicenter case series measured the incidence of RD in patients receiving intravitreal anti‐VEGF. A total of 35 942 intravitreal anti‐VEGF injections (the number of the injections determined by review of injection log books over a 3 year period) were performed under sterile conditions with the patient in a supine position. Injections were given 3.5–4.0 mm behind the limbus in a tunnelled fashion. Results: During 36 consecutive months, five RD were reported, between 2 and 6 days after the injection. Of the affected eyes, four were myopic ?1.75 to ?5.5 dpt. The incidence rate of rhegmatogenous RD was 0.013% (5/35 942) per injection. Conclusions: The incidence of RD in our community setting was very low (1 per 7188 injections). All RD occurred during the early postoperative period. The risks of RD can be minimized by a careful injection technique.     

玻璃体切割联合玻璃体注药治疗眼内炎

对２８例２８眼化脓性眼内炎经平坦部行玻璃体切割联合玻璃体注药、眼内异物摘出,配合全身及局部应用抗生素、皮质类固醇药物或抗真菌药物治疗患者,回顾性分析了玻璃体切割联合玻璃体注药治疗化脓性眼内炎的临床应用价值。结果：随访６～１２月２８例２８眼眼内感染全部控制,２６眼视力有不同程度的提高,２眼眼球萎缩,无１眼眼球摘除。结论：玻璃体切割联合玻璃体注药是治疗化脓性眼内炎最有效方法。     

玻璃体切割联合玻璃体注药治疗眼内炎

目的 回顾性分析玻璃体切割联合玻璃体注药治疗化脓性眼内炎的临床应用价值。方法 对２８例２８眼化脓性眼内炎经平坦部行玻璃体切割联合玻璃体注药、眼内异物摘出,配合全身及局部应用抗生素、玻质类固醇药物或抗真菌药物治疗。结果 随访６～１２ｍｏ,２８例２８眼内感染全部控制,２６眼视力有没程度的提高,２眼眼球萎缩,无１眼眼球摘出。结论 玻璃体切割联合玻璃体注药是治疗化脓性眼内炎最有效方法。     

Prospective comparisons of intravitreal injections of triamcinolone acetonide and bevacizumab for macular oedema due to branch retinal vein occlusion

Purpose: To compare the efficacy of intravitreal injections of triamcinolone acetonide (TA) and that of bevacizumab for macular oedema because of branch retinal vein occlusion (BRVO). Design: Prospective, comparative, randomized, interventional clinical trial. Methods: Forty‐three eyes of 43 patients with macular oedema because of BRVO were randomly assigned to 4‐mg intravitreal injections of TA (IVTA)(21 patients, IVTA group) or 1.25‐mg intravitreal injections of bevacizumab (IVB) (22 patients, IVB group) and followed for 12 months. No additional treatments were administered for 3 months after the initial injection; additional injections were administered when macular oedema recurred between 3 and 12 months after the initial injection. The best‐corrected visual acuity (BCVA) and the central retinal thickness (CRT) were measured at baseline and monthly. The main outcome measures were changes in the logarithm of the minimal angle of resolution BCVA and CRT from baseline to 12 months. Results: Eighteen eyes of 18 patients in the IVTA group and 18 eyes of 18 patients in the IVB group completed follow‐up at 12 months. The mean improvements in BCVA from baseline to 12 months were 0.12 in the IVTA group and 0.33 in the IVB group, which was significantly (p = 0.032) higher than in the IVTA group. There was no significant difference between the two groups in the mean reduction in CRT from baseline to 12 months after the initial injection. Two eyes in the IVTA group required intraocular pressure–lowering medications. Conclusion: Intravitreal injection of bevacizumab may be of greater benefit than that of TA for macular oedema because of BRVO.     

Posterior vitreous detachment rate following intravitreal dexamethasone injection

AIM: To determine whether intravitreal dexamethasone (DEX) implant induces posterior vitreous detachment or not. METHODS: We retrospectively reviewed 810 eyes of 405 patients who underwent intravitreal DEX implantation due to macular edema caused by diabetic and retinal venous occlusion in our clinic. The eyes having no injection were determined as the control group. The examination findings of the patients before the injection and 3mo after the injection and optical coherence tomography (OCT) images were scanned. The pre-injection OCT findings and OCT findings of the patients having no posterior vitreous detachment (PVD) and determined to have partial PVD were compared. RESULTS: The separation in vitreoretinal adhesion and total PVD development of DEX-injected 56/208 (26.9%) eyes were statistically greater in comparison with the 12/129 (9.3%) eyes that had not been injected (P=0.001). PVD development was observed more in the patients that were younger, had larger macula thickness and lower visual acuity. CONCLUSION: It can be stated that intravitreal DEX implant induces PVD development. Prospective, controlled studies are required in order to determine prognosis of vitreoretinal disease in PVD-developed patients and in non-PVD-developed patients.     

