Tamponade in surgery for retinal detachment associated with proliferative vitreoretinopathy

Abstract

Background

Retinal detachment (RD) with proliferative vitreoretinopathy (PVR) often requires surgery. During surgery, a tamponade agent is needed to reduce the rate of recurrent retinal detachment.

Objectives

The objective of this review was to evaluate the benefits and adverse outcomes of surgery with various tamponade agents.

Search methods

We searched the Cochrane Controlled Register (CENTRAL), MEDLINE, EMBASE, Latin America and Carribbean Health Sciences (LILACS) and the UK Clinical Trials Gateway (UKCTG). There were no language or date restrictions in the search for trials. The electronic databases were last searched on 9 July 2009.

Selection criteria

We included randomized clinical trials comparing patients treated with various tamponade agents.

Data collection and analysis

Two individuals screened the search results independently. One study with two trials was eligible for inclusion in the review.

Main results

One study with two trials was included in the review. The first trial randomized 151 eyes to receive either silicone oil or sulfur hexafluoride (SF₆) gas tamponades; the second trial randomized 271 eyes to receive either silicone oil or perfluropropane (C₃F₈ ) gas tamponades. In patients with RD associated with PVR, pars plana vitrectomy and infusion of either silicone oil or perfluropropane gas appear comparable for a broad variety of cases. Sulfur hexafluoride gas was associated with worse anatomic and visual outcomes than either silicone oil or perfluropropane gas.

Authors’ conclusions

The use of either C₃F₈ or silicone oil appears reasonable for most patients with RD associated with PVR. Because there do not appear to be any major differences in outcomes between the two agents, the choice of a tamponade agent should be individualized for each patient.

Plain language summary

Tamponade in surgery for retinal detachment associated with proliferative vitreoretinopathy

Retinal detachment (RD) remains a significant cause of vision loss. Most recurrent RDs are associated with varying degrees of proliferative vitreoretinopathy (PVR), or the growth of fibrous membranes (similar to scar tissue) along the surface of the retina. The only proven therapy for RD with PVR is surgery. Injection of a tamponade agent is performed at the time of surgery to reduce the rate of fluid flow through open retinal tears, which would cause recurrent RD. The major tamponade agents available today are various gases and silicone oils. One study consisting of two independently randomized clinical trials was included in this review. The Silicone Study compared the use of silicone oil tamponades to either sulfur hexafluoride (SF₆) gas or perfluropropane (C₃F₈) gas tamponades in patients undergoing surgery to treat RD associated with PVR. When silicone oil was compared to SF₆ gas, eyes randomized to receive silicone oil were more likely to achieve a final visual acuity of 5/200 or better at one year, and more likely to achieve macular attachment at one year; both of these differences were statistically significant. When silicone oil was compared with C₃F₈ gas, there were no statistically significant differences between the groups with respect to visual acuity or macular attachment at one year. The use of either C₃F₈ gas or silicone oil appears to offer similar benefits, in terms of their ability to reattach the retina and to preserve or improve visual function.

Background

Description of the condition

Introduction

Retinal detachment (RD) remains a significant cause of vision loss. A variety of surgical techniques are available to treat RD. In general, these procedures have a very high rate of successful anatomic retinal reattachment for primary RD (overall above 90%) (Schwartz 2004). The recent Scleral Buckling versus Primary Vitrectomy in Rhegmatogenous Retinal Detachment (SPR) study, which excluded many relatively straightforward cases, reported single operation success rates between 60% to 80%, depending on the subgroup, and 73% overall (Heimann 2007). Most recurrent RDs are associated with varying degrees of proliferative vitreoretinopathy (PVR), or the growth of fibrous membranes (similar to scar tissue) along the surface of the retina, which leads to traction on the retina (TRSTC 1983).

Epidemiology

Recurrent RD with PVR occurs in about 5% to 10% of patients (Charteris 2002). Major risk factors include RD in the inferior (lower) portion of the eye (Singh 1986), severe ocular trauma (Kruger 2002), and giant retinal tear (Scott 2002). Other reported risk factors for recurrent RD with PVR include: the inability to identify a retinal break, the use of pars plana vitrectomy in the initial repair, preoperative PVR, preoperative choroidal detachment, and relatively greater use of cryopexy ( Cowley 1989). Recurrent RD with PVR may require multiple additional surgeries and is associated with poorer visual outcomes. These additional surgeries are associated with significantly increased costs (Patel 2004).

Presentation and diagnosis

Proliferative vitreoretinopathy is usually diagnosed within the first few months after RD surgery. Symptoms include decreased vision in the affected eye. The diagnosis is made by dilated fundus examination in the office or outpatient clinic.

