Pathophysiology Controversies.pdf

Accepted Manuscript Controversies in the pathophysiology and management of hyphema Dr Svati Bansal, Dr Dinesh Visva Gunasekeran, Dr Bryan Ang, Dr Jiaying Lee, Dr Rekha Khandelwal, Mr Paul Sullivan, Dr Rupesh Agrawal PII:

S0039-6257(15)00217-9

DOI:

10.1016/j.survophthal.2015.11.005

Reference:

SOP 6602

To appear in:

Survey of Ophthalmology

Received Date: 9 May 2015 Revised Date:

12 November 2015

Accepted Date: 23 November 2015

Please cite this article as: Bansal S, Gunasekeran DV, Ang B, Lee J, Khandelwal R, Sullivan P, Agrawal R, Controversies in the pathophysiology and management of hyphema, Survey of Ophthalmology (2015), doi: 10.1016/j.survophthal.2015.11.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Controversies in the pathophysiology and management of hyphema.

Authors:

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Dr Svati Bansal1 Dr Dinesh Visva Gunasekeran2 Dr Bryan Ang2

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Dr Jiaying Lee2 Dr Rekha Khandelwal3

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Mr Paul Sullivan4 Dr Rupesh Agrawal2,4,5

1. Singapore National Eye Centre, Singapore

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2. National Healthcare Group Eye Insitute, Tan Tock Seng Hospital, Singapore 3. NKP Salve Institute of Medical Sciences, Nagpur, India 4. Moorfields Eye Hospital, NHS Foundation Trust, London, UK

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Singapore

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5. School of Material Science and Engineering, Nanyang Technological University,

Corresponding author: Adj Asst Prof Rupesh Agrawal Consultant

National Healthcare Group Eye Institute Tan Tock Seng Hospital Singapore 308433 Email: [email protected]

ACCEPTED MANUSCRIPT Outline: 1. Introduction 2. Pathophysiology of hyphema

4. Complications a. Increased intraocular pressure b. Rebleeding (secondary hemorrhage)

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c. Corneal blood staining

a. Medical management b. Surgical management

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d. Optic atrophy 5. Management

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3. Clinical features and examination

c. Hospitalisation & Follow ups

descent 6. Special situations

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d. Screening for sickle cell disease or trait in patients of African

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a. Sickle cell hemoglobinopathy

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b. Hyphema in pediatric age group c. Cataract and refractive surgery d. Uveitis

7. Outcome measures 8. Conclusion 9. References 10. Table 11. Figures

ACCEPTED MANUSCRIPT Abstract:

Traumatic hyphemas present dilemmas to physicians. There are numerous controversies pertaining to the optimal approach to traumatic hyphema and

no

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standardised guidelines for its management We address some of these controversies and present a pragmatic approach. We discuss the various medical agents and surgical techniques available for treatment, along with the indications for

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their use. We address the complications associated with hyphema and how to diagnose and manage them and consider the management of hyphema in special

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situations such as in children and sickle cell anemia and in rare clinical syndromes such as recurrent hyphema after placement of anterior chamber intraocular lenses.

Hyphema Traumatic glaucoma

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Surgical drainage

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Key words:

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Angle recession

ACCEPTED MANUSCRIPT 1. Introduction:

Hyphema, the accumulation of blood in the anterior chamber, most common cause is ocular trauma (blunt or penetrating)33,63 ;however, it can also be seen after

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intraocular surgery or spontaneously in conditions such as rubeosis iridis, juvenile xanthogranuloma, retinoblastoma, metastatic tumors, iris melanoma, myotonic dystrophy, keratouveitis, leukemia, hemophilia, thrombocyotopenia, and Von 2,6,9,53,61,64,65,75,95

. Hyphema can be a herald sign of major

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Willebrand disease

intraocular trauma and can itself cause complications such as secondary

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hemorrhage and glaucoma104. Even small hyphemas may be associated with significant damage to intraocular tissue.

Despite being a common condition, the management protocols for hyphema are still

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unclear. Conservative management options include bed rest, head elevation, an eye shield, and use of pharmacological agents (topical or systemic steroids, antifibrinolytics, cycloplegics, miotics, aspirin, TCM and conjugated estrogen)34.

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Aside from the use of antifibrinolytics to prevent secondary hemorrhage, however,

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there is no evidence of benefit from the use of these conservative measures34. Furthermore, there is a lack of consensus regarding a treatment and follow-up strategy targeted at preventing delayed visual loss from complications of hyphema, as well as the management of certain special situations such as concurrent sickle cell anaemia.

We aim to address the controversies in the pathophysiology, evaluation, and management of hyphema. Since trauma is the commonest cause, we focus our

ACCEPTED MANUSCRIPT discussion on closed-globe traumatic hyphema; however, we also analyse special situations such as uveitis, pediatric hyphema, cataract surgery, refractive surgery, and hyphema in patients with sickle cell anaemia.

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2. Pathophysiology of hyphema

The mean annual incidence rate of traumatic hyphema is estimated as 17/100,000

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population in individuals less than 18 years of age1 and 20.7/100,000 population in individuals less than 20 years of age50. Direct orbital injury resulting in traumatic

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hyphema usually consists of a high-energy blow to the orbit (61% to 66%), impact from a projectile (30.2% to 36%), or injury secondary to an explosion (2.4% to 3%)50,98. Athletic injuries have become a major cause of traumatic hyphema, while accidents at work have become relatively less frequent. Kearns reported that athletic

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injuries accounted for 39.2 % of 314 cases of traumatic hyphema, whereas accidents at work were responsible for 9.9% of the cases49.

