Medical interventions for traumatic hyphema

Almutez Gharaibeh; Howard I Savage; Roberta W Scherer; Morton F Goldberg; Kristina Lindsley

doi:10.1002/14651858.CD005431.pub4

. 2019 Jan 14;2019(1):CD005431. doi: 10.1002/14651858.CD005431.pub4

Medical interventions for traumatic hyphema

Almutez Gharaibeh ¹, Howard I Savage ², Roberta W Scherer ^3,^✉, Morton F Goldberg ⁴, Kristina Lindsley ³

Editor: Cochrane Eyes and Vision Group

PMCID: PMC6353164 PMID: 30640411

Abstract

Background

Traumatic hyphema is the entry of blood into the anterior chamber (the space between the cornea and iris) subsequent to a blow or a projectile striking the eye. Hyphema uncommonly causes permanent loss of vision. Associated trauma (e.g. corneal staining, traumatic cataract, angle recession glaucoma, optic atrophy, etc.) may seriously affect vision. Such complications can lead to permanent impairment of vision. People with sickle cell trait/disease may be particularly susceptible to increases of elevated intraocular pressure. If rebleeding occurs, the rates and severity of complications increase.

Objectives

To assess the effectiveness of various medical interventions in the management of traumatic hyphema.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 6); MEDLINE Ovid; Embase.com; PubMed (1948 to June 2018); the ISRCTN registry; ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The date of the search was 28 June 2018.

Selection criteria

Two review authors independently assessed the titles and abstracts of all reports identified by the electronic and manual searches. In this review, we included randomized and quasi‐randomized trials that compared various medical (non‐surgical) interventions versus other medical intervention or control groups for the treatment of traumatic hyphema following closed‐globe trauma. We applied no restrictions regarding age, gender, severity of the closed‐globe trauma, or level of visual acuity at the time of enrollment.

Data collection and analysis

Two review authors independently extracted the data for the primary outcomes, visual acuity and time to resolution of primary hemorrhage, and secondary outcomes including: secondary hemorrhage and time to rebleed; risk of corneal blood staining, glaucoma or elevated intraocular pressure, optic atrophy, or peripheral anterior synechiae; adverse events; and duration of hospitalization. We entered and analyzed data using Review Manager 5. We performed meta‐analyses using a fixed‐effect model and reported dichotomous outcomes as risk ratios (RR) and continuous outcomes as mean differences (MD).

Main results

We included 20 randomized and seven quasi‐randomized studies with a total of 2643 participants. Interventions included antifibrinolytic agents (systemic and topical aminocaproic acid, tranexamic acid, and aminomethylbenzoic acid), corticosteroids (systemic and topical), cycloplegics, miotics, aspirin, conjugated estrogens, traditional Chinese medicine, monocular versus bilateral patching, elevation of the head, and bed rest.

We found no evidence of an effect on visual acuity for any intervention, whether measured within two weeks (short term) or for longer periods. In a meta‐analysis of two trials, we found no evidence of an effect of aminocaproic acid on long‐term visual acuity (RR 1.03, 95% confidence interval (CI) 0.82 to 1.29) or final visual acuity measured up to three years after the hyphema (RR 1.05, 95% CI 0.93 to 1.18). Eight trials evaluated the effects of various interventions on short‐term visual acuity; none of these interventions was measured in more than one trial. No intervention showed a statistically significant effect (RRs ranged from 0.75 to 1.10). Similarly, visual acuity measured for longer periods in four trials evaluating different interventions was also not statistically significant (RRs ranged from 0.82 to 1.02). The evidence supporting these findings was of low or very low certainty.

Systemic aminocaproic acid reduced the rate of recurrent hemorrhage (RR 0.28, 95% CI 0.13 to 0.60) as assessed in six trials with 330 participants. A sensitivity analysis omitting two studies not using an intention‐to‐treat analysis reduced the strength of the evidence (RR 0.43, 95% CI 0.17 to 1.08). We obtained similar results for topical aminocaproic acid (RR 0.48, 95% CI 0.20 to 1.10) in two studies with 121 participants. We assessed the certainty of these findings as low and very low, respectively. Systemic tranexamic acid had a significant effect in reducing the rate of secondary hemorrhage (RR 0.31, 95% CI 0.17 to 0.55) in five trials with 578 participants, as did aminomethylbenzoic acid as reported in one study (RR 0.10, 95% CI 0.02 to 0.41). The evidence to support an associated reduction in the risk of complications from secondary hemorrhage (i.e. corneal blood staining, peripheral anterior synechiae, elevated intraocular pressure, and development of optic atrophy) by antifibrinolytics was limited by the small number of these events. Use of aminocaproic acid was associated with increased nausea, vomiting, and other adverse events compared with placebo. We found no evidence of an effect in the number of adverse events with the use of systemic versus topical aminocaproic acid or with standard versus lower drug dose.

The number of days for the primary hyphema to resolve appeared to be longer with the use of systemic aminocaproic acid compared with no use, but this outcome was not altered by any other intervention.

The available evidence on usage of systemic or topical corticosteroids, cycloplegics, or aspirin in traumatic hyphema was limited due to the small numbers of participants and events in the trials.

We found no evidence of an effect between a single versus binocular patch or ambulation versus complete bed rest on the risk of secondary hemorrhage or time to rebleed.

Authors' conclusions

We found no evidence of an effect on visual acuity by any of the interventions evaluated in this review. Although evidence was limited, it appears that people with traumatic hyphema who receive aminocaproic acid or tranexamic acid are less likely to experience secondary hemorrhaging. However, hyphema took longer clear in people treated with systemic aminocaproic acid.

There is no good evidence to support the use of antifibrinolytic agents in the management of traumatic hyphema other than possibly to reduce the rate of secondary hemorrhage. Similarly, there is no evidence to support the use of corticosteroids, cycloplegics, or non‐drug interventions (such as binocular patching, bed rest, or head elevation) in the management of traumatic hyphema. As these multiple interventions are rarely used in isolation, further research to assess the additive effect of these interventions might be of value.

Plain language summary

Medical interventions for traumatic hyphema

What is the aim of this review?  The aim of this Cochrane Review was to find out what medical treatments are effective for traumatic hyphema, a condition in which blood collects in the eye following trauma, usually a blow to the eye. We collected and analyzed all relevant studies to answer this question.

Key messages  We found no evidence that any medical intervention affected vision, whether measured within a few weeks or longer. We also found that no medical intervention resulted in fewer complications from the hyphema itself, although this evidence is weak because few events occurred. We found limited evidence that antifibrinolytics, drugs that affect how blood is clotted, reduced the risk of new bleeding in the eye.

What was studied in the review?  It was important to evaluate current medication interventions for traumatic hyphema because complications from the condition can affect final vision. We found 27 studies with a total of 2643 participants addressing this question. Studies were from the USA, Canada, Sweden, Denmark, China, South Africa, Malysia, Iran, and Israel. The studies included more males than females, and participants tended to be children or young adults. Interventions included antifibrinolytic agents taken orally or applied directly to the eye (aminocaproic acid, tranexamic acid, and aminomethylbenzoic acid), oral or topical corticosteroids, other kinds of eyedrops, aspirin, estrogens, traditional Chinese medicine, patching, elevation of the head, and bed rest. Most studies looked at how often fresh bleeding occurred, because this secondary bleeding is often associated with more complications. Other outcomes examined included visual acuity and the length of time it took for the blood in the eye to be absorbed.

What are the main results of the review?  We found no evidence that any medical intervention affected final vision, but we graded the evidence as generally of low certainty. Antifibrinolytic agents did appear to reduce the risk of new bleeding in the eye, but participants taking oral aminocaproic acid (an antifibrinolytic agent) appeared to have more nausea and vomiting compared with participants in the control group. It was unclear whether antifibrinolytics reduced complications of secondary bleeding, because these events were infrequent in the studies. We found no evidence for effectiveness of any other medical intervention in reducing the rate of fresh bleeding or the number of complications, but the evidence for a beneficial effect of any of these interventions was uncertain because the numbers of participants and events were small.

How up‐to‐date is this review?  We reviewed studies published up to 28 June 2018.

Summary of findings

Background

Description of the condition

Introduction

Traumatic hyphema is the entry of blood into the anterior chamber (the space between the cornea and iris) subsequent to a blow or a projectile striking the eye. Apart from the direct consequences of the initial trauma, traumatic hyphema is usually a self limiting condition that rarely causes permanent loss of vision in the absence of associated damage to the cornea, lens, or optic nerve. Traumatic hyphema is an important clinical entity because of the risks associated with significant initial reduction in vision and because of associated injuries to the tissues of the eye. In young children, it can lead to the development of irreversible amblyopia. Complications resulting from secondary hemorrhage, such as glaucoma, corneal blood staining, or optic atrophy, can lead to permanent impairment of vision, especially if the hyphema is prolonged in association with elevated intraocular pressure (IOP).

Epidemiology

Traumatic hyphema is usually seen in children or young adults, with an incidence of approximately 2 per 10,000 children per year (Wright 2003). Males predominate, with a male‐to‐female ratio of 3:1 (Crouch 1993). Sports injuries account for 60% of traumatic hyphemas (Crouch 1999).

Presentation and diagnosis

Patients usually present with a sudden decrease or loss of vision following an injury to the eye. The loss of vision depends on the level of hyphema: a patient with a microhyphema occasionally may present with normal vision or with somewhat blurred vision, whereas a patient with a full hyphema may present with almost complete loss of vision. With time, blood in the anterior chamber is forced by gravity to the bottom of the anterior chamber. Subsequently, vision clears gradually unless associated injuries, traumatic uveitis, glaucoma, optic atrophy, or corneal blood staining contributes to further losses of vision.

The severity of traumatic hyphema varies from microhyphema, where red blood cells are suspended in the anterior chamber, to a layered hyphema, where fresh or clotted blood may be observed grossly in the lower anterior chamber. In a full or total hyphema, the entire anterior chamber is filled with blood.

Recurrent hemorrhage, occurring at a rate of 2% to 38% (Walton 2002), increases the time to visual recovery and is associated with poorer visual outcomes. Secondary hemorrhage typically occurs three to five days after the incident hyphema and may occur due to clot lysis and retraction within the traumatized vessels.

Hyphema in the setting of sickle cell trait/disease appears to be particularly dangerous because the naturally hypoxic and relatively acidotic anterior chamber induces sickling of red blood cells. Sickling in turn prevents normal egress of those blood cells through the trabecular meshwork. Hyphema patients with sickle cell trait/disease may be at a higher risk for elevated IOP (Lai 2001).

The most important sign for diagnosing hyphema is the presence of blood in the anterior chamber assessed by a slit‐lamp exam. Various grading schemes for hyphema have been proposed. Objective quantification of the level of hyphema is critical, because a sudden increase in the height of a layered hyphema is indicative of 'rebleed.' Immediate measurement of IOP and a dilated ophthalmoscopic exam (to rule out traumatic retinal tears, dialyses, and detachment) are also indicated at a relatively early time after clearance of hyphema.

