Review

The cyanoacrylate topical skin adhesives^B

Adam J. Singer MD^a,?, James V. Quinn MD, MS^b, Judd E. Hollander MD^c

^aDepartment of Emergency Medicine, University Hospital, Stony Brook, NY 11794-7400, USA ^bDepartment of Surgery, Division of Emergency Medicine, Stanford University, Palo Alto, CA, USA ^cDepartment of Emergency Medicine, University of Pennsylvania, Philadelphia, PA, USA

Received 6 May 2007; accepted 11 May 2007

Abstract Each year there are over 7 million lacerations requiring wound closure in the emergency department. Traditionally, most lacerations have been closed with sutures. Topical cyanoacrylate skin adhesives offer many advantages over traditional wound closure devices. Recently, the Food and Drug Administration has reclassified the topical skin adhesives. As a result, new topical skin adhesives are expected to enter the market in the near future. This article will review the structure and function of cyanoacrylates as well as their advantages, indications, and usage.

(C) 2008

Introduction

Each year there are over 7 million traumatic lacerations

[1] and between 26 and 90 million surgical incisions requiring closure by surgeons, emergency physicians, and primary care practitioners [2]. Traditionally, these wounds and incisions have been closed with sutures, staples, or surgical tapes, and more recently tissue adhesives. Ideally, a wound closure device should be easy to use, rapid, painless, result in excellent cosmesis, not require device removal, and be cost-effective [3]. Although none of the currently available closure devices meet all of these needs, the topical cyanoacrylate tissue adhesives offer many of the character- istics of this ideal wound closure device.

The cyanoacrylates were initially synthesized by a Ger- man chemist in 1949 [4]. Wound closure with a cyanoacrylate was reported 10 years later [5]. The first, short-chain

^? All of the authors have served on the speakers’ bureau of Ethicon Inc, the manufacturer of Dermabond (an octylcyanoacrylate). J.V.Q. is a consultant for Chemence Medical Products Inc.

* Corresponding author.

E-mail address: [email protected] (A.J. Singer).

cyanoacrylates were crudely manufactured and found to be toxic to animals in pharmacological doses [6]. Longer-chain derivatives lacking the associated toxicity of the short-chain derivatives and more sophisticated manufacturing techniques have lead to the development of pure nontoxic monomers and the acceptance of the adhesives into clinical practice. Multiple studies have demonstrated that when properly used, the rates of Wound infection and dehiscence as well as the cosmetic outcome with adhesives are similar to sutures [7-9]. The Food and Drug Administration (FDA) approval of several new cyanoacrylate tissue adhesives over the last decade has led to their increased use and popularity. With the recent decision of an FDA expert panel to reclassify the cyanoacrylate topical skin adhesives from a class III device (that requires performance of a new clinical trial to receive approval) to a class II device (requiring demonstration of substantial equivalency to a currently approved predicate device), it is anticipated that many new cyanoacrylate adhesives will become available in the United States in the near future. We therefore thought that it would be timely to review the properties, advantages, and indications for the various cyanoacrylate topical skin adhesive formulations as well as their clinical application for optimal use.

0735-6757/$ - see front matter (C) 2008 doi:10.1016/j.ajem.2007.05.015

Structure and mechanical properties

The cyanoacrylates are formed by the condensation of cyanoacetate and formaldehyde in the presence of heat and a vacuum [10]. The resultant cyanoacrylate monomer can subsequently be distilled to achieve purity and remove any toxic byproducts of the synthesis [11]. Furthermore, the resultant monomer can be formulated with stabilizers, plasticers, and other additives such as viscosifying agents to improve its biocompatibility, stability, and clinical perfor- mance [11].