雷珠单抗联合视网膜光凝治疗新生血管性青光眼的临床研究

目的：探讨雷珠单抗联合视网膜光凝治疗有视功能的新生血管性青光眼的临床疗效。
　　方法：回顾性分析2012-10/2013-09就诊于我院30例36眼有视功能的新生血管性青光眼采用雷珠单抗联合视网膜光凝治疗前及治疗后1 wk;1,3 mo的视力、眼压、虹膜表面新生血管消退情况及术中、术后并发症。
　　结果：采用雷珠单抗玻璃体腔注射后5d,36眼的虹膜表面新生血管全部消退,平均消退时间3.7±1.4d;治疗前平均眼压30.5±3.6mmHg,治疗后1wk;1,3mo的平均眼压分别是18.2±2.1,16.8±3.1,17.2±2.4mmHg,差异具有统计学意义;视力较治疗前无下降或有不同程度提高。术中均无眼内出血,术后无眼内炎等并发症发生。
　　结论：雷珠单抗联合视网膜光凝是治疗有视功能的新生血管性青光眼的一种安全、有效的方法。     

Effects of moxifloxacin exposure on the conjunctival flora and antibiotic resistance profile following repeated intravitreal injections

AIM:To evaluate the effects of moxifloxacin exposure on the conjunctival flora and antibiotic resistance profile following repeated intravitreal injections.METHODS:Seventy-two eyes of 36 patients [36 eyes in control group, 36 eyes in intravitreal injection (IVI) group] were enrolled in the study. All the eyes had at least one IVI and had diabetic macular edema (DME) or age-related macular degeneration (ARMD). Moxifloxacin was prescribed to all the patients four times a day for five days following injection. Conjunctival cultures were obtained from the lower fornix via standardized technique with every possible effort made to minimize contamination from the lids, lashes, or skin. Before the application of any ophthalmic medication, conjunctival cultures were obtained from both eyes using sterile cotton culture. An automated microbiology system was used to identify the growing bacteria and determine antibiotic sensitivity. RESULTS:The bacterial cultures were isolated from 72 eyes of 36 patients, sixteen of whom patients (44.4%) were male and twenty (55.6%) were female. Average age was 68.4±9.0 (range 50-86). The average number of injections before taking cultures was 3.1+1.0. Forty-eight (66.7%) of 72 eyes had at least one significant organism. There was no bacterial growth in 8 (20.5%) of IVI eyes and in 16 (44.4%) of control eyes (P=0.03). Of the bacteria isolated from culture, 53.8% of coagulase negative staphylococci (CoNS) in IVI eyes and 47.2% CoNS in control eyes. This difference between IVI eyes and control eyes about bacteria isolated from culture was not statistically significant (P=0.2). Eleven of 25 bacteria (44.0%) isolated from IVI eyes and 11 (57.9%) of 19 bacteria isolated from control eyes were resistant to oxacillin. The difference in frequency of moxifloxacine resistance between two groups was not statistically significant (12.0% in IVI eyes and 21.1% in control eyes) (P=0.44). There were no cases of resistance to vancomycin, teicoplanin and linezolid.CONCLUSION:There was no difference in species of bacteria isolated from cultures, or in the frequency of resistance to antibiotics between eyes that had recurrent IVI followed by moxifloxacin exposure compared with control eyes. However, the number of eyes that had bacterial growth was higher in IVI group than in the control group.     

Pharmacokinetics of intravitreal glial cell line-derived neurotrophic factor: experimental studies in pigs