Description of the intervention

Management of traumatic hyphema focuses on preventing repeated eye trauma and rebleed, promoting the settling of blood away from the visual axis, controlling traumatic anterior uveitis, and monitoring in order to initiate early prophylaxis or treatment for both secondary glaucoma and corneal blood staining. Methods employed to prevent recurrent or iatrogenic trauma include shielding the eye, bed rest, and avoidance of diagnostic interventions such as scleral depression or gonioscopy that could deform the globe. Elevation of the head while sleeping, topical corticosteroids, and cycloplegic medications are mainstays in the management of traumatic hyphema. Hospitalization, once considered essential in order to enforce bed rest, has been questioned and is currently advocated only for patients perceived to be at high risk of rebleed, at risk of noncompliance with bed rest at home, or possibly with sickle cell trait/disease.

The use of antifibrinolytic agents such as epsilon‐aminocaproic acid and tranexamic acid in traumatic hyphema is controversial. These agents are reported to potentially reduce the rate of recurrent hemorrhage, but are known to have several possible side effects, such as nausea, vomiting, muscle cramps, conjunctival suffusion, headache, rash, pruritis, dyspnea, toxic confusional states, arrhythmias, and systemic hypotension. Epsilon‐aminocaproic acid is contraindicated in women who are pregnant and in people with coagulopathies or renal diseases, and should be used cautiously in people with hepatic, cardiovascular, or cerebrovascular diseases. A topical gel form of epsilon‐aminocaproic acid has not yet received US Food and Drug Administration (FDA) approval; it appears to have comparable effectiveness, with fewer side effects, as compared with the oral form, and thus might be used on an outpatient basis. Tranexamic acid (Cyklokapron) is reported to be more potent than epsilon‐aminocaproic acid and has similar side effects, but with fewer gastric side effects (Rahmani 1999).

Corticosteroids have also been used to treat hyphema and are reported to be effective (Walton 2002). Investigators have studied both topical and systemic corticosteroids, applying these agents for varying lengths of time with or without other interventions, such as bed rest or cycloplegics. Topical administration of corticosteroids avoids the side effects of systemic corticosteroid use, but it is not known whether topically applied corticosteroids are as effective as systemic corticosteroids in reducing the rate of rebleed. The mechanism of action of corticosteroids is thought to be due to stabilization of the blood‐ocular barrier, direct inhibition of fibrinolysis, or reduced inflammation (Walton 2002).

Surgical evacuation of hyphema is generally not needed. In the past, surgical evacuation was often contraindicated due to the possibility of sudden decreases in IOP and increased risk of recurrent hemorrhage (due to decompression of the damaged iris and ciliary body). However, surgical 'washout' is advocated in patients with non‐clearing hyphema, in whom secondary glaucoma threatens to cause permanent visual loss due to glaucomatous optic neuropathy or to corneal blood staining. Surgical washout is often performed (via simple paracentesis) in patients with sickle cell trait because of the increased risk of elevated IOP.

How the intervention might work

The mode of action of medications used to treat traumatic hyphema, especially the antifibrinolytics, is through slowing or inhibiting the resorption of the blood clot within traumatized blood vessels. Aminocaproic acid slows the dissolution of the fibrin blood clot by competing at sites that bind lysine, including lysine sites on tissue plasminogen activator, inhibiting the conversion of plasminogen to plasmin, the enzyme involved in the breakdown of the fibrin clot (Sheppard 2009; Walton 2002). Aminocaproic acid also competitively inhibits the binding of plasmin to the fibrin clot itself. Both of these mechanisms result in a slowing of the breakdown of the fibrin clot, thus stabilizing it and reducing the risk of secondary hemorrhage. Tranexamic acid also binds to fibrin and is believed to act through a similar mechanism. The action of aminobenzoic acid involves inhibition of fibrinolysis, and estrogens decrease antithrombin activity, both of which result in delays of clot resorption (Westlund 1982). In addition to inhibition of fibrinolysis, corticosteroids are also believed to stabilize the blood‐ocular barrier and reduce inflammation.

The goal of most of the other interventions used in the management of traumatic hyphema is to prevent complications from the trauma or from a rebleed, including further trauma, anterior uveitis, secondary glaucoma, optic atrophy, or corneal blood staining. These interventions include bed rest and eye patching to prevent further trauma; use of mydriatic or miotic agents to prevent motion of the iris, increased IOP, or uveitis; corticosteroids to prevent inflammation; and elevation of the head to facilitate settling of the blood in the anterior chamber. Hospitalization facilitates close monitoring of more severe cases of trauma or rebleeding (or both), allowing more timely medical or surgical intervention, if warranted.

Why it is important to do this review

Despite the existence of guidelines for the management of traumatic hyphema (Crouch 1999; Rhee 1999; Sheppard 2009), the safety and effectiveness of various therapeutic modalities such as use of antifibrinolytic agents, their routes of administration, use of corticosteroids, and hospitalization are controversial. The evidence for the impact of rebleed on visual outcomes, glaucoma, optic atrophy, and blood staining is limited. Furthermore, rebleed, which is a surrogate outcome (rather than visual outcome), dominates the published literature on management of traumatic hyphema. It is important to examine the impact of the various antifibrinolytic medications, routes of administration, and dosages used across various populations.

Objectives

To assess the effectiveness of various medical interventions in the management of traumatic hyphema.

Methods

Criteria for considering studies for this review

Types of studies

We included randomized and quasi‐randomized trials.

Types of participants

We included trials in which the study population consisted of people with traumatic hyphema following closed‐globe trauma. We applied no restrictions regarding age, gender, or severity of the closed‐globe trauma or level of visual acuity (VA) at the time of enrollment.

Types of interventions

We considered trials in which:

antifibrinolytic agents (e.g. epsilon‐aminocaproic acid, tranexamic acid) or corticosteroids in any form or dosage, with the intention to treat or reduce the signs or symptoms of traumatic hyphema, were compared with other treatments, placebo, or no treatment. There was no time limit on the duration of treatment;
bed rest was compared with ambulatory management;
bilateral patching was compared with unilateral or no patching;
outpatient management was compared with inpatient management; or
any other medical (non‐surgical) intervention was compared with another medical intervention or no intervention.

Types of outcome measures

Primary outcomes

Proportion of participants with best‐corrected visual acuity (BCVA) of 20/40 or better assessed at short‐, medium‐, and long‐term follow‐up, defined respectively as two weeks or less; more than two weeks but within two months; and more than two months from the traumatic event. We also assessed VA at resolution of hyphema.
Time to resolution of primary hemorrhage (hyphema) defined as the length of time from onset to resolution of hyphema.

Secondary outcomes

Secondary outcomes for this review were sequelae of traumatic hyphema assessed at the time of last study follow‐up.

Proportion of participants with rebleed (i.e. secondary hemorrhage), defined as (a) an increase in height of layered hyphema using a biomicroscopic caliper or by any other method; or (b) the occurrence of fresh (red) blood in the eye with the existing clot. We also reported the average time to rebleed among participants with rebleed when this information was available.
Proportion of participants with corneal blood staining.
Proportion of participants with peripheral anterior synechiae (PAS) formation.
Proportion of participants with pathologic increase in IOP or glaucoma development, as defined by trial investigators.
Proportion of participants with optic atrophy development.

Adverse effects

We summarized the reported adverse effects related to treatment.

Quality of life outcomes

We described available data on indicators of quality of life.

Economic outcomes

We assessed the need for bed rest or hospitalization versus outpatient care. We also compared length of hospital stay as described in the primary reports. No other economic outcomes were reported.

Follow‐up

There were no restrictions based on length of follow‐up.

Search methods for identification of studies

Electronic searches

The Cochrane Eyes and Vision Information Specialist conducted systematic searches in the following electronic databases for RCTs and controlled clinical trials. There were no language or publication year restrictions. The date of the search was 28 June 2018.

Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 6) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (searched 28 June 2018) (Appendix 1).
MEDLINE Ovid (1946 to 28 June 2018) (Appendix 2).
Embase.com (1980 to 28 June 2018) (Appendix 3).
PubMed (1948 to 28 June 2018) (Appendix 4).
ISRCTN registry (www.isrctn.com/editAdvancedSearch; searched 28 June 2018) (Appendix 6).
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 28 June 2018) (Appendix 6).
World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp; searched 28 June 2018) (Appendix 7).

Searching other resources

We searched the reference lists of included trial reports to find additional trials. We also searched the ISI Web of Science Social Sciences Citation Index (SSCI) to find studies that have cited the included trials. We planned to contact the primary investigators of included trials for details of additional trials, but were unable to do so because most trials were published more than 10 years ago. We did not conduct manual searches of conference proceedings or abstracts specifically for this review.

Data collection and analysis

Selection of studies

Two review authors independently assessed the titles and abstracts of all reports identified by the electronic and manual searches as per the Criteria for considering studies for this review. We classified the abstracts as (a) definitely include, (b) unsure, or (c) definitely exclude. We obtained full copies of those abstracts classified as (a) or (b) and reassessed them as per the Criteria for considering studies for this review. We assessed the studies as (1) include, (2) awaiting assessment, or (3) exclude. We documented the concordance between review authors and resolved any disagreements by consensus or by consulting a third review author. We planned to contact authors of studies classified as (2) for clarification of unclear inclusion and exclusion criteria, but were unable to do so. We excluded from the review studies identified by both review authors as (3) and documented our reasons for exclusion in the Characteristics of excluded studies table. We included studies identified as (1) in the review and described them in the Characteristics of included studies table. The review authors were unmasked to the reports' authors, institutions, and trial results during this assessment.

Data extraction and management

Two review authors independently extracted the data for the primary and secondary outcomes onto data collection forms developed by the Cochrane Eyes and Vision Group. Any discrepancies were resolved by discussion. We attempted to contact primary investigators for missing data, but were unable to do so. One review author entered all data into Review Manager 5 (RevMan 5) (Review Manager 2014), and a second review author verified all values.

Assessment of risk of bias in included studies

Two review authors assessed the sources of systematic bias in trials according to methods described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). We considered the following parameters: adequate sequence generation and allocation concealment (selection bias), masking of participants and researchers (performance bias), masking of outcome assessors (detection bias), adequate handling of incomplete data by reporting rates of follow‐up and using intention‐to‐treat analysis (attrition bias), and complete reporting of outcomes (reporting bias). We assessed each of the parameters as low, unclear, or high risk of bias. We documented agreement between authors and resolved any disagreements by consensus or by involving a third review author. We used masking of participants and care providers as a quality criterion only in interventions where masking was feasible. We contacted the authors of trials categorized as at unclear risk of bias for additional information when contact information for the trial authors was available. In cases where we were unable to contact the study authors or the study authors did not respond to our request, we assigned a grade based on the available information.