The basic cyanoacrylate monomer is a low-viscosity liquid. On contact with various anionic substances, such as blood, the cyanoacrylates polymerize into long chains forming a solid film that bridges the wounds and holds the apposed wound edges together [11]. Because the adhesive film generally sloughs off within 5 to 10 days as the epidermis regenerates, there is no need to remove the adhesive. Although the monomers can be formulated to improve their performance, the general properties are distinguished by the number of carbons in their side chain (Fig. 1) [11]. In general, the strength and other physical properties of the cyanoacrylate adhesives are directly related to the length and complexity of their alkyl side chain. Short, straight-chain derivatives (ethyl or butyl cyanoacrylate) form tight and stronger bonds compared with complex or long-chain derivatives (propox- ypropyl cyanoacrylate and octylcyanoacrylate). Although these tight bonds are desirable when used as an interface bond, they tend to form brittle bonds that fracture prematurely when used as a topical bridge leading to lower clinical tensile strength than the longer chain derivatives [11]. The bursting strength of incisional wounds closed topically with the 8- carbon octylcyanoacrylate is greater than that of wounds closed with either the 4-carbon (butyl-cyanoacrylate) [12,13] or 2-carbon (ethyl-cyanoacrylate) adhesive [13]. Because of the brittle nature and lower bursting strength failure of the shorter-chain adhesives (ethyl- and butyl-cyanoacrylate),

Fig. 1 The structure of the cyanoacrylate tissue adhesives.

when device failure occurs resulting in wound dehiscence, it tends to be the result of the adhesive breaking in the middle (ie, cohesive failure). In contrast, when device failure occurs with the longer chain octylcyanoacrylate, it is usually a result of the adhesive peeling away from the skin surface (ie, interfacial failure) [13]. Although the mechanical properties and application of the cyanoacrylate topical adhesives can be influenced by the presence of various chemical additives such as initiators and plasticizers to increase strength, viscosity, flexibility, and improve set times, the structure of the monomer is responsible for most of the properties of the polymer. The side chain is also responsible for the set time and degradation rate of the polymer (faster with short chains). All cyanoacrylate adhesives eventually degrade into for- maldehyde and cyanoacetate. Although formaldehyde is known to be a histotoxic irritant, any significant degradation occurs long after the adhesives have sloughed off the skin and these breakdown products do not contribute to any toxicity when cyanoacrylate adhesives are used topically.

Clinical appraisal of the topical skin adhesives

After the first clinical report of successful wound closure using a cyanoacrylate in 1959 by Coover et al [5], a series of mostly observational studies were published on the use of butyl-cyanoacrylates in Europe, Canada, and Israel for traumatic laceration and surgical incision closure. Mizrahi et al [14] reported the use of butyl-cyanoacrylate for the closure of scalp, face, and Limb lacerations in over 1500 children. They found that the overall cosmetic results were excellent, and there were very few adverse events such as infection (1.9%) and wound dehiscence (0.6%). Similarly, Ellis and Shaikh [15] evaluated butyl-cyanoacrylate for the closure of surgical incisions after facial plastic and recon- structive surgery in 178 patients. No postoperative complica- tions were noted in any of the wounds. The first prospective, randomized clinical trial comparing butyl-cyanoacrylate to sutures for the closure of short (b4 cm) pediatric facial lacerations was performed in 1993 [7]. In this study of 81 children that were followed for 3 months, wound closure with the adhesive was faster and less painful than sutures with similar cosmetic results. A similar study in 1997 demon- strated that lacerations closed with octylcyanoacrylate had comparable rates of wound infection, dehiscence, and excellent aesthetic results in comparison with sutured wounds [8]. A large randomized controlled trial compared over 900 lacerations and surgical incisions closed with octylcyanoa- crylate or a standard closure device (mostly sutures) at 10 Clinical sites [9]. Wound closure was faster using the adhesive, whereas the rates of wound infection, dehiscence, and optimal cosmetic results at 3 months were comparable. Similar results (using both the butyl- and octylcyanoacry- lates) have been reported in a wide variety of clinical settings

advantages and disadvantages of the cya”>and specialties including general surgery, plastic surgery, neurosurgery, cardiothoracic surgery, pediatric surgery, urology, otolaryngology, ophthalmology, obstetrics, gyne- cology, orthopedics, and interventional cardiology [14-32].A recent meta-analysis comparing tissue adhesives to sutures has concluded that the use of the cyanoacrylate topical adhesives is associated with similar rates of wound infection and cosmetic outcome after repairing surgical incisions [33]. There are also a few studies suggesting less optimal outcomes after repairing surgical incisions and traumatic lacerations with the topical skin adhesives. For example, a systematic review of 8 randomized controlled trials compar- ing tissue adhesives and standard wound closure for traumatic lacerations found a small statistically significant increase in the rate of dehiscence with the adhesives (number needed to harm, 25; 95% confidence interval, 14-100) [34,35]. As a result, the topical skin adhesives should be limited to low-tension lacerations and surgical incisions. Alternatively, the topical skin adhesives may be used cautiously with higher tension wounds in conjunction with deep, tension-relieving sutures and immobilization [36]. A