The purpose of this study was to establish the intravitreal (ITV) pharmacokinetics of glial cell line-derived neurotrophic factor (GDNF) and observe possible complications after ITV injection. Twenty Danish landrace pigs and 34 eyes were included in the study; 30 were injected with 100 ng of GDNF, two controls were injected without GDNF, and two received no injection. At post-injection time points of 1, 2, 3, 6 hours (h), 1, 2, 4 or 7 days (d) eyes were enucleated and the ITV concentration of GDNF (cGDNF) was determined by enzyme-linked immunosorbent assay, and activity was tested using a retinal ganglion cell line (RGC5) bioassay. Indirect ophthalmoscopy, intraocular pressure assessment, and fundus photography were performed before enucleation. There was initial variability in the cGDNF, but after 24 h GDNF was cleared in a monoexponential fashion with a half-life of 37 h (CL 33–43 h). Therapeutic concentrations were present for 15 d (CL 13–18 d) when an extrapolation was done. GDNF-injected vitreous samples stimulated increased survival of RGC5s at 24 h post-delivery (p = 0.002) compared with no-GDNF vitreous controls. This effect was independent of intraocular incubation time when cGDNF was normalized to 5 ng/ml. A semi-logarithmic dose–response curve showed linearity between 0.1 and 10 ng/ml. None of the eyes showed any signs of inflammation or other complications. A single ITV GDNF injection of 100 ng leads to therapeutic levels for 15 days in the porcine eye. The GDNF was stable in the intraocular environment and no adverse events were observed. GDNF might therefore play a role in the future treatment of acute retinal damage.     

头孢哌酮/舒巴坦兔玻璃体腔注射视网膜毒性的研究

目的 确定头孢哌酮／舒巴坦在兔玻璃体腔注射的安全有效剂量，以指导人玻璃体腔用药。方法 成年健康青紫兰兔15只，随机分为5组，每组3只(6眼)。每组注射头孢哌酮／舒巴坦质量浓度分别为：0、5、10、20、40mg／0．1mL。注药后1、2、4、8、12、24h各观察1次，以后每天观察1次。比较注药前及注药后第1、3、7、14d ERG检查结果。2周后行大体标本观察及光镜和透射电镜观察。对ERG的a、b波振幅变化用方差分析进行检验。结果 5和10mg药物注射组FERG各波振幅和视网膜组织学检查均无明显改变，但在20、40mg剂量组，头孢哌酮／舒巴坦在兔玻璃体腔注射后可见FERG各波的明显下降和电镜下视网膜各层细胞的水肿和空泡样变。结论 10mg／0．1mL的头孢哌酮／舒巴坦玻璃体腔注射是一个安全剂量。     

Efficacy of intravitreal captopril on oxygen-induced retinopathy in mice

AIM: To study the inhibitory effect of intravitreal captopril on oxygen-induced retinopathy (OIR) in mice. METHODS: Eighty postnatal day (P)7 C57BL/6J mice were randomly divided into treated group and control group with forty mice in each group. The mice were exposed to 75% ± 2% oxygen for 5 days (P7-P11) and then returned to room air for 5 days (P12-P17) to induce retinal neovascularization (RNV). Beginning on P12, the mice in treated group received daily intravitreal injections of captopril (3.0mL/kg), while those in control group received daily intravitreal injections of phosphate-buffered saline (PBS) (3.0mL/kg) through P17. After anesthetized at P17, one eye was chosen randomly as experimental eye and were enucleated. RNV was examined by Adenosine diphosphate-ase (ADPase) stained retina flat-mounts and was quantitated histologically by counting the neovascular endothelial cell nuclei anterior to inner limiting membrane (ILM). The expressions of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) were measured by immunohistochemical method. RESULTS: Comparing with control group, more regular distributions, better branch and reduced density of RNV were observed in eyes of treated group. The number of neovascular cell nuclei was less in treated group than that in control group (t=6.135, P<0.01). Stain of MMP-2 and VEGF was weaker in treated group than that in control group. CONCLUSION: The results indicate that captopril can significantly inhibit RNV in OIR mice.     

Testing toxicity of multiple intravitreal injections of bevacizumab in rabbit eyes

Objective: To evaluate the potential toxicity of repeated intravitreal injections of bevacizumab in rabbit eyes.Design: Randomized, placebo-controlled experimental animal study.Participants: Fourteen chinchilla rabbits; 12 assigned to the experimental group and 2 assigned to the normal control group.Methods: Three sequential, biweekly, intravitreal injections of bevacizumab in doses of 2.5 mg/0.1 mL or 5.0 mg/0.2 mL were performed on each rabbit. Evaluations included intraocular pressure (IOP), aqueous flare, B-scan ultrasound, fundus photography, ultrasound biomicroscopy, electroretinography (ERG), and visually evoked potentials (VEPs) performed at baseline and during the follow-up period. The eyes were enucleated at 1 week and 4 weeks after the last intravitreal injection, and underwent light and electron microscopic evaluations, as well as testing for apoptotic activity.Results: After intravitreal injections, no changes were found by regular clinical observation and IOP tests. There was no significant difference in the anterior chamber inflammatory activity evaluated by the laserflare meter. No evidence of retinal toxicity was seen after intravitreal bevacizumab at doses of 2.5 and 5.0 mg by either ERG or flash VEPs. Electron microscopy did show the presence of inflammatory cells and some ultrastructural changes in the photo-receptor cells in the 5.0 mg experimental group 1 week after the third injection. Mild to moderate apoptosis of photoreceptors was detected in the 5.0 mg group at the same time.Conclusions: The biweekly, multiple intravitreal injections of bevacizumab did not result in evidence of toxicity in regular clinical and functional observations at both 2.5 mg and 5.0 mg doses. The 5.0 mg dose may induce transient inflammation, ultrastructural abnormalities, and apoptosis.     