Measures of treatment effect

Dichotomous data

For dichotomous outcomes, we calculated summary risk ratios (RR) with 95% confidence intervals (CIs). We analyzed VA outcomes as dichotomous variables. For each follow‐up period with sufficient data, we compared the proportion of participants with VA 20/40 or better between the treatment and control groups. We analyzed data on the proportion of participants with secondary hemorrhage, corneal blood stain, PAS formation, glaucoma development, and optic atrophy development as dichotomous data.

Continuous data

We calculated mean differences (MD) for continuous outcomes. We analyzed the time to resolution of primary hemorrhage (hyphema), defined as the length of time from onset to resolution, as a continuous variable. We also analyzed the length of time to rebleed, the duration of hospitalization, and other quality of life and economic outcomes as continuous data.

Ordinal data

We summarized ordinal data qualitatively.

Counts and rate data

We summarized counts and rate data in rate ratios when the event was rare, and as continuous outcome data when the event was more common. We analyzed adverse events data as counts and rates.

Unit of analysis issues

The unit of analysis for this review was the affected eye or eyes of the individual participant.

Dealing with missing data

We contacted the authors of included studies to obtain additional data when contact information for the trial authors was available. When we were unable to retrieve additional data because we were unable to contact the authors or received no response, we imputed data with the information that was available in the study report. We reported loss to follow‐up for each study when this information was available. We also noted when intention‐to‐treat analyses were performed.

Assessment of heterogeneity

We used the I² statistic to assess for statistical heterogeneity and examined clinical heterogeneity using forest plots. We considered I² values greater than 40% to represent statistical heterogeneity between studies.

Assessment of reporting biases

We did not use funnel plots to assess the possibility of small‐study effects or reporting biases because we included no more than 10 studies in a meta‐analysis.

Data synthesis

We analyzed data according to the guidelines in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2017). We tested for statistical heterogeneity. When we detected no statistical heterogeneity and there was no clinical heterogeneity among the trials, we combined the results in a meta‐analysis using a fixed‐effect model. In cases of statistical or clinical heterogeneity, we did not combine study results but presented a tabulated summary.

Subgroup analysis and investigation of heterogeneity

We planned subgroup analyses according to age, race, presence of sickle cell trait/disease, presenting IOP, and severity of hyphema, but we did not perform these because sufficient numbers of trials were not available. We planned to present results by subgroup as an Additional table.

Sensitivity analysis

We conducted sensitivity analyses to determine the impact of excluding studies of lower methodologic quality. We had planned to conduct sensitivity analyses to determine the impact of excluding unpublished studies or industry‐funded studies, but did not because we included no studies with these characteristics.

Summary of findings

We assessed each outcome using the GRADE approach, which judges the certainty of the evidence based on risk of bias, inconsistency, indirectness, imprecision, and publication bias in Chapter 11 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2017). We prepared a 'Summary of findings' table for each main comparison and included the following outcomes.

Proportion of participants with BCVA of 20/40 or better assessed at short‐term follow‐up, defined as two weeks or less from the traumatic event.
Proportion of participants with BCVA of 20/40 or better assessed at medium‐term follow‐up, defined as more than two weeks but within two months of the traumatic event.
Proportion of participants with BCVA of 20/40 or better assessed at long‐term follow‐up, defined as more than two months from the traumatic event.
Proportion of participants with BCVA of 20/40 or better assessed at resolution of hyphema.
Time to resolution of primary hemorrhage (hyphema), defined as the length of time from onset to resolution of hyphema.
Proportion of participants with rebleed (i.e. secondary hemorrhage).
Proportion of participants with adverse effects.

Results

Description of studies

Results of the search

The original electronic literature searches conducted in June 2010 identified 836 potentially relevant references for this review. After duplicate review of the titles and abstracts, we classified 748 references as 'definitely exclude,' 23 as 'definitely include,' and 65 as unsure. Seventeen of the 65 references assessed as unsure were letters or editorials that did not report original data and were excluded. We obtained full‐text copies of the 48 remaining references classified as unsure and reviewed them in duplicate. Of these, we excluded 40 and included eight. A manual search of other resources, including reference lists of included studies and citation index databases, yielded four additional potentially relevant full‐text references for this review, of which we included two and excluded two. In the 2011 publication of this review (Gharaibeh 2011), we included 26 studies as reported in 33 publications and excluded 41 studies in 42 publications.

After revising and updating the electronic searches as of August 2013, we identified 460 additional references for review. After duplicate review of the titles and abstracts, we classified 438 references as definitely exclude and 22 as unsure. We obtained full‐text copies of the references classified as unsure and reviewed them in duplicate. Seventeen of the references were not in the English language, and we identified colleagues who read the relevant languages to assist with assessing the articles in duplicate. Of the 22 references reviewed in full, we excluded 20; one was a reference for a study already included in the review; and one was included as a new study in the review. A manual search of other resources, including reference lists of included studies and citation index databases, yielded four additional potentially relevant full‐text references for this review, of which one was excluded and the remaining three were from studies already included in this review. In the 2013 publication of this review (Gharaibeh 2013), we included 27 studies reported by 38 publications, and excluded 62 studies reported by 63 publications.

We updated the searches for this review in June 2018 (Figure 1). Of 479 records identified by the searches, we examined the full‐text reports of two studies and excluded both (Zhang 2013; Zhang 2014). We identified no new eligible trials since the 2013 version of this review, thus the review includes 27 studies.

Included studies

The 27 studies included in this review are described in the Characteristics of included studies table. Twenty of the included studies were randomized controlled trials (RCTs), and seven used a quasi‐randomized method to assign participants to treatment groups. The review outcomes reported by the included studies are listed in Table 7.

1. Summary of outcomes* reported by intervention.

Interventions	Primary outcomes		Secondary outcomes						Adverse effects	Duration of hospitalization or quality of life outcomes
	VA	Time to resolution of primary hemorrhage	Secondary hemorrhage		Risk of corneal blood staining	Risk of PAS formation	Risk of pathologic increase in IOP or glaucoma	Risk of optic atrophy
	VA	Time to resolution of primary hemorrhage	Risk of rebleed	Time to rebleed	Risk of corneal blood staining	Risk of PAS formation	Risk of pathologic increase in IOP or glaucoma	Risk of optic atrophy
Aminocaproic acid vs placebo
*Oral aminocaproic acid*
Christianson 1979	Not reported	Partially reported**	Risk of rebleed reported	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported
Crouch 1976	Long‐term VA reported	Days to resolution reported	Risk of rebleed reported	Time to rebleed reported	Risk of corneal blood staining reported	Partially reported**	Not reported	Risk of optic atrophy reported	Not reported	Not reported
Kraft 1987	Long‐term VA reported	Days to resolution reported	Risk of rebleed reported	Time to rebleed reported	Not reported	Not reported	Persistent increases in IOP reported	Not reported	Adverse effects reported	Not reported
Kutner 1987	Short‐term VA reported	Days to resolution reported	Risk of rebleed reported	Time to rebleed reported	Not reported	Not reported	Persistent increases in IOP reported	Not reported	Adverse effects reported	Not reported
McGetrick 1983	Final VA reported	Days to resolution reported	Risk of rebleed reported	Time to rebleed reported	Not reported	Not reported	Not reported	Not reported	Adverse effects reported	Partially reported**
Teboul 1995	Final VA reported	Days to resolution reported	Risk of rebleed reported	Time to rebleed reported	Not reported	Not reported	Transient increases in IOP reported	Not reported	Not reported	Duration of hospitalization reported
*Topical aminocaproic acid*
Karkhaneh 2003	Reported as NS	Days to resolution reported	Risk of rebleed reported	Time to rebleed reported	Not reported	Not reported	Reported as NS	Not reported	Not reported	Not reported
Pieramici 2003	Short‐term VA reported	Reported as NS	Risk of rebleed reported	Time to rebleed reported	Not reported	Not reported	Transient increases in IOP reported	Not reported	Adverse effects reported	Not reported
Low‐dose vs standard‐dose aminocaproic acid
Palmer 1986	Final VA reported	Days to resolution reported	Risk of rebleed reported	Time to rebleed reported	Not reported	Not reported	Transient increases in IOP reported	Not reported	Adverse effects reported	Duration of hospitalization reported
Oral vs topical aminocaproic acid
Crouch 1997	Final VA reported	Not reported	Risk of rebleed reported	Time to rebleed reported	Risk of corneal blood staining reported	Partially reported**	Not reported	Risk of optic atrophy reported	Adverse effects reported	Not reported
Tranexamic acid vs control
Rahmani 1999	Short‐term VA reported	Days to resolution reported	Risk of rebleed reported	Time to rebleed reported	Not reported	Not reported	Transient increases in IOP reported	Not reported	Adverse effects reported	Duration of hospitalization reported
Sukumaran 1988	Short‐term VA reported	Days to resolution reported	Risk of rebleed reported	Time to rebleed reported	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported
Vangsted 1983	Short‐term VA reported	Partially reported**	Risk of rebleed reported	No rebleeds occurred	Risk of corneal blood staining reported	Not reported	Transient increases in IOP reported	Not reported	Not reported	Duration of hospitalization and days off work reported
Varnek 1980	Partially reported**	Not reported	Risk of rebleed reported	Time to rebleed reported	Risk of corneal blood staining reported	Not reported	Transient increases in IOP reported	Risk of optic atrophy reported	Not reported	Duration of hospitalization reported
Welsh 1983	Not reported	Partially reported**	Risk of rebleed reported	Not reported	Not reported	Not reported	Transient increases in IOP reported	Not reported	Adverse effects reported	Not reported
Aminomethylbenzoic acid vs placebo
Liu 2002	Not reported	Not reported	Risk of rebleed reported	Not reported	Not reported	Not reported	Not reported	Not reported	Adverse effects reported	Not reported
Corticosteroids vs control
*Oral corticosteroids*
Rahmani 1999	Short‐term VA reported	Days to resolution reported	Risk of rebleed reported	Time to rebleed reported	Not reported	Not reported	Transient increases in IOP reported	Not reported	Adverse effects reported	Duration of hospitalization reported
Spoor 1980	Final VA reported	Days to resolution reported	Risk of rebleed reported	Time to rebleed reported	Risk of corneal blood staining reported	Risk of PAS formation reported	Transient increases in IOP reported	Not reported	Not reported	Not reported
*Topical corticosteroids*
Rakusin 1972	Short‐term VA reported	Partially reported**	Risk of rebleed reported	Not reported	Partially reported**	Partially reported**	Not reported	Not reported	Not reported	Not reported
Zetterstrom 1969	Short‐term VA reported	Not reported	Risk of rebleed reported	Not reported	Risk of corneal blood staining reported	Not reported	Transient increases in IOP reported	Risk of optic atrophy reported	Not reported	Duration of hospitalization reported
Oral aminocaproic acid vs oral prednisone
Farber 1991	Short‐term VA reported	Partially reported**	Risk of rebleed reported	Not reported	Not reported	Not reported	Reported as NS	Not reported	Not reported	Not reported
Conjugated estrogen vs placebo
Spaeth 1966	Partially reported**	Not reported	Risk of rebleed reported	Partially reported**	Risk of corneal blood staining reported	Partially reported**	Partially reported**	Not reported	Not reported	Not reported
Cycloplegics vs miotics
Bedrossian 1974	Not reported	Days to resolution reported	Risk of rebleed reported	Time to rebleed reported	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported
Rakusin 1972	Short‐term VA reported	Partially reported**	Risk of rebleed reported	Not reported	Reported as NS	Reported as NS	Not reported	Not reported	Not reported	Not reported
Aspirin vs observation
Marcus 1988	Not reported	Not reported	Risk of rebleed reported	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported
Traditional Chinese medicine vs control treatment
Wang 1994	Partially reported**	Partially reported**	Partially reported**	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported	Not reported
Monocular vs binocular patching
Edwards 1973	Final VA reported	Not reported	Risk of rebleed reported	Time to rebleed reported	Risk of corneal blood staining reported	Not reported	Risk of secondary glaucoma reported	Not reported	Not reported	Quality of life outcomes reported
Rakusin 1972	Short‐term VA reported	Partially reported**	Risk of rebleed reported	Not reported	Reported as NS	Reported as NS	Not reported	Not reported	Not reported	Not reported
Ambulatory vs conservative treatment
Rakusin 1972	Short‐term VA reported	Partially reported**	Risk of rebleed reported	Not reported	Reported as NS	Reported as NS	Not reported	Not reported	Not reported	Not reported
Read 1974	Partially reported**	Days to resolution reported	Risk of rebleed reported	Partially reported**	Risk of corneal blood staining reported	Not reported	Transient increases in IOP reported	Not reported	Not reported	Not reported
Elevation of the head vs control
Zi 1999	Not reported	Days to resolution reported	Not reported	Not reported	Not reported	Not reported	Risk of secondary glaucoma reported	Not reported	Not reported	Not reported