recent randomized trial comparing wound outcomes after repair of lower eyelid incisions in 45 patients found that wound depth in the adhesive groups was greater than in the sutured group [37]. Although overall cosmetic outcomes were similar, subgroup analysis demonstrated superior cosmetic outcome in the younger sutured patients. In contrast, an earlier randomized clinical trial that compared wound outcomes in 111 patients undergoing skin closure after facial plastic surgery found superior cosmetic outcome in wounds closed with octylcyanoacrylate [18].

Most studies evaluating wound closure with a topical cyanoacrylate skin adhesive have been limited to relatively short lacerations and incisions. However, a recent study of

209 patients with long surgical incisions (mean length, 16 cm; range, 4-69 cm) demonstrated that a high viscosity octylcyanoacrylate provided epidermal wound closure equivalent to that of other commercially available wound closure devices with a trend toward a decreased incidence of wound infection [38]. In contrast, the experience with wound closure using the butyl-cyanoacrylates has generally been limited to shorter lacerations and incisions up to 4 to 8 cm in length. Few clinical studies have directly compared butyl-cyanoacrylate to octylcyanoacrylate for wound clo- sure. A study comparing wound closure with butyl- cyanoacrylate and octylcyanoacrylate in 94 children with short (mean length, 1.3 cm), low-tension, simple facial lacerations found similar short- and longer-term outcomes [39]. Similar short, low-tension lacerations may also be closed using surgical tapes alone [40,41]. In contrast, a study comparing wound closure with butyl-cyanoacrylate and octylcyanoacrylate in 167 children with groin incisions found lower dehiscence rates and higher parental satisfac- tion with the octylcyanoacrylate [42]. A recent study comparing wound closure using a butyl-cyanoacrylate (Indermil) and sutures in children with groin incisions

also suggests that closure of these high tension wounds may result in a higher rate of wound dehiscence after repair (26% vs 0%) [43].

Advantages and disadvantages of the cyanoacrylate adhesives

Some of the advantages of the cyanoacrylate topical adhesives over traditional devices are obvious. For example, the application of the adhesives is relatively rapid and painless. As a result, no local anesthetics are necessary. In addition, because the cyanoacrylate adhesives slough off spontaneously within 5 to 10 days, there is no need to remove the device, a procedure that may be painful and threatening, especially in children. Although the cost of the cyanoacrylate adhesives is higher than most sutures, a formal Cost-effective analysis conducted several years ago that included the costs of the suture kits, suture removal kits, and dressing materials demonstrated that use of the adhesives reduces the costs [44]. Unfortunately, more recent cost- effective studies are lacking. The use of the topical cyanoacrylate adhesives also reduces the risks of needle sticks [45] and prevents the formation of suture marks on either side of the wound. Unlike suturing that has a learning curve of up to 2 years [46], proficiency using the cyanoacrylate adhesives is rapidly attained [47]. They also have the potential to save operative time, especially with longer incisions and lacerations. Finally, when surveyed, most surgical patients prefer topical adhesive to sutures or staples [32,48,49]. In contrast, in a study of 724 emergency department patients, of which two thirds had a prior or current laceration, more patients preferred sutures to adhesives [50]. The surgical tapes offer many of the same advantages that the topical skin adhesives offer and are a reasonable alternative for closure of appropriate wounds [40,41]. The surgical tapes are easy to use, rapid, painless, comfortable, do not require removal, and are less costly than any of the wound closure devices. However, because of their low bursting strength and tendency to fall off, the use of surgical tapes is limited to simple very-low-tension wounds. Furthermore, the surgical tapes do not have microbial barrier properties. A summary of the advantages, disadvantages, and common indications for the various wound closure devices is presented in Table 1.

