- Email: [email protected]
Fibrin Glue for Closure of Conjunctival Incision in Strabismus Surgery
Ophthalmic Technology Assessment
Fibrin Glue for Closure of Conjunctival Incision in Strabismus Surgery A Report by the American Academy of Ophthalmology Michael B. Yang, MD,1 Michele Melia, ScM,2 Scott R. Lambert, MD,3 Michael F. Chiang, MD,4 Jennifer L. Simpson, MD,5 Angela N. Buffenn, MD, MPH6 Objective: To evaluate the severity of postoperative inflammation, degree of patient discomfort, adequacy of wound closure, and length of operating time when using fibrin glue compared with sutures to close limbal conjunctival incisions after strabismus surgery. Methods: Literature searches of the PubMed and Cochrane Library databases were last conducted on January 24, 2013, and resulted in 24 citations, including 2 not in the English language. All citations were reviewed in full text. Five studies compared fibrin glue (68 eyes) with sutures (74 eyes) for closure of limbal conjunctival incisions in patients undergoing strabismus surgery and were included in this assessment; no studies were found that evaluated fornix incisions. A quality rating was assigned to each study using criteria specifically developed for this assessment. Results: No level I studies were found, and 5 level II studies were identified. There was significantly less postoperative inflammation and patient discomfort for 1 to 3 weeks after strabismus surgery for eyes treated with fibrin glue compared with sutures. In 3 studies that evaluated wound apposition, 2 of 50 eyes (4%) with conjunctival incisions that were initially closed using fibrin glue subsequently developed a wound gap that required suture repair. In the 2 studies that compared surgical time, fibrin glue required 1 to 5 minutes less time than suturing in 1 study and 55% less time (3.8 vs. 8.4 minutes) in a second study. These 5 studies did not evaluate the cost-effectiveness or risk of viral transmission from fibrin glue. Conclusions: Studies in the literature suggest that the off-label use of fibrin glue to close limbal conjunctival incisions in strabismus surgery resulted in less postoperative inflammation and required shorter operating time compared with sutures, but it increased the percentage of wounds requiring subsequent repair with sutures. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2013;120:1935-1941 ª 2013 by the American Academy of Ophthalmology.
The American Academy of Ophthalmology prepares Ophthalmic Technology Assessments to evaluate new and existing procedures, drugs, and diagnostic and screening tests. The goal of an assessment is to systematically review the available research for clinical efficacy and safety. After review by members of the Ophthalmic Technology Assessment Committee, other Academy committees, relevant subspecialty societies, and legal counsel, assessments are submitted to the Academy’s Board of Trustees for consideration as official Academy statements. The purpose of this assessment is to compare fibrin glue and sutures for the closure of limbal conjunctival incisions in strabismus surgery.
Background Surgical technique is one of several variables that may influence the degree of pain experienced by patients after strabismus surgery.1,2 Different techniques, such as the fornix incisional approach3 and minimally invasive strabismus surgery,4 have the potential to reduce 2013 by the American Academy of Ophthalmology Published by Elsevier Inc.
postoperative irritation and discomfort because they generally do not require sutures.5 These techniques have not been formally compared with the limbal incisional approach, which requires a minimum of 2 sutures to close a winged conjunctival peritomy and thus may be more irritating.6 For strabismus surgeons who nevertheless prefer limbal incisions or in strabismus surgeries where limbal incisions are advantageous (e.g., reoperations or surgery in older adults), tissue adhesives represent an alternative to sutures that can potentially maintain adequate wound closure while decreasing operating time and reducing postoperative inflammation. Reports of the use of fibrin glue for closing conjunctival incisions in strabismus surgery first appeared in Europe in the 1960s and subsequently in the English-language literature in 1988.7,8 Although cyanoacrylate has long been used in ophthalmic surgery, fibrin glue seems to be more appropriate for conjunctival closure because it produces a smooth seal along the wound edge, resulting in fewer postoperative complications. In contrast, cyanoacrylate is ISSN 0161-6420/13/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2013.05.008
1935
Ophthalmology Volume 120, Number 9, September 2013
Figure 1. The blood coagulation cascade.
impermeable to fluids and may cause giant papillary conjunctivitis and corneal neovascularization.9,10 Several commercially manufactured fibrin glues are available, including TISSEEL and ARTISS (Baxter, Deerfield, IL); EVICEL (a modified successor of Quixil or Crosseal, distributed by Ethicon, Johnson and Johnson, Somerville, NJ, manufactured by Omrix, Kiryat Ono, Israel); Beriplast P (CSL Behring, Marburg, Germany); and Greenplast (Green Cross Corp., Seoul, South Korea). These vary in their performance on hemostasis and skin adhesion tests.11 Only TISSEEL, ARTISS, and EVICEL have received approval for marketing by the US Food and Drug Administration. Their use for the closure of conjunctival incisions is off-label. TISSEEL and EVICEL are specifically approved for use “as an adjunct to hemostasis in patients undergoing surgery, when control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical.”12,13 In addition, TISSEEL is approved as “a fibrin sealant indicated as an adjunct to standard surgical techniques (such as suture and ligature) to prevent leakage from colonic anastomoses following the reversal of temporary colostomies.”12 In contrast, in Europe, Beriplast P is approved “as a tissue [glue] to promote adhesion/sealing or as suture support.”14 Thus, the closure of conjunctival wounds in strabismus surgery seems to fall under Beriplast P’s approved uses in Europe. ARTISS, a more recent product that is essentially identical to TISSEEL with the exception of a reduced concentration of thrombin, is indicated in burns “to adhere autologous skin grafts to surgically prepared wound beds” or “to adhere tissue flaps during facial rhytidectomy surgery (face-lift).”15 The longer setting time for ARTISS may be suitable for its indicated procedures but may not be as attractive as TISSEEL to strabismus surgeons seeking to minimize operating time while maximizing wound adherence.
Description of the Technology Fibrin glue works by combining 2 initially separate components, fibrinogen and thrombin, which activate the final pathway of the coagulation cascade in which fibrinogen
1936
is converted into fibrin (Fig 1). Both TISSEEL and EVICEL, approved by the Food and Drug Administration, come in 2 prefilled syringes that separately contain the fibrinogen and thrombin components. These should be kept frozen until near the time of surgery.12,13 When ready for use, the 2 components of fibrin glue can be combined in a Y-split injection device and applied via a common cannula. After the fibrin glue is applied, the 2 surfaces to be adhered (in this case, the conjunctiva and sclera) have to be held together for at least 2 minutes until sufficient polymerization of the fibrin glue occurs.
Risk of Transmission of Infectious Agents The risk of viral transmission through commercially manufactured plasma products is low because the plasma used is pooled from licensed US collection centers. Nucleic acid technology is used to detect viral contamination, and various physicochemical techniques, such as vapor heat and solvent/ detergent treatment, are used to remove and inactivate any virus.16 For TISSEEL and EVICEL, a 5.6 log10 to 15.6 log10 and a 4.0 log10 to 10.6 log10 reduction, respectively, in the counts of human immunodeficiency virus-1, hepatitis A virus, hepatitis C virus, and hepatitis B virus during the manufacturing process has been documented.12,13 For these specific viruses, the risk of transmission has been estimated to be approximately 1 in 1015 vials of thrombin and fibrin.17 Because parvovirus is more difficult to eliminate, lower levels of log10 reduction in viral counts have been reported during manufacturing,12,13 and the estimated risk of parvovirus transmission is 1 in 500 000 vials of fibrinogen and 1 in 107 vials of thrombin.17 However, the clinical risk may be higher than these estimates. In Japan, 3 cases of aplastic anemia have been linked to parvovirus transmission from fibrin glue,18 and among patients undergoing pulmonary resection using Beriplast fibrin sealant, 20% of patients who were negative for human parvovirus B19 before surgery subsequently developed reticulocytopenia and tested positive for parvovirus B19 by polymerase chain reaction and serologic tests for immunoglobulin-G after surgery.19 There has never been a reported case of
Yang et al
Ophthalmic Technology Assessment
transmission of CreutzfeldteJakob disease or prion infection through manufactured plasma products16; however, the theoretic risk has been estimated as 1 in 106 vials of fibrinogen and 1 in 109 vials of thrombin.17 Of note, the volume of fibrin glue used in general surgical procedures is usually greater and the surgical field deeper and more vascular than for conjunctival closure in strabismus surgery. How these differences affect the risk of viral and prion transmission is unknown.