Systemic aminocaproic acid compared with placebo for traumatic hyphema
Patient or population: people with traumatic hyphema Settings: hospital Intervention: 100 mg aminocaproic acid every 4 hours Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Systemic aminocaproic acid
Short‐term visual acuity 20/40 or better ≤ 2 weeks after treatment	769 per 1000	699 per 1000 (438 to 1015)	RR 0.87 (0.57 to 1.32)	34 (1)	⊕⊕⊝⊝  low^1,2	Outcome not reported by 5 other studies.
Medium‐term visual acuity 20/40 or better > 2 weeks and ≤ 2 months after treatment	See comment	‐	‐	‐	‐	Outcome not reported.
Long‐term visual acuity 20/40 or better > 2 months after treatment	731 per 1000	752 per 1000  (599 to 942)	RR 1.03 (0.82 to 1.29)	108 (2)	⊕⊕⊝⊝  low^1,3	Outcome not reported by 4 other studies.
Final visual acuity 20/40 or better at resolution of hyphema	866 per 1000	908 per 1000  (805 to 1021)	RR 1.05 (0.93 to 1.18)	143 (2)	⊕⊕⊝⊝  low^1,2	Outcome not reported by 4 other studies.
Time to resolution of primary hemorrhage	See comment	‐	‐	330 (6)	⊕⊕⊝⊝  low^1,2	Average time to resolution of the hemorrhage ranged from 4.1 to 6.7 days in participants receiving oral aminocaproic acid and from 2.4 to 6.3 days in participants receiving placebo (data not meta‐analyzable).
Secondary hemorrhage at any time point	148 per 1000	42 per 1000  (19 to 89)	RR 0.28 (0.13 to 0.60)	330 (6)	⊕⊕⊝⊝  low^2,3
Adverse effects: nausea or vomiting	17 per 1000	148 per 1000  (36 to 612)	RR 8.60 (2.09 to 35.50)	131 (3)	⊕⊕⊕⊝  moderate¹	Outcome not reported by 3 other studies.
The basis for the assumed risk* is the control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low certainty: We are very uncertain about the estimate.

Topical aminocaproic acid compared with placebo for traumatic hyphema
Patient or population: people with traumatic hyphema Settings: hospital Intervention: 25% to 30% aminocaproic acid in gel every 6 hours Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Topical aminocaproic acid
Short‐term visual acuity 20/40 or better ≤ 2 weeks after treatment	481 per 1000	419 per 1000  (226 to 770)	RR 0.87 (0.47 to 1.60)	51 (1)	⊕⊕⊝⊝  low¹	Outcome not reported by 1 other study.
Medium‐term visual acuity 20/40 or better > 2 weeks and ≤ 2 months after treatment	See comment	‐	‐	‐	‐	1 study reported no difference between groups after 2 weeks of follow‐up.
Long‐term visual acuity 20/40 or better > 2 months after treatment	See comment	‐	‐	‐	‐	Outcome not reported.
Final visual acuity 20/40 or better at resolution of hyphema	See comment	‐	‐	‐	‐	Outcome not reported.
Time to resolution of primary hemorrhage	See comment	‐	‐	142 (2)	⊕⊕⊝⊝  low^2,3	In 1 study, average time to resolution of the hemorrhage was 11.1 days in participants receiving topical aminocaproic acid and 9.3 and 9.5 days in those receiving placebo; in the second study, the authors reported "no difference" in time to resolution between study groups.
Secondary hemorrhage at any time point	227 per 1000	109 per 1000  (45 to 250)	RR 0.48 (0.20 to 1.10)	131 (2)	⊕⊕⊝⊝  low^3,4
Adverse effects: systemic hypotension	See comment	‐	‐	‐	‐	1 study reported that 13% of participants in the topical aminocaproic acid group versus 11% of participants in the placebo group had systemic hypotension.
The basis for the assumed risk* is the control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low certainty: We are very uncertain about the estimate.

Systemic tranexamic acid compared with control for traumatic hyphema
Patient or population: people with traumatic hyphema Settings: hospital Intervention: 25 to 75 mg/kg tranexamic acid per day Comparison: control
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Tranexamic acid
Short‐term visual acuity 20/40 or better ≤ 2 weeks after treatment	680 per 1000	754 per 1000 (666 to 850)	RR 1.11 (0.98 to 1.25)	303 (3)	⊕⊕⊝⊝  low^1,2	Outcome not reported by 2 other studies.
Medium‐term visual acuity 20/40 or better > 2 weeks and ≤ 2 months after treatment	See comment	‐	‐	‐	‐	Outcome not reported.
Long‐term visual acuity 20/40 or better > 2 months after treatment	See comment	‐	‐	‐	‐	Outcome not reported.
Final visual acuity 20/40 or better at resolution of hyphema	See comment	‐	‐	‐	‐	Outcome not reported.
Time to resolution of primary hemorrhage	See comment	‐	‐	549 (5)	⊕⊝⊝⊝  very low^1,3,4	In 1 study, average time to resolution of the hemorrhage was 4.0 days in 72 participants receiving tranexamic acid and 3.7 days in 59 participants recieving placebo. In another study, average time to resolution was 4.6 days in 17 participants receiving tranexamic acid and 3.9 days in 18 participants not receiving drug. A third study reported that resolution was delayed in the tranexamic acid group, and a fourth study reported faster resolution in the tranexamic acid group.
Secondary hemorrhage at any time point	150 per 1000	46 per 1000  (25 to 82)	RR 0.31 (0.17 to 0.55)	578 (5)	⊕⊕⊝⊝  low^1,4
Adverse effects: nausea	See comment	‐	‐	‐	‐	1 study reported that 1 of 19 participants receiving tranexamic acid complained of nausea; another study reported that no adverse events were observed in either the drug‐treated or the control group.
The basis for the assumed risk* is the control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low certainty: We are very uncertain about the estimate.

Systemic or topical corticosteroids compared with usual treatment for traumatic hyphema
Patient or population: people with traumatic hyphema Settings: hospital Intervention: oral or topical corticosteroids Comparison: usual treatment
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Corticosteroids	Usual treatment
Short‐term visual acuity between 20/20 and 20/40 ≤ 2 weeks after treatment; oral corticosteroids	438 per 1000	534 per 1000  (385 to 739)	RR 1.22 (0.88 to 1.99)	155 (1)	⊕⊕⊝⊝  low^1,2
Final visual acuity between 20/20 and 20/40 at end of treatment; oral corticosteroids	900 per 1000	909 per 1000 (756 to 1107)	RR 1.01 (0.84 to 1.23)	41 (1)	⊕⊕⊝⊝  low^1,2
Short‐term visual acuity between 20/20 and 20/40 ≤ 2 weeks after treatment; topical corticosteroids	619 per 1000	464 per 1000  (235 to 910)	RR 0.75 (0.38 to 1.47)	34 (1)	⊕⊝⊝⊝  very low^1,2,3
Final visual acuity between 20/20 and 20/25 at end of treatment; topical corticosteroids	943 per 1000	962 per 1000 (887 to 1047)	RR 1.02 (0.94 to 1.11)	111 (1)	⊕⊕⊝⊝  low^1,3
Time to resolution of primary hemorrhage; oral corticosteroids	See comment	See comment	‐	166 (2)	⊕⊕⊝⊝  low^1,2	First study reported that average resolution of primary hemorrhage was 3.5 days in the oral corticosteroid group and 3.7 days in the control group. The second study reported that average resolution of primary hemorrhage was 4.45 days in the oral corticosteroid group and 4.48 days in the control group.
Time to resolution of primary hemorrhage; topical corticosteroids	See comment	See comment	‐	34 (1)	⊕⊝⊝  very low^1,2,3	A single study reported that hyphema had cleared in 10/13 participants in the corticosteroid group and 16/21 participants in control group.
Risk of secondary hemorrhage; oral corticosteroids	250 per 1000	170 per 1000  (98 to 295)	RR 0.68 (0.39 to 1.18)	201 (2)	⊕⊕⊝⊝  low^1,2
Risk of secondary hemorrhage; topical corticosteroids	75 per 1000	22 per 1000  (4 to 115)	RR 0.29 (0.05 to 1.53)	151 (2)	⊕⊝⊝⊝  very low^1,2,3
The basis for the assumed risk* is the control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low certainty: We are very uncertain about the estimate.

Other pharmaceutical agents compared with placebo or other control interventions for traumatic hyphema
Patient or population: people with traumatic hyphema Settings: hospital Intervention: other pharmaceutical agent Comparison: placebo or usual care
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Pharmaceutical agent
Short‐term visual acuity between 20/20 and 20/60 at end of treatment; cycloplegics versus miotics	529 per 1000	434 per 1000  (211 to 768)	RR 0.82 (0.46 to 1.45)	34 (1)	⊕⊕⊝⊝  low^1,2	1% homatropine versus 4% pilocarpine Visual acuity measured at end of treatment, typically within 2 weeks of occurence of hyphema.
Risk of secondary hemorrhage; conjugated estrogen	217 per 1000	257 per 1000  (120 to 552)	RR 1.18 (0.55 to 2.54)	85 (1)	⊕⊕⊕⊝  moderate¹	Conjugated estrogen, 5 to 10 mg intramuscularly for children under 10 years of age and 20 mg intravenously for children 10 years of age or older and adults, versus placebo
Risk of secondary hemorrhage; cycloplegics	22 per 1000	22 per 1000  (3 to 149)	RR 1.03 (0.15 to 6.99)	92 (2)	⊕⊝⊝⊝  very low^1,2,3	1% homatropine versus 4% pilocarpine in first study; 1% atropine versus 2% pilocarpine in second study
Risk of secondary hemorrhage; aspirin	71 per 1000	130 per 1000  (24 to 716)	RR 1.83 (0.33 to 10.02)	51 (1)	⊕⊕⊝⊝  low^1,2	500 mg aspirin 3 times/day for 5 days versus observation
The basis for the assumed risk* is the control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low certainty: We are very uncertain about the estimate.