Description of the intervention

Vitreoretinal surgery is standard treatment for recurrent RD with PVR. Pars plana vitrectomy (PPV), removal of the epiretinal membranes, treatment of the retinal breaks, and injection of a tamponade agent are performed. In some cases, removal of the lens (either the crystalline lens or a previously placed intraocular lens) is performed. Tamponade is necessary to reduce the rate of fluid flow through open retinal tears, which would cause recurrent RD. The major tamponade agents available today are various gases and silicone oils. Currently available gases include air, sulfur hexafluoride (SF₆), hexafluroethane (C₂F₆ ) and perfluropropane (C₃F₈). The major advantage of gas tamponade is that the gas spontaneously dissipates, usually over several weeks. Currently available silicone oils come in 1000-centistoke and 5000-centistoke viscosities. Silicone oil is permanent and may eventually require surgical removal.

There are several investigational tamponade agents, including heavy silicone oil (polydimethylsiloxane (PDMS) 1000) ( Tognetto 2005), perfluorohexylethan (O62) (Hoerauf 2005), perfluoro-n-octane (PFO) (Rofail 2005), a mixture of perfluorohexyloctane (F₆H₈) in silicone oil (Stappler 2008), and a mixture of perfluorohexyloctane (F₆H₈) in PDMS 1000 (Tognetto 2008; Heimann 2008). Various tamponade agents with a specific gravity greater than that of water have shown evidence of toxicity in animal models, in rat retinal cell cultures in vitro, and in clinical reports (Eckardt 1990; Matteucci 2007; Singh 2001).

Tamponade agents are useful in four broad categories of patients with RD:

1. Patients with primary RD, treated with PPV as a first-line procedure. These patients are generally treated with gas tamponade, rather than silicone oil.

2. Patients with complex or recurrent RD associated with PVR. These patients are the focus of this review. These patients are generally treated with either gas or silicone oil.

3. Patients with RD associated with giant retinal tear. These patients are generally treated with either gas or silicone oil.

4. Patients with inferior RD, treated with PPV as a first-line procedure. Some surgeons are using heavy liquids, such as PFO or heavy silicone oil, as investigational agents in these patients.

How the intervention might work

Tamponade agents are believed to work by reducing or eliminating fluid vectors through open retinal breaks until the applied retinopexy (typically photocoagulation or cryopexy) creates a permanent seal. Gases, such as SF₆ and C₃F₈, spontaneously dissipate, while silicone oil is permanent and may eventually require removal.

Why it is important to do this review

The various tamponade agents offer different advantages and disadvantages in terms of safety and effectiveness (Krzystolik 2000; Young 2005). A systematic review may assist surgeons in selection of a tamponade agent.

Objectives

The objective of this review was to assess the relative safety and effectiveness of various tamponade agents used with PPV for RD complicated by PVR. The specific comparisons depended on the trials we identified in the search. We intended to compare:

1. the various gas tamponade agents with each other;

2. the two silicone oil preparations to each other;

3. the various gas agents versus the various silicone oils;

4. the established agents (gases, silicone oil) versus the investigational agents.

Methods

Criteria for considering studies for this review

Types of studies

We included randomized controlled trials. There were no limitations on the various treatment arms compared.

Types of participants

We included trials in which participants underwent surgical repair of RD associated with PVR. There were no limitations with respect to age or cause of RD.

Types of interventions

We included trials which studied agents used as tamponade in the treatment of RD associated with PVR, such as air, sulfur hexafluoride (SF₆), hexafluroethane (C₂F₆), perfluropropane (C₃F₈) and silicone oil, as well as investigational agents such as heavy silicone oil (polydimethylsiloxane 1000), perfluorohexylethan (O62), and perfluoro-n-octane (PFO).

Types of outcome measures

Primary outcomes

The primary outcome for this review was visual acuity at one year. We analyzed outcomes at additional times of follow up as reported in included trials. We intended to compare visual acuity as a dichotomous outcome (the proportion of participants who lost 3 or more lines of logMAR visual acuity; patients who lost 1 or 2 lines of logMAR visual acuity were considered stabilized) and also as a continuous outcome (mean logMAR scores). We considered other dichotomous and continuous visual acuity outcomes as reported in included trials.

Secondary outcomes

The secondary outcome for this review was macular attachment at one year.

Adverse effects (severe, minor)

Severe:

1. Retina detached at one year;

2. Visual acuity worse than 20/200 (regardless of anatomic outcome).

Minor:

1. Intraocular pressure (IOP) greater than 21 mmHg;

2. Visually significant cataract.

Quality of life measures

We intended to examine patient satisfaction, subjective visual improvement and other quality of life measures evaluated using a validated scale.

Economic data

We intended to summarize direct and indirect costs of surgery and rehabilitation and any other economic data in the included studies.

Follow up

We restricted studies to those with at least one year of follow-up. We believe that shorter follow-up periods are less clinically relevant.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library, Issue 3, 2009), MEDLINE (January 1950 to July 2009), EMBASE (January 1980 to July 2009), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to July 2009) and the UK Clinical Trials Gateway (UKCTG). There were no language or date restrictions in the search for trials. The electronic databases were last searched on 9 July 2009.

See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), LILACS (Appendix 4) and the UKCTG (Appendix 5).

Searching other resources

We searched the reference lists of the studies included in the review for other potential inclusions. We did not search conference proceedings for the purpose of this review. Although we did not initially intend to contact individuals or organizations specifically for this review, because we did not believe that doing so would add significantly to the data obtainable through published trials, we contacted the investigators of included studies for clarification of methods and other data reported in published manuscripts.