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The commonest source of blood in hyphema is a tear in the anterior face of the

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ciliary body108. A direct blow to the eye can rupture the blood vessels at the root of the iris. The most frequently ruptured vessels are the major arterial circle of the iris and its branches, the recurrent choroidal arteries, and the veins crossing the suprachoroidal space between the ciliary body and episcleral venous plexus96,108 .

Blunt injury is also associated with antero-posterior compression of the globe and simultaneous equatorial globe expansion. Equatorial expansion induces stress on anterior chamber angle structures, which may lead to rupture of iris stromal and/or

ACCEPTED MANUSCRIPT ciliary body vessels with subsequent hemorrhage22,96. Another possible source of initial hemorrhage is a rapid increase in intra-ocular pressure (IOP) immediately after the contusive trauma. This eventually leads to rupture of the fragile vasculature of

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the iris from the pupillary sphincter and/or angle22.

Lacerating injury may be associated with direct damage to blood vessels and hypotony, both of which can precipitate hyphema108. There is no consensus

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regarding the predominant source of bleeding (angle vessels or iris sphincter vessels) and their respective risks of rebleeding; however, current opinion is that

the major arterial circle of the iris22.

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fragile angle vessels have the higher risk of bleeding as a result of their proximity to

Delayed hyphema after intraocular surgery may be the result of granulation tissue at

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the wound margin or caused by damaged uveal vessels (e.g., from surgical trauma or from intraocular lens-induced uveal trauma)64,95. This mechanism should be

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hyphema.

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considered in patients with a history of ocular surgery who present with spontaneous

In the pediatric age group (less than 18 years of age), hyphemas in the absence of predisposing ocular or systemic disease/medication should arouse the suspicion of non-accidental injury (NAI)60. A significant but rare cause of spontaneous hyphema in children is juvenile xanthogranuloma (JXG). JXG is a predominantly dermatological disorder most commonly presenting in children less than 2 years old characterized by a raised, orange skin lesions occurring either singly or in crops that will regress spontaneously. The most common ocular

ACCEPTED MANUSCRIPT finding is diffuse or discrete iris nodules that are often quite vascular and may bleed spontaneously. Occasionally, the lesions may present in other areas such as ciliary body, anterior choroid, cornea, lids, and orbit47. Complications include uveitis and glaucoma with resulting visual loss and phthisis. Biopsy of skin lesions

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helps to confirm the diagnosis. The lesions classically contain an infiltrate of lipidladen histiocytes, lymphocytes, eosinophils and Touton giant cells.

Histologic examination of hyphemas reveals an erythrocyte aggregate enveloped by

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a pseudocapsule of fibrin-plated coagulum47 .Clot absorption takes place by breakdown of fibrin by fibrinolytic agents and escape of red blood cells through the

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trabecular meshwork and Schlemm’s canal47 . Agents that open the trabecular meshwork thus accelerate clot absorption.

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3. Clinical features and examination

The importance of a detailed history and a thorough ocular and systemic evaluation cannot be stressed enough. The nature of the injury points to the likely type of

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damage sustained and therefore the prognosis. The priority in trauma is always to

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stabilize airway, breathing, and circulation, and make an assessment for threats to life. This is followed by an ophthalmic evaluation that includes inspection for gross ocular injury, evaluation of the adnexae, visual acuity, pupillary function, ocular motility, and the position of the globes.

Extensive conjunctival chemosis and hemorrhage may indicate an occult scleral rupture (Figure 1). Proptosis may be secondary to a retrobulbar hematoma, and restriction in ocular motility may suggest an orbital blowout fracture or a contusive

ACCEPTED MANUSCRIPT head injury. Every attempt should be made to examine the adnexal region carefully and rule out any associated orbital or head trauma. Hyphema can be associated with open globe (Figure 2A) or closed globe injuries. In patients with open globe injury, primary wound closure is the priority (Figure 2B). One should not attempt surgical

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washout of hyphema in open globe injuries as the blind approach could lead to adverse consequences. Surgical washout can be considered in patients with nonresolving hyphema or sickle cell trait because of the

higher risk of secondary

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glaucoma and permanent visual loss34. We shall focus on hyphema following closed

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globe trauma.

Patients should be examined carefully to document and grade the hyphema (Table 1). The following clinical grading system is commonly used in the assessment of

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traumatic hyphemas:

Grade 1 - Layered blood occupying less than one third of the anterior chamber Grade 2 - Blood filling one third to one half of the anterior chamber

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Grade 3 - Layered blood filling one half to less than total of the anterior chamber

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Grade 4 - Total clotted blood, often referred to as “eight ball” or “black” hyphema

"Eight ball" or "black hyphema" occurs when the entire anterior chamber is filled with blood, which takes on a darker red colour due to the impaired circulation in the aqueous. The term “eight-ball hyphema” or “black-ball hyphema” was coined by Smith and Regan in 1957 (after the dark ‘eight ball’ in snooker)94; however, we have observed that these total hyphemas often still retain a bright or dull red appearance that more closely resembles the ‘third’ or the ‘eleventh’ ball in snooker. Therefore, it

ACCEPTED MANUSCRIPT may be a worthwhile consideration to revise the traditionally named ‘eight ball’ hyphema to a “red-ball” or “three-ball hyphema” (Figure 3). A true dark “eight-ball” hyphema carries a much worse prognosis than a bright red hyphema.

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In addition to anterior segment examination, an assessment of visual acuity, pupillary reactions, intraocular pressure, and extraocular movements must be made. Hyphema may be associated with other signs of anterior segment trauma such as

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traumatic cataract, damage to the trabecular meshwork, corneat, zonules, and iris

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(Figure 4).