Classical studies conducted by Winter [51] and Hinman et al [52] in the early 1960s clearly demonstrated that a moist wound environment was optimal for wound healing. Both the butyl-cyanoacrylates and the octylcyanoacrylates create an occlusive wound healing environment and a barrier to microbial penetration [53,54]. This antimicrobial barrier may be particularly important in the treatment of surgical incisions with a trend toward decreased wound infection rates in comparison with sutures [35,55]. This occlusive property has also resulted in the popular use of cyanoacrylate adhesives as consumer liquid bandages

Less meticulous approximation Painful

Require removal

Hear bearing area Hear bearing area Uncooperative patients Proximity to moist areas Circumferential use

around digits

Proximity to moist areas

Occlusive dressing Comfortable

Lower tensile strength than sutures

Highest risk of dehiscence Limited moisture resistance No moisture resistance

Long linear incisions and lacerations

Scalp wounds

Contraindications

Infected or heavily contaminated wounds (all devices)

Inadequate hemostasis

Linear low tension wounds and lacerations Fragile skin

(flaps and skin tears) Wound support after suture/staple removal Under splints/casts Inadequate hemostasis

Linear low tension wounds and lacerations Fragile skin

(flaps and skin tears) Under splints/casts

Inadequate hemostasis

Complex irregular wounds

High tension

High tension

Prolonged learning curve Require removal

May leave suture marks Risk of needle stick Most reactive

Most incisions and lacerations

Indications

No need for removal Comfortable

Lowest tensile strength

Painful

Disadvantages

Simple

No risk of needle stick No need for removal Microbial barrier

Simple Inexpensive Minimal reactivity

No risk of needle stick

Good tensile strength Simple

Lower tissue reactivity Lower risk of

needle stick

Adhesives

Fast

Tapes

Fast

Staple

Fast

Sutures

Most meticulous approximation

Great tensile strength Low dehiscence rate Time honored

Advantages

Table 1 Comparison of the wound closure devices

[56]. Of note, the commercially available octylcyanoacry- late liquid bandage does not have adequate tensile strength to serve as a wound closure device. The microbial barrier is dependent on the integrity of the adhesive over time. A study in animals suggests that the integrity of the barrier formed by a butyl-cyanoacrylate may be impaired as early as 1 hour after application [13]. The cyanoacrylates have also been shown to have antimicrobial properties (espe- cially against Gram-positive organisms that are responsible for most wound infection) both in vitro and in animal models [57-59].

Although the topical skin adhesives have many potential advantages, they also have several notable disadvantages when compared to the other wound closure devices. For example, they are not as strong as 3/0 and some 4/0 sutures. Therefore, when used alone, there is an increased risk of wound dehiscence with high-tension wounds. Because frequent exposure to moisture may result in adhesive failure, the cyanoacrylate topical skin adhesives should not be used in proximity to mucous membranes such as the

mouth. Finally, the adhesives cannot be used over hair- bearing areas.

Indications and contraindications

The cyanoacrylate tissue adhesives are indicated for low- tension surgical incisions and traumatic lacerations whose edges are easily approximated [3]. The tissue adhesives may also be used for skin tears [60] and closure of flaps and fragile skin because they do not tear through tissues or strangulate them, as do encircling sutures. There have also been several reports of off-label uses of the cyanoacrylate adhesives including sealing of nephrostomy tube sites and cerebrospinal fluid (CSF) leaks as well as for nail-bed repairs [61-63].

The cyanoacrylate tissue adhesives should be avoided over mucous membranes and over areas exposed to frequent moisture and/or friction such as the hands and feet. A recent study in volunteers suggests that frequent exposure of octylcyanoacrylate to daily soaking in warm soapy water for

Fig. 2 Use of adhesive tape to facilitate closure of long wound. The wound (left) is approximated with 2 adhesive tapes (middle), and then the topical adhesive is applied over the taped wound approximating its edges (right).

1 hour at a time may shorten the time to sloughing by 1 day [64]. In our experience, prolonged exposure to water increases the likelihood of premature sloughing.

One study suggested that the bursting strength of wounds closed with octylcyanoacrylate is comparable to that of an intracuticular layer of 4/0 Monocryl suture [65]. Therefore, the cyanoacrylate topical adhesives should not be used alone for closure of high-tension wounds such as those located over major joints. However, the adhesives may be used to close high-tension wounds after placement of deep tension relieving sutures and/or when the wound will be splinted [36], especially if reenforced with surgical tapes. Infected or heavily contaminated wounds should not be closed with the cyanoacrylate tissue adhesives. The cyanoacrylate topical adhesives may be used over hair-bearing areas if the hair is clipped or trimmed.

