Ординатура / Офтальмология / Учебные материалы / Clinical Diagnosis and Management of ocular trauma

Management of Iatrogenic Inflammation of the Eye

227

of concurrent corticosteroid therapy. Topical NSAIDs

US food and Drug Administration (FDA) has approved

also are effective in the treatment of angiographically

the use of the diclofenac 0.1% four times daily, starting

documented subclinical CME, and this can translate

24 hours after cataract surgery for this purpose. Thus,

into improved visual function. Oral NSAIDs have also

it is possible to substitute a topical NSAID for a topical

been shown to be effective in both the prevention

corticosteroid to control postoperative inflammation,

and treatment of CME after cataract surgery. However,

especially in eyes with significant steroid responsive

a study demonstrating a positive effect on visual

glaucoma.

function with oral promote one NSAID still is lacking.

There is no strong evidence to promote one NSAID

Uveitis

over another.

In contrast to post-surgical inflammation, many forms

Postoperative Inflammation

of uveitis require prolonged steroid therapy to control

inflammation. At times, the therapeutic effort must be

Fluorophotometric analysis has made available a

escalated to the use of subtenon injections or oral

quantitative means of studying anterior chamber

administration of corticosteroid. Of course, the risk of

inflammation. With this tool, it has been possible to

iatrogenic glaucoma and cataract becomes substantial

evaluate, in a reproducible fashion, the effect of

in these situations. Therefore, NSAIDs are gaining a

NSAIDs on postoperative inflammation. By using both

more secure position in the treatment of certain forms

slit lamp and fluorophotometric analysis as a part of

of uveitis.

randomized double-masked placebo-controlled

studies, several topical NSAIDs like indomethacin

Scleritis and Episcleritis

1.0%,5 flurbiprofen 0.03%,6 ketorolac 0.5%7,8 and

Topical NSAIDs have no proven efficacy in the

diclofenac 0.1%9 have been shown to reduce

treatment of episcleritis. In fact, they appear to be

postoperative inflammation. The positive effect of

less effective than topical corticosteroids in reducing

NSAIDs was seen in both intracapsular and

episcleral injection and pain associated with

extracapsular cataract surgery. It is important to note

episcleritis12. In contrast, systemic NSAIDs are the

that whereas in most of the studies, corticosteroids were

agents of choice in the treatment of non-necrotizing

given concurrently, two of these studies were

simple, diffuse, and nodular scleritis.13 One may have

conducted without concurrent corticosteroid therapy7,8.

to proceed sequentially through several different

In these studies, topical ketorolac 0.05% proved to

NSAIDs until one finds the one that

works.

be better than placebo in controlling inflammation

Furthermore, when a steroid is needed, the duration

after cataract surgery.

and dose of the steroidal may be reduced with the

In the treatment of postsurgical inflammation, the

adjunctive use of an NSAID.

superiority of NSAID over placebo has led to a

comparison of NSAIDs with corticosteroid. Ketorolac

0.5%10 and diclofenac11 were compared to

Allergic and Giant Papillary Conjunctivitis

dexamethasone and prednisolone, respectively. In both

Vernal keratoconjunctivitis most commonly occurs in

studies, there was no significant difference in the

children and young adults. It shares with contact lens-

reduction of postoperative inflammation by slit-lamp

associated giant papillary conjunctivitis (GPC) the

examination between patients on NSAIDs and those

common finding of giant papillary conjunctivitis (GPC)

on corticosteroid topical therapy. However, it should

on the upper palpebral conjunctiva. The standard

be noted that in the ketorolac study, a subtenon

treatment for both is topical steroids until a topical mast

injection of corticosteroid was given to all the patients

cell stabilizer takes effect.

and this may have contributed to the lack of difference

between the two treatment groups. Concurrent

corticosteroid therapy was not a factor in the study

Side Effects of NSAIDs

comparing diclofenac with prednisolone. When

fluorophotometry was used in both comparative

Common adverse effects following instillation of topical

studies, it was found that control of inflammation in

NSAIDs include burning, stinging, and hyperemia of

the topical NSAID treatment group was better achieved

conjunctiva. Allergic and hypertensive reactions are

than in the corticosteroid groups.

also reported following use of topical NSAIDs. Systemic

Regardless of the preceding findings, it is a common

side effects following use of NSAIDs mainly include

practice to use topical corticosteroid alone to control

gastritis, but are unlikely to occur with topical

post-cataract surgery inflammation. Nevertheless, the

administration.