Data collection and analysis

Selection of studies

At least two authors, working independently, reviewed the titles and abstracts resulting from the searches. Each author reviewed the full text manuscripts of all possibly or definitely relevant studies to determine eligibility for inclusion. We resolved any discrepancies through discussion. We did not mask trial details in this process.

Data extraction and management

Extraction of study characteristics

We extracted the following information for each trial.

Methods: method of allocation, masking (blinding), exclusions after randomization, losses to follow up and compliance, unusual study design.

Participants: country where participants enrolled, number randomized, age, sex, inclusion/exclusion criteria.

Interventions: test intervention, comparison intervention (control), duration of intervention.

Outcomes: visual acuity, retinal reattachment rate, complication rates, adverse effects, quality of life and economic outcomes.

Notes: additional details (such as funding sources).

Data extraction and entry

Two authors, working independently, extracted the outcome data. One review author entered the data into RevMan 5 and a second author verified the data entry. Main outcome measures were visual acuity, retinal reattachment rate and various complication rates. This included dichotomous data (such as retinal reattachment, percentage of participants who lost 3 or more lines of logMAR visual acuity) as well as continuous data (such as logMAR visual acuity).

Assessment of risk of bias in included studies

We reviewed the risk of bias of included studies as outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). At least two authors assessed the risk of bias for each included study according to the following criteria:

1. Selection bias (randomized sequence generation and allocation concealment).

2. Performance bias (masking of participants and researchers).

3. Attrition bias (incomplete outcome data adequately addressed).

4. Detection bias (masking of outcome assessors).

5. Reporting bias (free of selective outcome reporting).

Each area of potential bias was judged as ‘Yes’ for low risk of bias, ‘No’ for high risk of bias, or ‘Unclear’ risk of bias. We considered methods such as centralized randomization, and use of sequential opaque envelopes as evidence of adequate allocation concealment. We evaluated any exclusions after randomization, losses to follow up and differential reasons for losses to follow up in the treatment groups. Any discrepancies were resolved through discussion.

We recognized that masking of patients and surgeons (performance bias) and masking of persons assessing outcome (detection bias) may not be possible in studies comparing gas to silicone oil. However, if we identified studies that had successfully masked outcome data (such as studies in which visual acuity is obtained by an examiner masked to the tamponade agent), these studies were emphasized.

Measures of treatment effect

We reported unpooled risk ratios with 95% confidence intervals for dichotomous outcomes visual acuity and macular attachment for Silicone Study 1992a and Silicone Study 1992b. If continuous outcomes are included in future updates of the review, we will calculate mean differences or standardized mean differences.

We intended to focus on ‘all gases versus silicone oil’, but the outcomes as reported in the included studies were not appropriately compared in this manner. This will be considered for future updates of the review.

Unit of analysis issues

The unit of analysis for outcomes was eyes of individuals.

Dealing with missing data

Primary authors of included studies were contacted to provide 12 month visual acuity and macula status outcome data. Data were not imputed using available information, but will be considered for future updates of the review. The assumptions made during imputation will be indicated.

Assessment of heterogeneity

We intended to test for heterogeneity using the Chi² test and the I² value, but since no pooled estimates were included, tests of heterogeneity were not applicable. If data synthesis is considered at the time of an update to this review, we will follow the following guidelines. If the I² value is greater than 50% we will consider it to indicate substantial heterogeneity. In such a situation we will not report a pooled estimate. Instead, we will report a narrative or tabulated summary of the included studies. We will use a random-effects model to incorporate the heterogeneity if the I² value is less than 50% unless there are fewer than three studies. If we detect no statistical or clinical heterogeneity (from details listed in the table of included studies), we will use a fixed-effect model.

Assessment of reporting biases

Assessment of reporting biases will be explored, as appropriate, in future updates of the review according to the guidelines in Chapter 10 of the Cochrane Handbook for Systematic Review of Interventions (Sterne 2008).

Data synthesis

No pooled estimates of included studies are reported. If pooled estimates are considered for future updates of the review, we will follow the guidelines in Chapter 9 of the Cochrane Handbook for Systematic Review of Interventions (Deeks 2008).

Subgroup analysis and investigation of heterogeneity

We will consider subgroup analyses as appropriate in future updates of this review and will consult the guidelines for investigating heterogeneity in Chapter 9 of the Cochrane Handbook for Systematic Review of Interventions (Deeks 2008). One possible strategy is to divide patients by surgical history, such as patients with chronic RD with PVR and no previous surgery, patients with recurrent RD following scleral buckling only, and patients with recurrent RD following PPV and previous intravitreal tamponade (gas or oil). Another possible strategy is to divide patients with certain high-risk clinical features, such as patients with giant retinal tear, patients with open-globe trauma, and pediatric patients.

Sensitivity analysis

We planned to examine the impact of the exclusion of unpublished and industry-funded studies in sensitivity analyses, but this is not applicable to the current systematic review.