Risk of Anaphylactic Reaction Although the risk of an anaphylactic response is small (<0.01%), TISSEEL should not be used in patients with a known allergy to aprotinin (an antifibrinolytic agent included in TISSEEL to prevent dissolution of the fibrin clot) or within 12 months of a previous application of TISSEEL.12,20,21 This restriction would limit its use in early reoperations for strabismus. In contrast, EVICEL is free of aprotinin.13,22
Resource Requirements A detailed economic analysis was not included in this evaluation, but the approximate cost to a surgical facility of a 2-ml package of TISSEEL or EVICEL fibrin sealant ($167 and $155, respectively) is 7 to 24 times greater than for individual packages of 6-0 polyglactin (Vicryl, Ethicon, Inc., Somerville, NJ), 7-0 polyglactin, or 6-0 plain gut sutures ($7e$22), unless the surgeon uses the remainder of the sutures used for reattachment of muscle at no added cost. A 2-ml quantity of fibrin sealant is adequate to cover an 8- to 20-cm2 area. Fibrin sealants are recommended for use in a single patient.12,13
Question for Assessment The focus of this assessment is to address the following question: Compared with using sutures for the closure of limbal conjunctival incisions in strabismus surgery, does fibrin glue result in decreased postoperative inflammation, increased patient comfort, similar efficacy in maintaining wound closure, and reduced operating time?
Description of Evidence Literature searches were last conducted January 24, 2013, in the PubMed and Cochrane Library databases using the following search terms as MeSH, text, or both. No age restrictions were used in the literature search. The search strategy in the PubMed database was as follows: #1 e (glue*[tiab] OR adhesive*[tiab] OR bioadhesive* [tiab]) AND (strabismus[tiab]) #2 e (glue*[tiab] OR adhesive*[tiab] OR bioadhesive* [tiab]) AND (extraocular[tiab]) AND (surg*[tiab]) #3 e (glue*[tiab] OR adhesive*[tiab] OR bioadhesive* [tiab]) AND (conjunctiva*[tiab]) AND (incision[tiab]) #4 e (sutureless[tiab]) AND (strabismus[tiab])
#5 e (sutureless[tiab]) AND (extraocular[tiab]) AND (surg*[tiab]) #6 e (Fibrin Tissue Adhesive[mh] OR Tissue Adhesives [mh]) AND (Strabismus[mh]) #7 e (Wound Closure Techniques[mh] OR Suture Techniques[mh]) AND (Strabismus[mh]) AND (glue* [tw] OR adhesive*[tw] OR bioadhesive*[tw]) #8 e (Oculomotor Muscles[mh]) AND (Fibrin Tissue Adhesive[mh] OR Tissue Adhesives[mh]) #9 e (Oculomotor Muscles[mh]) AND (Wound Closure Techniques[mh] OR Suture Techniques[mh]) AND (glue*[tw] OR adhesive*[tw] OR bioadhesive*[tw]) #10 e (Conjunctiva/surgery[mh]) AND (Fibrin Tissue Adhesive[mh] OR Tissue Adhesives[mh]) #11 e (Conjunctiva/surgery[mh]) AND (Wound Closure Techniques[mh] OR Suture Techniques[mh]) AND (glue*[tw] OR adhesive*[tw] OR bioadhesive*[tw]) The search strategy in the Cochrane Library database was as follows: #1 e (glue* OR adhesive* OR bioadhesive*):ti,ab,kw and (strabismus):ti,ab,kw - 6 references (clinical trials) #2 e (glue* OR adhesive* OR bioadhesive*):ti,ab,kw and (extraocular):ti,ab,kw AND (surg*):ti,ab,kw #3 e (glue* OR adhesive* OR bioadhesive*):ti,ab,kw and (conjunctiva*):ti,ab,kw e 31 references (clinical trials) #4 e (sutureless):ti,ab,kw and (strabismus):ti,ab,kw #5 e (sutureless):ti,ab,kw and (extraocular):ti,ab,kw and (surg*):ti,ab,kw #6 e (MeSH descriptor Fibrin Tissue Adhesive explode all trees OR MeSH descriptor Tissue Adhesives explode all trees) AND (MeSH descriptor Strabismus explode all trees) e 3 references (clinical trials) #7 e (MeSH descriptor Wound Closure Techniques explode all trees OR MeSH descriptor Suture Techniques explode all trees) AND (MeSH descriptor Strabismus explode all trees) AND (glue* OR adhesive* OR bioadhesive*):ti,ab,kw #8 e (MeSH descriptor Oculomotor Muscles explode all trees) AND (MeSH descriptor Fibrin Tissue Adhesive explode all trees OR MeSH descriptor Tissue Adhesives explode all trees) e 2 references (clinical trials) #9 e (MeSH descriptor Oculomotor Muscles explode all trees) AND (MeSH descriptor Wound Closure Techniques explode all trees OR MeSH descriptor Suture Techniques explode all trees) AND (glue* OR adhesive* OR bioadhesive*):ti,ab,kw e 1 reference (clinical trial) #10 e (MeSH descriptor Conjunctiva explode all trees with qualifier: SU) AND (MeSH descriptor Fibrin Tissue Adhesive explode all trees OR MeSH descriptor Tissue Adhesives explode all trees) #11 e (MeSH descriptor Conjunctiva explode all trees with qualifier: SU) AND (MeSH descriptor Wound Closure Techniques explode all trees OR MeSH descriptor Suture Techniques explode all trees) AND (glue* OR adhesive* OR bioadhesive*):ti,ab,kw The searches retrieved 24 references, 2 of which were published in non-English languages.
1937
Ophthalmology Volume 120, Number 9, September 2013 The primary author independently assessed the abstracts resulting from the electronic searches. He then reviewed the full text of 23 citations (including 1 foreign-language paper) and the relevant portion of the remaining foreign language citation to determine inclusion according to the criterion of whether the study compared fibrin glue and suture for the closure of conjunctival incisions in strabismus patients of any age. Fifteen citations, 1 in a foreign language, were excluded because they consisted of studies of bioadhesives for pterygium surgery or for reattachment of rectus muscles to sclera, a review article, a case report of dellen formation after the use of fibrin glue, and a letter to the editor. The remaining 9 articles were evaluated by a methodologist and assigned a level of evidence using a simplified version of the Center for Evidence-Based Medicine rating scale.23 A level I rating was assigned to well-designed clinical trials with narrow confidence intervals, a level II rating was assigned to low-quality clinical trials, and a level III rating was assigned to case series or other studies lacking a comparison group. Four articles, including the remaining foreign-language article, lacked a comparison group and were classified as level III evidence. These 4 studies were consequently excluded from this assessment, leaving 5 studies that were fully evaluated.24e28 All 5 included studies were rated level II (low-quality clinical trial) because of lack of randomization, lack of masking, or both. In addition, all 5 studies had small sample sizes. Although 2 of the 5 studies reviewed used an independent observer, the observer could not be considered masked regarding the treatment modality in any of the studies because the suture was potentially visible whether a purple-dyed polyglactin, a nondyed (white) polyglactin, or a plain-gut suture was used. Two of the 5 studies compared fibrin glue and suture in terms of the total procedural time or only the time required for closure of the conjunctival incision. In 3 of the 5 studies, the fibrin glue was applied to sclera, and the conjunctival flap was in turn held against the sclera.24,25,27 In 1 of the 5 studies, fibrin glue was also applied along the entire length of the winged conjunctival incision, which was held together as well as down to the sclera.28 In the remaining study, no details of the procedure were given.26 A summary of the studies is presented in Table 1.
Published Results Biedner and Rosenthal24 compared 6 children who underwent bilateral symmetric strabismus surgery. The conjunctival incisions (presumed to be limbal) were closed using 6-0 polyglactin in the right eye and fibrin glue (no trade name given; Boehringer-Ingelheim, Germany) in the left eye. Evaluations were performed at 1, 5, and 14 days after surgery by an “outside observer.” Transient ptosis was observed in 3 of 6 eyes (50%) in the suture group compared with 0 of 6 eyes (0%) in the fibrin glue group at postoperative days 1 and 5. Signs of conjunctival injection or chemosis and subjective patient symptoms of increased eye redness and tearing were worse in the sutured eye compared with the fibrin glue eye for all 6 patients on postoperative days 1 and 5. By 14 days, there was no difference between the 2 groups.
