Enbucrilate

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented publication which meets basic scientific principles

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1993

Materials and methods

Study type:

clinical case study

Endpoint addressed:

eye irritation

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Clinical case study with volunteers with regard to the application of n-butyl cyanoacrylate for the treatment of corneal perforations, descemetoceles, leaking filtering blebs, progressive corneal thinning, and wound leaks.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Indermil (n-butyl 2-cyanoacrylate, CAS 6606-65-1)

IUPAC Name:

Indermil (n-butyl 2-cyanoacrylate, CAS 6606-65-1)

Test material form:

liquid: viscous

Details on test material:

Nexacryl (n-butyl cyanoacrylate, Tri Point Medical L.P., Raleigh, NC)

Method

Type of population:

general

Subjects:

- Number of subjects exposed: 44
- Sex: 23 females, 21 males
- Age: from 4 months up to 84 years
- Race: unknown (US-population)

Ethical approval:

confirmed and informed consent free of coercion received

Remarks:

Johns Hopkins Medical Institution clinical investigation consent form for the ocular use

Route of exposure:

ocular

Reason of exposure:

intentional

Exposure assessment:

not specified

Details on exposure:

see 'any other information on materials and methods'

Examinations:

see 'any other information on materials and methods'

Medical treatment:

see 'any other information on materials and methods'

Results and discussion

Clinical signs:

see 'any other information on results'

Results of examinations:

Frank or impending corneal perforations, stromal melts, leaking filtering blebs, and wound leaks can positively be treated with this tissue adhesive.

Effectivity of medical treatment:

The application of n-butyl cyanoacrylate as tissue adhesive for the treatment of corneal perforations, descemetoceles, leaking filtering blebs, progressive corneal thinning, and wound leaks demonstrates its effectiveness for both frank and impending perforations of the conjunctiva, cornea, and sclera.

Outcome of incidence:

see 'any other information on results'

Any other information on results incl. tables

OBSERVATIONS AND RESULTS

Polymerization occurred within 1 to 2 seconds. Topical antibiotic coverage was used in all patients with the glue in place.

Many of the eyes required more than one application of the tissue adhesive. The number of applications per eye ranged from one to six (mean, 1.6 times per eye). Twenty-nine patients required a single application of the tissue adhesive, whereas 15 patients required two or more applications. The gIue's adhesiveness to the eye varied (range, 1-660 days). The average length of time the n-butyl cyanoacrylate adhered to the eye was 72 days. A bandage contact lens was used to cover the dried tissue adhesive in 38 of the 44 eyes.

Penetrating keratoplasty was eventually required in 43% (19/44) of eyes. Thirty-three percent (14/44) of eyes required no further surgical intervention. Enucleation was performed in 9% (4/44) of eyes. One of the eyes enucleated had unrelated trauma, two had persistent corneal melts, and one presented as a no light perception perforated corneal ulcer. Surgical revision of a trabeculectomy conjunctival flap was required in 5% (2/44) of eyes. A scleral graft 2% (1/44) of eyes, conjunctival transplant 2% (1/44), a failed tarsorrhaphy 2% (1/44), resuturing of a wound leak 2% (1/44 eyes), and a lamellar graft 2% (1/44 eyes) were the additional outcomes.

Visual acuity before the application of the tissue adhesive ranged from 20/25 to no light perception. After glue placement and any additional procedures required, visual acuity ranged from 20/25 to no light perception. Visual acuity improved two lines or more in 52% (23/44) of eyes, there was no change in visual acuity in 32% (14/44), and visual acuity was worse in 16% (7/44). The reasons for the decreased visual acuity in these seven eyes are that three had been enucleated, one had endophthalmitis, one had a conjunctival transplant, one presented as a perforated fungal uIcer, and one had herpetic keratitis with chronic wound leaks since 1988.

Recurrent corneal ulcers in 5% (2/44) of eyes and endophthalmitis in 2% (1/44) were the infectious complications observed. Two of these cases were previously reported. Other complications seen were scarring of conjunctival filtering bleb in 5% (2/44) of eyes and symblepharon formation in 2% (1/44).

The author's experience with this tissue adhesive for the treatment of corneal perforations, descemetoceles, leaking filtering blebs, progressive corneal thinning, and wound leaks demonstrates its effectiveness for both frank and impending perforations of the conjunctiva, cornea, and sclera. The 14 eyes that stabilized after glue application alone had an original diagnosis of conjunctival bleb leak (5 eyes), descemetoceles (3 eyes), corneal perforation (3 eyes), wound leaks (2 eyes), and corneal melt (1 eye) .

The 19 eyes that received a penetrating keratoplasty after application of tissue adhesive benefited from the glue treatment. It allowed for tectonic support so that two of these patients could have a penetrating keratoplasty immediately after application of the glue, whereas the remainder

was done when adequate tissue was available and the eye was not inflamed. One patient (case 22) who eventually needed a transplant presented with a corneal perforation secondary to progressive stromal thinning after an alkali burn. The tissue adhesive remained on the eye for 660 days. The adhesive sloughed, and 30 days later it perforated from recurrent stromal thinning. This illustrates that the glue while in place can stop

progressive stromal melts.