Non‐pharmaceutical interventions compared with usual care for traumatic hyphema
Patient or population: people with traumatic hyphema Settings: hospital Intervention: non‐pharmaceutical interventions Comparison: control
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Non‐pharmacuetical agent
Short‐term visual acuity between 20/20 and 20/60 at end of treatment; monocular versus binocular eye patching	808 per 1000	662 per 1000  (541 to 808)	RR 0.82 (0.67 to 1.00)	46 (1)	⊕⊕⊝⊝  low^1,2	Visual acuity measured at end of treatment, typically within 2 weeks of occurrence of hyphema.
Final visual acuity between 20/20 and 20/50; monocular versus binocular eye patching	846 per 1000	803 per 1000  (652 to 998)	RR 0.95 (0.77 to 1.18)	53 (1)	⊕⊕⊝⊝  low^1,2	Time frame when visual acuity measured not reported.
Short‐term visual acuity between 20/20 and 20/50 at end of treatment; ambulatory versus bed rest	846 per 1000	931 per 1000  (710 to 1218)	RR 1.10 (0.84 to 1.44)	52 (1)	⊕⊕⊝⊝  low^1,2	Visual acuity measured at end of treatment, typically within 2 weeks of occurrence of hyphema.
Time to resolution of primary hemorrhage; ambulatory versus bed rest	See comment	See comment	‐	137 (1)	⊕⊕⊝⊝  low^1,2	A single study reported that mean resolution of primary hemorrhage was 5.8 days in ambulatory group and 5.6 days in bed rest group.
Risk of secondary hemorrhage; monocular versus binocular eye patching	148 per 1000	114 per 1000  (51 to 254)	RR 0.77 (0.35 to 1.72)	117 (2)	⊕⊕⊝⊝  low^1,2
Risk of secondary hemorrhage; ambulatory treatment versus bed rest	185 per 1000	238 per 1000  (108 to 445)	RR 1.28 (0.68 to 2.40)	189 (2)	⊕⊕⊝⊝  low^1,3
The basis for the assumed risk* is the control group risk across studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence  High certainty: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low certainty: We are very uncertain about the estimate.

Time to resolution of primary hemorrhage (days)
Study	Mean (SD) time to resolution in drug treated group	Number of participants in drug treated group	Mean (SD) time to resolution in control group	Number of participants in control group
Christianson 1979	NR	22	NR	23
Crouch 1976	4.1 days (4.0 days in study participants without secondary hemorrhage)	32 (31 without a secondary hemorrhage)	3.8 days (2.8 days in study participants without secondary hemorrhage)	27 (18 without a secondary hemorrhage)
Kraft 1987	8 days (5.3 days in study participants without secondary hemorrhage)	24 (22 without a secondary hemorrhage)	5 days (2.6 days in study participants without a secondary hemorrhage)	25 (24 without a secondary hemorrhage)
Kutner 1987	4.8 days in all study participants	21 (no participant had a secondary hemorrhage	2.4 days in all study participants	10 study participants without a secondary hemorrhage
McGetrick 1983	4.5 days in all study participants	28 (1 study participant had a secondary hemorrhage)	6.3 days in all study participants	21 (7 study participants had a secondary hemorrhage)
Teboul 1995	6.7 days in all study participants	48 (1 study participant had a secondary hemorrhage)	2.6 days in all study participants	46 (2 study participants had a secondary hemorrhage)