1938
Dadeya and Kamlesh25 compared 19 children and adults who underwent bilateral symmetric strabismus surgery involving only the horizontal rectus muscles. Limbal conjunctival incisions were closed using interrupted 6-0 polyglactin sutures in the right eye and fibrin glue (source not reported) in the left eye. An independent observer evaluated the patients at day 1 and at weeks 1, 2, and 3 after surgery. On postoperative day 1, there were signs of excessive watering, redness, and chemosis in 8 of 19 sutured eyes (42%) compared with 0 of 19 fibrin glue eyes (0%). Of the 19 patients, 8 had ocular discomfort in the sutured eye, but none had discomfort in the fibrin glue eye (P ¼ 0.005). By postoperative week 2, only 2 of 19 sutured eyes (11%) showed signs of inflammation or were symptomatic, whereas the fibrin glue eyes presumably continued to show no such findings. By 3 weeks, there was no difference between the 2 groups. In addition, at postoperative week 2, transient ptosis was present in 2 of 19 sutured eyes (11%) compared with 0 of 19 fibrin glue eyes (0%). On postoperative day 1, 15 of 19 fibrin glue eyes (79%) had well-apposed conjunctival incisions, 3 (16%) had a 1-mm retraction of the conjunctival wound, and 1 (5%) had a 2-mm retraction of the conjunctival wound. This last eye required sutures for repair of the conjunctival wound. Presumably none of the sutured eyes developed a conjunctival wound retraction. Basmak et al26 evaluated 29 children and adults who underwent strabismus surgery using limbal incisions. However, in procedures involving oblique muscles or where adjustable sutures were used, a Swan incision parallel to the limbus but posterior to the rectus muscle insertion was made. Each patient received exclusively TISSEEL fibrin glue or 7-0 polyglactin suture for closure of the conjunctiva, regardless of whether the strabismus surgery was unilateral or bilateral. In bilateral surgery cases, only the right eye was included in the statistical analysis. Twelve patients were in the fibrin glue group, and 17 patients were in the suture group. Group assignment was not randomized. Suture knots were not buried but trimmed as short as possible. Postoperative severity of signs and symptoms, such as redness, tearing, pain, and discomfort when opening the operated eye, were rated on a 4-point scale (0 ¼ none; 3 ¼ most severe) and recorded at 1, 12, and 24 hours and 2 weeks after surgery. There was no difference between the fibrin glue and suture groups in the degree of conjunctival redness observed (by an unmasked care provider) at any time point after surgery. However, the severity of pain and tearing experienced by patients was significantly less for the fibrin glue group at 12 and 24 hours after surgery compared with the suture group (P < 0.0001). The degree of discomfort experienced by patients on attempted eye opening also was significantly less for the fibrin glue group compared with the suture group at 1, 12, and 24 hours after surgery (P < 0.0001 to 0.01). Fibrin glue was as effective as sutures in closing the conjunctival incision, with the exception of 1 patient who underwent lateral rectus recession using an adjustable suture technique and a Swan incision. A 3-mm gap developed on postoperative day 3 in the fibrin glue eye and had to be repaired by suturing. Guo and colleagues27 evaluated 12 children who underwent bilateral symmetric strabismus surgery on horizontal rectus muscles using limbal conjunctival incisions. TISSEEL fibrin glue was used to close the conjunctival incision of 1 eye, and 60 plain gut sutures were used for the fellow eye. However, the study was neither randomized nor masked. Postoperative pain, irritation, and epiphora, as well as conjunctival chemosis and injection, were evaluated using a 4-point scale (1 ¼ better; 4 ¼ worse) at 1 and 4 weeks after surgery. The fibrin glue eyes had less postoperative inflammation compared with sutured eyes, with
Yang et al
Ophthalmic Technology Assessment
Table 1. Quality Assessment of Tissue Glue Studies Study Biedner and Rosenthal,24 1996
Dadeya and Kamlesh,25 2001
Basmak et al,26 2011
Guo et al,27 2010
Lee and Kang,28 2011
Subjects
Outcomes Evaluated
Comments
6 children with bilateral symmetric surgery Right eye 6-0 polyglactin suture Left eye fibrin glue (Boehringer-Ingelheim, Germany) 19 children or adults; bilateral horizontal strabismus surgery Right eye 6-0 polyglactin suture Left eye fibrin glue (source unknown) 29 children or adults; unilateral or bilateral strabismus surgeries, with or without oblique muscles involved 12 patients; fibrin glue (TISSEEL, Baxter, Deerfield, IL) 17 patients 7-0 polyglactin suture 12 children; bilateral horizontal strabismus surgery 1 eye 6-0 plain gut suture Fellow eye fibrin glue (TISSEEL, Baxter) 40 children or adults; unilateral or bilateral horizontal strabismus surgery 19 patientsz; fibrin glue (Greenplast, Green Cross Corp., Seoul, South Korea) 20 patients; 8-0 polyglactin suture
Lid asymmetry, conjunctival injection/chemosis, symptoms (redness, watering)
Not randomized; not maskedy
Level of Evidence* II
Excessive watering, redness, chemosis, discomfort, transient ptosis, conjunctival wound apposition
Not randomized; not maskedy
II
Redness, tearing, pain, discomfort, conjunctival wound apposition
Not randomized; not maskedy
II
Pain, irritation, epiphora, chemosis, injection, surgery time
Not randomized; not maskedy
II
Pain, tearing, inflammation, time to eye opening, duration of ocular discomfort, conjunctival wound apposition, conjunctival engorgement, surgery time
Randomized; not maskedy
II
*Level II indicates a low-quality clinical trial. The studies were all rated as low quality because of lack of randomization, lack of masking (and subjective outcome[s]), or small sample size. y An independent observer performed outcome assessment, but because sutures were used, it is assumed that the observer might have known the treatment assignment because of the possibility of seeing whether the suture material was dyed. z One patient was excluded from the study after randomization.
a mean patient discomfort score at postoperative week 1 of 1.4 for fibrin glue eyes and 3.1 for sutured eyes. Although the total amount of time needed to close the conjunctival incisions was not provided, it was 1 to 5 minutes less for fibrin glue eyes compared with sutured eyes, depending on whether an ophthalmologist or an ophthalmology resident performed the closure. The difference was attributed to residents taking longer to close sutures than the ophthalmologists; the fibrin glue application times were similar between the 2 groups of surgeons. Lee and Kang28 compared fibrin glue (Greenplast) with 80 polyglactin suture for the closure of limbal conjunctival incisions in strabismus surgery. Forty patients were randomized to fibrin glue or sutures (20 patients per group), regardless of whether the surgery was unilateral or bilateral. One patient from the fibrin glue group was subsequently excluded because of inadvertent early removal of an eye patch that resulted in dehiscence of the conjunctival wound, thus leaving 19 patients in that group. The number of patients with unilateral or bilateral
surgery, 1 or 2 conjunctival incisions per operated eye, and esotropia or exotropia in each group was similar. With the use of a 4-point scale (0 ¼ absent; 3 ¼ most severe), pain, tearing, and inflammation were analyzed and compared at 1 day and 1, 3, and 6 weeks after surgery. For the first 3 weeks after surgery, postoperative pain and inflammation were significantly less for patients in the fibrin group compared with the suture group (P < 0.001). Tearing scores were lower for the fibrin glue group compared with the suture group at postoperative day 1 and week 1 (P < 0.001). The mean duration of ocular discomfort was 1.00.2 days (mean standard deviation) for patients in the fibrin glue group compared with 3.11.1 days in the suture group (P < 0.001). Patients treated with fibrin glue were able to open their eyes easily 1 day after surgery, compared with 2.7 days after surgery for the suture group. No wound dehiscence occurred in any of the patients in the fibrin glue or suture group. No patients in the fibrin glue group required additional sutures to repair the conjunctival incisions,
1939
Ophthalmology Volume 120, Number 9, September 2013 whereas 2 eyes (11%) developed conjunctival defects larger than 2 mm. Nevertheless, secondary re-epithelialization and healing occurred within 3 weeks. The size of postoperative conjunctival gaps at the limbus was slightly larger for the fibrin glue group (P ¼ 0.019) on day 1, but was not significantly different at 1, 3, or 6 weeks after surgery. At 6 weeks after surgery, the perilimbal conjunctival incision had retracted in 5 of 19 patients (26%) in the fibrin glue group compared with 3 of 20 patients (15%) in the suture group. All patients in the fibrin glue group had a greater degree of conjunctival vascular engorgement compared with the suture group at postoperative week 6 (P < 0.001), but this engorgement subsequently resolved spontaneously. The mean conjunctival closure times for a subset of 10 patients in the fibrin glue and the suture groups were 3.80.9 and 8.40.6 minutes, respectively, which represents a 55% reduction in closure time. None of the 5 studies were designed to evaluate patients for the development of viral or prion infection. In addition, none of the authors commented specifically on the occurrence of an allergic response to fibrin glue in their study patients with the exception of Lee and Kang,28 who reported none.
Conclusions There is level II evidence from 5 studies that suggests the use of fibrin glue to close limbal conjunctival incisions reduces postoperative inflammation and patient discomfort compared with sutures. In contrast, there was a small failure rate associated with fibrin glue use compared with no failures when sutures were used. Combined results from 3 of the studies evaluated show that 2 of 50 eyes (4%) required sutures to repair a retracted conjunctival wound that was initially closed using fibrin glue.25,26,28 Overall, the time needed to close conjunctival incisions with fibrin glue was shorter than with suturing, but the time difference was less for skilled attending surgeons than for ophthalmology residents. In general, the validity of these studies was weakened by the absence of randomization of treatment groups (with the exception of Lee and Kang28), the lack of a detailed description of an objective rating scale for signs and symptoms (possibly excepting Lee and Kang), and the absence of a masked observer for the treatment groups, all of which increased the potential for observer bias. In the broader surgical literature, the transmission of infectious agents from commercially available fibrin glue seems to be extremely low, with the possible exception of parvovirus, and the risk of anaphylactic response to aprotinin also seems to be small.