Results

Description of studies

Results of the search

Our literature search yielded a total of 348 titles and abstracts. After independent review of the references by two review authors we identified 19 studies which appeared to be relevant.

Included studies

We identified one study that consisted of two trials that met our inclusion criteria. Enrollment for the first trial comparing silicone oil to SF₆ gas occurred between September 1985 to September 1987 (Silicone Study 1992a). For the second part of the study period, SF₆ gas was replaced with the longer-lasting C₃F₈ gas. Enrollment for the second trial comparing silicone oil to C₃F₈ occurred between September 1987 to October 1990 (Silicone Study 1992b). Patients aged 18 years or older, and with RD associated with PVR, were offered randomization. One eye per patient was randomized and grouped as (Group 1) eyes that had not undergone prior vitrectomy or (Group 2) eyes that had undergone vitrectomy but without silicone oil injection. The first trial included 113 eyes in Group 1 and 38 eyes in Group 2; the second trial included 132 eyes in Group 1 and 139 eyes in Group 2. The exclusion criteria were uncontrolled concomitant eye disease, a history of blunt trauma within three months of entry into the study, a history of penetrating trauma, a giant retinal tear of 90 degrees or greater, proliferative diabetic retinopathy, and any medical condition that could preclude participation in a three-year study.

There was one reference for an ongoing study (HSO Study) that has yet to publish results, described in the ‘Characteristics of ongoing studies’ table, and one reference for an American Academy of Ophthalmology (AAO) abstract (Oncel 2006) that may be relevant to this review, currently listed in the ‘Characteristics of studies awaiting classification’ table until further details are reported.

Characteristics of ongoing studies

HSO Study
Study name	The Heavy Silicone Oil versus Standard Silicone Oil Study (HSO)
Methods	Randomized controlled trial to determine safety and efficacy of vitrectomy with two types of endotamponades
Participants	Multicenter study enrolling patients with inferior and posterior PVR grade C-A6, P12 according to Machemer or inferior detachment with giant retinal tear in the inferior hemisphere
Interventions	Two-arm parallel group design: Heavy silicone oil (endotamponade with heavy silicone oil) Standard silicone oil (endotamponade with silicone oil of viscosity: 1000 or 5000 cSt)
Outcomes	Main endpoints: Complete retinal attachment at 12 months and change of visual acuity at 12 months postoperatively
	Secondary endpoints: Complete retinal attachment before endotamponade removal, quality of life analysis, and the evaluation of the number of retina affecting re-operation within 1 year of follow-up
	Other endpoints: Emulsification of the compound, cataract formation, number of eyes with constantly raised intraocular pressure from baseline, and the number of eyes with glaucoma
Starting date	January 2004
Contact information	Antonia M Joussen, Department of Ophthalmology, University of Düsseldorf, Moorenstrasse 5, Düsseldorf, Germany;
Notes	The present article describes the methods and design. The investigators have not published results.

Characteristics of studies awaiting classification

Oncel 2006
Methods	Randomized controlled trial of 45 participants with complicated retinal detachments
Participants	Patients with complicated retinal detachments
Interventions	Heavy silicone oil (viscosity of 1400cSt, density = 1.06 gr/cm3)
	Standard silicone oil
Outcomes	Retinal reattachment (time of follow-up is unknown)
Notes	Conference abstract from the American Academy of Ophthalmology Meeting (2006)

Excluded studies

We excluded the remaining 16 studies, listed in the ‘Characteristics of excluded studies’ table with reasons for exclusion.

Characteristics of excluded studies

Avci 2001
Reason for exclusion	Patients were not randomized
Brazitikos 2005
Reason for exclusion	Investigated tamponade agents after pars plana vitrectomy surgery
Gao 1993
Reason for exclusion	Case series
Hammer 1997
Reason for exclusion	Study reported only 180 days of follow-up
Hutchins 2003
Reason for exclusion	Case series
Krasnik 1999
Reason for exclusion	Not relevant to the review
Latecka-Krajewska 1998
Reason for exclusion	Not randomized
Li 1995
Reason for exclusion	Case series
Lu 2002
Reason for exclusion	Retrospective study
Pastor 1998
Reason for exclusion	Retrospective study
Pertile 1999
Reason for exclusion	Not relevant to the review
Peyman 1987
Reason for exclusion	Average follow-up 8.4 months
Soheilian 2006
Reason for exclusion	Retrospective study
Stefer 1991
Reason for exclusion	Case series
Tufail 1997
Reason for exclusion	Not relevant to the review
van Effenterre 1987
Reason for exclusion	Case series

Risk of bias in included studies

Two trials, reported as the Silicone Study, met the inclusion criteria for this review (Silicone Study 1992a; Silicone Study 1992b). Since the two included trials were part of the same study protocol, they follow the same design, methods, and analyses (Azen 1991 in Silicone Study 1992a). This study was of good methodological quality and at low risk of bias (Figure 1).

Figure 1.

Methodological quality summary: review authors’ judgements about each methodological quality item for each included study.