Fundus examination should be performed at the earliest possible opportunity to rule out concomitant posterior segment trauma such as giant retinal tears that may require prompt intervention. Indirect ophthalmoscopy using scleral depression in an

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eye with traumatic hyphema is controversial. Clinicians are concerned that pressing on the globe may cause a rebleed by mechanical distraction of the formed clot. The exact pathophysiology behind the rebleed following scleral depression is not well

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established. One explanation is a coup-countercoup mechanism similar to that in

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blunt ocular trauma, which results in clot retraction and causes rebleeding.

We recommend gentle scleral depression to examine the peripheral retina in closed globe injury. This will allow the ophthalmologist to exclude peripheral retinal tears and retinal dialysis, as these complications may require surgical intervention. An exception would be eyes that have had severe contusion, in which case we recommend deferring scleral depression until several weeks have passed. Unlike giant retinal tears, post-traumatic detachments caused by retinal dialysis progress

ACCEPTED MANUSCRIPT slowly, and indentation may be safely deferred for several months. If scleral depression is not performed, a super field condensing lens should be used to examine the periphery. Furthermore, B-scan should be done if the hyphema

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obscures the view of the posterior segment.

Radiological investigations (X-Ray or CT scans) are required in cases of suspected intraocular foreign body, blowout fracture of the orbit, or head injury. Ultrasound

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biomicroscopy can identify suspected anterior segment injury not clearly visible on clinical examination. Ultrasound biomicroscopy is a proven ancillary tool useful for

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ruling out angle recession, iridodialysis or cyclodialysis cleft, and occult foreign body in the anterior chamber.

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4. Complications

a. Increased intraocular Pressure (IOP)

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Almost 30% of patients with post-traumatic hyphema have an increased IOP22. An acute rise in IOP occurs from obstruction of the trabecular meshwork by

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erythrocytes, fibrin, debris, and platelets. The likelihood of increased IOP is proportionate to the severity of hyphema17. Secondary glaucoma is seen in 10% of eyes with ≤50% hyphema, 25% if there is >50% hyphema, and 50% if the hyphema is total79. Patients with eight-ball hyphema carry a 100% risk of secondary glaucoma; however, eight-ball hyphema is rarely encountered.

Late secondary glaucoma may develop weeks to years after hyphema. The incidence of late-onset glaucoma in eyes with a history of traumatic hyphema

ACCEPTED MANUSCRIPT ranges from 0–20%10,102,103. The main causes of late onset glaucoma are peripheral anterior synechiae formation, increased outflow resistance in angle recession, fibrosis of the trabecular meshwork, and siderosis of the trabecular

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endothelium.

Gonioscopic evaluation is recommended conventionally after seven to eight days after resolution of hyphema to rule out angle recession; however, like indentation, we

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prefer to wait for several weeks before attempting gonioscopy. Up to 10% of patients are prone to develop late-onset glaucoma if the degree of angle recession exceeds

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180°12,70,102,103. Angle recession in excess of 270° would further i ncrease the risk of glaucoma. Blanton described two periods of elevated IOP, between 2 months and 2 years after the injury and 10 to 15 years after injury. Careful gonioscopy has revealed that between 71% and 86% of traumatized eyes have angle recession46.

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The degree of angle recession is not proportional to the amount of hyphema. Some small hyphemas produce large, deep recessions. A recent review by Ng et al demonstrated a statistically significant association between angle recession greater

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than 180° and the development of glaucoma 46. It has already been recognised in earlier literature that this group of patients should undergo lifelong annual

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examination to detect late-onset glaucoma67; however, there is no consensus in the literature regarding the frequency of follow-up required for patients with angle recession of less than 180 degrees.

b. Rebleeding (secondary hemorrhage)

ACCEPTED MANUSCRIPT Rebleeding or secondary hemorrhage occurs in 0.4% to 35% of patients, usually 2-7 days after trauma73,85. This is attributed to lysis and retraction of clot and fibrin within traumatized vessels as part of the subacute healing process40.

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It is important to arrange early follow-up to detect this condition as it can significantly alter the visual prognosis through serious complications such as corneal blood staining, amblyopia, secondary glaucoma, and optic atrophy.

to 67%

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Estimates of the incidence of glaucoma with rebleeding are high, ranging from 45 23,42

. Rebleeding can be recognized clinically by the following

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characteristics.

(i) An increase in the size of the hyphema

(ii) Presence of a layer of fresh blood over the older, darker clot in the anterior

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chamber

(iii) Dispersed erythrocytes over the clot after the blood has settled.

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Total and near total hyphemas often appear dark red. Their color lightens as they start to liquefy and resolve as part of the normal healing process. This change in

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colour should be distinguished from secondary hemorrhage. A significant reduction of vision (<20/200), an initial hyphema of more than one third of the anterior chamber, and elevated IOP at presentation are significant risk factors for secondary bleeding59. One-fourth of the patients with grade I hyphemas experience rebleeding into the anterior chamber of the eye, as compared with twothirds of patients with grade III or IV hyphema54.

ACCEPTED MANUSCRIPT There has been shown to be an association of rebleeding with race

44,79

. The rates of

rebleed are higher in darker skinned persons, especially African Americans, when compared with Caucasians. One hypothesis is that melanin interferes with the

rebleeding rates47.

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clearance of erythrocytes from the anterior chamber, causing these differences in

Patients with haemophilia, von Willebrand’s disease, and sickle cell trait also have

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c. Corneal blood staining

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higher risk of secondary haemorrhage44,68.

