Pharmacological adjuvants for diabetic vitrectomy surgery

Abstract

Diabetic vitrectomy is a highly intricate surgical procedure performed during the advanced stages of diabetic retinopathy (DR). It is used to treat conditions such as tractional or combined retinal detachment, vitreous hemorrhage, and subhyaloid hemorrhage, which are all severe manifestations of proliferative DR. The results of the surgery are uncertain and variable. Vitreoretinal surgery has made significant progress since the early stages of vitrectomy. In the past ten years, advancements in intravitreal pharmacotherapy have emerged, offering new possibilities to improve the surgical results for our patients. Within the realm of medical terminology, an "adjunct" refers to a pharmaceutical or substance employed to aid or expedite the primary therapeutic intervention for a particular ailment. Their introduction has broadened the range of therapeutic choices that are accessible prior to, during, and following surgical procedures. This review article will specifically analyze the pharmacological adjuncts used in diabetic vitrectomy surgery, with a focus on their role in facilitating or aiding specific steps of the procedure. The implementation of this system of categorization offers benefits to the surgeon by allowing them to foresee potential difficulties that may occur during the surgical procedure and to choose the appropriate pharmacological agent to effectively tackle these challenges, thus enhancing surgical success rates.

Key Words: Diabetic retinopathy; Vitrectomy; Intravitreal injections; Anti-vascular endothelial growth factor; Adjuvants; Outcomes

Core Tip: For advanced diabetic retinopathy, diabetic vitrectomy is a complex procedure with unpredictable outcomes. In the last decade, intravitreal pharmacotherapy has advanced, providing new ways to improve surgical outcomes for our patients. In medicine, an "adjunct" refers to a drug or substance that supplements the main treatment. This review will look at the pharmacological adjuncts used in diabetic vitrectomy surgery and how they affect specific steps. The categorization system enables surgeons to anticipate surgical issues and select the appropriate pharmacological agent to address them, thereby increasing surgical success rates.

INTRODUCTION

The treatment approach for diabetic retinopathy (DR), which poses a risk to vision, typically involves medical management using intravitreal pharmacological agents and/or laser therapy or in some cases, surgical management in the form of pars plana vitrectomy[1,2]. The primary goals of vitrectomy in the context of DR encompass several key objectives. These include reducing the presence of vascular endothelial growth factor (VEGF) within the vitreous cavity, enhancing oxygen supply to the retinal tissue, eliminating any media opacities, alleviating any antero-posterior or tangential forces exerted on the retinal surface, and impeding the advancement of angiogenesis and the subsequent emergence of end-stage neovascular glaucoma[3–5]. Therefore, the primary indications for vitrectomy in DR are as follows: Severe non-clearing vitreous hemorrhage (VH), significant dense premacular blood, taut posterior hyaloid with macular traction with or without associated macular tractional retinal detachment, combined retinal detachment, diabetic macular edema (DME) associated with overlying tractional epiretinal membrane (ERM), and early stages of neovascular glaucoma secondary to DR[3,6–11]. In recent years, advancements in vitrectomy instrumentation have led to better surgical success and improved patient recovery times. This has prompted a desire amongst the clinicians to decrease treatment costs and complications associated with repeated laser photocoagulation and intravitreal pharmacological therapies. As a result, the criteria for primary vitrectomy in cases of DR have expanded. This now also includes eyes with non-tractional DME, including both treatment-naïve and persistent cases[12–14]. Additionally, eyes with early proliferative DR, with or without minimal preretinal hemorrhage, are now considered eligible for primary vitrectomy[15,16]. The decision to perform repeat vitrectomy in cases of DR is typically based on several factors, including the recurrence of VH, the presence of residual premacular blood, the development of rhegmatogenous retinal detachment, the formation of an ERM with increased macular traction, as well as progression to neovascular glaucoma[17–19].

The main challenges frequently encountered during vitrectomy in the management of DR involve insufficient removal of posterior cortical vitreous and dissection of tractional membranes, massive intraoperative hemorrhage and the occurrence of iatrogenic retinal breaks[3,10,20,21]. In medical terminology, an "adjunct" is a drug or substance used to "assist or facilitate" the primary treatment of a disease. The use of pharmacological adjuncts to vitrectomy surgery is beneficial for achieving surgical success and improved anatomical and functional outcomes. Their introduction has expanded the therapeutic options available before, during, and after surgical procedures[22,23].

In this review article, we will focus on the pharmacological adjuncts utilized in diabetic vitrectomy surgery, specifically examining their role in facilitating or aiding specific steps of the surgical procedure for DR. The utilization of this categorization system provides advantages to the surgeon by enabling them to anticipate potential challenges that may arise during the surgical procedure. This allows the surgeon to select the appropriate pharmacological agent to effectively address these challenges, thereby improving surgical success rates and enhancing patient outcomes.

CHALLENGES FACED BEFORE, DURING AND AFTER DIABETIC VITRECTOMY

Pre-operative decision-making for planning vitrectomy in eyes suspected with co-existent tractional and non-tractional components of DME

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.

Facilitation of intraoperative posterior cortical vitreous separation

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.

Intraoperative assistance for peeling the ERM and ILM during diabetic vitrectomy surgery

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].

Intraoperative assistance during membrane dissection

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.

Minimizing the intraoperative bleeding during diabetic vitrectomy

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].

Preventing post-operative vitreous cavity hemorrhage

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.

Table 1 Summary of pharmacological adjuvants used in patients with advanced diabetic eye disease requiring vitrectomy.

Stage of vitrectomy	Objective	Adjuvants used
Before vitrectomy	To differentiate between tractional and non-tractional DME	Intravitreal anti VEGF agents
		Intravitreal TA
During vitrectomy	Facilitation of intraoperative posterior cortical vitreous separation	Use of autologous plasmin enzyme
		Use of intravitreal TA
	Dissection of ERM and ILM	Use of intravitreal pharmacological agents such as TA, Tryphan blue and Brilliant blue G
	Dissection of proliferative membranes	Use of intravitreal pharmacological agents such as TA, Tryphan blue and Brilliant blue G
		Blunt dissection with the use of intravitreal viscoelastic
	Minimizing the intraoperative bleed	Use of pre-operative intravitreal anti VEGF agents
		Use of intraoperative perfluorocarbon liquid or performing fluid air-exchange
		Intraoperative fibrin glue
After vitrectomy	Treatment of recurrent vitreous hemorrhage	Intravitreal anti VEGF agent
		Repeat fluid air exchange and gas endotamponade

DME: Diabetic macular edema; VEGF: Vascular endothelial growth factor; TA: Triamcinolone acetonide; ERM: Epiretinal membrane; ILM: Internal limiting membrane.

CONCLUSION

In summary, despite the utilization of state-of-the-art vitrectomy equipment, retinal surgeons face a multitude of challenges when performing diabetic vitrectomy surgery. At present, there exists a wide range of pharmacotherapies that can be employed prior to, during, and subsequent to surgical procedures with the aim of optimizing the surgical outcome for our patients. The utilization of individualized medical interventions before, during, and after vitrectomy is expected to rise due to the emergence of additional evidence that supports the advantages of pharmacotherapy as a supplementary treatment alongside vitrectomy.