Allocation

The randomization scheme was centralized through the Data Coordinating Center and employed stratification and blocking methods to ensure equal treatment assignments within each clinical center. The treatment allocation was adequately concealed for the randomization process with sequential opaque envelopes delivered to each study site and opened at the time of tamponade injection.

Blinding

The study outcome assessors and surgeons were not masked.

Incomplete outcome data

Last observation carried forward method was used for missing data. Data were inferred for patients who missed intermediate examinations, but attended prior and subsequent examinations only when findings were deemed consistent. In the event that a retinal detachment reoccurred during the study period and required surgery, patients were analyzed using the original randomized treatment allocation. Randomized participants from a study center that ceased recruitment during the study period were excluded from the analysis (12 participants from the first trial and six from the second trial).

Selective reporting

This study appeared to be free of selective reporting since primary and secondary outcomes were published a priori in a methods paper (Azen 1991 in Silicone Study 1992a).

Other potential sources of bias

Fourteen baseline characteristics were compared between treatment arms (age, sex, study eye, prior scleral buckle, other ocular surgery, mean duration of RD, Retina Society classification, visual acuity, refractive status, IOP, corneal status, aqueous flare, aqueous cell, and neovascularization). The Silicone Study investigators reported one statistically significant difference in baseline characteristics between eyes of patients assigned to receive SF₆ gas and those assigned to receive silicone oil (Silicone Study 1992a). The estimated duration of RD was greater in Group 2 eyes (eyes of patients with prior vitrectomy but without silicone oil injection) randomized to SF₆ compared to Group 2 eyes randomized to silicone oil.

Effects of interventions

The Silicone Study conducted two trials, one comparing silicone oil (1000 centistokes) with SF₆, and one comparing silicone oil (1000 centistokes) with C₃F₈. When silicone oil (1000 centistokes) was compared with SF₆, the study investigators reported that Group 1 eyes randomized to receive silicone oil were more likely to achieve a visual acuity of 5/200 or better at one year, and more likely to achieve macular attachment at one year; both of these differences were statistically significant. There was no statistically significant difference between the groups with respect to IOP greater than or equal to 30 mmHg. At baseline, about 60% of the eyes were pseudophakic or aphakic, and the crystalline lens was subsequently removed in 81% of the phakic eyes (Silicone Study 1992a). At 24 months, there was no difference in the proportion of eyes of achieving a visual acuity of 5/200 among Group 1 eyes randomized to silicone oil or SF₆ (risk ratio (RR): 1.57; 95% confidence interval (CI): 0.93, 2.66; Analysis 1.1, Figure 2), but Group 1 eyes randomized to silicone oil were more likely than eyes randomized to SF to achieve macular attachment at 24 months (RR: 1.37; 95% CI: 1.01, 1.86; Analysis 1.2, Figure 3).

Figure 2.

(Analysis 1.1). Forest plot of comparison: 1 Silicone oil versus SF₆, outcome: 1.1 Visual acuity ≥ 5/200 at 24 months.

Figure 3.

(Analysis 1.2). Forest plot of comparison: 1 Silicone oil versus SF₆, outcome: 1.2 Macular attachment at 24 months.

When silicone oil (1000 centistokes) was compared with C₃F₈, there were no statistically significant differences between the groups with respect to visual acuity of 5/200 or better at one year or last follow-up examination (Analysis 2.1, Figure 4), macular attachment at one year or last follow-up examination (Analysis 2.2, Figure 5), or IOP greater than or equal to 30 mmHg. In the subgroup of eyes which had not undergone previous PPV (Group 1), eyes randomized to receive C₃F₈ were associated with an increased likelihood of achieving macular attachment beyond one year following surgery, which was of borderline statistical significance. Overall, eyes randomized to receive either C₃F₈ or silicone oil achieved better anatomic and visual outcomes than eyes randomized to receive SF₆ (Silicone Study 1992b).

Figure 4.

(Analysis 2.1). Forest plot of comparison: 2 Silicone oil versus perfluropropane (C₃F₈), outcome: 2.1 Visual acuity ≥ 5/200 at last follow-up examination.

Figure 5.

(Analysis 2.2). Forest plot of comparison: 2 Silicone oil versus perfluropropane (C₃F₈), outcome: 2.2 Macular attachment at last follow-up examination.

SF₆, C₃F₈, and silicone oil can worsen cataracts. However, it seems unlikely that cataract progression played a major role in the visual outcomes, because most eyes were pseudophakic or aphakic at one year. In the silicone oil versus SF₆ study, about 40% of the eyes were phakic at baseline, and the lens was subsequently removed in 81% of these eyes (Silicone Study 1992a). In the silicone oil versus C₃F₈ study, 48% of eyes were phakic at baseline, and the lens was subsequently removed in about 90% of these eyes (Silicone Study 1992b).

The Silicone Study recorded visual acuity using Diabetic Retinopathy Vitrectomy Study protocol and charts. The Silicone Study did not specifically address quality of life measurements and economic analysis.