Corneal blood staining (Figure 5) after hyphema has been reported in 2-11% of cases11,79,82. The incidence increases in the presence of larger hyphemas, secondary hemorrhage, prolonged clot retraction, sustained increase in IOP and

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presence of previous endothelial dysfunction22,40,80. Read and Goldberg81 found that an IOP of 25mmHg or greater for more than 6 days significantly increases the risk of developing corneal blood staining. They subsequently proposed surgical intervention

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in cases where the hyphema does not decrease by 50% after day 680. Corneal blood

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staining starts as central straw yellow discoloration of the deep stroma which spreads peripherally. Blood staining causes endothelial decompensation by mechanical disruption of the endothelium and also by photosensitization of the endothelium by hemoglobin-derived porphyrins in the presence of light39,40. The blood staining clears centripetally and may take anywhere from several months to 2 years to clear15,19. In children, corneal blood staining may be further complicated by amblyopia15.

ACCEPTED MANUSCRIPT d. Optic atrophy In the setting of post -traumatic hyphema, optic atrophy may develop secondary to traumatic nerve contusion or secondary glaucoma.

The risk of developing optic

atrophy related to elevated intraocular pressure is greater if the pressure is allowed

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to remain at 50 mmHg or more for 5 days or 35 mmHg or more for 7 days in otherwise healthy individuals81. Patients with sickle cell disease/trait develop optic

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atrophy at lower intraocular pressures90. 5. Management of hyphema

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The management of traumatic hyphema is directed towards accelerating the absorption of the blood and the prevention of complications detailed above. There is no conclusive evidence that hospital admission, sedation, or complete bed rest with eye patching improves outcomes22,34,81,110 The indications and advantages of various

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management options are discussed below.

Bed rest: Some clinicians advocate strict bed rest in hyphema to decrease the chances of secondary haemorrhage; however, studies do not support this and most

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have shown no advantage of bed rest over quiet ambulation10,81. Hospitalization and

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strict bed rest is mainly advised for patients with severe hyphema, sickle cell trait/disease,

non-compliant

patients,

children,

and

patients

with

bleeding

predisposition92,110. Head elevation allows blood to layer inferiorly. This will promote visual rehabilitation and prevent clot formation in the pupillary axis. Eye patching: Traditionally, eye patching with metal shield protection was advocated until resolution of hyphema. It was believed that the patching increases patient comfort and provides immobilization for proper healing of corneal abrasions if any. Gottsch et al39,40 hypothesised that patients with longstanding hyphema and

ACCEPTED MANUSCRIPT prolonged light exposure might be at risk of developing endothelial dysfunction and corneal bloodstaining. Although there is no evidence in the literature to support these claims34, it is still recommended that patients with hyphema wear a hard plastic shield at all times (including sleep) for the practical purpose of preventing further

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trauma to the injured eye.

Anti-coagulant and anti-platelet medications: Anti-coagulant (e.g. warfarin sodium, heparin) and anti-platelet (e.g. aspirin, dipyridamole, clopidogrel)

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medications have not been shown to increase the risk of spontaneous haemorrhage

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during intraocular surgery7,27,48. Hence, they do not have to be stopped prior to this type of surgery. After the occurrence of a hyphema, however, these medications are at risk factors for its persistence or re-bleeding. The risk of bleeding complications of anticoagulant medications have been reported to be significantly greater than that of antiplatelet medications87. Common indications for anti-coagulation therapy include

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atrial fibrillation, prosthetic heart valves, and deep vein thrombosis. Anti-platelet therapy is commonly indicated for the prevention of acute cardiac and

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cerebrovascular events in at-risk patients87. Therefore, the decision to stop these medications after the occurrence of hyphema must be made on a case-by-case

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basis in consultation with the patient’s primary care physician. Evaluation of the patient’s suitability to stop or reduce these medications involves consideration of the desired therapeutic international normalized ratio (INR) range for the patient’s medical condition, co-existing medical conditions which may further affect clotting ability (e.g. chronic liver disease, bone marrow suppression), and the time taken for normal clotting and coagulation to be restored after stopping these medications.

ACCEPTED MANUSCRIPT a. Medical management: Mydriatics and cycloplegics: Most studies have not found that the use of mydriatics or cycloplegics in hyphema improves the final visual acuity or prevents the occurrence of complications such as re-bleeding10,34,35,69,81. The use of cycloplegic

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agents such as topical atropine (an antimuscarinic cycloplegic) decreases the risk of development of posterior synechiae, provides greater comfort in patients with concurrent iritis, and permits visualization of the posterior pole35. They also have the

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theoretical benefit of reducing the risk of secondary hemorrhage from the iris/ ciliary body by immobilizing these tissues, increasing uveo-scleral flow, and preventing the

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formation of posterior synechia35. Current recommendations are to use atropine sulphate drops three times a day for two weeks; however, optimal dosage has yet to be established through formal clinical studies34 and less frequent dosing should suffice as long as adequate cycloplegia is maintained. That being said, cycloplegics

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must be used cautiously in patients with narrow angles. Antifibrinolytic agents: Antifibrinolytic agents such as trans-hexamic acid and

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aminocaproic acid (ACA) have been proven to lower significantly the rate of rebleeding after traumatic hyphema84,85; however, in most studies, antifibrinolytic

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agents do not offer any major advantage in preventing most of the complications related to hyphema, and may possibly delay clot resorption34. ACA, a lysine analogue, competitively inactivates plasmin, thereby preventing clot lysis by stabilizing the interface between the clot and vessel wall. Studies reveal that topical ACA is as effective as systemic ACA in reducing the incidence of rebleeding8. In some studies, ACA was found to decrease the incidence of rebleeding from 22– 33% to 0–4%21,66,109. Crouch and Crouch19 recommended using either systemic ACA

ACCEPTED MANUSCRIPT (50 mg/kg for 5 days with a maximum dose of 30 g/d) or topical ACA, 1 drop every 4 hours in the affected eye for 5 days in patients with hyphema. Topical ACA is safer because it does not cause side effects of systemic ACA such as nausea, vomiting, and hypotension8,19. The use of ACA is contraindicated in pregnancy (as it is a

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teratogen), with renal or hepatic dysfunction, hand in patients with high thromboembolic risk8,19. Trans-hexamic acid, another lysine analogue, has also been shown to inhibit clot fibrinolysis at the site of injured blood vessels8. We recommend

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routine prescription of antiemetics with these drugs if systemic preparations are

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used.

