Aims: To compare the amount of intraoperative intraocular bleeding in patients with diabetes with macula-involving tractional retinal detachment (TRD) undergoing pars plana vitrectomy (PPV) with and without preoperative intravitreal bevacizumab (IVB) injection.
Methods: An institutional study was carried out with consecutive patients with diabetic retinopathy and macula-involving TRD of recent (3 months) onset who were randomly assigned to PPV only (PPV group) or PPV combined with one IVB (1.5 mg/0.06 ml) injection 2 weeks prior to surgery (bevacizumab (BEV)/PPV group). All patients underwent 23-gauge PPV 3 weeks after baseline. The main outcome measure was erythrocyte count in the fluid retrieved from the vitrectomy cassette using a Neubauer counting chamber.
Results: The study included 20 patients. The mean erythrocyte count was 14 865×103 (SD 19 332×103; median 4500×103) cells in the BEV/PPV group, and 176 240×103 (SD 108 375×103; median 166 600×103) cells in the PPV group. The mean erythrocyte count was significantly lower in the BEV/PPV group than in the PPV group (p<0.0001). No major adverse events were identified.
Conclusion: Preoperative IVB injection was associated with reduced intraocular bleeding during 23-gauge PPV for diabetic macula-involving TRD. Further studies are needed to confirm our preliminary findings.
Trial registration number: NCT00690768.
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Tractional retinal detachment (TRD) is a major cause of severe vision loss in patients with proliferative diabetic retinopathy (PDR)1 2 and a common indication for pars plana vitrectomy (PPV) in patients with diabetes.3 4 PPV is generally indicated when the TRD is macula-involving or macula-threatening, and the postoperative functional result may not be as good as the anatomical outcome.3 5 6 The surgical technique includes removal of the fibrovascular membranes and relief of vitreoretinal traction. Particular attention is focused on minimising intraoperative bleeding and avoiding iatrogenic retinal breaks.1 3
Intraoperative bleeding is one of the main complications associated with PPV in PDR7 8 and may hinder the surgical outcome or even be uncontrollable.9 In addition, intraoperative bleeding during PPV increases the risk of vitreous haemorrhage in the early postoperative period, further emphasising the need for careful haemostasis during surgery.10
Bevacizumab has been widely used for the treatment of several choroidal and retinal vascular diseases11–16 as well as in patients with TRD and PDR undergoing PPV.7 17 18 We hypothesise that since intravitreal bevacizumab is associated with regression of persistent neovascularisation in eyes with PDR,19 its use in the preoperative management of patients with TRD and PDR may minimise intraoperative bleeding, thus facilitating surgery and contributing to a better outcome. The purpose of the current study is to compare the amount of intraoperative intraocular bleeding in patients with diabetes with macula-involving TRD undergoing PPV with versus without preoperative intravitreal bevacizumab injection.
MATERIALS AND METHODS
The study was approved by the local Institutional Review Board and registered at ClinicalTrials.gov (NCT00690768). A prospective, randomised clinical trial was conducted including all patients with PDR, macula-involving TRD and absence of clinically evident vitreous or preretinal haemorrhage admitted to the Division of Vitreoretinal Surgery of the Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto between 1 March 2008 and 31 May 2008. This study protocol followed the principles of the Declaration of Helsinki and was approved by the local Research Ethics Committee. All patients signed a free consent form before joining the study.
Patient eligibility and baseline evaluation
Patients were offered study participation if they had: (1) PDR and macula-involving TRD (defined as the presence of retinal elevation within two disc diameters of the centre of macula associated with epiretinal fibrovascular membranes on dilated biomicroscopic fundus examination); (2) macular TRD of recent onset (as confirmed by the absence of macular elevation on ophthalmic evaluation performed within the past 3 months according to patients’ medical records); and (3) best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (BCVA) between 20/800 and 20/60. Exclusion criteria included: (1) previous history of a thromboembolic event (including acute myocardial infarction and cerebrovascular accident); (2) haemodialysis, known coagulation disorders, or receiving anticoagulants other than aspirin; (3) abnormal prothrombin time, activated partial thromboplastin time or abnormal platelet count; (4) history of glaucoma without clinical treatment; (5) previous intraocular surgery other than cataract surgery; (6) clinically evident vitreous or preretinal haemorrhage; and (7) any other clinical condition that impeded the examination of the ocular fundus or patient follow-up.