Discussion

Summary of main results

The Silicone Study was a series of two well-designed prospective, multicenter, randomized clinical trials of patients with RD associated with PVR. The first trial, comparing silicone oil to SF₆, was conducted between 1985 to 1987. The second trial, comparing silicone oil to C₃F₈, was conducted between 1987 to 1990. Pars plana vitrectomy and infusion of either silicone oil or C₃F₈ gas appeared to show comparable results for final visual acuities of 5/200 or better at one year and macular attachments at one year. SF₆ gas was associated with worse anatomic and visual outcomes than either silicone oil or perfluropropane gas, although some of these differences diminished after two years.

Overall completeness and applicability of evidence

In the intervening two decades since the study began, there have been many advances in vitrectomy instrumentation, intraoperative viewing systems, and surgical techniques. The silicone oil used in the Silicone Study was not approved by the U.S. Food and Drug Administration (FDA) and differed in many respects from the higher quality, more purified oils used today.

In addition, although SF₆ and C₃F₈ are still used today, many surgeons now prefer 5000-centistoke silicone oil to the 1000-centistoke oil used in the Silicone Study, although anatomic and visual outcomes are generally similar with either oil viscosity (Scott 2005).

Perfluoro-n-octane (PFO) became available in 1988 as an intraoperative tool to achieve retinal reattachment. Perfluoro-n-octane was not available for any of the patients enrolled in the first trial (oil versus SF₆), which completed enrolment in 1987. Perfluoro-n-octane was available for some, but not all, patients enrolled in the second trial (oil versus C₃F₈). In addition, the investigational use of PFO and other heavy liquids as intermediate-term tamponade agents was not described until more recently.

The Silicone Study also excluded participants with a history of penetrating trauma, giant retinal tears greater than 90 degrees, and proliferative diabetic retinopathy. For these reasons, the results reported by the Silicone Study may not be applicable to patients undergoing contemporary surgical procedures.

Authors’ conclusions

Implications for practice

Based on results from the Silicone Study, patients with recurrent RD associated with PVR appear to have good results with PPV with either C₃F₈ gas or silicone oil tamponades. There is a suggestion that C₃F₈ may have certain advantages with respect to long-term anatomic outcomes in some patients, although the visual results appear similar between the tamponade agents. The choice of tamponade agent is usually made on an individual, patient-by-patient basis. Factors to be considered include the configuration of the detachment, the location of the retinal breaks, the lens status, the visual status of the fellow eye, the patient’s ability to comply with postoperative positioning requirements, the patient’s need to travel by air in the early postoperative period, and individual physician and patient preferences.

As tamponade agents, C₃F₈ and silicone oil appear to have visual and anatomic advantages over SF₆, especially within the first year after surgery, but SF₆ may be a reasonable choice in certain clinical situations.

Implications for research

The Silicone Study delineated various relative advantages and disadvantages of 1000-centistoke silicone oil, SF₆, and C₃F₈ as tamponade agents. Formal evaluation of 5000-centistoke silicone oil in a prospective clinical trial appears warranted, but to our knowledge there are no plans to do so at this time. Future research may develop alternative tamponade agents. Properties of an ideal tamponade agent include: optical clarity, lack of toxicity, no effect on the eye’s refractive state, no effect on IOP or cataract formation, inhibition of cellular migration, inhibition of gliosis or glial proliferation, and density greater than water, which would reduce the postoperative positioning requirements for many patients.