228

Clinical Diagnosis and Management of Ocular Trauma

Conclusion

5.

Sanders DR, Kraff ML: Steroidal and nonsteroidal anti-

inflammatory agents. Effects on postsurgical inflammation

NSAIDs have wide potential for use in various ocular

and blood-aqueous barrier breakdown. Arch.

disorders, though the effects vary from one individual

Ophthalmol 1984;102:1453-56.

6.

Sabiston MB, Tessler D, Summersk H, et al: Reduction

to another and the effect is unpredictable. More

of inflammation following cataract surgery by flurbiprofen.

research is required to develop newer NSAIDs which

Ophthalmic Surg 1987;18:873-77.

can be used for various inflammatory disorders of the

7.

Flach AJ, Graham J, Kruger LP, et al: Quantitative

eye with more effective action with minimal ocular

assessment of postsurgical breakdown of the blood-

toxicities.

aqueous barrier following administration of ketorolack

tromethmine solution. A double-masked, paired

Currently corticosteroids are still the drugs of choice

comparison with vehicle-placebo solution study. Arch.

in the treatment of ocular inflammation. However,

Ophthalmol 1988;106:344-47.

because their prolonged use may result in severe ocular

8.

Flach AJ, Lavelle CJ, Olander KW, et al. The effect of

side effects, it would be therapeutically beneficial to

ketorolac 0.5% solution in reducing postsurgical

develop nonsteroidal anti-inflammatory drugs that

inflammation following ECCE with IOL. Double masked,

parallel comparison with vehicle. Ophthalmology.

have similar or greater efficacy than steroids but not

1988;95:1277-84.

their ocular side effects.

9.

Vickers FF, McGuigan LJB, Ford C, et al. The effect of

diclofenac sodium ophthalmic drops on the treatment of

postoperative inflammation. Invest. Ophthalmol. Vis. Sci.

References

(ARVO suppl) 1991;32:793.

10.

Flach AJ, Kraff MC, Sanders DR, et al. The quantitative

1. Flck AJ: Cyclo-oxygense inhibitors in Ophthalmology.

effect of 0.5% ketorolac tromethamine solution and 0.1%

dexamethasone sodium phosphate solution on

Surv. Ophthalmol 1992;36:259-84.

postsurgical blood aqueous barrier. Arch. Ophthalmol

2. Gilman AG, Rall TC,

Nies AS, Taylor P: The

1988;106:480-83.

pharmacologic basis of therapeutics. Elmsford: Pergamon

11.

Kraff MC, Sanders DR, McGuigan L, et al. Inhibition of

1990:638-81.

blood aqueous humour barrier breakdown with

3. Abramson SB, Weisman G: The mechanism of

diclofenac. A fluorophotometric study. Arch. Ophthalmol

nonsteroidal anti-inflammatory drugs. Arthritis Rheum

1990;108:380-83.

1989;32:1-9.

12.

Lyons CH, Hakin KN, Watson PG. Topical flurbiprofen:

4. Flach AJ, Jampol LM, Weinberg D, et al: Improvement

an effective treatment for epoiscleritis? Eye 1990;4:

in visual acuity in chronic aphakic and pseudophakic

521-25.

cystoid macular edema after treatment with topical 0.5%

13.

Vitale A, Foster CS: Nonsteroidal anti-inflammatory

ketorolac tromethamine. Am. J. Ophthalmol 1991;

drugs. In: Zimmerman TJ, ed. Textbook of ocular

112:514-19.

pharmacology, New York: Lippincott-Raven, 1995.

230

Clinical Diagnosis and Management of Ocular Trauma

In 2004, the epidemic of atypical mycobacteria that

the cornea for 1-2 minutes to improve flap adherence

was seen in 2001 (Fig. 35.1B) ended. Cases from

and then apply antibiotic directly on the dehydrated

atypical mycobacteria decreased from 48 to 5%. This

flap to improve antibiotic absorption into the cornea.

decrease is presumably due to the use of fourth-

With PRK, we place the antibiotic directly onto the

generation fluoroquinolones and improved sterile

stromal bed and soak the bandage contact lens in

technique. It was interesting to note that no patient

antibiotic for 30 seconds prior to placing the contact

who received a 4th generation fluoroquinolone as

lens on the eye. Postoperatively, patients receive a

prophylaxis developed an atypical mycobacteria

fourth generation fluoroquinolone four times a day

infectious keratitis in the 2004 survey. However, the

for 5 days with LASIK and for one day after the

overall incidence of infectious keratitis increased in

epithelial defect has closed with PRK.

