Multiple mechanisms have been ascribed to the etiology of the diffuse form of DME. The conditions encompassed in this category consist of vitreomacular traction, extrafoveal vitreopapillary and/or vitreoretinal traction, contraction resulting from the overlying ERM, as well as the presence of vasoactive factors such as VEGF, protein kinase C, nitrous oxide, erythropoietin, and various others[8,24–27]. In contemporary clinical practice, it is not uncommon to encounter instances of DME that exhibit multifactorial etiology. There exist scenarios in which both the tractional and non-tractional components of DME are present concurrently, leading to a quandary regarding the appropriate course of action, namely whether to pursue treatment through vitrectomy or intravitreal pharmacological agents in such circumstances[28]. In cases like these, it may be prudent to initially consider the use of intravitreal pharmacological agents, such as anti-VEGF drugs or triamcinolone acetonide (TA). The reduction of macular edema can be accomplished through the reduction of vasoactive factors as previously mentioned, either with or without the release of posterior vitreous traction from the retinal surface. The absence of any change in the DME's condition suggests a prevailing tractional element in the DME, thereby favoring the consideration of vitrectomy as a potential treatment approach. Therefore, the utilization of intravitreal pharmacological agents for the initial treatment of DME may aid clinicians in comprehending the precise pathogenesis underlying its development and selecting the appropriate course of treatment.

Bleeding within the eye in cases of proliferative DR is observed in three distinct spaces: The intravitreal space, sub hyaloid space, and sub internal limiting membrane (ILM) space. These occurrences are clinically characterized as VH, sub hyaloid hemorrhage, and sub ILM hemorrhage, respectively[29]. This can arise from either the antero-posterior force exerted by the posterior cortical vitreous or the tangential force exerted by the ERM or ILM on the angiogenetic vessels[30]. The removal of the posterior cortical vitreous is considered a crucial determinant for the success of diabetic vitrectomy surgery[5]. In cases where there is severe sub hyaloid hemorrhage, either with or without accompanying VH, there is a notable degree of posterior cortical vitreous separation. This separation greatly facilitates surgical intervention and is associated with favorable outcomes. Nevertheless, in cases where there is a boat-shaped sub hyaloid premacular hemorrhage with limited separation of the posterior cortical vitreous, it is imperative to actively induce posterior vitreous detachment. The utilization of enzymatic vitrectomy or pharmacological vitreolysis through intravitreal injection of autologous plasmin enzyme has been suggested as a viable neoadjuvant therapy for vitreous surgery[31–33]. This approach aims to enhance the surgical separation of the posterior hyaloid and vitreoretinal membranes. Diaz-Llopis et al[34] conducted a study to investigate the impact of enzymatic vitrectomy on individuals with DR and DME[34]. The study observed that a full posterior vitreous detachment occurred in 38% of cases (24 eyes) following a single injection of plasmin. Subsequently, after the administration of a second injection, separated by a minimum of one month, the overall occurrence of complete PVD increased to 51% (32 eyes). In all instances, there was a notable improvement of the central macular thickness, with a 100% success rate. Additionally, there was an improvement in best-corrected visual acuity in 89% of cases. Ultimately, it was observed that a significant reduction in the regression of new vessels occurred in 50% of eyes affected by proliferative DR. In their study, Rizzo and Bacherini[35] investigated the impact of ocriplasmin on eyes afflicted with DR and vitreomacular traction syndrome[35]. To administer the drug, a dosage of 125 μg in 0.1 mL was injected intravitreally. In these eyes, the authors successfully demonstrated the enzymatic release of the posterior cortical vitreous. Hence, the utilization of enzymatic vitreolysis involving the intravitreal administration of autologous plasmin enzyme may be regarded as a viable therapeutic option and can be employed as a neo-adjuvant treatment approach in individuals with proliferative DR and DME.

The visualization of the vitreous, preretinal membranes, and retinal surface is a crucial necessity in the context of vitrectomy surgery. TA is currently predominantly employed as an additional treatment to vitrectomy for this specific purpose[36–39]. The utilization of TA during pars plana vitrectomy for DR enables the visualization of the posterior hyaloid, preretinal membrane, and ILM within the intraoperative setting. This application of TA contributes to the enhancement of safety and efficacy in the procedure. TA-assisted vitrectomy is commonly utilized in the surgical treatment of DR, as well as other vitreoretinal procedures such as macular hole repair, rhegmatogenous retinal detachment, proliferative vitreoretinopathy, uveitis, and various other conditions. Furthermore, this methodology has the capability to reveal the remaining hyaloid cortex pattern subsequent to surgical posterior vitreous detachment. The presence of diffuse posterior hyaloid cortex is a common occurrence in individuals with DR and high myopia. In such cases, it is not uncommon for a residual island-like cortex to remain on the macula. This residual cortex has the potential to serve as a structural framework for the development of future macular pucker.

