Rebleeding After Diabetic Vitrectomy

Recurrence of hemorrhage after vitrectomy can be a troublesome complication.

Jonathan M. Smith, MD • David H. W. Steel, MD

As retinal surgeons, we are surely blessed. Our surgical procedures are technically satisfying, and the results usually good, giving us happy and grateful patients. However, despite the wide variety of treatments available in our extensive armamentariums and the amazing innovations in vitreoretinal surgery, disappointing outcomes can still occur.

There is nothing more frustrating and “gray hair-inducing” than patients who present after otherwise successful diabetic delamination surgery with a sudden postoperative vitreous cavity hemorrhage (POVCH). A patient under my care, shortly after I started as a consultant, who experienced successive (and soul-destroying) POVCHs stimulated an interest that has persisted to this day.

POVCH is a significant clinical problem, and its occurrence is distressing for patients, as well as surgeons. In addition to delaying recovery, repeat interventions expose the patient to further operative risk and anxiety and add to the overall cost of care.

INCIDENCE

Pars plana vitrectomy is an established and successful treatment for the complications of proliferative diabetic retinopathy, with vitreous hemorrhage being the mot common indication.^1,2

Unfortunately, postoperative hemorrhage is not uncommon either. It has been recorded as occurring in approximately 10% to 30% of cases, although the reported range is large, at 5% to 80% of cases.^3-10 Revision surgery to remove nonclearing POVCH is needed in approximately one-third to one-half of patients who experience POVCH and in approximately 10% of all patients under-going surgery.^4,6,7,11-15

Despite improvements in diabetic care, the number of patients undergoing diabetic vitrectomy is increasing, due to the increasing prevalence of diabetes, a reducing surgical threshold with improved results,¹⁶ and new indications for surgery. In 2000, Kaiser et al. found that vitrectomy was required within one year in up to 10% of patients presenting with PDR.¹⁷

Estimates based upon data from our own part of North East England suggest that approximately 4,000 vitrectomies for the complications of diabetic retinopathy are currently performed annually in the United Kingdom. If 10% require revision surgery, this equates to 400 patients per annum in our country alone.

CLASSIFICATION

Although there can be some overlap, POVCH occurs in two main forms.

1. Persistent (or “early”) POVCH, which is generally present from the first few postoperative days. Hemorrhages occurring within the first three postoperative weeks are, however, also usually included in this category
2. Recurrent (or “late”) POVCH occurs later during follow-up, commonly at two to six months postoperatively after a period of the vitreous cavity being clear.

ETIOLOGY

Persistent hemorrhage can result from operative and postoperative oozing of the remnants of new vessels or dissected tissue, as well as directly from the sclerostomies used to perform surgery. It can also occur from clot lysis in the first few postoperative days.

Leaching of red blood cells can occur from retained old hemorrhages in residual anterior vitreous, causing apparent POVCH.^6,7,18 Recurrent hemorrhage can also result from late hemorrhage from dissected tissue, recurrent traction on residual new vessels, or postoperative new vessel growth in the posterior retina.

Recent studies have shown that a common cause for recurrent hemorrhage, accounting for perhaps 50% of cases, is anterior new vessel growth at the inner sclerostomy sites associated with fibrous traction.^19-25 This has been termed “entry-site neovascularization” (ESNV).²⁶ It is thought to be an aberrant wound-healing response related to the presence of retinal and pars plana ischemia (Figure 1).^22,27

Figure 1. Optos widefield fundal SLO images (A and B): Sometimes despite prompt and adequate PRP, proliferative diabetic retinopathy can progress and require vitrectomy surgery.

The presence of ESNV is difficult to observe clinically because of the extreme anterior location, but it can be confirmed at the time of revision surgery with deep scleral indentation²⁵ or with endoscopic techniques. It can also be localized, with anterior-segment high-resolution ultrasonography of the inner sclerostomy sites.^19-21,24

Anterior hyaloidal neovascularization, with extensive new vessel formation along the anterior vitreous face toward the lens, unassociated with the sclerostomies, although reported in the past, now appears to be relatively rare.

RISK FACTORS

It is difficult to predict who is at the greatest risk for POVCH. Soto-Pedre et al. found that iris neovascularization and a history of lower extremity amputations increased the risk of POVCH, while antihypertensive treatment before vitrectomy decreased the risk.²⁸

Intuitively, it would seem most likely in those with the greatest ischemic drive and vascularity; however, this has been difficult to prove, perhaps partly related to the difficulty in measuring “disease activity” in PDR. Certainly eyes without any preoperative laser would seem to be at greater risk. Future studies based on VEGF levels may be useful in this regard.

PREVENTION STRATEGIES

At the time of the initial vitrectomy surgery, several surgical procedures have been recommended to prevent POVCH and avoid the need for repeat surgery. Some of these are widely accepted, while others are more debatable.