Study	Severity scale	Reported severity	Secondary hemorrhage	Other outcomes
Systemic aminocaproic acid vs control
Christianson 1979	NR	NR	NR	Time to resolution of the primary hyphema was significantly longer (P < 0.05) for participants receiving drug for whom the hyphema filled more than ½ of the anterior chamber.
Crouch 1976	Blood filling < ⅓ of anterior chamber	Reported no statistically significant differences across groups	NR	NR
	Blood filling ⅓ to ½ of anterior chamber
	Blood filling > ½ to ¾ of anterior chamber
	Blood filling > ¾ to total of anterior chamber, but excluded total hyphema
Kraft 1987	Blood filling < ⅓ of anterior chamber	30/49 (61%) participants: 13/24 (54%) in drug group; 17/25 (68%) in placebo group	1/3 (33%) secondary hemorrhage (in placebo group)	Excluding secondary hemorrhages, mean time to resolution of 3.4 days in drug group (range 1 to 11 days); mean time to resolution of 2.2 days in placebo group (range 1 to 4 days)
	Blood filling ⅓ to ½ of anterior chamber	14/49 (29%) participants: 9/24 (37.5%) in drug group; 5/25 (20%) in placebo group	1/3 (33%) secondary hemorrhage (in drug group)	Excluding secondary hemorrhages, mean time to resolution of 7.1 days in drug group (range 6 to 9 days); mean time to resolution of 4.0 days in placebo group (range 3 to 4 days)
	Blood filling ½ or more of anterior chamber	5/49 (10%) participants: 2/24 (8.3%) in drug group; 3/25 (12%) in placebo group	1/3 (33%) secondary hemorrhage (in drug group)	Excluding secondary hemorrhages, time to resolution of 10 days in drug group; mean of placebo 4.3 days (range 3 to 5 days)
Kutner 1987	Mean hyphema height	2.2 mm (SD 1.7, n = 21) in drug group; 1.7 mm (SD 1.0, n = 13) in placebo group	"All who rebled had initial hyphemas of 15% or less"	NR
McGetrick 1983;	Mean hyphema height	100% (28/28) hyphemas in drug group were < 25% of anterior chamber; 86% (18/21) hyphemas in placebo group were < 25% of anterior chamber.	1 secondary hemorrhage in drug group; 6 secondary hemorrhages in placebo group	NR
Teboul 1995	Blood filling < ⅓ of anterior chamber	88/94 (94%) participants: 44/48 (92%) in drug group; 44/46 (96%) in placebo group	1 secondary hemorrhage in drug group and 2 secondary hemorrhages in placebo group	NR
Teboul 1995	Blood filling ⅓ to ½ of anterior chamber	6/94 (6%) participants: 4/48 (8%) in aminocaproic acid group; 2/46 (4%) in placebo group	No rebleeds	NR
Topical aminocaproic acid vs control
Karkhaneh 2003	Blood filling < ¼ of anterior chamber; excluded microscopic hyphemas	65/80 (81%) participants: 34/41 (83%) in drug group; 31/39 (79.5%) in placebo group	Reported no effect of hyphema size on secondary hyphema (RR 0.7, 95% CI 0.2 to 2.5)	NR
	Blood filled ¼ to ½ of anterior chamber	14/80 (18%) participants: 7/41 (17%) in drug group; 7/39 (18%) in placebo group
	Blood filling > ½ of anterior chamber; excluded total or blackball hyphemas	1/80 (1%) participants: 0/41 in drug group; 1/39 (2.5%) in placebo group
Pieramici 2003	Mean hyphema height in millimeters	1 mm (SE 0) in drug group (range 0 to 4 mm); 2 mm (SE 0) in placebo group (range 0 to 8 mm)	Size of primary hyphema in 2 participants with secondary hemorrhages in drug group: 0.3 and 1 mm; in 8 participants in the placebo group: 0.8, 0.9, 1, 1.4, 1.8, 2, 2, and 4.5 mm	NR
Low‐dose vs standard‐dose aminocaproic acid
Palmer 1986	Mean hyphema height in millimeters	1.7 mm (SD 2.0, range 0.1 to 9.9) in low‐dose group (n = 25); 1.5 mm (SD 2.2, range 0.1 to 9.9) in standard‐dose group (n = 33)	1 secondary hemorrhage in low‐dose group; 5 secondary hemorrhages in standard‐dose group	NR
Systemic vs topical aminocaproic acid
Crouch 1997	Blood filling < ⅓ of anterior chamber	44/64 (69%) participants	NR	NR
	Blood filling ⅓ to ½ of anterior chamber	6/64 (9%) participants
	Blood filling > ½ to ¾ of anterior chamber	8/64 (13%) participants
	Blood filling > ¾ to total of anterior chamber	6/64 (9%) participants
Tranexamic acid vs control
Rahmani 1999	Microscopic, but excluding individuals with unlayered microscopic hyphemas	17/238 (7%) participants: 6/80 (7%) in aminocaproic acid group; 4/78 (5%) in prednisolone group; 7/80 (9%) in placebo group	2/43 (5%) secondary hemorrhages	NR
	Blood filling < ¼ of anterior chamber	173/238 (72%) participants: 56/80 (70%) in aminocaproic acid group; 61/78 (78%) in prednisolone group; 56/80 (70%) in placebo group	30/43 (70%) secondary hemorrhages
	Blood filling ¼ to ½ of anterior chamber	36/238 (15%) participants: 13/80 (16%) in aminocaproic acid group; 10/78 (13%) in prednisolone group; 13/80 (16%) in placebo group	7/43 (16%) secondary hemorrhages
	Blood filling > ½ of anterior chamber; excluded total hyphemas	12/238 (5%) participants: 5/80 (6%) in aminocaproic acid group; 3/78 (4%) in prednisolone group; 4/80 (5%) in placebo group	4/43 (9%) secondary hemorrhages
Sukumaran 1988	Hyphema height of 0 to 1 mm	8/35 (23%) participants: 4/17 (24%) in drug group; 4/18 (22%) in control group	NR	NR
	Hyphema height of 2 to 3 mm	12/35 (34%) participants: 6/17 (35%) in drug group; 6/18 (33%) in control group
	Hyphema height of 4 to 5 mm	10/35 (29%) participants: 5/17 (29%) in drug group; 5/18 (28%) in control group
	Hyphema height of 6 to 7 mm	5/35 (14%) participants: 2/17 (12%) in drug group; 3/18 (17%) in control group
Vangsted 1983	Hyphema height of 1 mm	10/112 (9%) participants: 8/59 (14%) in drug group; 2/53 (4%) in control group	NR	NR
	Hyphema height of 2 mm	33/112 (29%) participants: 15/59 (25%) in drug group; 18/53 (34%) in control group
	Hyphema height of 3 mm	37/112 (33%) participants: 18/59 (31%) in drug group; 19/53 (36%) in control group
	Hyphema height of 4 mm	18/112 (16%) participants: 9/59 (15%) in drug group; 9/53 (17%) in control group
	Hyphema height of 5 mm	9/112 (8%) participants: 6/59 (10%) in drug group; 3/53 (6%) in control group
	Hyphema height of 6 mm	4/112 (4%) participants: 3/59 (5%) in drug group; 1/53 (2%) in control group
	Hyphema height of 7 mm	None in either group
	Hyphema height of 8 mm	1/112 (1%) participants: 0/59 (0%) in drug group; 1/53 (2%) in control group
Varnek 1980	Mean hyphema height in millimeters	2.0 mm in drug group (n = 102); 2.1 mm in control group (n = 130)	1.0 mm in 2 participants in drug group with a secondary hemorrhage; 2.2 mm in 12 participants in control group with a secondary hemorrhage	NR
Welsh 1983	Mean of proportion of anterior chamber area filled with blood	68% in drug group (n = 19); 63% in placebo group (n = 20)	NR	NR
Aminomethylbenzoic acid vs control
Liu 2002	Blood filling < ⅓ of anterior chamber and level is lower than the inferior border of pupil	47/92 (51%) participants: 31/60 (52%) in drug group; 16/32 (50%) in control group	NR	NR
	Blood filling ½ of anterior chamber and level is higher than the inferior border of the pupil, but not exceeding the median line	30/92 (33%) participants: 19/60 (32%) in drug group; 11/32 (34%) in control group
	Blood filling > ½ of anterior chamber or filling the entire anterior chamber	15/92 (16%) participants: 10/60 (17%) in drug group; 5/32 (16%) in control group
Systemic corticosteroids vs control
Spoor 1980	0% to 33% of anterior chamber area filled with blood	38/43 (88%) participants: 21/23 (91%) in prednisone group; 17/20 (85%) in placebo group	2/4 (50%) secondary hemorrhages	1. 30 hyphemas resolved in 5 days or less; 8 hyphemas resolved in more than 5 days 2. 34 participants with final visual acuity between 20/20 and 20/50
	> 33% to 75% of anterior chamber filled with blood	5/43 (12%) participants: 2/23 (9%) in prednisone group; 3/20 (15%) in placebo group	2/4 (50%) secondary hemorrhages	1. 1 hyphema resolved in 5 days or less; 4 hyphemas resolved in more than 5 days 2. 5 participants with final visual acuity between 20/20 and 20/50
Rahmani 1999	See above under "Tranexamic acid vs control"
Topical corticosteroids vs control
Zetterstrom 1969	Mean hyphema height in millimeters	2.5 mm in topical corticosteroid group (n = 58); 3.5 mm in control group (n = 59)	No participant with secondary hemorrhage in topical corticosteroid group; 4 participants with secondary hemorrhage in control group	NR
Antifibrinolytics vs systemic corticosteroids
Farber 1991	Microscopic	24/112 (21%) participants: 11/56 (20%) in aminocaproic acid group; 13/56 (23%) in prednisone group	3/8 (38%) secondary hemorrhages: 2 in aminocaproic acid group; 1 in prednisone group	NR
	Hyphema height 0.1 to 3.9 mm	80/112 (71%) participants: 41/56 (73%) in aminocaproic acid group; 39/56 (70%) in prednisone group	4/8 (50%) secondary hemorrhages: 1 in aminocaproic acid group; 3 in prednisone group
	Hyphema height 4.0 to 5.9 mm	4/112 (4%) participants: 3/56 (6%) in aminocaproic acid group; 1/56 (2%) in prednisone group	No secondary hemorrhages in either group
	Hyphema height 6.0 to 11 mm	2/112 (2%) participants: 0/56 (0%) in aminocaproic acid group; 2/56 (4%) in prednisone group	No secondary hemorrhages in either group
	Total hyphema	2/112 (2%) participants: 1/56 (2%) in aminocaproic acid group; 1/56 (2%) in prednisone group	1/8 (12%) secondary hemorrhage: 1 in aminocaproic acid group; none in prednisone group
Rahmani 1999	See above under "Tranexamic acid vs control"
Conjugated estrogens vs control
Spaeth 1966	Blood filling < 20% of anterior chamber	55/85 (65%) participants: 28/39 (72%) in estrogen group; 27/46 (59%) in control group	13/20 (65%) secondary hemorrhages: 8 in estrogen group; 5 in control group	NR
	Blood filling 20% to 40% of anterior chamber	17/85 (20%) participants: 5/39 (13%) in estrogen group; 12/46 (26%) in control group	4/20 (20%) secondary hemorrhages: 1 in estrogen group; 3 in control group
	Blood filling 40% to 60% of anterior chamber	5/85 (6%) participants: 2/39 (5%) in estrogen group; 3/46 (7%) in control group	1/20 (5%) secondary hemorrhage: none in estrogen group; 1 in control group
	Blood filling 60% to 80% of anterior chamber	2/85 (2%) participants: 1/39 (3%) in estrogen group; 1/46 (2%) in control group	No secondary hemorrhages in either group
	Blood filling > 80% of anterior chamber	6/85 (7%) participants: 3/39 (8%) in estrogen group; 3/46 (7%) in control group	2/20 (10%) secondary hemorrhages: 1 in estrogen group; 1 in control group
Cycloplegics vs miotics
Bedrossian 1974	Hyphema height of 1 mm	20/58 (34%) participants: 10/28 (36%) in the cycloplegic group; 10/30 (33%) in the miotic group	1/1 (100%) secondary hemorrhage (in cycloplegic group)	Mean time to resolution in cycloplegic group of 1.9 days (SD 1.4); mean time to resolution in miotic group of 2.5 days (SD 1)
	Hyphema height of 2 mm	22/58 (38%) participants: 10/28 (36%) in the cycloplegic group; 12/30 (40%) in the miotic group	No secondary hemorrhages in either group	Mean time to resolution in cycloplegic group of 3.3 days (SD 1.8); mean time to resolution in miotic group of 4.2 days (SD 1.3)
	Hyphema height of 3 mm	12/58 (21%) participants: 6/28 (21%) in the cycloplegic group; 6/30 (20%) in the miotic group	No secondary hemorrhages in either group	Mean time to resolution in cycloplegic group of 3.2 days (SD 1.9); mean time to resolution in miotic group of 4.0 days (SD 1.1)
	Hyphema height of 4 mm	4/58 (7%) participants: 2/28 (7%) in the cycloplegic group; 2/30 (7%) in the miotic group	No secondary hemorrhages in either group	Mean time to resolution in cycloplegic group of 2.5 days (1 resolved on day 2 and 1 on day 3); mean time to resolution in miotic group of 4.0 days (1 resolved on day 3 and 1 on day 5)
Aspirin vs no aspirin
Marcus 1988	Reported that "the two groups were comparable with respect to age, cause, and extent of hyphema" and that 2 of 3 eyes with a secondary hemorrhage in the aspirin group (n = 23) had an initial total hyphema, while of the 2 eyes with a secondary hemorrhage in the control group (n = 28), 1 had 30% and 1 had almost total hyphema			NR
Traditional Chinese medicine vs control treatment
Wang 1994	Any level	No significant differences between groups	NR	Proportion of participants who were "cured" (defined as the resolution of the primary hemorrhage after 5 days of treatment, visual acuity of 0.7 or better after resolution of the primary hemorrhage, and no recurrence of bleeding for 1 week following resolution of the primary hemorrhage) was 29/45 (64%) in the traditional Chinese medicine group and 10/38 (26%) in the control group.
Monocular vs binocular patching
Edwards 1973	Blood filling < ⅓ of anterior chamber	42/64 (66%) participants: 21/35 (60%) in the monocular patching group; 21/29 (72%) in the binocular patching group	7/14 (50%) secondary hemorrhages: 4 in the monocular group; 3 in the binocular group	62% (13/21) of participants with final visual acuity of 20/50 or better in the monocular group; 71% (15/21) of participants with final visual acuity of 20/50 or better in the binocular group
	Blood filling ⅓ to ½ of anterior chamber	14/64 (22%) participants: 9/35 (26%) in the monocular patching group; 5/29 (17%) in the binocular patching group	7/14 (50%) secondary hemorrhages: 4 in the monocular group; 3 in the binocular group	57% (8/14) of participants with final visual acuity of 20/50 or better in the monocular group; 62% (5/8) of participants with final visual acuity of 20/50 or better in the binocular group
	Blood filling ½ or more of anterior chamber	8/64 (12%) participants: 5/35 (14%) in the monocular patching group; 3/29 (10%) in the binocular patching group
Ambulatory vs conservative treatment
Read 1974	Blood filling < ⅓ of anterior chamber	79/137 (58%) participants: 47/71 (66%) in the ambulatory group; 32/66 (48%) in the conservative group	16/30 (53%) secondary hemorrhages: 9 in the ambulatory group; 7 in the conservative group	NR
	Blood filling ⅓ to ½ of anterior chamber	28/137 (20%) participants: 11/71 (16%) in the ambulatory group; 17/66 (26%) in the conservative group	5/30 (17%) secondary hemorrhages: 4 in the ambulatory group; 1 in the conservative group
	Blood filling ½ but not total anterior chamber	19/137 (14%) participants: 8/71 (11%) in the ambulatory group; 11/66 (17%) in the conservative group	6/30 (20%) secondary hemorrhages: 3 in the ambulatory group; 3 in the conservative group
	Total hyphema	11/137 (8%) participants: 5/71 (7%) in the ambulatory group; 6/66 (9%) in the conservative group	3/30 (10%) secondary hemorrhages: 2 in the ambulatory group; 1 in the conservative group
Elevation of head vs lying flat
Zi 1999	Blood filling < ½ of anterior chamber, and level was lower than the inferior border of pupil	36/74 (49%) participants: 18/35 (51%) with elevation of the head; 18/39 (46%) lying flat	NR	NR
	Blood filling ½ of anterior chamber, and level was higher than the inferior border of the pupil	19/74 (26%) participants: 6/35 (17%) with elevation of the head; 13/39 (33%) lying flat	NR	NR
	Blood filling > ½ of anterior chamber or filling the entire anterior chamber	19/74 (26%) participants: 11/35 (31%) with elevation of the head; 8/39 (21%) lying flat	NR	NR
Other
Rakusin 1972 *	Blood filling < ½ of anterior chamber	213 participants	NR	1. 4% (8/213) of participants with elevated intraocular pressure across all participants 2. 22% (47/213) of participants with complications 3. 78% (166/213) of participants with final visual acuity better than 20/60
Rakusin 1972 *	Blood filling > ½ of anterior chamber	157 participants	NR	1. 85% (133/157) of participants with elevated intraocular pressure across all participants 2. 78% (123/157) of participants with complications 3. 28% (44/157) of participants with final visual acuity better than 20/60