Corticosteroids: Topical corticosteroids are useful in preventing rebleeds. They may stabilize the blood-ocular barrier, thereby reducing the influx of plasminogen into the anterior chamber8,84,85. In addition, the anti-inflammatory activity of steroids reduces posterior synechiae formation34. In a retrospective review of 462 patients

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treated over 10 years, Ng et al69 found a statistically significant decreae in the frequency of secondary hemorrhage among patients treated with topical steroids. A

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5% rebleeding rate was seen for the group of patients treated with topical steroids (with or without cycloplegics) vs. a 12% rebleeding rate for the group treated without

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topical steroids (with or without cycloplegics). Although a short course of topical steroids is recommended as a first line therapy for hyphema, they should not be used on a long term basis due to the risk of steroid-induced glaucoma. The role of oral steroids however still remains controversial74,84,85. Romano et al84 have suggested that use of a systemic steroid regimen in the Yasuna “No Touch” and “No Touch PLUS” protocols, provide the best results in non-Scandinavian populations. This protocol, first implemented in 1967, uses 40 mg/d of oral prednisone in divided doses for adults and corresponding doses by weight for

ACCEPTED MANUSCRIPT children (approximately 0.6 mg/kg). In a series of studies using the Yasuna protocol, the rebleed rate for all patients combined was 0.7%. Farber et al30 showed that patients treated with systemic steroids had an incidence of secondary hemorrhage equal to that of patients treated with systemic ACA. Further randomized controlled

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trials are required to determine the efficacy of systemic corticosteroids compared with systemic ACA. From our perspective, oral prednisone can be a reasonable alternative to antifibrinolytic therapy for patients with high re-bleeding risk (Table 2).

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For instance, in patients with von Willebrand disease, elevated IOP associated with the primary or secondary bleed can lead to grave consequences, and oral

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corticosteroid therapy should be considered. This is particularly relevant in patients with sickle cell disease or other intravascular clotting disorders and in pregnant patients, as aminocaproic acid is contraindicated and cannot be prescribed. Anti-glaucoma medication: Elevated IOP (greater than 24 mm Hg) can be with

topical

beta-blockers

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controlled

and

carbonic

anhydrase

inhibitors8.

Acetazolamide lowers plasma pH, which promotes sickling of erythrocytes8. Therefore, methazolamide is preferred in patients with sickle cell trait or anemia, as it

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has a lower propensity for metabolic acidosis compared to acetazolamide20. Severe,

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uncontrolled IOP (greater than 35 mmHg) may require additional systemic medication. 1-1.5g/Kg of mannitol may be administered intravenously over 45 minutes twice a day19. Systemic osmotics should be used cautiously in renal dysfunction because they can lead to hemoconcentration. Aspirin and NSAIDS: The use of aspirin and other NSAIDS significantly increases the risk of secondary haemorrhage owing to their antiplatelet effect18. The decision to stop these medications have to be made in discussion with the patient’s general physician.

ACCEPTED MANUSCRIPT b. Surgical Management: Our experience is consistent with current evidence that surgical management is only warranted in a small proportion of carefully selected patients, approximately 5% to 7.2% of all patients with hyphema10,80,98. As a rule, patients with true eight-ball

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hyphemas require prompt surgical intervention. In other cases it is required only if medical therapy fails (Table 3). Clinical indications for surgical evacuation are persistently elevated intraocular pressure, corneal blood staining, and high grade

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hyphema. These parameters should therefore be monitored and recorded in the clinical evaluation and follow-up of these patients. We recommend that surgical

Goldberg26,81 as follows: 1. 2.

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evacuation be considered according to the empirical criteria proposed by Read and

IOP greater than 60 mm Hg for 2 days (to prevent optic atrophy). IOP greater than 24 mm Hg over the first 24 hours or if repeated IOP spikes

3.

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more than 30 mm Hg in sickle cell disease or trait. IOP greater than 25 mmHg with a total hyphema for 5 days (to prevent corneal

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bloodstaining).

Microscopic corneal bloodstaining.

5.

The hyphema fails to resolve to less than 50% of the anterior chamber volume

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4.

by 8 days (to prevent peripheral anterior synechiae formation). There are varied surgical modalities for management of hyphema depending on the severity and density of hyphema. These will be elaborated on in the following section. Anterior chamber washout and clot removal: The most common surgical approach used is the limbal paracentesis needle drainage. Surgeons may opt to do this as an outpatient procedure. A 27-gauge needle attached to a tuberculin syringe

ACCEPTED MANUSCRIPT may be used to aspirate the blood slowly. This will only remove liquefied portions of the clot, but is often sufficient to normalise the IOP and restore aqueous flow. Anterior chamber washout using an irrigating Simcoe cannula can be done if the hyphema has not yet organized. When managing organized hyphema, anterior

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chamber washout using an automated anterior vitrectomy through limbal or clear corneal incisions can be performed. Vitrectomy can debulk the clot without shearing the anatomical structures and causing re-bleed. Anterior chamber stability must be

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maintained (by raising the height of the bottle and through use of cohesive viscoelastic agents) and hypotony should be avoided to minimize subsequent

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bleeding. The infusion port can be used to maintain a constant irrigation and the clot cut and aspirated with the help of a vitrectomy cutter introduced through a clear corneal incision. Care should be taken to avoid iatrogenic trauma to the lens, iris, or corneal endothelium.