Future Research The use of fibrin glue for closing limbal conjunctival incisions will ultimately depend on the strabismus surgeon’s assessment of the relative benefits, risks, and costs. The potential benefits of fibrin glue include lower postoperative inflammation and shorter operating time. The disadvantages include the need to repair wounds that are not adequately closed using fibrin glue (taking into account its associated costs and the risks of anesthesia), the higher cost of fibrin glue, and the potential risk of transmission of infectious agents or an anaphylactic response. Future studies can improve the evidence for evaluating fibrin glue by
1940
randomizing patients or eyes to treatment modality, using a standardized and reproducible rating scale for postoperative signs and symptoms of ocular inflammation and using masked examiners to lessen the chance of observer bias. When performing an economic analysis of a new surgical technique, the following factors should be considered. The higher cost of fibrin glue compared with conjunctival sutures may be mitigated by less postoperative inflammation and improved patient comfort. This may produce a cost savings in work productivity for parents of a child receiving strabismus surgery or for an adult undergoing strabismus surgery being able to return to work sooner. A reduction in operating time associated with the use of fibrin glue compared with sutures also reduces costs, whether actual or opportunity costs. However, this reduction must be weighed against the additional cost associated with a wound-gap repair under general anesthesia that results from inadequate closure using fibrin glue. Improvement and standardization of techniques for applying fibrin glue to ophthalmic tissues may enhance the strength of the sealed wounds and reduce the need for reoperations.29,30 Consideration of a fornix incision rather than a limbal incision may obviate the need for closure with suture or fibrin glue. Although the estimated infectious risks associated with fibrin glue derived from human plasma seem to be low (with the exception of parvovirus), they may be eliminated altogether by using recombinant thrombin or fibrinogen in future fibrin glue formulations. The use of aprotinin-free fibrin glues (currently available in EVICEL) may reduce the risk of an anaphylactic response.
References 1. Finley GA, McGrath PJ, Forward SP, et al. Parents’ management of children’s pain following ‘minor’ surgery. Pain 1996;64:83–7. 2. Anninger W, Forbes B, Quinn G, Schreiner MS. The effect of topical tetracaine eye drops on emergence behavior and pain relief after strabismus surgery. J AAPOS 2007;11:273–6. 3. Parks MM. Fornix incision for horizontal rectus muscle surgery. Am J Ophthalmol 1968;65:907–15. 4. Mojon DS. Minimally invasive strabismus surgery for horizontal rectus muscle reoperations. Br J Ophthalmol 2008;92:1648–52. 5. Sami DA. Conjunctival incisions for strabismus surgery: a comparison of techniques. Tech Ophthal 2007;5:125–9. 6. von Noorden GK. The limbal approach to surgery of the rectus muscles. Arch Ophthalmol 1968;80:94–7. 7. Gareis-Helferich E, de Decker W, Gross G, et al. Closure of the conjunctiva using fibrinous tissue adhesives [in German]. Klin Monbl Augenheilkd 1968;153:74–8. 8. Zauberman H, Hemo I. Use of fibrin glue in ocular surgery. Ophthalmic Surg 1988;19:132–3. 9. Panda A, Kumar S, Kumar A, et al. Fibrin glue in ophthalmology. Indian J Ophthalmol 2009;57:371–9. 10. Carlson AN, Wilhelmus KR. Giant papillary conjunctivitis associated with cyanoacrylate glue. Am J Ophthalmol 1987;104: 437–8. 11. Dickneite G, Metzner H, Pfeifer T, et al. A comparison of fibrin sealants in relation to their in vitro and in vivo properties. Thromb Res 2003;112:73–82.
Yang et al
Ophthalmic Technology Assessment
12. TISSEEL (Fibrin Sealant) [package insert]. Westlake Village, CA: Baxter Healthcare Corp.; January 2012. Available at: http://www.baxter.com/downloads/healthcare_professionals/ products/Tisseel_PI.pdf. Accessed December 6, 2012. 13. EVICEL Fibrin Sealant (Human) [package insert]. Kiryat Ono, Israel: Omrix Biopharmaceuticals Ltd.; December 2009. Available at: http://www.ethicon360.com/sites/default/files/products/ 123009%20EVICEL%20PI_0.PDF. Accessed December 6, 2012. 14. Beriplast P Combi-Set. EU-Summary of product characteristics. Marburg, Germany: CSL Behring; July 22, 2008. Available at: http://www.cslsurgery.com/international/beriplast/product/pdf/eu/ Expert.pdf. Accessed December 6, 2012. 15. ARTISS [Fibrin Sealant (Human)] [package insert]. Westlake Village, CA: Baxter Healthcare Corp.; August 2011. Available at: http://www.baxter.com/downloads/healthcare_professionals/ products/ARTISS_PI.pdf. Accessed January 28, 2013. 16. Cai K, Gierman TM, Hotta J, et al. Ensuring the biologic safety of plasma-derived therapeutic proteins: detection, inactivation, and removal of pathogens. BioDrugs 2005;19:79–96. 17. Horowitz B, Busch M. Estimating the pathogen safety of manufactured human plasma products: application to fibrin sealants and to thrombin. Transfusion 2008;48:1739–53. 18. Hino M, Ishiko O, Honda KI, et al. Transmission of symptomatic parvovirus B19 infection by fibrin sealant used during surgery. Br J Haematol 2000;108:194–5. 19. Kawamura M, Sawafuji M, Watanabe M, et al. Frequency of transmission of human parvovirus B19 infection by fibrin sealant used during thoracic surgery. Ann Thorac Surg 2002;73:1098–100. 20. Scheule AM, Beierlein W, Wendel HP, et al. Fibrin sealant, aprotinin, and immune response in children undergoing operations for congenital heart disease. J Thorac Cardiovasc Surg 1998;115:883–9.
21. Kober BJ, Scheule AM, Voth V, et al. Anaphylactic reaction after systemic application of aprotinin triggered by aprotinin-containing fibrin sealant. Anesth Analg 2008;107: 406–9. 22. Dhillon S. Fibrin sealant (Evicel(R) [Quixil(R)/Crosseal]): a review of its use as supportive treatment for haemostasis in surgery. Drugs 2011;71:1893–915. 23. Oxford Centre for Evidence-Based Medicine. Levels of evidence (March 2009). Available at: http://www.cebm.net/ index.aspx?o¼1025. Accessed September 6, 2012. 24. Biedner B, Rosenthal G. Conjunctival closure in strabismus surgery: Vicryl versus fibrin glue. Ophthalmic Surg Lasers 1996;27:967. 25. Dadeya S, Kamlesh MS. Strabismus surgery: fibrin glue versus vicryl for conjunctival closure. Acta Ophthalmol Scand 2001;79: 515–7. 26. Basmak H, Gursoy H, Cakmak AI, et al. Tissue adhesives as an alternative for conjunctival closure in strabismus surgeries. Strabismus 2011;19:59–62. 27. Guo S, Wagner RS, Forbes BJ, et al. Cut and paste: sutureless conjunctival closure in strabismus surgery. J Pediatr Ophthalmol Strabismus 2010;47:228–30. 28. Lee JH, Kang NY. Comparison of fibrin glue and sutures for conjunctival wound closure in strabismus surgery. Korean J Ophthalmol 2011;25:178–84. 29. Zarbin M. Declining use of sutures for wound closure. Arch Ophthalmol 2012;130:1596. 30. Chaurasia SS, Champakalakshmi R, Angunawela RI, et al. Optimization of fibrin glue spray systems for ophthalmic surgery. Transl Vis Sci Technol [serial online] 2012;1:2. Available at: http://tvstjournal.org/doi/pdf/10.1167/tvst.1.2.2. Accessed December 14, 2012.
Footnotes and Financial Disclosures
Manuscript no. 2013-654.
6 The Vision Center, Children’s Hospital Los Angeles; Orbit and Eye Movement Institute, Strabismus and Pediatric Ophthalmology; Fellowship Program, Pediatric Ophthalmology and Strabismus; University of Southern California Keck School of Medicine, Los Angeles, California.
Abrahamson Pediatric Eye Institute, Cincinnati Children’s Hospital Medical Center, Department of Ophthalmology, University of Cincinnati, College of Medicine, Cincinnati, Ohio.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
2
Funded without commercial support by the American Academy of Ophthalmology. Prepared by the Ophthalmic Technology Assessment Committee Pediatric Ophthalmology/Strabismus Panel and approved by the American Academy of Ophthalmology’s Board of Trustees February 23, 2013.
Originally received: April 20, 2013. Final revision: May 6, 2013. Accepted: May 6, 2013. Available online: June 29, 2013. 1
Jaeb Center for Health Research, Tampa, Florida.
3
R. Howard Dobbs Professor of Ophthalmology, Professor of Pediatrics, Department of Ophthalmology, Emory University, Atlanta, Georgia. 4
Knowles Professor of Ophthalmology & Medical Informatics and Clinical Epidemiology, Casey Eye Institute, Oregon Health and Science University, Portland, Oregon. 5 Clinical Professor, Gavin Herbert Eye Institute, University of California, Irvine, California.
Correspondence: Nicholas Emptage, MAE, American Academy of Ophthalmology, Quality of Care and Knowledge Base Development, 655 Beach St., San Francisco, CA 94109. E-mail: [email protected].