雷珠单抗治疗视网膜中央静脉阻塞并发黄斑水肿的报告

目的：：探讨玻璃体腔内注射雷珠单抗治疗视网膜中央静脉阻塞并发黄斑水肿的临床疗效。方法：选取2015-03/09我院收治的视网膜中央静脉阻塞并发黄斑水肿患者30例30眼行雷珠单抗玻璃体腔内注射,1次/mo,治疗1~3mo,治疗结束后随诊3mo,比较患者注射后最佳矫正视力、眼压、黄斑中心凹视网膜厚度、黄斑水肿消退率及眼底荧光血管造影检查结果。结果：随着雷珠单抗注射次数的增加,患者的最佳矫正视力逐渐提高(P<0.05),黄斑中心凹视网膜厚度明显下降(P<0.05),眼压与治疗前比较并无明显变化(P>0.05)。第1、2、3次注射后患者黄斑水肿消退率分别为47%、68%、94%。结论：玻璃体腔内注射雷珠单抗能够有效缓解视网膜中央静脉阻塞继发的黄斑水肿,明显改善患者的视力。     

单纯玻璃体腔注气治疗高度近视黄斑裂孔视网膜脱离的临床疗效:北京同仁眼科中心的结果

目的探讨单纯玻璃体腔注气治疗高度近视合并黄斑裂孔视网膜脱离的疗效。设计前瞻性随机对照研究。研究对象北京同仁医院24例(24眼)屈光度超过–6.0D黄斑裂孔视网膜脱离患者。方法随机分为单纯C3F8注气组(A组)14例、玻璃体切割联合C3F8注气组(B组)10例。手术前后检查矫正视力、眼压、裂隙灯显微镜、眼底、眼部超声波和相干光断层扫描(OCT)。术后平均随诊(27.3±12.8)个月。主要指标视网膜复位例数,术后视力,手术费用。结果术后最后随诊时,单纯C3F8注气组、玻璃体切割联合C3F8注气组间手术复位率分别为28.6%(4/14例)和20%(2/10例),视力改善≥2行例数亦分别为4例和2例(P均=1.00)。两组间手术费用比较有显著性差异(P=0.000)。结论单纯玻璃体腔C3F8注气治疗高度近视合并黄斑裂孔视网膜脱离是一种可供选择的经济、有效的手术方式。     

Effect of individualized therapy for AIDS patients with cytomegalovirus retinitis in intravitreal ganciclovir injections

The effect of intravitreal ganciclovir injection combined with intravenous infusion on acquired immune deficiency syndrome (AIDS) patients with cytomegalovirus retinitis (CMVR) was investigated. A total of 32 eyes in 23 AIDS patients diagnosed as CMVR from 2017 to 2018 were included in the retrospective study. All patients underwent induction therapy by using intravenous drip of the anti-cytomegalovirus (CMV) agent ganciclovir (5 mg/kg q12h) combined with intravitreal ganciclovir injection (3 mg/time, 2 times/wk). The visual acuity, fundus photographs, lesion location, and number of intravitreal injections were observed preoperatively and postoperatively. Totally 14 eyes were cured during induction therapy. The number of injections [4.13 (2 to 6)] in CMVR patients with peripherally fundus lesions were significantly lower than those with central lesions [4.89 (2 to 6)]. The individualized therapy of intravitreal ganciclovir injections for AIDS patients with CMVR can effectively reduce the numbers of intravitreal injections.     