Viscodissection can be used to separate the adherent

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hyphema from underlying iris. Also, the settings of the vitrector should be on irrigate - cut – aspirate (ICA) rather than irrigate-aspirate-cut (IAC) as the latter setting may result in rebleeding due to traction on the clot and blood vessels. An eight-ball

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hyphema can be removed with the conventional limbal clot delivery method.

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Trabeculectomy and iridectomy: Trabeculectomy and iridectomy are useful adjuncts with clot removal in management of clots associated with large hyphema. Trabeculectomy modulated with either mitomycin C or 5-flurouracil can be combined with clot expression in patients with glaucoma not controlled by maximal medical therapy41,107. Glaucoma shunts as a primary procedure have shown promising results in such cases as well. However this surgery can be complicated by postoperative hypotony, choroidal effusion and secondary haemorrhage41 and is best reserved for patients with intractable glaucoma.

ACCEPTED MANUSCRIPT In summary, the various surgical methods are associated with significant risks, including damage to corneal endothelium, lens injury, prolapse of intraocular contents, and rebleeding88. Hence surgical management should be reserved for

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carefully selected patients at high risk of developing sight threatening complications.

c. Hospitalization and Follow-up: There are no standardised guidelines for the

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admission of a patient with hyphema and similarly for frequency of follow-up visits. Both hospitalization and follow up are governed by the degree of hyphema and risk

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of rebleeding3,91,110. Patients with high grade hyphema or high risk of rebleed (Table 2) may be admitted for daily examination and close monitoring. Other patients will benefit from close outpatient follow up on day 2 and 7, to allow early detection of rebleeding (which can occur in up to one third of patients) or indications for surgical

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intervention (as outlined in the previous section). Subsequently, once hyphema has resolved and the patient is no longer on topical medication, physicians can safely opt for quarterly follow up to monitor intraocular pressure92. Based on presence or

EP

absence of raised intraocular pressure, optic nerve damage, or angle recession,

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attending physicians can gradually lengthen follow up intervals.

d. Screening for sickle cell disease or trait in patients of African descent: Patients with sickle cell disease or trait have a higher incidence of secondary hemorrhage, increased IOP, and optic atrophy in the setting of traumatic hyphema compared to non-sickle cell patients55,68,90,106. Hence, screening is warranted in patients of African descent90. Even low grade hyphema can lead to significant

ACCEPTED MANUSCRIPT impairment of aqueous outflow, intractable increase in intraocular pressure, and optic neuropathy in sickle cell disease, posing a serious threat to vision90.

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6. SPECIAL SITUATIONS a. Sickle cell hemoglobinopathies: As outlined above, patients with sickle cell disease are at significantly elevated risk of developing complications of hyphema.

SC

These patients have been found to have enhanced fibrinolysis which explains the predisposition to secondary hemorrhage43. Furthermore, sickled erythrocytes face

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greater resistance in passing through the outflow channels of the trabecular meshwork, as they are less pliable than normal biconcave erythrocytes. Hence they slow the process of hyphema resolution, and lead to exaggerated increase in IOP37,38. Making matters worse, patients with sickle cell disease are susceptible to

of high pressures76.

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vascular occlusion at relatively low intraocular pressures or relatively brief durations

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Medical treatment of glaucoma poses a serious challenge in these patients as most commonly used systemic agents are contraindicated36. Use of hyperosmotic/ diuretic

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agents (e.g., glycerine, isosorbide, and mannitol) should be avoided, as they may cause

hemoconcentration

and

increased

blood

viscosity

in

the

ocular

microvasculature31,36.

Systemic carbonic anhydrase inhibitors (CAI) cause systemic acidosis in addition to the hemoconcentration, which increases erythrocyte sickling31. ACA, a CAI, increases the concentration of ascorbic acid in aqueous humor and exacerbates the sickling process. This is postulated to be due to it acting as a reducing agent4.

ACCEPTED MANUSCRIPT A literature search did not reveal any definitive evidence for the risk of systemic acidosis and hemoconcentration in topical CAI; however, it has been reported that their

local

efficacy

may

be

less

than

that

of

their

systemic

counterparts24.Methazolamide is the only systemic drug reported to be used safely

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for increased IOP in hyphema with background sickle cell disease20.

In conclusion, we recommend treating hyphema aggressively in this subgroup of patients. The IOP should be kept low by using a combination of topical drugs such

SC

as timolol, apraclonidine, or brimonidine. Systemic therapy with methazolamide can be considered in recalcitrant cases. Surgical intervention should be instituted earlier

damage26.

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and at lower IOP thresholds than normal patients in order to prevent optic nerve

b. Management of hyphema in children management

of

hyphema

in

infants

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The

and

children

requires

special

considerations. First, the possibility of non-accidental injury (NAI) or abuse must be considered.

Furthermore,

non-traumatic

etiologies

of

hyphema

such

as

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retinoblastoma, juvenile xanthogranuloma of the iris, and bleeding diathesis from blood dyscrasias such as leukemia should also be explored.