1941
Fibrin Glue for Closure of Conjunctival Incision in Strabismus Surgery A Report by the American Academy of Ophthalmology Michael B. Yang, MD,1 Michele Melia, ScM,2 Scott R. Lambert, MD,3 Michael F. Chiang, MD,4 Jennifer L. Simpson, MD,5 Angela N. Buffenn, MD, MPH6 Objective: To evaluate the severity of postoperative inflammation, degree of patient discomfort, adequacy of wound closure, and length of operating time when using fibrin glue compared with sutures to close limbal conjunctival incisions after strabismus surgery. Methods: Literature searches of the PubMed and Cochrane Library databases were last conducted on January 24, 2013, and resulted in 24 citations, including 2 not in the English language. All citations were reviewed in full text. Five studies compared fibrin glue (68 eyes) with sutures (74 eyes) for closure of limbal conjunctival incisions in patients undergoing strabismus surgery and were included in this assessment; no studies were found that evaluated fornix incisions. A quality rating was assigned to each study using criteria specifically developed for this assessment. Results: No level I studies were found, and 5 level II studies were identified. There was significantly less postoperative inflammation and patient discomfort for 1 to 3 weeks after strabismus surgery for eyes treated with fibrin glue compared with sutures. In 3 studies that evaluated wound apposition, 2 of 50 eyes (4%) with conjunctival incisions that were initially closed using fibrin glue subsequently developed a wound gap that required suture repair. In the 2 studies that compared surgical time, fibrin glue required 1 to 5 minutes less time than suturing in 1 study and 55% less time (3.8 vs. 8.4 minutes) in a second study. These 5 studies did not evaluate the cost-effectiveness or risk of viral transmission from fibrin glue. Conclusions: Studies in the literature suggest that the off-label use of fibrin glue to close limbal conjunctival incisions in strabismus surgery resulted in less postoperative inflammation and required shorter operating time compared with sutures, but it increased the percentage of wounds requiring subsequent repair with sutures. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2013;120:1935-1941 ª 2013 by the American Academy of Ophthalmology.
The American Academy of Ophthalmology prepares Ophthalmic Technology Assessments to evaluate new and existing procedures, drugs, and diagnostic and screening tests. The goal of an assessment is to systematically review the available research for clinical efficacy and safety. After review by members of the Ophthalmic Technology Assessment Committee, other Academy committees, relevant subspecialty societies, and legal counsel, assessments are submitted to the Academy’s Board of Trustees for consideration as official Academy statements. The purpose of this assessment is to compare fibrin glue and sutures for the closure of limbal conjunctival incisions in strabismus surgery.
Background Surgical technique is one of several variables that may influence the degree of pain experienced by patients after strabismus surgery.1,2 Different techniques, such as the fornix incisional approach3 and minimally invasive strabismus surgery,4 have the potential to reduce 2013 by the American Academy of Ophthalmology Published by Elsevier Inc.
postoperative irritation and discomfort because they generally do not require sutures.5 These techniques have not been formally compared with the limbal incisional approach, which requires a minimum of 2 sutures to close a winged conjunctival peritomy and thus may be more irritating.6 For strabismus surgeons who nevertheless prefer limbal incisions or in strabismus surgeries where limbal incisions are advantageous (e.g., reoperations or surgery in older adults), tissue adhesives represent an alternative to sutures that can potentially maintain adequate wound closure while decreasing operating time and reducing postoperative inflammation. Reports of the use of fibrin glue for closing conjunctival incisions in strabismus surgery first appeared in Europe in the 1960s and subsequently in the English-language literature in 1988.7,8 Although cyanoacrylate has long been used in ophthalmic surgery, fibrin glue seems to be more appropriate for conjunctival closure because it produces a smooth seal along the wound edge, resulting in fewer postoperative complications. In contrast, cyanoacrylate is ISSN 0161-6420/13/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2013.05.008
1935
Ophthalmology Volume 120, Number 9, September 2013
Figure 1. The blood coagulation cascade.
impermeable to fluids and may cause giant papillary conjunctivitis and corneal neovascularization.9,10 Several commercially manufactured fibrin glues are available, including TISSEEL and ARTISS (Baxter, Deerfield, IL); EVICEL (a modified successor of Quixil or Crosseal, distributed by Ethicon, Johnson and Johnson, Somerville, NJ, manufactured by Omrix, Kiryat Ono, Israel); Beriplast P (CSL Behring, Marburg, Germany); and Greenplast (Green Cross Corp., Seoul, South Korea). These vary in their performance on hemostasis and skin adhesion tests.11 Only TISSEEL, ARTISS, and EVICEL have received approval for marketing by the US Food and Drug Administration. Their use for the closure of conjunctival incisions is off-label. TISSEEL and EVICEL are specifically approved for use “as an adjunct to hemostasis in patients undergoing surgery, when control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical.”12,13 In addition, TISSEEL is approved as “a fibrin sealant indicated as an adjunct to standard surgical techniques (such as suture and ligature) to prevent leakage from colonic anastomoses following the reversal of temporary colostomies.”12 In contrast, in Europe, Beriplast P is approved “as a tissue [glue] to promote adhesion/sealing or as suture support.”14 Thus, the closure of conjunctival wounds in strabismus surgery seems to fall under Beriplast P’s approved uses in Europe. ARTISS, a more recent product that is essentially identical to TISSEEL with the exception of a reduced concentration of thrombin, is indicated in burns “to adhere autologous skin grafts to surgically prepared wound beds” or “to adhere tissue flaps during facial rhytidectomy surgery (face-lift).”15 The longer setting time for ARTISS may be suitable for its indicated procedures but may not be as attractive as TISSEEL to strabismus surgeons seeking to minimize operating time while maximizing wound adherence.
Description of the Technology Fibrin glue works by combining 2 initially separate components, fibrinogen and thrombin, which activate the final pathway of the coagulation cascade in which fibrinogen
1936
is converted into fibrin (Fig 1). Both TISSEEL and EVICEL, approved by the Food and Drug Administration, come in 2 prefilled syringes that separately contain the fibrinogen and thrombin components. These should be kept frozen until near the time of surgery.12,13 When ready for use, the 2 components of fibrin glue can be combined in a Y-split injection device and applied via a common cannula. After the fibrin glue is applied, the 2 surfaces to be adhered (in this case, the conjunctiva and sclera) have to be held together for at least 2 minutes until sufficient polymerization of the fibrin glue occurs.
Risk of Transmission of Infectious Agents The risk of viral transmission through commercially manufactured plasma products is low because the plasma used is pooled from licensed US collection centers. Nucleic acid technology is used to detect viral contamination, and various physicochemical techniques, such as vapor heat and solvent/ detergent treatment, are used to remove and inactivate any virus.16 For TISSEEL and EVICEL, a 5.6 log10 to 15.6 log10 and a 4.0 log10 to 10.6 log10 reduction, respectively, in the counts of human immunodeficiency virus-1, hepatitis A virus, hepatitis C virus, and hepatitis B virus during the manufacturing process has been documented.12,13 For these specific viruses, the risk of transmission has been estimated to be approximately 1 in 1015 vials of thrombin and fibrin.17 Because parvovirus is more difficult to eliminate, lower levels of log10 reduction in viral counts have been reported during manufacturing,12,13 and the estimated risk of parvovirus transmission is 1 in 500 000 vials of fibrinogen and 1 in 107 vials of thrombin.17 However, the clinical risk may be higher than these estimates. In Japan, 3 cases of aplastic anemia have been linked to parvovirus transmission from fibrin glue,18 and among patients undergoing pulmonary resection using Beriplast fibrin sealant, 20% of patients who were negative for human parvovirus B19 before surgery subsequently developed reticulocytopenia and tested positive for parvovirus B19 by polymerase chain reaction and serologic tests for immunoglobulin-G after surgery.19 There has never been a reported case of
Yang et al
Ophthalmic Technology Assessment
transmission of CreutzfeldteJakob disease or prion infection through manufactured plasma products16; however, the theoretic risk has been estimated as 1 in 106 vials of fibrinogen and 1 in 109 vials of thrombin.17 Of note, the volume of fibrin glue used in general surgical procedures is usually greater and the surgical field deeper and more vascular than for conjunctival closure in strabismus surgery. How these differences affect the risk of viral and prion transmission is unknown.