DR has been identified as a risk factor associated with the proliferation of ERMs. The incidence of ERM in individuals with DME is significant affecting approximately 27-35% of individuals diagnosed with diabetes[24]. There exist notable distinctions in the optical coherence tomography characteristics between an idiopathic ERM and a secondary ERM caused by DR. The expression of glial fibrillary acidic protein, a known indicator of Muller cell activity, is observed to be higher in the eyes affected by diabetic ERMs[40]. This elucidates the rationale behind the increased difficulty in peeling diabetic ERMs as opposed to idiopathic ERMs. The study conducted by Rabina et al[41] examined the effects of ERM peeling, both with and without ILM peeling, on visual acuity gain, central macular thickness reduction, and the frequency of intravitreal injections per year[41]. Additionally, the presence of residual ERM resulting from incomplete removal, presence of ILM and development of retinal breaks intraoperatively has the potential to serve as a framework for the recurrence of proliferative growths[42–44]. Therefore, it is imperative to perform thorough staining and ensure the complete removal of the ERM, as well as the peeling of the ILM in the majority of cases involving DR, regardless of its severity in the presence of DME. The application of various pharmacological agents, such as dyes, enables the staining of both the ERM and the ILM. TA consists of suspended particles that, upon intravitreal injection, exhibit the ability to stain the boundaries of the ERM[45]. There is no established association between retinal toxicity and the use of TA. However, it is important to exercise caution when using this medication in individuals who are responsive to steroids or who have glaucoma, as retained triamcinolone may lead to increased intraocular pressure. Additionally, the use of TA may potentially contribute to the progression of cataracts. Trypan Blue is employed as a visualization agent for the purpose of selectively staining ERM[46]. Additionally, the utilization of this technique aids in distinguishing the ERM from any remaining posterior cortical vitreous, thereby ensuring the thorough extraction of the ERM. The brilliant blue G (BBG) dye exhibits selective staining of the ILM, albeit with varying intensities[47]. When employing BBG, the ILM is stained, while the ERM does not exhibit staining. Consequently, negative staining can be utilized to identify the ERM[47].

The primary goal of conducting a diabetic vitrectomy in cases of proliferative DR is to effectively eliminate all membranes that exert traction on the surface of the retina[5]. Achieving an accurate visualization of the primary and secondary membranes, as well as establishing the appropriate dissection plane, would be necessary for this task. The visualization of preretinal membranes and the ILM can be accomplished through the administration of pharmacological agents, including trypan blue, TA, and BBG[48]. During diabetic vitrectomy, it is necessary to have an open tissue plane situated between the retinal surface and the membranes in order to facilitate the dissection of the membranes. In many instances, this goal can be accomplished through the utilization of the blunt dissection technique, wherein the vitrectomy cutter probe is carefully inserted between the membrane and the surface of the retina[7]. In situations where the appropriate plane is not achieved through blunt dissection, it is possible to inject dispersive viscoelastic agents, either in their plain form or when combined with BBG, using small gauge cannulas positioned between the membranes and retina[49]. This technique allows for the attainment of the desired dissection plane.

The dissection of extensive angio-fibrotic membranes has the potential to result in significant intraoperative bleeding, incomplete removal of the membranes, and consequently, unfavorable anatomical and visual outcomes. This may necessitate additional surgical interventions and impede the recovery process. The administration of anti-VEGF agents via intraocular injection prior to surgery, typically within a timeframe of 3-5 days, has been suggested as a potential strategy for mitigating the occurrence of these complications[50]. The utilization of anti-VEGF agents has been shown to effectively decrease the quantity and vascularity of abnormal neovascularization linked to proliferative DR. This reduction in abnormal vessels can aid in their dissection during surgical procedures, leading to a decrease in bleeding both during and after surgery. Consequently, the implementation of anti-VEGF agents holds the potential to enhance surgical outcomes in patients with proliferative DR. In a prospective study conducted by Li et al[51] a comparison was made between the utilization of pre-operative and intraoperative intravitreal ranibizumab[51]. The findings of the study revealed that the administration of preoperative anti-VEGF injection resulted in notable reductions in surgery duration, as well as a decrease in the occurrence of intraoperative bleeding, utilization of intraocular electrocoagulation, iatrogenic retinal breaks, relaxing retinotomy, and the need for silicone oil tamponade during surgery. The term "anti-VEGF crunch syndrome" refers to the development of tractional retinal detachment in the context of intravitreal anti-VEGF therapy in a patient with proliferative DR[52]. In cases where anti-VEGF treatment is administered prior to a scheduled vitrectomy procedure, it is advisable to closely observe patients for the manifestation of crunch warning signs. If there is any indication of new or advancing tractional retinal detachment, it is recommended to promptly proceed with the surgical intervention. In cases where individuals with minimal preexisting traction in their eyes experience the development of crunch following anti-VEGF treatment, it is recommended that surgeons proceed with vitrectomy within a period of seven days[52]. The utilization of perfluorocarbon liquid intraoperatively, for a brief period or to perform fluid-gas exchange during surgical procedures, can effectively induce a tamponade on the bleeding vessels, thereby facilitating hemostasis. In some cases of persistent intraoperative bleeding, fibrin glue can be used to achieve intraoperative hemostasis[53].

The occurrence of post-operative vitreous cavity hemorrhage subsequent to diabetic vitrectomy has a significant impact on visual outcomes, leading to a higher incidence of resurgery and hampering patient recovery. According to a review conducted by Smith and Steel and published in the Cochrane database, the utilization of pre- or intraoperative anti-VEGF has been found to reduce the occurrence of early post-operative vitreous cavity hemorrhage[54]. Moreover, the incidence of complications associated with the administration of these anti-VEGF agents appears to be minimal. Furthermore, the utilization of intraoperative gas tamponade has demonstrated a decrease in the occurrence of post-operative vitreous cavity hemorrhage[55].

Table 1 summarises the roles of various pharmacological adjuvants used at different stages of diabetic vitrectomy.