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Hyphema is a common admitting diagnosis in children sustaining ocular trauma25. Injury with toys (balls, stones, projectiles) is the predominant etiology22. The rate of rebleeding of hyphema in children is similar to that in adults15,22,52. In the past, hospitalization had been recommended for the first few days after the injury15,22,28,52,69; however, few ophthalmologists would advocate hospitalisation for hyphema today. Instead, patients can be discharged with emphasis and advice on strict avoidance of physical activity. Children younger than 5 years of age are more

ACCEPTED MANUSCRIPT likely to develop long term visual impairment secondary to amblyopia from visual deprivation by media opacity (hyphema, traumatic cataract, or corneal blood staining)11. Minimizing the interval between the injury and the restoration of media clarity is hence a priority in these patients. Monocular occlusion after injury to protect

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against further mechanical injury should be minimized, as the expected benefit from an occlusive dressing must be weighed against the risk of inducing amblyopia in young children.

SC

Some authors report the use of systemic steroids with or without topical steroids, instead of aminocaproic acid, in managing children with traumatic hyphema. This

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was done with the rationale to control inflammation and reduce the risk of secondary haemorrhage86; however, because of the potential for systemic steroids to interfere with growth, we do not recommend this. Final visual outcome and prognosis of

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hyphema in children remains similar to adult patients15,22,25.

c. Hyphema associated with cataract and refractive surgery:

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Cataract surgery may also be associated with various degrees of hyphema64,95 from either surgical trauma or erosion by the haptic of the intraocular lens into the iris.

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With manual small incision cataract surgery, there may be hypotony from poor approximation of wound on the first postoperative day associated with a complete hyphema. With more and more anterior chamber implantable lenses available, there is an increase in incidence of hyphema. Some peculiar syndromes described with cataract surgery and associated hyphema are as follows: Swan syndrome: Characterized by recurrent intraocular bleeds even months to years after cataract surgery involving a scleral incision99 Swan syndrome usually

ACCEPTED MANUSCRIPT presents with blurred vision with associated mild to moderate degree of pain. On examination there is hyphema and/or vitreous hemorrhage and neovascularisation of the angle that is best managed by either focal argon laser photocoagulation or direct diathermy of the new vessels or surgical excision of the vessels or scleral wound

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resuturing. With clear corneal incision cataract surgery becoming more widely used, the incidence of this syndrome has reduced greatly; however, in developing countries where manual small incision cataract surgery is still performed, one may

SC

need to consider this entity in cases of recurrent hyphema seen post cataract

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surgery.

d. Uveitis with hyphema: Anterior uveitis has been described to be associated with hyphema in cases of Reiter syndrome, juvenile chronic arthritis, ankylosing

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spondylitis, idiopathic anterior uveitis and Herpes simplex. In these cases, hyphema has been found to be associated with increased inflammation. Conservative management with topical steroids is the treatment of choice. Bleeding in the anterior

EP

chamber (Amsler sign) following paracentesis has been described in Fuchs heterochromic iridocyclitis (FHI)29 and is also seen in other uveitic cases following

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anterior chamber decompression. Although not pathognomonic for FHI, Amsler sign often occurs in FHI from rupturing of the fine rubeotic vessels crossing the trabecular meshwork. These fragile vessels may also lead to hyphema secondary to pressure from gonioscopy or applanation tonometry.

7. Outcome measures Proposed primary outcome measures that can be evaluated in the management of hyphema are visual acuity and stage of hyphema. Secondary outcome measures

ACCEPTED MANUSCRIPT include the incidence of complications such as corneal blood staining, ocular hypertension requiring surgical intervention, optic atrophy, and re-bleeding. Poor visual outcome following resolution of hyphema is often attributed to associated injuries from blunt trauma, and is less commonly directly from

poorer than subtotal hyphema11,79,81.

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hyphema14,49,69.71,77,97,105. Visual outcomes following total hyphema are generally

Varying incidence of glaucoma has been reported in patients with and without

SC

rebleeding, with a significantly higher risk in patients with

rebleeding16,23,42,45,51,60,62,89,101. Read and Goldberg81 found optic atrophy without

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glaucomatous damage in 6% of eyes in a series of 135 cases. Corneal blood staining occurs in 2-11% of cases of traumatic hyphemas11,17,81,88. Reported incidence of secondary hemorrhage varies from 2% to 37%

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5,13,20,21,30,50,54,55,56,58,68,72,77,81,83,88,93,100

8. Conclusions and recommendations

EP

In summary, hyphema is a common clinical condition that carries a good visual prognosis if managed timely and appropriately (Table 4). A careful systemic and

AC C

ophthalmic examination to rule out any associated injuries is important. It is also imperative to rule out a history of sickle cell disease or trait, particularly in African patients with hyphema. Most patients can be followed-up as outpatients on day 2 and 7, with admission reserved for patients with high grade hyphema or high risk of re-bleeding. The primary aim of treatment is to prevent the development of complications. Supportive treatment and medical management with cycloplegics and topical steroids are the mainstay of treatment. Anti-fibrinolytic agents such as ACA remain

ACCEPTED MANUSCRIPT an alternative to topical steroids in certain patients, such as children or those with a history of steroid-induced glaucoma; however, if systemic treatment is used, we recommend co-prescription of anti-emetic. Physicians must also remember to exclude contraindications such as history of intravascular clotting disorders, or

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pregnancy.