Risk of Anaphylactic Reaction Although the risk of an anaphylactic response is small (<0.01%), TISSEEL should not be used in patients with a known allergy to aprotinin (an antifibrinolytic agent included in TISSEEL to prevent dissolution of the fibrin clot) or within 12 months of a previous application of TISSEEL.12,20,21 This restriction would limit its use in early reoperations for strabismus. In contrast, EVICEL is free of aprotinin.13,22
Resource Requirements A detailed economic analysis was not included in this evaluation, but the approximate cost to a surgical facility of a 2-ml package of TISSEEL or EVICEL fibrin sealant ($167 and $155, respectively) is 7 to 24 times greater than for individual packages of 6-0 polyglactin (Vicryl, Ethicon, Inc., Somerville, NJ), 7-0 polyglactin, or 6-0 plain gut sutures ($7e$22), unless the surgeon uses the remainder of the sutures used for reattachment of muscle at no added cost. A 2-ml quantity of fibrin sealant is adequate to cover an 8- to 20-cm2 area. Fibrin sealants are recommended for use in a single patient.12,13
Question for Assessment The focus of this assessment is to address the following question: Compared with using sutures for the closure of limbal conjunctival incisions in strabismus surgery, does fibrin glue result in decreased postoperative inflammation, increased patient comfort, similar efficacy in maintaining wound closure, and reduced operating time?
Description of Evidence Literature searches were last conducted January 24, 2013, in the PubMed and Cochrane Library databases using the following search terms as MeSH, text, or both. No age restrictions were used in the literature search. The search strategy in the PubMed database was as follows: #1 e (glue*[tiab] OR adhesive*[tiab] OR bioadhesive* [tiab]) AND (strabismus[tiab]) #2 e (glue*[tiab] OR adhesive*[tiab] OR bioadhesive* [tiab]) AND (extraocular[tiab]) AND (surg*[tiab]) #3 e (glue*[tiab] OR adhesive*[tiab] OR bioadhesive* [tiab]) AND (conjunctiva*[tiab]) AND (incision[tiab]) #4 e (sutureless[tiab]) AND (strabismus[tiab])
#5 e (sutureless[tiab]) AND (extraocular[tiab]) AND (surg*[tiab]) #6 e (Fibrin Tissue Adhesive[mh] OR Tissue Adhesives [mh]) AND (Strabismus[mh]) #7 e (Wound Closure Techniques[mh] OR Suture Techniques[mh]) AND (Strabismus[mh]) AND (glue* [tw] OR adhesive*[tw] OR bioadhesive*[tw]) #8 e (Oculomotor Muscles[mh]) AND (Fibrin Tissue Adhesive[mh] OR Tissue Adhesives[mh]) #9 e (Oculomotor Muscles[mh]) AND (Wound Closure Techniques[mh] OR Suture Techniques[mh]) AND (glue*[tw] OR adhesive*[tw] OR bioadhesive*[tw]) #10 e (Conjunctiva/surgery[mh]) AND (Fibrin Tissue Adhesive[mh] OR Tissue Adhesives[mh]) #11 e (Conjunctiva/surgery[mh]) AND (Wound Closure Techniques[mh] OR Suture Techniques[mh]) AND (glue*[tw] OR adhesive*[tw] OR bioadhesive*[tw]) The search strategy in the Cochrane Library database was as follows: #1 e (glue* OR adhesive* OR bioadhesive*):ti,ab,kw and (strabismus):ti,ab,kw - 6 references (clinical trials) #2 e (glue* OR adhesive* OR bioadhesive*):ti,ab,kw and (extraocular):ti,ab,kw AND (surg*):ti,ab,kw #3 e (glue* OR adhesive* OR bioadhesive*):ti,ab,kw and (conjunctiva*):ti,ab,kw e 31 references (clinical trials) #4 e (sutureless):ti,ab,kw and (strabismus):ti,ab,kw #5 e (sutureless):ti,ab,kw and (extraocular):ti,ab,kw and (surg*):ti,ab,kw #6 e (MeSH descriptor Fibrin Tissue Adhesive explode all trees OR MeSH descriptor Tissue Adhesives explode all trees) AND (MeSH descriptor Strabismus explode all trees) e 3 references (clinical trials) #7 e (MeSH descriptor Wound Closure Techniques explode all trees OR MeSH descriptor Suture Techniques explode all trees) AND (MeSH descriptor Strabismus explode all trees) AND (glue* OR adhesive* OR bioadhesive*):ti,ab,kw #8 e (MeSH descriptor Oculomotor Muscles explode all trees) AND (MeSH descriptor Fibrin Tissue Adhesive explode all trees OR MeSH descriptor Tissue Adhesives explode all trees) e 2 references (clinical trials) #9 e (MeSH descriptor Oculomotor Muscles explode all trees) AND (MeSH descriptor Wound Closure Techniques explode all trees OR MeSH descriptor Suture Techniques explode all trees) AND (glue* OR adhesive* OR bioadhesive*):ti,ab,kw e 1 reference (clinical trial) #10 e (MeSH descriptor Conjunctiva explode all trees with qualifier: SU) AND (MeSH descriptor Fibrin Tissue Adhesive explode all trees OR MeSH descriptor Tissue Adhesives explode all trees) #11 e (MeSH descriptor Conjunctiva explode all trees with qualifier: SU) AND (MeSH descriptor Wound Closure Techniques explode all trees OR MeSH descriptor Suture Techniques explode all trees) AND (glue* OR adhesive* OR bioadhesive*):ti,ab,kw The searches retrieved 24 references, 2 of which were published in non-English languages.
1937
Ophthalmology Volume 120, Number 9, September 2013 The primary author independently assessed the abstracts resulting from the electronic searches. He then reviewed the full text of 23 citations (including 1 foreign-language paper) and the relevant portion of the remaining foreign language citation to determine inclusion according to the criterion of whether the study compared fibrin glue and suture for the closure of conjunctival incisions in strabismus patients of any age. Fifteen citations, 1 in a foreign language, were excluded because they consisted of studies of bioadhesives for pterygium surgery or for reattachment of rectus muscles to sclera, a review article, a case report of dellen formation after the use of fibrin glue, and a letter to the editor. The remaining 9 articles were evaluated by a methodologist and assigned a level of evidence using a simplified version of the Center for Evidence-Based Medicine rating scale.23 A level I rating was assigned to well-designed clinical trials with narrow confidence intervals, a level II rating was assigned to low-quality clinical trials, and a level III rating was assigned to case series or other studies lacking a comparison group. Four articles, including the remaining foreign-language article, lacked a comparison group and were classified as level III evidence. These 4 studies were consequently excluded from this assessment, leaving 5 studies that were fully evaluated.24e28 All 5 included studies were rated level II (low-quality clinical trial) because of lack of randomization, lack of masking, or both. In addition, all 5 studies had small sample sizes. Although 2 of the 5 studies reviewed used an independent observer, the observer could not be considered masked regarding the treatment modality in any of the studies because the suture was potentially visible whether a purple-dyed polyglactin, a nondyed (white) polyglactin, or a plain-gut suture was used. Two of the 5 studies compared fibrin glue and suture in terms of the total procedural time or only the time required for closure of the conjunctival incision. In 3 of the 5 studies, the fibrin glue was applied to sclera, and the conjunctival flap was in turn held against the sclera.24,25,27 In 1 of the 5 studies, fibrin glue was also applied along the entire length of the winged conjunctival incision, which was held together as well as down to the sclera.28 In the remaining study, no details of the procedure were given.26 A summary of the studies is presented in Table 1.
Published Results Biedner and Rosenthal24 compared 6 children who underwent bilateral symmetric strabismus surgery. The conjunctival incisions (presumed to be limbal) were closed using 6-0 polyglactin in the right eye and fibrin glue (no trade name given; Boehringer-Ingelheim, Germany) in the left eye. Evaluations were performed at 1, 5, and 14 days after surgery by an “outside observer.” Transient ptosis was observed in 3 of 6 eyes (50%) in the suture group compared with 0 of 6 eyes (0%) in the fibrin glue group at postoperative days 1 and 5. Signs of conjunctival injection or chemosis and subjective patient symptoms of increased eye redness and tearing were worse in the sutured eye compared with the fibrin glue eye for all 6 patients on postoperative days 1 and 5. By 14 days, there was no difference between the 2 groups.