Time to rebleed (days)
Study	Number of rebleeds in drug treated group	Time to rebleed in drug treated group	Number of rebleeds in control group	Time to rebleed in control group
Christianson 1979	2 of 22	NR	1 of 23	NR
Crouch 1976	1 of 32	Day 1	9 of 27	Days 2 to 7: 2 on day 2; 2 on day 3; 4 on day 4; and 1 on day 7
Kraft 1987	2 of 24	Days 3 and 4	1 of 25	Day 4
Kutner 1987	0 of 21	NA	3 of 13	All rebled on Day 2
McGetrick 1983	1 of 28	Day 4	7 of 21	Days 3 to 6: 5 on day 3; 1 on day 5; and 1 on day 6
Teboul 1995	1 of 48	Day 6	2 of 46	Days 2 and 7

Study	Test intervention	No. with outcome/no. in group	Control intervention	No. with outcome/no. in group	Total no. with outcome/total no.
*Aminocaproic acid*
Crouch 1976	Sytemic aminocaproic acid	0/32	Placebo	2/27	2/59
Crouch 1997	Systemic aminocaproic acid	0/29	Topical aminocaproic acid	0/35	0/64
*Tranexamic acid*
Vangsted 1983	Tranexamic acid	0/59	Bed rest only	0/53	0/112
Varnek 1980	Tranexamic acid	1/102	Conservative treatment	0/130	1/232
*Prednisone/cortisone*
Spoor 1980	Systemic prednisone	NR	Placebo	NR	1/43
Zetterstrom 1969	Atropine plus cortisone eyedrops	0/58	Conservative treatment	1/59	1/117
*Estrogen*
Spaeth 1966	Estrogen	2/39	Placebo	2/46	4/85
*Non‐drug medical interventions*
Edwards 1973	Monocular patching	1/35	Binocular patching	1/29	2/64
Read 1974	Moderate ambulatory activity, patching and shielding of injured eye	5/71	Bed rest with elevation of the head, bilateral patches and eye shield	4/66	9/137

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Unspecified time for visual acuity between 20/20 and 20/40	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Time to resolution of primary hemorrhage (days)	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3 Risk of secondary hemorrhage	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Time to rebleed (days)		Other data	No numeric data
5 Risk of glaucoma or elevated IOP	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6 Adverse effects	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6.1 Nausea or vomiting	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.2 Dizziness or hypotension	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.3 Syncope	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.4 Diarrhea	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.5 Rash or pruritis	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.6 Hot flashes	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.7 Dry mouth or nose	1	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Duration of hospitalization (days)	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected

Risk of glaucoma or increases in IOP
Study	Odds Ratio [95% CI]	Total patients (N)	Definition of outcome	Patients with sickle cell/trait
Transient increase in IOP
Teboul 1995	0.96 [0.18, 5.00]	94	Transient IOP greater than 25 mmHg, all patients had normal IOP at discharge (5 days)	None (excluded)
Persistent increase in IOP
Kraft 1987	1.04 [0.06, 17.69]	49	IOP greater than 25 mmHg at follow‐up (6 weeks to 18 months)	None (excluded)
Kutner 1987	0.17 [0.02, 1.81]	34	Elevated IOP at time of discharge (6 days)	None (excluded)

Study ID	Comparison	Type of complication	Results
*Aminocaproic acid*
Kraft 1987	Systemic aminocaproic acid vs placebo	Nausea	Drug group: 8 of 24; placebo group 1 of 25
Kutner 1987	Systemic aminocaproic acid vs placebo	Nausea or vomiting	Drug group: 6 of 21; placebo group: 0 of 13
		Lightheadedness	Drug group: 7 of 21; placebo group: 1 of 13
		Systemic hypotension	Drug group: 4 of 21; placebo group: 1 of 13
		Total complications	Drug group: 10 of 21; placebo group: 1 of 13
McGetrick 1983	Systemic aminocaproic acid vs placebo	Nausea or vomiting	Drug group: 6 of 28; placebo group: 0 of 20
		Diarrhea	Drug group: 2 of 28; placebo group: 0 of 20
		Muscle cramps	Drug group: 1 of 28; placebo group: 0 of 20
Pieramici 2003	Topical aminocaproic acid vs placebo	Systemic hypotension	Drug group: 3 of 24; placebo group: 3 of 27
Crouch 1997	Systemic vs topical aminocaproic acid	Dizziness, nausea, vomiting	Oral group: 5 of 29; topical group: 1 of 35
Palmer 1986	Low‐dose vs standard‐dose systemic aminocaproic acid	Nausea or vomiting	Low‐dose group: 5 of 25; standard‐dose group: 9 of 33
		Dizziness and hypotension	Low‐dose group: 0 of 25; standard‐dose group: 5 of 33
		Syncope	Low‐dose group: 0 of 25; standard‐dose group: 2 of 33
		Diarrhea	Low‐dose group: 1 of 25; standard‐dose group: 0 of 33
		Rash or pruritis	Low‐dose group: 1 of 25; standard‐dose group: 2 of 33
		Hot flashes	Low‐dose group: 1 of 25; standard‐dose group: 0 of 33
		Dry mouth or nose	Low‐dose group: 1 of 25; standard‐dose group: 0 of 33
Farber 1991	Systemic aminocaproic acid vs oral prednisone	Any adverse event	Aminocaproic acid group: 0 of 56; prednisone group: 0 of 56
*Tranexamic acid*
Welsh 1983	Tranexamic acid vs placebo	Nausea	Drug group: 1 of 19; placebo group: 0 of 20
Rahmani 1999	Tranexamic acid vs placebo	Nausea	Drug group: 0 of 80; placebo group: 0 of 80
*Aminomethylbenzoic acid*
Liu 2002	Systemic aminomethylbenzoic acid vs placebo	Nausea and vomiting	Drug group: 7 of 60; placebo group: NR

Duration of hospitalization (days)
Study	Mean (SD) duration of hospitalization for drug treated group	Number of participants in drug treated group	Mean (SD) duration of hospitalization in control group	Number of participants in control group
McGetrick 1983	5.7 days	28	7.3 days	20
Teboul 1995	7.3 days	48	5.4 days	46

Time to rebleed (days)
Study	Number of rebleeds in the low dose group	Time to rebleed in the low dose group	Number of rebleeds in the standard dose group	Time to rebleed in the standard dose group
Palmer 1986	1 of 25	Day 4	5 of 32	Days 2 to 6: 1 on day 2; 2 on day 3; and 2 on day 6

Study	Outcome	Test intervention	No. with outcome/no. in group	Control intervention	No. with outcome/no. in group	Total no. with outcome/total no.
*Aminocaproic acid*
Crouch 1997	Conjunctival/corneal foreign body sensation	Topical aminocaproic acid	4/35	Systemic aminocaproic acid	0/29	4/64
Crouch 1997	Transient punctate corneal staining	Topical aminocaproic acid	3/35	Systemic aminocaproic acid	0/29	3/64
*Tranexamic acid*
Varnek 1980	Vitreous and retinal hemorrhage	Tranexamic acid	5/102	Conservative treatment	5/130	10/232
Varnek 1980	Traumatic cataract	Tranexamic acid	2/102	Conservative treatment	0/130	2/232
*Non‐drug medical intervention*
Read 1974	Traumatic cataract	Moderate ambulatory activity, patching and shielding of injured eye	NR	Bed rest with elevation of the head, bilateral patches and eye shield	NR	8/137
	Vitreous hemorrhage	Moderate ambulatory activity, patching and shielding of injured eye	NR	Bed rest with elevation of the head, bilateral patches and eye shield	NR	11/137
	Commotio retinae	Moderate ambulatory activity, patching and shielding of injured eye	NR	Bed rest with elevation of the head, bilateral patches and eye shield	NR	4/137
	Occluded pupil	Moderate ambulatory activity, patching and shielding of injured eye	NR	Bed rest with elevation of the head, bilateral patches and eye shield	NR	2/137
	Optic atrophy with nasalization of optic cup	Moderate ambulatory activity, patching and shielding of injured eye	NR	Bed rest with elevation of the head, bilateral patches and eye shield	NR	4/137
	Optic atrophy without nasalization of optic cup	Moderate ambulatory activity, patching and shielding of injured eye	NR	Bed rest with elevation of the head, bilateral patches and eye shield	NR	8/137

Time to resolution of primary hemorrhage (days), systemic corticosteroids
Study	Time to resolution in drug group	Number of participants in drug group	Time to resolution in control group	Number of participants in control group
Rahmani 1999	3.5 days (SD = 1.8) in study participants without a secondary hemorrhage	64	3.7 days (SD = 1.6) in study participants without a secondary hemorrhage	59
Spoor 1980	4.45 days (4.01 days in study participants without a secondary hemorrhage)	23 (20 without a secondary hemorrhage)	4.48 days (3.60 days in study participants without a secondary hemorrhage)	20 (16 without a secondary hemorrhage)

Time to rebleed (days), systemic corticosteroids
Study	Number of rebleeds in the drug group	Mean time to rebleed in the drug group	Number of rebleeds in the control group	Mean time to rebleed in the control group
Rahmani 1999	14 of 78	3.2 days (SD = 0.8)	21 of 80	3.8 days (SD = 1.0)
Spoor 1980	3 of 23	2.3 days	4 of 20	2.6 days

Time to rebleed (days)
Study	Number of rebleeds in the cycloplegic group	Mean time to rebleed in the cycloplegic group	Number of rebleeds in the miotic group	Mean time to rebleed in the miotic group
Bedrossian 1974	1 of 28	2 days	0 of 30	NA

Time to rebleed (days)
Study	Number of rebleeds in monocular patching group	Time to rebleed in monocular patching group	Number of rebleeds in binocular patching group	Time to rebleed in binocular patching group
Edwards 1973	8 of 35	Mean 3 days	8 of 29	Mean 3 days

Time to resolution of primary hemorrhage
Study	Time to resolution in ambulatory group	Number of participants in ambulatory group	Time to resolution in control group	Number of participants in control group
Read 1974	5.8 days		5.6 days

PERMALINK

Medical interventions for traumatic hyphema

Almutez Gharaibeh

Howard I Savage

Roberta W Scherer

Morton F Goldberg

Kristina Lindsley

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Introduction

Epidemiology

Presentation and diagnosis

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Adverse effects

Quality of life outcomes

Economic outcomes

Follow‐up

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Dichotomous data

Continuous data

Ordinal data

Counts and rate data

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings

Results

Description of studies

Results of the search

1.

Included studies

1. Summary of outcomes* reported by intervention.

Aminocaproic acid

Tranexamic acid

Aminomethylbenzoic acid

Corticosteroids

Antifibrinolytic agents versus corticosteroids

Conjugated estrogen

Cycloplegics versus miotics

Aspirin

Traditional Chinese medicine

Monocular versus binocular patching

Ambulatory versus conservative treatment

Combination and other interventions

Excluded studies

Risk of bias in included studies

Allocation

2.

Date	Event	Description
18 December 2018	New search has been performed	Issue 1, 2019: Searches updated, no new studies identified for inclusion.
18 December 2018	New citation required but conclusions have not changed	Issue 1, 2019: Summary of findings tables have been included.