Surgical intervention is reserved for patients whom are nonresponsive to medical therapy or at high risk of complications that lead to visual impairment. Secondary

SC

hemorrhage and glaucoma are the most common complications. Secondary

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glaucoma can develop even years after the initial insult, hence the importance of routine quarterly follow up visits after the primary condition has resolved. Hyphema in children is best managed by head elevation and refrain from physical activity, along with medical management. Shielding the eye should be considered to

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prevent further mechanical trauma to the eye during the initial healing process. Attending physicians must also be aware of special conditions and syndromes associated with hyphema which impact management strategy. For instance, rare

EP

entities such as sickle cell disease and blood dyscrasias should be kept in mind, especially in patients that develop intractable hyphemas.

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Methods of literature search:

Articles were selected for review using a search in pubmed, scopus and medline database

using

"hyphema"[MeSH

the

key

Terms]

words: OR

Hyphema:

"hyphema"[All

"hyphaema"[All

Fields];

Traumatic

Fields]

OR

hyphema:

traumatic[All Fields] AND ("hyphaema"[All Fields] OR "hyphema"[MeSH Terms] OR "hyphema"[All Fields]); Spontaneous hyphema: spontaneous[All Fields] AND ("hyphaema"[All Fields] OR "hyphema"[MeSH Terms] OR "hyphema"[All Fields]).

ACCEPTED MANUSCRIPT

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Conflict of interest statement:

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational

SC

grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing

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arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

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Disclosure: No financial disclosure or conflict of interest. RA is supported by Clinician Scientist Career Scheme grant awarded by National Healthcare Group,

AC C

EP

Singapore.

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FM

II.Traumatic

Ophthalmology.1980;87:910.

hyphema:

Pathogenesis

and

management.

ACCEPTED MANUSCRIPT 109.

Wilson TW, Jeffers JB, Nelson LB. Aminocaproic acid prophylaxis in traumatic

hyphema. Ophthalmic Surg.1990;21:807–9. 110.

Wilson TW, Nelson LB, Jeffers JB, et al. Outpatient management of traumatic

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hyphemas. Ann Ophthalmol.1990;22:366.

ACCEPTED MANUSCRIPT Table 1: Grading of Hyphema

Micro-

in AC

picture

Circulating RBC’s only

<1/3rd of AC

II

1/3-1/2 of AC

EP

>1/2 of AC

AC C

III

TE D

I

IV

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hyphema

Diagrammatic representation & clinical

Volume of blood

RI PT

Grade

Total

ACCEPTED MANUSCRIPT Table 2: High risk factors for rebleed in a patient with hyphema

Sickle cell trait or anemia

2

Secondary hemorrhage

3

Penetrating ocular trauma

4

Suspected child abuse

5

Grade III or IV hyphema

6

Non-compliant patients

7

Intractable glaucoma

AC C

EP

TE D

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SC

1

RI PT

Predisposing high risk factor

ACCEPTED MANUSCRIPT Table 3: Indications for surgical intervention for hyphema Clinical indications for surgical intervention

1

Microscopic corneal blood staining In sickle cell trait or sickle cell disease, hyphemas of any size and IOP > 24 mm Hg for more than 24 hours


RI PT

2

Hyphema >1/2 of the anterior chamber for > 8 days (to prevent 3 peripheral anterior synechiae)


SC

Total hyphema with IOP of >50 mm Hg for 4 days (to prevent optic 4

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atrophy)

Total hyphema or >3/4 of anterior chamber volume present for 6 days 5

AC C

EP

TE D

with IOP of > 25 mm Hg (to prevent corneal blood staining)

ACCEPTED MANUSCRIPT Table 4: Pearls in management of hyphema All patients of hyphema should be evaluated in detail for systemic injuries A and retained IOFB B

Absolute bed rest and hospitalization is not mandatory

RI PT

Topical steroids and cycloplegics are used frequently for initial control of C inflammation and rebleed D

Beta blockers and prostaglandin analogues should be used to control IOP

SC

Avoid carbonic anhydrase inhibitors, alpha agonists and hyperosmotics in E Sickle cell disease/trait

Most aggressive treatment is needed to prevent optic nerve damage

G

Recurrent haemorrhage can occur 2-7 days after trauma

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F

Regular ophthalmic evaluation is required in patients with angle recession H

AC C

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TE D

> 180 degrees

ACCEPTED MANUSCRIPT Figure Legends: Figure 1: Total Hyphema associated with occult scleral dehiscence Figure 2: Hyphema associated with open globe injury and iris prolapse (2A) and

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hyphema post primary corneal laceration repair (2B) Figure 3: Different shades of red: Old traditional terminology is based on black (8th) ball of snooker (3E), however as seen in 3B and 3C, there is presence of more

of snooker (3A).

AC C

EP

TE D

Figure 5: Corneal blood staining

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Figure 4: Presence of Iridodialysis with Hyphema

SC

bright red colour and dull red colour in 3D which closely resembles Red (3rd or 11th)

ACCEPTED MANUSCRIPT

AC C

EP

TE D

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SC

RI PT

Figure 1: Total Hyphema associated with occult scleral dehiscence

ACCEPTED MANUSCRIPT Figure 2: Hyphema associated with open globe injury and iris prolapse (2A) and

AC C

EP

TE D

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SC

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hyphema post primary corneal laceration repair (2B)

ACCEPTED MANUSCRIPT Figure 3: Different shades of red: Old traditional terminology is based on black (8th) ball of snooker (3E), however as seen in 3B and 3C, there is presence of more bright red colour and dull red colour in 3D which closely resembles Red (3rd or 11th)

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SC

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of snooker (3A).

AC C

EP

TE D

Figure4: Presence of Iridodialysis with Hyphema

ACCEPTED MANUSCRIPT

AC C

EP

TE D

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Figure 5: Corneal blood staining