反复玻璃体内注射阿柏西普对黄斑水肿患者角膜的影响

目的　观察反复玻璃体内注射阿柏西普对黄斑水肿患者的角膜内皮细胞和中央角膜厚度的影响。方法　选取2018年3月至2020年10月在我院行玻璃体内注射阿柏西普治疗黄斑水肿的患者46例46眼。每位患者均接受玻璃体内注射阿柏西普2 mg/0.05 mL,每月1次,连续注射3次。对比分析注药前1 d和注药后1个月、3个月、5个月患眼眼压、中央角膜厚度、角膜内皮细胞密度、六边形细胞比例、角膜内皮细胞面积变异系数和角膜内皮细胞数的变化。结果　注药前1 d和注药后1个月、3个月、5个月患眼中央角膜厚度分别为（538.85±31.87）μm、（536.02±30.87）μm、（535.43±31.48）μm、（536.46±32.50）μm,差异无统计学意义（P>0.05）。注药前1 d和注药后1个月、3个月、5个月,患眼眼压差异无统计学意义（P>0.05）。注药前1 d和注药后1个月、3个月、5个月患眼角膜内皮细胞密度分别为（2678.72±421.72）个·mm^-2、（2658.30±461.71）个·mm^-2、（2661.96±407.26）个·mm^-2、（2656.41±427.74）个·mm^-2,差异无统计学意义（P=0.611）。注药前和注药后1个月、3个月、5个月相比,患眼六边形细胞比例、角膜内皮细胞面积变异系数、角膜内皮细胞数差异均无统计学意义（均为P>0.05）。结论　反复玻璃体内注射阿柏西普,短期内对角膜内皮细胞的形态和中央角膜厚度没有明显影响。     

玻璃体腔内注射康柏西普治疗黄斑部小分支视网膜静脉阻塞导致的黄斑水肿

目的：评价玻璃体腔内注射康柏西普治疗黄斑部小分支视网膜静脉阻塞继发黄斑水肿的有效性及安全性。

方法：回顾性分析2015-07/2016-09在我院确诊为黄斑小分支视网膜静脉阻塞继发黄斑囊样水肿的患者资料19例19眼,所有患者均按3+按需注射(pro re nata,PRN)的方法行玻璃体腔内注射康柏西普0.05mL(0.5mg),每月随诊观察最佳矫正视力、中央视网膜厚度、注射次数及眼部相关并发症等。

结果：治疗后1、2、3、6mo的最佳矫正视力与治疗前相比均有改善,差异具有统计学意义(P<0.01); 治疗后1、2、3、6mo的黄斑中心凹厚度与治疗前相比均下降,差异具有统计学意义(P<0.01); 其中有3眼出现反复发作的黄斑水肿,FFA检查显示微血管瘤渗漏,给予局部光凝封闭血管瘤后水肿吸收; 治疗及随诊期间所有患者均未出现玻璃体出血、视网膜脱离、持续高眼压和眼内炎等并发症。

结论：玻璃体腔注射康柏西普治疗黄斑小分支静脉阻塞继发的黄斑水肿安全有效,可以明显改善视力,减轻黄斑水肿; 顽固的黄斑水肿建议行FFA检查,如水肿为微血管瘤渗漏造成建议联合局部光凝治疗。     

Retinal toxicity of liposome-incorporated and free ofloxacin after intravitreal injection in rabbit eyes

Background: Ofloxacin (OFLX) is a fluoroquinolone-antibiotic with a broad antimicrobial spectrum that may have a potential role in the treatment of bacterial endophthalmitis. However, its elimination half life after intravitreal injection is short. To prolong the intravitreal antibacterial level OFLX was incorporated into liposomes. This study was performed to investigate the retinal toxicity of liposome-incorporated and free OFLX. Materials and methods: OFLX was incorporated into multilamellar large vesicles. 0,1 ml of this suspension (= 180.2 μg OFLX) was injected into the midvitreous of rabbit eyes (n = 6). Free OFLX in doses of 100 μg, 500 μg and 1,000 μg was injected into the midvitreous of a second group of rabbit eyes (n = 18). The other eye served as a control and received empty liposomes or normal saline solution, respectively. Before injection and at the end of follow-up an ERG was obtained. After a follow-up of 1 day, 14 and 28 days the animals were perfused with glutaraldehyde and the eyes were examined by light- and transmission electron microscopy. Results: The ERG as well as the histologic studies did not reveal any pathological changes after injection of liposome-incorporated OFLX compared to the control eyes. Significant reduction of the ERG was observed after 500 μg free OFLX in 2 out of 6 eyes after 1 and 14 days, respectively, and in 2 eyes 1 day after 1,000 μg free OFLX. Three days after injection of 1,000 μg OFLX the retina showed focal destruction in 1 out of 6 eyes. In another eye with the same dose 14 days after injection the photoreceptor outer segments showed disorganisation. Conclusion: This study shows that liposome-incorporated OFLX did not have any retinal toxicity in this animal model. Free OFLX appears to have no retinal toxicity in rabbit eyes at a dose of 100 μg after intravitreal injection. Injection of higher doses resulted in ERG changes and marked retinal damage. This revised version was published online in July 2006 with corrections to the Cover Date.