1938
Dadeya and Kamlesh25 compared 19 children and adults who underwent bilateral symmetric strabismus surgery involving only the horizontal rectus muscles. Limbal conjunctival incisions were closed using interrupted 6-0 polyglactin sutures in the right eye and fibrin glue (source not reported) in the left eye. An independent observer evaluated the patients at day 1 and at weeks 1, 2, and 3 after surgery. On postoperative day 1, there were signs of excessive watering, redness, and chemosis in 8 of 19 sutured eyes (42%) compared with 0 of 19 fibrin glue eyes (0%). Of the 19 patients, 8 had ocular discomfort in the sutured eye, but none had discomfort in the fibrin glue eye (P ¼ 0.005). By postoperative week 2, only 2 of 19 sutured eyes (11%) showed signs of inflammation or were symptomatic, whereas the fibrin glue eyes presumably continued to show no such findings. By 3 weeks, there was no difference between the 2 groups. In addition, at postoperative week 2, transient ptosis was present in 2 of 19 sutured eyes (11%) compared with 0 of 19 fibrin glue eyes (0%). On postoperative day 1, 15 of 19 fibrin glue eyes (79%) had well-apposed conjunctival incisions, 3 (16%) had a 1-mm retraction of the conjunctival wound, and 1 (5%) had a 2-mm retraction of the conjunctival wound. This last eye required sutures for repair of the conjunctival wound. Presumably none of the sutured eyes developed a conjunctival wound retraction. Basmak et al26 evaluated 29 children and adults who underwent strabismus surgery using limbal incisions. However, in procedures involving oblique muscles or where adjustable sutures were used, a Swan incision parallel to the limbus but posterior to the rectus muscle insertion was made. Each patient received exclusively TISSEEL fibrin glue or 7-0 polyglactin suture for closure of the conjunctiva, regardless of whether the strabismus surgery was unilateral or bilateral. In bilateral surgery cases, only the right eye was included in the statistical analysis. Twelve patients were in the fibrin glue group, and 17 patients were in the suture group. Group assignment was not randomized. Suture knots were not buried but trimmed as short as possible. Postoperative severity of signs and symptoms, such as redness, tearing, pain, and discomfort when opening the operated eye, were rated on a 4-point scale (0 ¼ none; 3 ¼ most severe) and recorded at 1, 12, and 24 hours and 2 weeks after surgery. There was no difference between the fibrin glue and suture groups in the degree of conjunctival redness observed (by an unmasked care provider) at any time point after surgery. However, the severity of pain and tearing experienced by patients was significantly less for the fibrin glue group at 12 and 24 hours after surgery compared with the suture group (P < 0.0001). The degree of discomfort experienced by patients on attempted eye opening also was significantly less for the fibrin glue group compared with the suture group at 1, 12, and 24 hours after surgery (P < 0.0001 to 0.01). Fibrin glue was as effective as sutures in closing the conjunctival incision, with the exception of 1 patient who underwent lateral rectus recession using an adjustable suture technique and a Swan incision. A 3-mm gap developed on postoperative day 3 in the fibrin glue eye and had to be repaired by suturing. Guo and colleagues27 evaluated 12 children who underwent bilateral symmetric strabismus surgery on horizontal rectus muscles using limbal conjunctival incisions. TISSEEL fibrin glue was used to close the conjunctival incision of 1 eye, and 60 plain gut sutures were used for the fellow eye. However, the study was neither randomized nor masked. Postoperative pain, irritation, and epiphora, as well as conjunctival chemosis and injection, were evaluated using a 4-point scale (1 ¼ better; 4 ¼ worse) at 1 and 4 weeks after surgery. The fibrin glue eyes had less postoperative inflammation compared with sutured eyes, with
Yang et al
Ophthalmic Technology Assessment
Table 1. Quality Assessment of Tissue Glue Studies Study Biedner and Rosenthal,24 1996
Dadeya and Kamlesh,25 2001
Basmak et al,26 2011
Guo et al,27 2010
Lee and Kang,28 2011
Subjects
Outcomes Evaluated
Comments
6 children with bilateral symmetric surgery Right eye 6-0 polyglactin suture Left eye fibrin glue (Boehringer-Ingelheim, Germany) 19 children or adults; bilateral horizontal strabismus surgery Right eye 6-0 polyglactin suture Left eye fibrin glue (source unknown) 29 children or adults; unilateral or bilateral strabismus surgeries, with or without oblique muscles involved 12 patients; fibrin glue (TISSEEL, Baxter, Deerfield, IL) 17 patients 7-0 polyglactin suture 12 children; bilateral horizontal strabismus surgery 1 eye 6-0 plain gut suture Fellow eye fibrin glue (TISSEEL, Baxter) 40 children or adults; unilateral or bilateral horizontal strabismus surgery 19 patientsz; fibrin glue (Greenplast, Green Cross Corp., Seoul, South Korea) 20 patients; 8-0 polyglactin suture
Lid asymmetry, conjunctival injection/chemosis, symptoms (redness, watering)
Not randomized; not maskedy
Level of Evidence* II
Excessive watering, redness, chemosis, discomfort, transient ptosis, conjunctival wound apposition
Not randomized; not maskedy
II
Redness, tearing, pain, discomfort, conjunctival wound apposition
Not randomized; not maskedy
II
Pain, irritation, epiphora, chemosis, injection, surgery time
Not randomized; not maskedy
II
Pain, tearing, inflammation, time to eye opening, duration of ocular discomfort, conjunctival wound apposition, conjunctival engorgement, surgery time
Randomized; not maskedy
II
*Level II indicates a low-quality clinical trial. The studies were all rated as low quality because of lack of randomization, lack of masking (and subjective outcome[s]), or small sample size. y An independent observer performed outcome assessment, but because sutures were used, it is assumed that the observer might have known the treatment assignment because of the possibility of seeing whether the suture material was dyed. z One patient was excluded from the study after randomization.
a mean patient discomfort score at postoperative week 1 of 1.4 for fibrin glue eyes and 3.1 for sutured eyes. Although the total amount of time needed to close the conjunctival incisions was not provided, it was 1 to 5 minutes less for fibrin glue eyes compared with sutured eyes, depending on whether an ophthalmologist or an ophthalmology resident performed the closure. The difference was attributed to residents taking longer to close sutures than the ophthalmologists; the fibrin glue application times were similar between the 2 groups of surgeons. Lee and Kang28 compared fibrin glue (Greenplast) with 80 polyglactin suture for the closure of limbal conjunctival incisions in strabismus surgery. Forty patients were randomized to fibrin glue or sutures (20 patients per group), regardless of whether the surgery was unilateral or bilateral. One patient from the fibrin glue group was subsequently excluded because of inadvertent early removal of an eye patch that resulted in dehiscence of the conjunctival wound, thus leaving 19 patients in that group. The number of patients with unilateral or bilateral
surgery, 1 or 2 conjunctival incisions per operated eye, and esotropia or exotropia in each group was similar. With the use of a 4-point scale (0 ¼ absent; 3 ¼ most severe), pain, tearing, and inflammation were analyzed and compared at 1 day and 1, 3, and 6 weeks after surgery. For the first 3 weeks after surgery, postoperative pain and inflammation were significantly less for patients in the fibrin group compared with the suture group (P < 0.001). Tearing scores were lower for the fibrin glue group compared with the suture group at postoperative day 1 and week 1 (P < 0.001). The mean duration of ocular discomfort was 1.00.2 days (mean standard deviation) for patients in the fibrin glue group compared with 3.11.1 days in the suture group (P < 0.001). Patients treated with fibrin glue were able to open their eyes easily 1 day after surgery, compared with 2.7 days after surgery for the suture group. No wound dehiscence occurred in any of the patients in the fibrin glue or suture group. No patients in the fibrin glue group required additional sutures to repair the conjunctival incisions,
1939
Ophthalmology Volume 120, Number 9, September 2013 whereas 2 eyes (11%) developed conjunctival defects larger than 2 mm. Nevertheless, secondary re-epithelialization and healing occurred within 3 weeks. The size of postoperative conjunctival gaps at the limbus was slightly larger for the fibrin glue group (P ¼ 0.019) on day 1, but was not significantly different at 1, 3, or 6 weeks after surgery. At 6 weeks after surgery, the perilimbal conjunctival incision had retracted in 5 of 19 patients (26%) in the fibrin glue group compared with 3 of 20 patients (15%) in the suture group. All patients in the fibrin glue group had a greater degree of conjunctival vascular engorgement compared with the suture group at postoperative week 6 (P < 0.001), but this engorgement subsequently resolved spontaneously. The mean conjunctival closure times for a subset of 10 patients in the fibrin glue and the suture groups were 3.80.9 and 8.40.6 minutes, respectively, which represents a 55% reduction in closure time. None of the 5 studies were designed to evaluate patients for the development of viral or prion infection. In addition, none of the authors commented specifically on the occurrence of an allergic response to fibrin glue in their study patients with the exception of Lee and Kang,28 who reported none.
Conclusions There is level II evidence from 5 studies that suggests the use of fibrin glue to close limbal conjunctival incisions reduces postoperative inflammation and patient discomfort compared with sutures. In contrast, there was a small failure rate associated with fibrin glue use compared with no failures when sutures were used. Combined results from 3 of the studies evaluated show that 2 of 50 eyes (4%) required sutures to repair a retracted conjunctival wound that was initially closed using fibrin glue.25,26,28 Overall, the time needed to close conjunctival incisions with fibrin glue was shorter than with suturing, but the time difference was less for skilled attending surgeons than for ophthalmology residents. In general, the validity of these studies was weakened by the absence of randomization of treatment groups (with the exception of Lee and Kang28), the lack of a detailed description of an objective rating scale for signs and symptoms (possibly excepting Lee and Kang), and the absence of a masked observer for the treatment groups, all of which increased the potential for observer bias. In the broader surgical literature, the transmission of infectious agents from commercially available fibrin glue seems to be extremely low, with the possible exception of parvovirus, and the risk of anaphylactic response to aprotinin also seems to be small.