All patients underwent an initial screening visit which included a detailed ophthalmic evaluation with BCVA measurement using a standard refraction protocol and modified ETDRS charts, applanation tonometry, biomicroscopy of the anterior segment, dilated biomicroscopic fundus examination and binocular indirect ophthalmoscopy as well as stereoscopic fundus photography. All patients who fulfilled eligibility criteria were informed verbally and in writing of the potential risks and benefits of the treatment, and those patients who agreed to participate signed a written informed consent form. Eight of the 28 eligible patients declined study participation due to the potential risk of TRD progression following intravitreal injection of bevacizumab. For patients who accepted study participation, the screening visit was used as the baseline examination. If both eyes were eligible for study participation, the eye with worse BCVA was included in the study. Patients in aspirin use were instructed to discontinue the medication 1 week before PPV.
Treatment assignment and study procedures
After baseline evaluation, patients were randomised in groups of two. The technician was asked to pick up one of two identical opaque envelopes, one containing the designation for PPV and the other containing the designation for bevacizumab (BEV)/PPV treatment. The next included patient was automatically assigned to the treatment group specified in the second envelope. In the BEV/PPV group, patients received an intravitreal injection of bevacizumab 1 week after baseline and were scheduled for a 23-gauge pars plana vitrectomy 3 weeks after baseline (ie, 2 weeks after the intravitreal injection). In the PPV group, patients were also scheduled for a 23-gauge pars plana vitrectomy 3 weeks after baseline, but no intravitreal injection procedure was performed. Patients assigned to the former group comprised the BEV/PPV group, and those assigned to the latter comprised the PPV group.
In the BEV/PPV group, 1.5 mg (0.06 ml) of bevacizumab (Avastin 100 mg/4 ml; Genentech, South San Francisco, California) was injected into the vitreous cavity using a 29-gauge needle 3.0 mm (pseudophakic) or 3.5 mm (phakic) posterior to the inferotemporal the limbus after topical anaesthetic administration under sterile conditions. One experienced retina specialist performed all intravitreal injection procedures. Ciprofloxacin (0.3%) eye-drops four times daily were prescribed for 5 days after the procedure.
All patients underwent another complete ophthalmic evaluation (identical to that performed at baseline) on the day of PPV, in order to investigate interval changes in the fundus, whether spontaneous (as part of the natural history; PPV group) or possibly associated with the intravitreal bevacizumab injection (in those patients assigned to the BEV/PPV group).
Pars plana vitrectomy was performed by a single experienced retina surgeon who was unaware of the randomisation assignment and consisted of: (1) inferotemporal placement of a 23-gauge valved trocar and infusion line (DORC, Zuidland, The Netherlands) for balanced salt solution (Alcon, Texas, Fortworth) infusion; (2) superonasal and superotemporal placement of 23-gauge valved trocars; (3) PPV and removal of fibrovascular tissue using the vitrectomy probe (Alcon, Fortworth, Texas) and intraocular picks if necessary; (4) intraocular diathermy and elevation of the BBS bottle as needed; (5) active aspiration of residual haemorrhage over the posterior pole; (6) endolaser photocoagulation to untreated midperipheral and peripheral retina; (7) fluid–gas exchange and vitreous substitute placement as indicated (silicone oil was used if any retinal break occurred during fibrovascular tissue dissection); and (8) removal of the 23-gauge trocars and injection of subconjunctival 1 mg of gentamicin and 4 mg of dexamethsone.
At the end of the surgery, the volume of fluid in the vitreoretinal surgical system was determined, and after shaking the vitrectomy cassette, a 3 ml sample of this material was retrieved and sent to the Laboratory of Hematology of the Hospital das Clínicas—Faculdade de Medicina de Ribeirão Preto for quantification of intraoperative intraocular haemorrhage by means of an erythrocyte count, which was performed manually using the Neubauer counting chamber.20 In order to obtain the final erythrocyte count, the number of erythrocytes found in the 3 ml samples retrieved from each patient was multiplied by the volume of BSS used during the surgery.
The main outcome of the current study is the amount of intraocular haemorrhage in patients with macula-involving TRD who underwent PPV compared with those who underwent PPV after an intravitreal injection of bevacizumab performed 2 weeks previously, as quantified objectively by erythrocyte count. Local and systemic adverse events were monitored throughout the study.
Study results were assessed using the analysis of variance and the F test, after logarithmic transformation of erythrocyte cell count values. The mean logarithmic values from both groups were compared using the Tukey test at a significance level of 5% (p<0.05).