2004 from 2001.

We divide infectious keratitis following LASIK into

The results of these surveys and an analysis of the

rapid onset within the first two weeks of surgery and

trends seen in the data can help to guide prophylaxis

late onset which can occur from 2 weeks to 3 months

and treatment of infections keratitis following LASIK.

following surgery.13 The organisms seen in early onset

Infectious keratitis is a potentially devastating

infectious keratitis within the first two weeks are

complication of LASIK. A high degree of suspicion

common bacterial pathogens such as staphylococcal

coupled with a rapid diagnosis and appropriate therapy

and streptococcal species. Gram-negative organisms

can result in visual recovery. For prophylaxis against

are rare. The organisms seen in late onset infectious

a post-LASIK infectious keratitis there are several steps

keratitis after two weeks are usually opportunistic such

which can be implemented. Preoperatively, all patients

as fungi, nocardia and atypical mycobacteria. The

considering refractive surgery should have a thorough

published literature review of LASIK-associated

examination of their eyelids and lacrimal apparatus.

infections by Chang and colleagues supports this

Treatment of infectious lid disease prior to LASIK with

classification of infection.5 Based on their study, gram-

hot compresses and a topical antibiotic ointment applied

positive organisms were more likely to present within

three times daily to the lid margin may decrease the

7 days of surgery (p = 0.001) while mycobacterial

risk of a bacterial keratitis. A small minority of clinicians

infections were more likely to present 10 or more days

recommend performing monocular surgery or the use

after surgery (p < 0.001).5

of separate instruments when performing bilateral

Since the organisms responsible for infectious

surgery.11 Some clinicians recommend the use of sterile

keratitis following LASIK often will not respond to

drapes, gowns, gloves and masks by the treating

empiric therapy, as with the results from the previous

physician and assisting technician. A10% betadine

survey, we recommend lifting the flap, scraping, and

solution lid prior to cataract surgery has been shown

culturing all suspicious cases, and selecting appropriate

to decrease the incidence of endophthalmitis following

culture media including blood agar, chocolate agar,

cataract surgery and is recommend by many clinicians

Sabouraud’s agar and thioglycolate broth.13 For

when performing LASIK.12 Proper sterilization

infectious keratitis after two weeks, we recommend a

techniques can prevent the use of contaminated

growth media for atypical mycobacteria such as

instruments. As several epidemics of atypical

Lowenstein-Jensen or Middlebrook 7H-9 media in

mycobacteria have been associated with the use of

addition to the previous culture media. If these special

non-sterile water to clean instruments or the use of

media are unavailable, we recommend using blood

ice during LASIK surgery, all fluids applied to the eye

agar as atypical mycobacteria grow quite well on these

before, during and after LASIK should be sterile.13

plates. At the time of culture we also recommend

Antibiotic prophylaxis for LASIK should emphasize

scraping the infiltrate and performing a Gram stain,

the need to provide broad-based spectrum coverage

Gomori-methenamine silver stain, and Ziehl-Neelsen

with gram-positive emphasis. The antibiotic should be

stain to rule out unusual pathogens such as nocardia,

non-toxic to promote epithelial healing and should

atypical mycobacteria, and fungi. In cases in which

provide coverage against atypical mycobacteria which

cultures are negative and the infection continues to

is the most common opportunistic organism responsible

a corneal biopsy or PCR should be considered.

for post-LASIK infections. Finally, the antibiotic should

For the treatment of both rapid-onset and delayed-

penetrate effectively into the cornea and achieve

onset infectious keratitis, it is recommended to elevate

therapeutic levels in the mid stroma. Fourth generation

the flap and culture. Irrigation of the flap interface with

fluoroquinolones (gatifloxacin 0.3% and moxifloxacin

an appropriate antibiotic solution (fortified vancomycin

0.5%) for antibiotic prophylaxis of LASIK and PRK are

50 mg/ml for rapid-onset keratitis and fortified amikacin

recommended as they best meet the criteria listed

20 mg/ml for delayed-onset keratitis) may be helpful.