Posterior Vitreoretinal Traction

Identify and remove all posterior vitreoretinal traction. Vitreoschisis is known to occur in patients with PDR, and identification of this and dissection in the true vitreoretinal plane are important to avoid recurrent traction and postoperative bleeding from neovascular tissue.^29,30

Getting into the correct surgical plane at the beginning of surgery saves time and reduces bleeding; we have found “inside-out” delamination a useful technique to achieve this. Dissection is started by the elevation of fibrovascular tissue on the disc head using forceps; delamination away from this area of separated vitreoretinal adhesion is then carried out using the cutter or scissors as needed.

Residual areas of vitreoschisis can be difficult to identify, even in experienced hands, and we routinely use diluted triamcinolone to search for residual vitreous after completion of dissection or during dissection if the plane is lost.

Hemostasis

Ensure adequate hemostasis at the time of vitrectomy, with either temporarily raised intraocular pressure or endocoagulation to reduce postoperative oozing of dissected blood vessels. Some surgeons routinely lower IOP toward the end of surgery to spot and treat residual bleeding points.

Deep Indentation

Employ deep indentation to remove blood in the vitreous base area, which reduces leaching of sequestered red blood cells postoperatively into the vitreous cavity. In addition, indented anterior vitrectomy around the inner sclerostomy sites and removal of Wiegert's ligament has been advocated (Figure 2).^2,26 This may be effective for preventing POVCH by reducing the concentration of growth factors around the inner sclerostomy sites and by removing the vitreous scaffold along which new anterior vessels could grow.

Figure 2. As well as posterior vitrectomy, a careful, indented anterior vitrectomy with incision of Wiegert's ligament, as in A, allows for the egress of red blood cells and growth factors from the posterior segment into the anterior segment. In B, residual anterior vitreous blocks the egress.

Some clinicians are advocating simultaneous or even preemptive cataract surgery to achieve these aims and reduce the risk of POVCH,³¹ but generally speaking, adequate basal vitrectomy can be achieved by careful indentation.

These maneuvers also increase the egress of red blood cells and growth factors from the posterior segment to the anterior segment, allowing for more rapid clearance of any POVCH if it does occur.

Supplementary PRP

Apply supplementary panretinal photocoagulation (Figure 3) to untreated areas of ischemic retina to reduce the production of VEGF.^5,27,32 In particular, many patients will have large areas of untreated peripheral retina. Endoscopic fluorescein angiogram studies³³ on patients undergoing vitrectomy for advanced PDR have shown that these peripheral areas are often frankly ischemic, and treatment of these areas, which are relatively inaccessible preoperatively, may help to reduce the occurrence of recurrent neovascularization postoperatively, particularly peripherally and at the sclerostomy sites. We routinely laser all eyes up to the ora serrata, particularly behind the sclerostomy sites, using curved illuminated endolaser probes, which allow for good access, even in aged, phakic eyes.¹⁰

Figure 3. Neovascularization at the inner sclerostomy sites, termed “entry-site neovascularization,” represents an aberrant healing response perhaps exacerbated by adjacent un-treated ischemic retina and high local levels of VEGF (as in A). If laser is extended to the ora serrata, treating areas of peripheral ischemic retina and reducing neovascular drive, the occurrence of ESNV can potentially be reduced (as in B).

Cryotherapy or Laser

Treat the inner sclerostomy sites directly, with either externally administered cryotherapy or laser¹⁰,²⁷; this may reduce the risk of ESNV and late rebleeding (although some studies have found no benefit³⁴).

Personal experience suggests this is more important in 20-gauge cases and only works when combined with thorough vitrectomy around the sclerostomy sites and up to the ora laser. This is thought to reduce the occurrence of entry-site neovascularization by inhibiting cellular migration through the sclerostomy wounds and causing focal atrophy of the ciliary epithelia. Our current practice is not to do this in small-gauge cases.

Tamponade

Some authors have advocated using tamponade at the end of surgery to act as a hemostatic agent perhaps by concentrating thrombotic factors next to the retinal surface. Air,³⁵ sodium hyaluronate,³⁶ and gas^37,38 have all been advocated with mixed results. In the same way, tranexamic acid, which inhibits fibrinolysis and hence clot dissolution, has been used to reduce POVCH.^39,40

Certainly, it is important to avoid hypotony at the end of surgery, which will more likely lead to postoperative ooze. This is particularly important in small-gauge cases, in which hypotony on the first day has been reported more commonly. For this reason, we routinely perform an air exchange, even if no tamponade is otherwise indicated, check carefully for any sclerostomy leak at a pressure of at least 26 mm Hg, and suture if needed.

Pharmacology

Pharmacologic agents have been used in attempts to reduce vascularity and postoperative reproliferation and, in turn, reduce POVCH. Triamcinolone acetonide has been used intra-operatively⁴¹ in this way to try to reduce POVCH, but great interest has recently been shown in anti-VEGF agents.

