The worldwide impact of ocular trauma
Trauma is an important cause of visual impairment and blindness worldwide and a leading cause of blindness in young adult males . Currently, it is estimated that almost 1 million people in the US live with trauma-related visual impairment, and 40,000 to 60,000 individuals are diagnosed as new cases of trauma-related blindness each year . Those patients with open globe injuries lose a mean 70 days of work . Prevent Blindness America estimated that in 1988 approximately 90,000 disabling eye injuries occurred at the workplace, resulting in a total direct cost of $354,870,000; with indirect cost (lost wages, medical expenses, and insurance administration cost), the sum reached $709,740,000. When the cost of all non-disabling eye injuries is included, the total easily exceeds $1 billion. (Prevent Blindness America Statement on the Scope of the Eye Injury Problem, Schamburg IL, 1996). Globally it has been estimated that 1.6 million people are blind as a result of ocular trauma, with 2.3 million suffering bilateral low vision and up to 19 million with unilateral blindness or low vision .
In the UK it is estimated that 5,000 patients per year sustain eye injuries serious enough to require hospital admission and of these 250 will be permanently blinded in the injured eye . Ocular trauma is the commonest cause of unilateral blindness in the world today and in developing countries the high incidence of ocular trauma has extensive socioeconomic costs .
It is clear from recent published data that although vitreoretinal surgical techniques have improved, outcomes remain unsatisfactory and that the development of proliferative vitreoretinopathy (PVR) is the leading cause of this [6–9].
Eyes sustaining penetrating or open globe trauma (OGT) are a group at high risk of severe visual impairment. Retinal detachment is common in these eyes and multiple surgical interventions are often necessary. PVR is the commonest cause of recurrent retinal detachment and visual loss in eyes with open globe trauma. It is estimated to occur in 10-45% of all OGTs [5–13].
PVR can be considered a wound-healing response in a specialised tissue. This results in the formation of fibrocellular membranes on both surfaces of the detached retina and the posterior hyaloid face. Contraction of these membranes results in retinal detachment in post-trauma eyes or in subsequent failure of surgical reattachment. Despite the improvements in vitreoretinal surgery over the past 15 years, a significant number of cases fail to achieve reattachment. The most common cause of anatomic failure in retinal detachment surgery is the development of new or recurrent proliferative vitreoretinopathy [14, 15].
Preclinical and clinical data
The cellular components of PVR peri-retinal membranes (RPE, glial, inflammatory and fibroblastic cells) proliferate and may also be contractile; they are thus targets for antiproliferative agents. There is a notable inflammatory component to the PVR process with marked blood-retinal barrier breakdown and a greater tendency to intraocular fibrin formation . Macrophages and T lymphocytes have been identified in PVR membranes  and, although relatively small in number, they may play an important role in membrane development and contraction through growth factor production. Thus, both cellular proliferation and the intraocular inflammatory response are realistic targets for adjunctive treatments in PVR.
Steroid treatment can potentially influence both inflammatory and proliferative components of PVR. Experimental work has suggested that the corticosteroid triamcinolone acetonide can reduce the severity of PVR. In addition, it has been demonstrated that periocular corticosteroids can reduce [18, 19] the severity of experimental PVR . Laboratory work has also demonstrated that triamcinolone appears to have no significant retinal toxicity  although in vitro it may be toxic to proliferating retinal cells.
Investigation of the pathobiology of PVR has demonstrated a process of fibrocellular proliferation and contractile periretinal membrane formation, which appears to be due to migrating RPE cells . Recent laboratory investigations by the senior author have demonstrated the central role of retinal glial upregulation and Müller cell process extension in the formation of PVR periretinal membranes [22, 23], suggesting that adjuncts that transiently affect free-floating intraocular cells may have limited effect on the PVR process. Hence, targeting the retinal glial response may be a more effective method of modifying the clinical development or recurrence of PVR. We have subsequently tested the effect of triamcinolone on the glial response in experimental retinal detachment and found a significant reduction in Müller cell proliferation in treated animals . The effect of triamcinolone on the glial response in experimental retinal detachment is evidence that clinically, in addition to their antiinflammatory effect, steroids will downregulate the intraretinal proliferative response seen in PVR.
Jonas et al. reported that intravitreal crystalline cortisone was well tolerated in PVR cases undergoing vitrectomy . Previous small-scale, uncontrolled clinical studies of PVR have suggested that systemic prednisolone , infused dexamethasone , and intravitreal triamcinolone  may reduce the severity of PVR, although none of these studies were of sufficient power to provide a definitive answer. An initial pilot study by the senior author has shown that triamcinolone is well tolerated in PVR cases undergoing vitrectomy and silicone oil exchange and that a combination of adjuncts targeting the inflammatory component of the PVR process may be a potential treatment to prevent PVR . A small, prospective, non-comparative clinical study by Cheema et al. concluded that triamcinolone may have some benefit as an adjunct in non-trauma related established PVR, whereas Ahmadieh et al. found no additional benefit in surgical outcome. Both groups concluded that further larger studies were required to definitively answer the question.
Investigational medicinal products
Triamcinolone acetonide is a hydrophobic long-acting steroid preparation, which is increasingly being administered intraocularly to treat a variety of retinal conditions. It is cheap and widely available with a long duration of action and good safety profile. It appears to be effective in preventing intraocular proliferation and stabilising the blood-retinal barrier, making it a useful adjunctive treatment for retinal diseases resulting in refractory macular oedema. It is particularly useful in patients who have isolated ocular disease, especially unilateral, providing an antiinflammatory and antiproliferative efficacy equal to or greater than that achieved with systemic administration while avoiding the unwanted systemic side effects of steroid use. Its effects last about 3 months , which covers the key active developmental stage of PVR that occurs over about 6 to 8 weeks following ocular injury.
Flurbiprofen is an oral non-steroidal antiinflammatory drug most commonly used to treat musculoskeletal disorders including rheumatoid disease, osteoarthritis, and bursitis, but in ophthalmic practice it is commonly used to treat scleritis. The rationale for its use in this study stems from evidence suggesting that non-steroidal antiinflammatory medications given perioperatively may limit the degree of blood-retinal barrier breakdown and have been shown to inhibit cellular proliferation in vitro [33–35].
Prednisolone acetate 1% is an eye drop suspension used commonly in the treatment of steroid-responsive inflammatory conditions of the eye. It remains the most potent topical steroid treatment licensed for use in the UK.
Combining corticosteroids and non-steroidal antiinflammatories has been shown to have a synergistic effect in reducing blood-ocular barrier breakdown .