A total of 20 patients (10 men, 10 women) were included in the study. Ten patients (10 eyes) were randomly assigned to the BEV/PPV group, and 10 patients (10 eyes) were assigned to the PPV group. The baseline characteristics of each group are summarised in table 1. No statistically significant difference was observed between the groups with respect to gender, age, type of diabetes, duration of diabetes, previous panretinal photocoagulation and BCVA at baseline. Prothrombin time, activated partial thromboplastin time and platelet count were within normal limits in all patients. Cataract surgery by phacoemulsification was performed by the same surgeon in six patients from the BEV/PPV group and five patients from the PPV group. Silicone oil was used in five patients in each group, and perfluoropropane was used in five patients from each group.
On the day of PPV (ie, 3 weeks after baseline, and 2 weeks after intravitreal bevacizumab injection for those patients assigned to the BEV/PPV group), neither progression of the TRD from baseline nor any other ophthalmic adverse events, such as endophthalmitis or rhegmatogenous retinal detachment, were evident in any of the study eyes on clinical examination. No systemic adverse events were reported.
Main outcome measures
The mean erythrocyte count retrieved from the vitrectomy cassette was 14 865×103 (SD 19 332×103) (median 4500×103) cells for patients in the BEV/PPV group, and 176 240×103 (SD 108 375×103) (median 166 600×103) cells for patients in the PPV group. The mean erythrocyte count was significantly lower in the BEV/PPV group than in the PPV group (F = 31,49; p<0.0001).
The use of preoperative intravitreal bevacizumab for patients undergoing PPV for vitreous haemorrhage17 and for diabetic TRD7 18 was recently suggested. According to Avery et al, intravitreal injection of bevacizumab between 2 and 11 days before PPV reduced intraocular bleeding noted by direct observation during surgery in patients with advanced PDR.17 Chen and Park reported one patient with diabetic TRD in whom the use of intravitreal bevacizumab prior to PPV induced regression of new vessels and reduced intraoperative bleeding, also determined by direct observation, making the surgery technically easier.18 Finally, Ishikawa et al advocated the use of intravitreal bevacizumab 7 days before PPV in order to reduce the risk of increasing tissue traction due to excessive fibrosis in patients with severe PDR and TRD.7
In the current study, we performed PPV 2 weeks after intravitreal bevacizumab injection because regression of actively leaking new vessels may not be complete as early as 1 week after intravitreal bevacizumab injection. This hypothesis is derived from the results of our previous study of intravitreal bevacizumab injection in patients with persistent new vessels in diabetic retinopathy, in which a small amount of residual perfusion of actively leaking new vessels was observed in 70% of patients at 1 week after the intravitreal injection, with absence of leakage from new vessels verified at 6 weeks postinjection.19 Therefore, we hypothesise that a higher rate of complete regression of active new vessels may be achieved if a period longer than 1 week is observed prior to PPV.
In order to provide objective, quantifiable data about the possible adjunctive role of preoperative intravitreal bevacizumab for PPV suggested by qualitative uncontrolled studies,7 18 we designed a prospective, randomised comparative study in which the effect of preoperative intravitreal bevacizumab on intraocular bleeding could be assessed quantitatively by counting erythrocytes retrieved from the vitrectomy cassette in patients who underwent PPV for macula-involving TRD. Groups were well balanced regarding demographic features and other factors that may have influenced intraoperative bleeding, such as previous panretinal photocoagulation, duration of retinal detachment, prothrombin time, activated partial thromboplastin time and platelet count. The mean erythrocyte count retrieved from the vitrectomy cassette in those patients undergoing PPV with intravitreal bevacizumab 2 weeks preoperatively (BEV/PPV group) was significantly lower than those undergoing PPV only (PPV group) despite the relatively low sample size in each treatment group. This reduction in intraoperative haemorrhage may have been followed by reduced postoperative haemorrhage,10 a topic not addressed in the present study.
In conclusion, the lower number of erythrocytes observed in those patients treated with intravitreal bevacizumab 2 weeks before surgery suggests that the preoperative use of intravitreal bevacizumab may reduce intraoperative bleeding during PPV for TRD. Larger studies are necessary to confirm our preliminary findings.
Competing interests: None.
Funding: Partially supported by CNPq (Brazilian National Council for Scientific and Technological Development), grant no 302940/2005-7.
Ethics approval: Ethics approval was provided by the local institutional review board (Comitê de Ética em Pesquisa HCRP e FMRP-USP).
Patient consent: Obtained.
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