above.13 We begin topical therapy 1 hour prior to

For rapid - onset keratitis, we recommend a fourth-

surgery and at the conclusion of LASIK we dehydrate

generation topical fluoroquinolone such as gatifloxacin

Management of Postrefractive Keratitis

231

0.3% or moxifloxacin 0.5% be given in a loading dose

misdiagnosis at initial presentation may result in

every 5 minutes for 3 doses and then every 30 minutes

significant vision loss. Antibiotic prophylaxis for LASIK

alternating with an antimicrobial which is rapidly

should emphasize the need to provide broad-based

bacteriocidal and has increased activity against gram-

spectrum coverage with gram-positive emphasis. For

positive organisms, such as cefazolin 50 mg/ml every

treatment, we do not recommend empiric therapy as

30 minutes.13 In patients who work in a hospital

most organisms are opportunistic and do not respond

environment or have been exposed to a hospital

to conventional therapy. A high degree of suspicion

surgical setting or health care environment, there is

with flap elevation and culturing should be performed

an added risk of methicillin-resistant Staphylococcus

on all eyes suspected of infectious keratitis following

aureus (Solomon R, Donnenfeld E, Perry H, et al.

LASIK.

methicillin resistant Staphylococcus aureus infectious

keratitis following refractive surgery. Presented as a

paper at the American Society of Cataract and

References

Refractive Surgery Symposium on Cataract, IOL, and

1.

Hersh PS, Brint SF, Maloney RK, et al. Photorefractive

Refractive Surgery, San Diego, Calif, 2004). In those

patients who work in a hospital environment or have

keratectomy versus laser in situ keratomileusis for

had exposure to a health care environment, we

moderate to high myopia: A randomized prospective

study. Ophthalmology 1998;105:1512-23.

recommend the substitution of vancomycin 50 mg/ml

2.

Azar DT, Farah SG. Laser in situ keratomileusis versus

every 30 minutes instead of cefazolin to provide more

photorefractive keratectomy: An update on indications

effective therapy against MRSA. In addition, we

and safety. Ophthalmology 1998;105:1357-58.

advocate the use of oral doxycycline 100 mg twice

3.

Garg P, Bansal AK, Sharma S, Vemuganti GK. Bilateral

daily (to inhibit collagenase production) and also

infectious keratitis after laser in situ keratomileusis: A case

recommend discontinuing corticosteroids.

report and review of the literature. Ophthalmology

2001;108:121-25.

For delayed-onset keratitis, which is commonly due

4.

Solomon A, Karp, CL, Miller D, et al. Mycobacterium

to atypical mycobacteria, nocardia and fungi, we

interface keratitis after laser in situ keratomileusis.

recommend beginning therapy with amikacin 35 mg/

Ophthalmology 2001;108:2201-08.

ml every 30 minutes alternating with vancomycin

5.

Perry HD, Doshi SJ, Donnenfeld ED, et al. Herpes

50 mg/ml every 30 minutes, starting oral doxycycline

simplex reactivation following laser in situ keratomileusis

and subsequent corneal perforation. CLAO

J

100 mg BID, and discontinuing corticosteroids.

2002;28:69-71.

Alternative therapy for delayed-onset keratitis, which

6.

Chang MA, Jain S, Azar DT. Infections following laser in

would cover atypical Mycobacteria, includes

situ keratomileusis: An integration of the published

clarithromycin and fourth-generation fluoro-

literature. Surv Ophthalmol 2004;49:269-80.

quinolones. This treatment will not cover fungal

7.

Stulting RD, Carr JD, Thompson KP, et al. Complications

infections, and therefore, treatment for all cases of

of laser in situ keratomileusis for the correction of myopia.

Ophthalmology 1999;106:13-20.

infectious keratitis should be modified based on culture

8.

Lin RT, Maloney RK. Flap complications associated with

and scraping results and response to therapy.

lamellar refractive surgery. Am J Ophthalmol 1999;

Infectious keratitis after LASIK frequently presents

127:129-36.

with inflammation in the corneal interface, which can

9.

Karp CL, Tuli SS, Yoo SH, et al. Infectious keratitis after

mimic diffuse lamellar keratitis (DLK). DLK usually

LASIK. Ophthalmology 2003;110:503-10.