Intravitreally injected bevacizumab (Avastin, Genentech, South San Francisco, CA) which acts to block the action of VEGF, is increasingly being used to reduce the vascularity of fibrovascular proliferations prior to vitrectomy, reducing the complexity of dissection and intraoperative bleeding. Several studies have reported rates of POVCH after pre- and intraoperative bevacizumab injection, and we recently completed a Cochrane review on the subject.⁴² Four randomized studies were included in the review,^43-46 and one more was recently published,⁴⁷ as well as a systematic review.⁴⁸

Results support the use of preoperative bevacizumab to reduce the incidence of early POVCH but not late POVCH. Similarly, no evidence supports the use of intraoperative bevacizumab in reducing late POVCH.

There were, however, methodological issues in some of the studies that should lead us to be cautious when interpreting findings and making definitive conclusions. In particular, future studies need to set clear definitions of the severity and duration of POVCH cases included. Power calculations must allow for the possibility of cancelling surgery after hemorrhage clearance preoperatively following bevacizumab, as well as in cases when oil is used postoperatively when POVCH cannot be accurately ascertained.

The preoperative timing of the intravitreal bevacizumab (1.25 mg is most commonly used in the RCTs) dose is an important consideration. A histological study suggested that seven to 10 days before surgery may be most effective, giving the bevacizumab enough time to act before significant contraction within the fibrovascular membranes takes place.⁴⁹

Managing Patients

The first priority in any patient presenting with a POVCH is to exclude complications. The retinal status should be assessed to ensure there is no retinal detachment. Ultrasonography is often necessary and, as well as assessing the retinal integrity, can sometimes identify the cause of the hemorrhage.

If the retina is stable, then the initial treatment of POVCH is observation.¹⁷ Spontaneous clearance occurs in many cases. Red blood cells no longer trapped in the gel structure of the vitreous can circulate and clear more freely from the vitreous cavity than in a nonvitrectomized eye. Clearance is related to the amount of hemorrhage, the frequency of recurrent bleeding, and the degree of communication between the anterior and posterior segments, allowing red blood cells to enter the anterior chamber and be cleared via the trabecular meshwork.²⁶

Indeed, IOP can become raised from trabecular meshwork obstruction and needs checking and treating if raised. In most cases, however the retina and IOP are both stable, and the decision to remove POVCH surgically therefore depends on several factors related to the visual demands of the patient, including the individual's social situation and fellow eye status. In patients with POVCH, visual acuity can often be worse than preoperatively; hence, a careful explanation and discussion of the management plan is important to keep the patient motivated and engaged.

As noted, revision surgery is needed in approximately one-third to one-half of those who experience POVCH and approximately 10% of all patients undergoing surgery. Signs that indicate a higher likelihood of spontaneous POVCH clearance include the following:

1. Seeing multiple RBCs in the anterior chamber indicates good posterior-anterior segment communication and, hence, more likely rapid hemorrhage clearance via the trabecular meshwork. In pseudophakic eyes, this can sometimes be improved by YAG capsulotomy outside the optic area.
2. The absence of ESNV on high-resolution anterior-segment ultrasound scanning is also a positive sign. If present in cases of late recurrent hemorrhage, ESNV is a poor prognostic sign in terms of spontaneous hemorrhage clearance.²⁴
3. Gradual improvement of red reflex and visual performance can also indicate spontaneous clearance. It only takes a relatively small amount of blood to cause a seemingly dense POVCH; the corollary of this is that vision can improve rapidly once a small amount of blood clears.

Intravitreal bevacizumab has recently been evaluated in eyes with POVCH and appears to improve clearance and may be a useful therapy to try, although success will depend on RBC clearance from the eye.⁵⁰

If surgery is required, and no clear cause for the POVCH is found on ultrasound scanning, then simple vitreous cavity washout can be tried, possibly with a fluid-air exchange. However, if a cause is found, eg, recurrent or persistent traction or ESNV, then more formal revision surgery is often required.

When operating on cases with suspected ESNV, removal of the lens with phacoemulsification may be required to access the old sclerostomy sites. Mechanical pupillary dilation to optimize the view is also useful. The areas of fibrovascular growth at the inner sclerostomies should be shaved down, using deep indentation and endo-cautery applied as needed. Dissection with scissors may occasionally be needed. Endolaser or cryotherapy can be applied to the area, as well as to the adjacent area of retroport retina.²⁵

In cases with POVCH and ESNV on scan that spontaneously clear, externally delivered treatment with a combination of cryotherapy and indirect laser to the area of ESNV can be considered to reduce the risk of further hemorrhage.¹⁰

CONCLUSION

POVCH is an important problem after vitrectomy for PDR. As is common in all surgery, attention to detail is important, and by adding a few simple additional surgical steps, its incidence can be reduced, although sadly not eliminated. RP

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