Date	Event	Description
22 November 2013	New search has been performed	Issue 12, 2013: Searches updated.
22 November 2013	New citation required but conclusions have not changed	Issue 12, 2013: One new study added.
7 August 2008	New search has been performed	Converted to new review format

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Short‐term visual acuity from 20/20 to 20/40	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Long‐term visual acuity between 20/20 and 20/40	2	108	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.82, 1.29]
3 Final visual acuity between 20/20 and 20/40	2	143	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.93, 1.18]
4 Time to resolution of primary hemorrhage (days)			Other data	No numeric data
5 Risk of secondary hemorrhage	6	330	Risk Ratio (M‐H, Fixed, 95% CI)	0.28 [0.13, 0.60]
6 Time to rebleed (days)			Other data	No numeric data
7 Risk of corneal blood stain	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8 Risk of glaucoma or increases in IOP			Other data	No numeric data
8.1 Transient increase in IOP			Other data	No numeric data
8.2 Persistent increase in IOP			Other data	No numeric data
9 Risk of glaucoma or elevated IOP	2	83	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.08, 1.82]
10 Risk of optic atrophy	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
11 Adverse effects: nausea or vomiting	3	131	Risk Ratio (M‐H, Fixed, 95% CI)	8.60 [2.09, 35.50]
12 Duration of hospitalization (days)			Other data	No numeric data

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Short‐term visual acuity from 20/20 to 20/40	3	303	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.98, 1.25]
2 Time to resolution of primary hemorrhage (days)			Other data	No numeric data
3 Risk of secondary hemorrhage	5	578	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.17, 0.55]
4 Time to rebleed (days)			Other data	No numeric data
5 Risk of corneal blood stain	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
6 Risk of glaucoma or elevated IOP	4	543	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.73, 1.98]
7 Adverse effects: nausea or vomiting	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
8 Duration of hospitalization (days)			Other data	No numeric data

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Short‐term (5 to 14 days) visual acuity from 20/20 to 20/40, systemic corticosteroids	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Visual acuity between 20/20 and 20/50 at resolution of hyphema, systemic corticosteroids	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Short‐term (5 to 14 days) visual acuity from 20/20 to 20/40, topical corticosteroids	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Final visual acuity between 20/20 and 20/25, topical corticosteroids	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5 Time to resolution of primary hemorrhage (days), systemic corticosteroids			Other data	No numeric data
6 Time to resolution of primary hemorrhage (days), topical corticostroids			Other data	No numeric data
7 Risk of secondary hemorrhage, systemic corticosteorids	2	201	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.39, 1.18]
8 Risk of secondary hemorrhage, topical corticosteroids	2	151	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.05, 1.53]
9 Time to rebleed (days), systemic corticosteroids			Other data	No numeric data
10 Risk of corneal blood stain, systemic cortiocsteroids	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
11 Risk of corneal blood stain, topical corticosteroids	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
12 Risk of peripheral anterior synechiae, systemic corticosteroids	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
13 Risk of glaucoma or elevated IOP, systemic corticosteroids	2	201	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.36, 1.68]
14 Risk of glaucoma or elevated IOP, topical corticosteroids	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
15 Risk of optic atrophy, topical corticosteroids	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
16 Duration of hospitalization (days), systemic corticosteroids	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
17 Duration of hospitalization (days), topical corticosteroids			Other data	No numeric data

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Risk of secondary hemorrhage	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Risk of corneal blood stain	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Short‐term visual acuity	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Time to resolution of primary hemorrhage (days)	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3 Risk of secondary hemorrhage	2	92	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.15, 6.99]
4 Time to rebleed (days)			Other data	No numeric data

Methods	Study design: Quasi‐randomized controlled series. Exclusions after allocation: None. Losses to follow‐up: None. Intention‐to‐treat: All participants were analyzed in the group to which they were assigned. Sample size calculations: Not reported.
Participants	Country: USA. Dates: Not reported. Number allocated: 58 consecutive patients alternately assigned to treatment group after classification based on the size of initial hyphema. Age: Not reported. Sex: Not reported. Race: Not reported. Sickle cell disease: Not reported. Participants appeared to be balanced with respect to baseline characteristics. Inclusion criteria: Non‐total traumatic hyphema.
Interventions	Cycloplegics (n = 28): 1% atropine ointment. Miotics (n = 30): 2% pilocarpine ointment (or eserine ointment). Treatment for both groups included: topical anesthetic if needed; bed rest; head of bed elevated 30° to 90°; binocular patching or pinhole glasses; no reading or watching television; metal shield over injured eye; soft, non‐chew diet; laxatives; room with other individuals; and sedation.
Outcomes	Primary outcome: Time to resolution of primary hemorrhage. Secondary outcomes: Risk of secondary hemorrhage Risk of iridodialysis Follow‐up: Days 1 to 7.
Notes	Funding source not reported.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Allocation was not randomized: participants alternately assigned to treatment groups based on the blood level in the anterior chamber.
Allocation concealment (selection bias)	High risk	Allocation was assigned on an alternate basis.
Blinding (performance bias and detection bias)   Participants	High risk	Masking was not reported.
Blinding (performance bias and detection bias)   Personnel and outcome assessors	High risk	Masking was not reported.
Incomplete outcome data (attrition bias)   Primary outcome	Low risk	All participants were analyzed in the group to which they had been assigned.
Incomplete outcome data (attrition bias)   Secondary outcomes	Low risk	All participants were analyzed in the group to which they had been assigned.
Selective reporting (reporting bias)	Low risk	Reported results for primary and secondary outcomes
Other bias	Low risk	No other sources of potential bias were identified.

Methods	Study design: Randomized, double‐masked, placebo‐controlled clinical trial. Exclusions after randomization: None reported. Losses to follow‐up: None reported. Intention‐to‐treat: All participants were analyzed in the group to which they had been randomly assigned. Sample size calculations: Not reported.
Participants	Country: USA. Dates: Not reported. Number randomized: 45. Age: Not reported. Sex: Not reported. Race: Not reported. Sickle cell disease: Not reported. Inclusion criteria: Traumatic hyphema. Exclusion criteria: Not reported.
Interventions	Treatment (n = 22): Oral aminocaproic acid, loading dose 75 mg/kg, followed by 60 mg/kg every 4 hours; length of treatment not reported. Control (n = 23): Placebo, presumably every 4 hours.
Outcomes	Primary outcome: Risk of secondary hemorrhage, details not reported. Secondary outcomes: Time to resolution of primary hyphema, details not reported.
Notes	Abstract of unpublished study
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomization not reported.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Blinding (performance bias and detection bias)   Participants	Low risk	Authors used a placebo control and stated that the study was double‐masked.
Blinding (performance bias and detection bias)   Personnel and outcome assessors	Low risk	Authors used a placebo control and stated that the study was double‐masked.
Incomplete outcome data (attrition bias)   Primary outcome	Low risk	Unclear if number randomized equaled the number reported and analyzed in the abstract, but no exclusions or losses to follow‐up were reported.
Incomplete outcome data (attrition bias)   Secondary outcomes	Low risk	Unclear if number randomized equaled the number reported and analyzed in the abstract, but no exclusions or losses to follow‐up were reported.
Selective reporting (reporting bias)	Unclear risk	Few study details available in the abstract, and no full version was published.
Other bias	Unclear risk	Few study details available in the abstract, and no full version was published.

Methods	Study design: Randomized, double‐masked clinical trial. Exclusions after randomization: 1 individual assigned to oral aminocaproic acid and topical placebo excluded due to side effect of drug (vomiting). Losses to follow‐up: None. Intention‐to‐treat: All participants were analyzed in the group to which they had been randomly assigned. Sample size calculations: Sample size was determined to be 25 to 30 participants in each of the 3 groups based on alpha of 0.05 and power of 80%. Additional comments: The investigators also studied a control group that did not receive either topical or systemic aminocaproic acid and had refused randomization. We did not include these individuals in our analyses.
Participants	Country: USA. Dates: March 1990 to May 1996. Number randomized: 64: 29 to oral aminocaproic acid plus topical placebo, 35 to oral placebo plus topical aminocaproic acid. Additional 54 participants included as control group. Age: 72% younger than 21 years. Sex: 67% male. Race: 50% black, 49% white, and 1% (1 participant) Asian. Sickle cell disease: 2/35 (6%) of participants assigned to topical aminocaproic acid, and 2/29 (7%) of participants assigned to oral aminocaproic acid had sickle cell trait. Participants appeared to be balanced with respect to baseline characteristics. Inclusion criteria: Traumatic hyphema. Exclusion criteria: Penetrating ocular injury History of anticoagulant or antiplatelet agent within 7 days of ocular trauma Oral or topical corticosteroid use within 48 hours of study History of a coagulopathy History of renal or hepatic insufficiency Previous intraocular surgery History of sensitivity to any component of topical aminocaproic acid Pregnancy Participation in any investigational drug trial within last 4 weeks
Interventions	Treatment: 0.2 mL of 30% aminocaproic acid in 2% carboxymethylene gel applied to inferior fornix every 6 hours plus oral placebo solution every 4 hours for 5 days. Control: Oral aminocaproic acid 50 mg/kg (up to 30 g/day) plus placebo gel every 4 hours for 5 days. Treatment for both groups included: moderate ambulation; head of bed elevated to 30°; shield on affected eye; no aspirin, corticosteroids, non‐steroidal anti‐inflammatory, or antiplatelet agents; and topical timolol maleate, apraclonidine hydrochloride, dipivefrine hydrochloride, or oral acetazolamide if IOP > 22 mmHg.
Outcomes	Primary outcome: Risk of secondary hemorrhage, assessed by daily slit‐lamp exam, and documented by a sketch each day. Secondary outcomes: VA, measured daily and at the end of the 5 days (final VA) Cell and flare, assessed daily for 5 days Corneal blood staining and toxicity, assessed daily by slit‐lamp exam for 5 days IOP assessed daily for 5 days by applanation tonometry Risk of complications and adverse events
Notes	Funded in part by the Lions Medical Eye Bank and Research Center of Eastern Virginia
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were assigned to treatment groups using computerized randomization.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Blinding (performance bias and detection bias)   Participants	Low risk	Authors used a placebo control and stated that the study was double‐masked. Placebo pills were given to the topical group and placebo gel administered to the systemic group to make both regimens similar.
Blinding (performance bias and detection bias)   Personnel and outcome assessors	Low risk	Authors used a placebo control and stated that the study was double‐masked. "Data were compiled by observers who did not know what patients were in the treated and untreated control groups."
Incomplete outcome data (attrition bias)   Primary outcome	Unclear risk	1 participant who was assigned to oral aminocaproic acid and topical placebo was excluded due to side effect of drug (vomiting). The remaining participants were analyzed in the group to which they had been randomly assigned.
Incomplete outcome data (attrition bias)   Secondary outcomes	Unclear risk	1 participant who was assigned to oral aminocaproic acid and topical placebo was excluded due to side effect of drug (vomiting). The remaining participants were analyzed in the group to which they had been randomly assigned.
Selective reporting (reporting bias)	Low risk	Reported results for primary and secondary outcomes
Other bias	Low risk	No other sources of potential bias were identified.