10.

Solomon R, Donnenfeld ED, Azar DT, Holland EJ,

occurs within the first few days following LASIK, unless

Palmon FR, Pflugfelder SC, Rubenstein JB. Infectious

there is postoperative ocular trauma.14 The appearance

keratitis after laser in situ keratomileusis: Results of an

of an interface inflammation more than one week

ASCRS survey. J Cataract Refract Surg 2003;29:

following LASIK should be presumed to be infectious

2001-06.

unless proven otherwise. Since DLK usually presents

11.

Kohnen T. Infections after corneal refractive surgery: Can

with a diffuse appearance while infectious keratitis has

we do better? (editorial). J Cataract Refract Surg 2002;

28:569-70.

focal area of infiltration, any focal infiltrate surrounded

12.

Speaker MG, Menikoff JA. Prophylaxis of

by inflammation following LASIK should be considered

endophthalmitis with topical povidone-iodine.

infectious until proven otherwise.

Ophthalmology 1991;98:1769-75.

In conclusion, infectious keratitis is a potentially

13.

Donnenfeld ED, Kim T, Holland E, et al. Management

devastating complication following LASIK. Culture

of infectious keratitis following laser in situ keratomileusis.

results reveal gram-positive bacteria as the most

J Cataract Refract Surg 2005;31:2008-11.

14.

Stulting RD, Randleman JB, Couser JM, Thompson KP.

common organisms. Infectious keratitis may present

The epidemiology of diffuse lamellar keratitis. Cornea

as late as months following LASIK, and its frequent

2004;23:680-88.

234

Clinical Diagnosis and Management of Ocular Trauma

Penetration Tracking

tested against a Staph. aureus ocular isolate using disk-

diffusion analysis. The moxifloxacin achieve a 24 mm

Antibiotic tissue penetration plays a key role in

zone of inhibition, and Gatifloxacin had no zone of

protecting against infection.

inhibition. This surrogate model accounts for tissue

This issue arises when examining the research on

penetration and potency at the potential site of

various antibiotics; some may have good potency

infection, thus defining protection.

statistics in vitro, but we fail to identify the in vivo

performance of the antibiotic. The latter will tell

ophthalmologists what levels of the drug our patients

Safety Evaluation

actually will get in the cornea, the anterior chamber,

In addition to potency and penetration, a solid

and the vitreous. Our research administering

fluoroquinolones to a cornea transplant model prior

evaluation of antibiotics for surgical prophylaxis should

to corneal transplant and then examining the antibiotic

assess whether the drug is non-toxic. Efforts to prevent

levels in the cornea showed Moxifloxacin had three

the use of non-toxic medication should look for

times the concentration of Gatifloxacin.

epithelial problems or endothelial problems.

Similar research at various International Research

As a class of drugs, the Fluoroquinolones have

Centres on aqueous concentrations of antibiotic

proven to by very safe and non-toxic.

applied a series of drops preoperative and measured

Our experience with all fourth-generation Fluoro-

aqueous concentration at the time of cataract surgery.

quinolones has found that they are very safe. Research

Those researchers identified the same three-fold

comparing corneal epithelial healing postoperative

greater penetration of Moxifloxacin. Protection can be

when Moxifloxacin or Gatifloxacin are used have

defined by overlaying these concentrations with the

found very similar would healing rates. In fact, an

MICs for potential pathogens.

independent well-controlled study evaluating wound

In vivo potency after tissue penetration is a better

healing post-PRK for Moxifloxacin and Gatifloxacin

measure of antibiotic efficacy than speed of kill in vitro.

were conducted in USA. The conclusion was that both

The latter removes all of the factors that determine

the drugs are safe. Generally, they found that eyes

how the antibiotic performs in human tissue. These

treated with Moxifloxacin healed faster and had smaller

studies disrergard the reality of penetration of the

defects than those treated with Gatifloxacin.

antibiotic through human tissue. For these reasons

Rabbit model studies that created epithelial defects

in vivo potency and penetration studies will always

and tracked healing when the two antibiotics are used

have more real-world resonance than in vitro speed

found similar results. Clinical trials looking at healing

of kill research. The aqueous humor concentrations

after PRK also identified similar healing. Both

achieved in the International Resarch Centres were

Fluoroquinolones are safe and non-toxic.