Characteristics of included studies

Silicone Study 1992a
Methods	Unmasked, multicenter randomized clinical trial
	Eyes of patients were stratified as follows (only one eye per patient randomized):
	Eyes that had not undergone prior vitrectomy (Group 1)
	Eyes that had undergone vitrectomy but without silicone oil injection (Group 2)
	Number of eyes randomized: 113 (Group 1) and 38 (Group 2)
Participants	Inclusion criteria: Patients with proliferative vitreoretinopathy with C-3 grade, at least age 18, visual acuity better than light perception, and sufficient contracture so intraocular dissection was required
	Exclusion criteria: Patients with uncontrolled concomitant eye disease, occurrence of blunt trauma to the eye within 3 months of randomization, history of penetrating trauma to the eye, presence of a giant tear ≥90°, presence of proliferative diabetic retinopathy, and the existence of any condition that would prevent 3-year follow-up
Interventions	Type of tamponade
	Sulfur hexafluoride gas (SF6): 49 eyes (Group 1), 15 eyes (Group 2)
	Silicone oil: 52 eyes (Group 1), 23 eyes (Group 2)
Outcomes	Visual acuity, retinal reattachment, refraction; development or change in ocular complications affecting the cornea, iris, or lens; and measurements of intraocular pressure at 10 days, and 1, 3, 6, 12, 18, 24, and 36 months following randomization
	Number of eyes included in the 24 month analysis: 40 of 49 eyes (Group 1) randomized to sulfur hexafluoride; 47 of 52 eyes (Group 1) randomized to silicone oil
Notes	Trial dates: September 1, 1985 to June 30, 1991; one center terminated follow-up in 1988 and patient data were excluded (n = 12 from Group 1).
	Twelve month visual acuity and macula status outcomes were displayed in graphs; investigators contacted for 12 month outcomes.
Risk of bias table
Item	Authors’ judgement	Support for judgement
Adequate sequence generation?	Yes	Randomization scheme generated by the Data Coordinating Center; Stratification and blocking methods employed to ensure equal treatment assignments within each clinical center.
Allocation concealment?	Yes	Investigators used sealed envelopes supplied in limited numbers by the Data Coordinating Center.
Blinding?	No	“A surgeon cannot be masked to the treatment during the operative procedure. During follow-up examinations, silicone fluid produces a characteristic appearance in the eye unlike that of a long-acting gas, making it impossible to mask study technicians.”
Incomplete outcome data addressed?	No	Last observation carried forward method used for missing data, but data inferred only if “consistent” findings for prior and subsequent examinations. Randomized participants from a center that ceased recruitment (n = 12) and randomized participants with a history of prior vitrectomy (n = 38) were excluded from the analysis.
Free of selective reporting?	Yes	This study appeared to be free of selective reporting. Primary and secondary outcomes were reported in a prior manuscript describing trial design and participant baseline characteristics.
Free of other bias?	Unclear	The baseline estimated duration of retinal detachment was greater in Group 2 eyes (eyes of patients with prior vitrectomy but without silicone oil injection) randomized to SF6 compared to Group 2 eyes randomized to silicone oil. Trial sponsored by the National Eye Institute. Silicone oil provided by the Dow Corning Corporation.
Silicone Study 1992b
Methods	Unmasked, multicenter randomized clinical trial
	Eyes of patients were stratified as follows (only one eye per patient randomized):
	Eyes that had not undergone prior vitrectomy (Group 1)
	Eyes that had undergone vitrectomy but without silicone oil injection (Group 2)
	Number of eyes randomized: 132 (Group 1) and 139 (Group 2)
Participants	Inclusion criteria: Patients with proliferative vitreoretinopathy (C-3 grade), at least age 18, visual acuity better than light perception, and sufficient contracture so intraocular dissection was required
	Exclusion criteria: Patients with uncontrolled concomitant eye disease, occurrence of blunt trauma to the eye within 3 months of randomization, history of penetrating trauma to the eye, presence of a giant tear ≥90°, presence of proliferative diabetic retinopathy, and the existence of any condition that would prevent 3-year follow-up
Interventions	Type of tamponade
	Perfluropropane gas (C3F8): 67 eyes (Group 1), 71 eyes (Group 2)
	Silicone oil: 64 eyes (Group 1), 63 eyes (Group 2)
Outcomes	Visual acuity, retinal reattachment, refraction; development or change in ocular complications affecting the cornea, iris, or lens; and measurements of intraocular pressure at 10 days, and 1, 3, 6, 12, 18, 24, and 36 months following randomization
	Number of eyes included in the last follow-up analysis: 67 of 67 eyes (Group 1) and 71 or 71 eyes (Group 2) randomized to C3F8 ; 63 of 64 eyes (Group 1) and 63 of 63 eyes (Group 2) randomized to silicone oil. One patient randomized to silicone oil in Group 1 died after the baseline visit.
Notes	Trial dates: September 1, 1987 to June 30, 1991; one center terminated follow-up in 1988 and patient data were excluded (n = 1 from Group 1; n = 5 from Group 2)
	Twelve month visual acuity and macula status outcomes were displayed in graphs; investigators contacted for 12 month outcomes.
Risk of bias table
Item	Authors’ judgement	Support for judgement
Adequate sequence generation?	Yes	Randomization scheme generated by the Data Coordinating Center; Stratification and blocking methods employed to ensure equal treatment assignments within each clinical center.
Allocation concealment?	Yes	Investigators used sealed envelopes supplied in limited numbers by the Data Coordinating Center.
Blinding?	No	“A surgeon cannot be masked to the treatment during the operative procedure. During follow-up examinations, silicone fluid produces a characteristic appearance in the eye unlike that of a long-acting gas, making it impossible to mask study technicians.”
Incomplete outcome data addressed?	No	Last observation carried forward method used for missing data, but data inferred only if “consistent” findings for prior and subsequent examinations. Randomized participants (n = 6) from center that ceased recruitment were excluded from the analysis.
Free of selective reporting?	Yes	This study appeared to be free of selective reporting. Primary and secondary outcomes were reported in a prior manuscript describing trial design and participant baseline characteristics.
Free of other bias?	Unclear	No differences in baseline characteristics; Trial sponsored by the National Eye Institute. Silicone oil provided by the Dow Corning Corporation.

Appendices

1 CENTRAL search strategy

• #1MeSH descriptor Retinal Detachment
• #2MeSH descriptor Retinal Perforations
• #3MeSH descriptor Vitreous Detachment
• #4retina* near/2 break*
• #5retina* near/2 tear*
• #6retina* near/2 detach*
• #7retina* near/2 perforat*
• #8(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7)
• #9MeSH descriptor Silicone Oils
• #10silicone oil*
• #11tamponade*
• #12MeSH descriptor Sulfur Hexafluoride
• #13sulfur hexafluoride*
• #14hexafluoroethane*
• #15MeSH descriptor Fluorocarbons
• #16MeSH descriptor Dimethylpolysiloxanes
• #17perfluoropropane*
• #18polydimethylsiloxane*
• #19perfluorohexylethan*
• #20perfluoro-n-octane
• #21(#9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20)
• #22(#8 AND #21)

2 MEDLINE search strategy

1. randomized controlled trial.pt.