Future Research The use of fibrin glue for closing limbal conjunctival incisions will ultimately depend on the strabismus surgeon’s assessment of the relative benefits, risks, and costs. The potential benefits of fibrin glue include lower postoperative inflammation and shorter operating time. The disadvantages include the need to repair wounds that are not adequately closed using fibrin glue (taking into account its associated costs and the risks of anesthesia), the higher cost of fibrin glue, and the potential risk of transmission of infectious agents or an anaphylactic response. Future studies can improve the evidence for evaluating fibrin glue by
1940
randomizing patients or eyes to treatment modality, using a standardized and reproducible rating scale for postoperative signs and symptoms of ocular inflammation and using masked examiners to lessen the chance of observer bias. When performing an economic analysis of a new surgical technique, the following factors should be considered. The higher cost of fibrin glue compared with conjunctival sutures may be mitigated by less postoperative inflammation and improved patient comfort. This may produce a cost savings in work productivity for parents of a child receiving strabismus surgery or for an adult undergoing strabismus surgery being able to return to work sooner. A reduction in operating time associated with the use of fibrin glue compared with sutures also reduces costs, whether actual or opportunity costs. However, this reduction must be weighed against the additional cost associated with a wound-gap repair under general anesthesia that results from inadequate closure using fibrin glue. Improvement and standardization of techniques for applying fibrin glue to ophthalmic tissues may enhance the strength of the sealed wounds and reduce the need for reoperations.29,30 Consideration of a fornix incision rather than a limbal incision may obviate the need for closure with suture or fibrin glue. Although the estimated infectious risks associated with fibrin glue derived from human plasma seem to be low (with the exception of parvovirus), they may be eliminated altogether by using recombinant thrombin or fibrinogen in future fibrin glue formulations. The use of aprotinin-free fibrin glues (currently available in EVICEL) may reduce the risk of an anaphylactic response.
References 1. Finley GA, McGrath PJ, Forward SP, et al. Parents’ management of children’s pain following ‘minor’ surgery. Pain 1996;64:83–7. 2. Anninger W, Forbes B, Quinn G, Schreiner MS. The effect of topical tetracaine eye drops on emergence behavior and pain relief after strabismus surgery. J AAPOS 2007;11:273–6. 3. Parks MM. Fornix incision for horizontal rectus muscle surgery. Am J Ophthalmol 1968;65:907–15. 4. Mojon DS. Minimally invasive strabismus surgery for horizontal rectus muscle reoperations. Br J Ophthalmol 2008;92:1648–52. 5. Sami DA. Conjunctival incisions for strabismus surgery: a comparison of techniques. Tech Ophthal 2007;5:125–9. 6. von Noorden GK. The limbal approach to surgery of the rectus muscles. Arch Ophthalmol 1968;80:94–7. 7. Gareis-Helferich E, de Decker W, Gross G, et al. Closure of the conjunctiva using fibrinous tissue adhesives [in German]. Klin Monbl Augenheilkd 1968;153:74–8. 8. Zauberman H, Hemo I. Use of fibrin glue in ocular surgery. Ophthalmic Surg 1988;19:132–3. 9. Panda A, Kumar S, Kumar A, et al. Fibrin glue in ophthalmology. Indian J Ophthalmol 2009;57:371–9. 10. Carlson AN, Wilhelmus KR. Giant papillary conjunctivitis associated with cyanoacrylate glue. Am J Ophthalmol 1987;104: 437–8. 11. Dickneite G, Metzner H, Pfeifer T, et al. A comparison of fibrin sealants in relation to their in vitro and in vivo properties. Thromb Res 2003;112:73–82.
Yang et al
Ophthalmic Technology Assessment
12. TISSEEL (Fibrin Sealant) [package insert]. Westlake Village, CA: Baxter Healthcare Corp.; January 2012. Available at: http://www.baxter.com/downloads/healthcare_professionals/ products/Tisseel_PI.pdf. Accessed December 6, 2012. 13. EVICEL Fibrin Sealant (Human) [package insert]. Kiryat Ono, Israel: Omrix Biopharmaceuticals Ltd.; December 2009. Available at: http://www.ethicon360.com/sites/default/files/products/ 123009%20EVICEL%20PI_0.PDF. Accessed December 6, 2012. 14. Beriplast P Combi-Set. EU-Summary of product characteristics. Marburg, Germany: CSL Behring; July 22, 2008. Available at: http://www.cslsurgery.com/international/beriplast/product/pdf/eu/ Expert.pdf. Accessed December 6, 2012. 15. ARTISS [Fibrin Sealant (Human)] [package insert]. Westlake Village, CA: Baxter Healthcare Corp.; August 2011. Available at: http://www.baxter.com/downloads/healthcare_professionals/ products/ARTISS_PI.pdf. Accessed January 28, 2013. 16. Cai K, Gierman TM, Hotta J, et al. Ensuring the biologic safety of plasma-derived therapeutic proteins: detection, inactivation, and removal of pathogens. BioDrugs 2005;19:79–96. 17. Horowitz B, Busch M. Estimating the pathogen safety of manufactured human plasma products: application to fibrin sealants and to thrombin. Transfusion 2008;48:1739–53. 18. Hino M, Ishiko O, Honda KI, et al. Transmission of symptomatic parvovirus B19 infection by fibrin sealant used during surgery. Br J Haematol 2000;108:194–5. 19. Kawamura M, Sawafuji M, Watanabe M, et al. Frequency of transmission of human parvovirus B19 infection by fibrin sealant used during thoracic surgery. Ann Thorac Surg 2002;73:1098–100. 20. Scheule AM, Beierlein W, Wendel HP, et al. Fibrin sealant, aprotinin, and immune response in children undergoing operations for congenital heart disease. J Thorac Cardiovasc Surg 1998;115:883–9.
21. Kober BJ, Scheule AM, Voth V, et al. Anaphylactic reaction after systemic application of aprotinin triggered by aprotinin-containing fibrin sealant. Anesth Analg 2008;107: 406–9. 22. Dhillon S. Fibrin sealant (Evicel(R) [Quixil(R)/Crosseal]): a review of its use as supportive treatment for haemostasis in surgery. Drugs 2011;71:1893–915. 23. Oxford Centre for Evidence-Based Medicine. Levels of evidence (March 2009). Available at: http://www.cebm.net/ index.aspx?o¼1025. Accessed September 6, 2012. 24. Biedner B, Rosenthal G. Conjunctival closure in strabismus surgery: Vicryl versus fibrin glue. Ophthalmic Surg Lasers 1996;27:967. 25. Dadeya S, Kamlesh MS. Strabismus surgery: fibrin glue versus vicryl for conjunctival closure. Acta Ophthalmol Scand 2001;79: 515–7. 26. Basmak H, Gursoy H, Cakmak AI, et al. Tissue adhesives as an alternative for conjunctival closure in strabismus surgeries. Strabismus 2011;19:59–62. 27. Guo S, Wagner RS, Forbes BJ, et al. Cut and paste: sutureless conjunctival closure in strabismus surgery. J Pediatr Ophthalmol Strabismus 2010;47:228–30. 28. Lee JH, Kang NY. Comparison of fibrin glue and sutures for conjunctival wound closure in strabismus surgery. Korean J Ophthalmol 2011;25:178–84. 29. Zarbin M. Declining use of sutures for wound closure. Arch Ophthalmol 2012;130:1596. 30. Chaurasia SS, Champakalakshmi R, Angunawela RI, et al. Optimization of fibrin glue spray systems for ophthalmic surgery. Transl Vis Sci Technol [serial online] 2012;1:2. Available at: http://tvstjournal.org/doi/pdf/10.1167/tvst.1.2.2. Accessed December 14, 2012.
Footnotes and Financial Disclosures
Manuscript no. 2013-654.
6 The Vision Center, Children’s Hospital Los Angeles; Orbit and Eye Movement Institute, Strabismus and Pediatric Ophthalmology; Fellowship Program, Pediatric Ophthalmology and Strabismus; University of Southern California Keck School of Medicine, Los Angeles, California.
Abrahamson Pediatric Eye Institute, Cincinnati Children’s Hospital Medical Center, Department of Ophthalmology, University of Cincinnati, College of Medicine, Cincinnati, Ohio.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
2
Funded without commercial support by the American Academy of Ophthalmology. Prepared by the Ophthalmic Technology Assessment Committee Pediatric Ophthalmology/Strabismus Panel and approved by the American Academy of Ophthalmology’s Board of Trustees February 23, 2013.
Originally received: April 20, 2013. Final revision: May 6, 2013. Accepted: May 6, 2013. Available online: June 29, 2013. 1
Jaeb Center for Health Research, Tampa, Florida.
3
R. Howard Dobbs Professor of Ophthalmology, Professor of Pediatrics, Department of Ophthalmology, Emory University, Atlanta, Georgia. 4
Knowles Professor of Ophthalmology & Medical Informatics and Clinical Epidemiology, Casey Eye Institute, Oregon Health and Science University, Portland, Oregon. 5 Clinical Professor, Gavin Herbert Eye Institute, University of California, Irvine, California.
Correspondence: Nicholas Emptage, MAE, American Academy of Ophthalmology, Quality of Care and Knowledge Base Development, 655 Beach St., San Francisco, CA 94109. E-mail: [email protected].
1941