The enucleation rate for these patients was similar to the 6% previously reported for corneal perforations. Four patients required enucleation, but one of these patients was hit in the glued eye with a fist, and extruded the ocular contents. Even with this patient included, the enucleation rate was only 9%. These eyes are severely diseased or traumatized, with a guarded prognosis. Before the use of tissue adhesives, one report cited a 19% enucleation rate.

One of the limitations in using the tissue adhesive was the size of the perforation and the condition of the surounding tissue. These factors influenced glue adherence. Of the 44 eyes, only 30 (67%) required one application of n-butyl cyanoacrylate, whereas 33% (14/44) of eyes lad multiple applications. Progressive stromal melting accounted for 50% of the eyes that needed more than one glue application (4 eyes had stromal melt, 2 eyes perforated from melt, and a descemetocele from a melt developed in 1 eye). Chronic wound leaks (3 eyes), corneal ulcers (2 eyes), and bleb leaks (2 eyes) accounted for the other 50% of eyes that required multiple applications. For all 44 eyes, the average number of applications per eye was 1.6.

The length of time of adherence and its effect varied greatly. The authors looked for vascularization and epithelization under the glue for complete healing, and tended to leave the glue in place until the time of surgery or allowed the glue to slough spontaneously. Whenever the tissue adhesive had to be removed at the time of surgery or when infections developed (3 patients), the glue was easily removed with a 0.12-mm forceps.

COMPLICATIONS

There were few but serious complications. In three of the eyes, infectious keratitis developed under the glue; however, in two of the ulcers, the same organism grew under the glue at presentation. The case of endophthalmitis involved a corneal perforation with recurrent melts in an 18-year-old woman with atopy and gammaglobulin deficiency. Haemophilus influenzae endophthalmitis was diagnosed at the time of penetrating keratopIasty after a progressive melt. All three of these cases had been on prophylactic topical antibiotics. After these infections developed, all patients had their antibiotic coverage switched every 2 to 3 weeks, so the development of a resistant organism was less likely to occur. Since this

change in antibiotic coverage was instituted, no additional cases of infectious keratitis have developed under n-butyl cyanoacrylate. Two eyes had scarring of the conjunctival bleb after button holes were treated with the glue. In one eye, a symblepharon developed after the glue had been in place over 1 year. However, this eye also had a history of an alkali burn.

Careful monitoring of the patients is essential to prevent the disastrous sequela of an infectious ulcer developing under the glue. However, the benefits of n-butyl cyanoacrylate outweigh the risks of an ulcer developing under the glue.

ADVANTAGES

Frank or impending corneal perforations, stromal melts, leaking filtering blebs, and wound leaks can positively be treated with this tissue adhesive. This cyanoacrylate adhesive may be a temporary measure until adequate donor tissue is available for a penetrating keratoplasty.

The greatest advantage of this tissue adhesive in treating severe ocular conditions is the fact that it only involves topical anesthesia and can be performed immediately at the slit lamp or under a microscope. A lamellar patch graft, an alternative method of treatment for a corneal perforation or descemetocele, requires a surgical procedure with donor tissue. A patient with tissue adhesive in place can have a nonemergent penetrating keratoplasty (if needed) when adequate tissue is available. The experiences indicate this glue is safe and effective in treating corneal perforations and descemetoceles up to 3 mm in length, all types of corneal melts, and various types of wound leaks. This tissue adhesive is the most efficient

method of immediate wound closure in these ocular conditions.

Patients need to be followed closely in the event the glue dislodges before the defect has healed. Tissue adhesive may need to be reapplied, or if several attempts to glue fail, a patch graft may then be indicated.

Applicant's summary and conclusion

Conclusions:

The authors' experience demonstrates that n-butyl cyanoacrylate is an effective ophthalmological method of temporary or permanent closure of an impending or frank perforation.

Executive summary:

BACKGROUND: To investigate the indications, outcomes, and complications of n-butyl cyanoacrylate tissue adhesive for ocular clinical use. This tissue adhesive is under investigation by the Food and Drug Administration.

METHODS: n-butyl cyanoacrylate was used as an investigational device on 44 patients at the authors' institution over a 2-year period. The charts of these patients were reviewed.

RESULTS: The indications for glue application included corneal perforation (19 eyes), descemetoceles (9 eyes), leaking filtering blebs (6 eyes), stromal thinning (5 eyes), wound leaks (4 eyes), and exposure keratopathy (1 eye). A bandage contact lens was used over the dried tissue adhesive in 38 of the 44 eyes. Length of glue adherence ranged from 1 to 660 days (mean, 72 days). Outcome was penetrating keratoplasty (19 eyes), no further intervention (14 eyes), enucleation (4 eyes), surgical revision of a filter (2 eyes), scleral patch graft (1 eye), conjunctival transplant (1 eye), failed tarsorrhaphy (1 eye), suturing of wound (1 eye), and a lamellar graft (1 eye). Vision improved in 52% (23/44) of eyes.

CONCLUSION: This tissue adhesive may soon be available to all ophthalmologists, and the authors' experience demonstrates that it is an effective method of temporary or permanent closure of an impending or frank perforation.