2. (randomized or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1–7

9. exp animals/

10. exp humans/

11. 9 not (9 and 10)

12. 8 not 11

13. exp retinal detachment/

14. exp retinal perforation/

15. exp vitreous detachment/

16. (retina$ adj2 break$).tw.

17. (retina$ adj2 tear$).tw.

18. (retina$ adj2 detach$).tw.

19. (retina$ adj2 perforat$).tw.

20. or/13–19

21. exp silicone oils/

22. silicone oil$.tw.

23. tamponade$.tw.

24. exp sulfur hexafluoride/

25. sulfur hexafluoride$.tw.

26. hexafluoroethane$.tw.

27. exp fluorocarbons/

28. exp dimethylpolysiloxanes/

29. perfluoropropane$.tw.

30. polydimethylsiloxane$.tw.

31. perfluorohexylethan$.tw.

32. perfluoro-n-octane.tw.

33. or/21–32

34. 20 and 33

35. 12 and 34

The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville et al (Glanville 2006).

3 EMBASE search strategy

1. exp randomized controlled trial/

2. exp randomization/

3. exp double blind procedure/

4. exp single blind procedure/

5. random$.tw.

6. or/1–5

7. (animal or animal experiment).sh.

8. human.sh.

9. 7 and 8

10. 7 not 9

11. 6 not 10

12. exp clinical trial/

13. (clin$ adj3 trial$).tw.

14. ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.

15. exp placebo/

16. placebo$.tw.

17. random$.tw.

18. exp experimental design/

19. exp crossover procedure/

20. exp control group/

21. exp latin square design/

22. or/12–21

23. 22 not 10

24. 23 not 11

25. exp comparative study/

26. exp evaluation/

27. exp prospective study/

28. (control$ or prospectiv$ or volunteer$).tw.

29. or/25–28

30. 29 not 10

31. 30 not (11 or 23)

32. 11 or 24 or 31

33. retina detachment/

34. retina tear/

35. vitreous body detachment/

36. (retina$ adj2 break$).tw.

37. (retina$ adj2 tear$).tw.

38. (retina$ adj2 detach$).tw.

39. (retina$ adj2 perforat$).tw.

40. or/33–39

41. silicone oil/

42. silicone oil$.tw.

43. tamponade$.tw.

44. sulfur hexafluoride/

45. sulfur hexafluoride$.tw.

46. hexafluoroethane$.tw.

47. fluorocarbon/

48. dimeticone/

49. perfluoropropane$.tw.

50. polydimethylsiloxane$.tw.

51. perfluorohexylethan$.tw.

52. perfluoro-n-octane.tw.

53. or/41–52

54. 40 and 53

55. 32 and 54

4 LILACS search strategy

retina$ and detach$ or perforat$ or break$ or tear and silicone or sulfur hexafluoride$ or hexafluoroethane$ or fluorocarbon$ or dimethylpolysiloxane$ or perfluoropropane$ or polydimethylsiloxane$ or perfluorohexylethan$

5 UK Clinical Trials Gateway search strategy

(tamponade or oil) and retina*

Data and analyses

1 Silicone oil versus sulfur hexafluoride (SF₆)

Outcome or Subgroup	Studies	Participants	Statistical Method	Effect Estimate
1.1 Visual acuity ≥ 5/200 at 24 months	1	87	Risk Ratio(M-H, Fixed, 95% CI)	1.57[0.93, 2.66]
1.2 Macular attachment at 24 months	1	87	Risk Ratio(M-H, Fixed, 95% CI)	1.37[1.01, 1.86]

2 Silicone oil versus perfluropropane (C₃F₈)

Outcome or Subgroup	Studies	Participants	Statistical Method	Effect Estimate
2.1 Visual acuity ≥ 5/200 at last follow-up examination	1	264	Risk Ratio(M-H, Fixed, 95% CI)	0.97[0.73, 1.31]
2.1.1 No prior vitrectomy	1	130	Risk Ratio(M-H, Fixed, 95% CI)	1.06[0.73, 1.56]
2.1.2 Prior vitrectomy	1	134	Risk Ratio(M-H, Fixed, 95% CI)	0.88[0.55, 1.39]
2.2 Macular attachment at last follow-up examination	1	264	Risk Ratio(M-H, Fixed, 95% CI)	1.00[0.86, 1.15]
2.2.1 No prior vitrectomy	1	130	Risk Ratio(M-H, Fixed, 95% CI)	0.98[0.80, 1.20]
2.2.2 Prior vitrectomy	1	134	Risk Ratio(M-H, Fixed, 95% CI)	1.02[0.83, 1.25]