Wound closure technique with the cyanoacrylates

Cyanoacrylates polymerize through an exothermic reac- tion and may release significant heat, especially if initiators are used [66]. The short-chain butyl-cyanoacrylate adhesives polymerize rapidly and should be applied to the apposed wound edges as a thin, single layer, either as discrete beads or as a continuous layer. The high viscosity octylcyanoacrylate uses an initiator and is applied in 2 thin continuous layers allowing 30 seconds to polymerize between layers. Care should be taken to avoid pooling or thick application of the adhesive to prevent the excessive release of heat, which may cause patient discomfort and have the potential for thermal injury.

Wound edges should be carefully opposed either manually or with the aid of surgical tapes. Application of direct pressure on the wound edges with the tip of the adhesive applicator should be avoided because this may result in wound margin separation and seepage of the adhesive into the wound that may result in scar tattooing [67]. Special care should be taken with the low-viscosity cyanoacrylate tissue adhesives, which may wick or seep into incompletely opposed wound edges and to avoid inadvertent runoff of these adhesives during their application. This is especially important when working in proximity to vital

structures such as the eyes [68]. Excessive runoff can be easily avoided by horizontal positioning of the wound surface and careful, controlled expression of the adhesive from the tip of the applicator. When the wound is located near the eye, it is advisable to cover the eyelids with an ointment (such as petrolatum) and to further protect the eyes with wet gauze. The likelihood of inadvertent runoff is reduced with the high-viscosity adhesives [65].

The secure closure of wounds may be further facilitated by applying a minimal number of porous surgical tapes to approximate the wound edges and then applying the adhesive over the top of the tape. The adhesive penetrates

Table 2 Potential cyanoacrylate pitfalls and pearls Potential pitfall Pearl

Runoff Position wound horizontally Apply small amount of adhesive

Spillage into eyes Cover eyelids with ointment and moist

gauze

Place patient in Trendelenburg for wound above eye and reverse Trendelenburg for wounds below eye Apply small amount of adhesive

Burning sensation Apply small amount of adhesive

Avoid pooling of adhesive Spread out evenly

Wound dehiscence Avoid in high tension wounds unless in

conjunction with deep tension relieving sutures, surgical tapes and immobilization

Wound infection Use proper wound preparation

Avoid in wounds with high risk of infection

Adherence to wound Apply small amount of adhesive

Horizontal positioning of wound Alternate the hand used to appose wound edges before complete polymerization

Introduction of Ensure meticulous wound apposition adhesive into Avoid pressing down on wound with wound applicator (glide over wound surface)

Remove adhesive by applying ointment Removal may be facilitated by using substance containing isopropyl merystate (such as silver sulfadiazine)

the porous tapes further securing them and seals the wound around and between the tapes. The bursting strength of wounds closed with octylcyanoacrylate on top of a layer of surgical tapes is actually greater than either device alone [69]. Use of tape also facilitates the closure of long wounds (Fig. 2). A summary of potential pitfalls associated with the cyanoacrylates together with possible solutions is presented in Table 2.

Care of wounds closed with the cyanoacrylates

Wounds should be kept clean and dry to prevent premature sloughing of the adhesive. With octylcyanoacrylate, the wound may be allowed to get wet briefly during showering or bathing immediately after application, but patients should avoid scrubbing or soaking the wound. In contrast, butyl- cyanoacrylate should be kept dry for at least 48 hours. Swimming and periods of heavy perspiration may also result in premature sloughing of the cyanoacrylate tissue adhesives. Because the cyanoacrylate tissue adhesives form their own waterproof, antimicrobial barrier dressing, no additional dressings are required. Some patients may prefer to cover their wound with a clean, dry dressing. Such coverings are permissible after the tissue adhesive has completely dried, but adhesive tape should not be applied directly to the tissue adhesive. No liquids or ointments, such as Topical antibiotics, should be applied over glued wounds because this may

loosen the adhesive film.

Summary

The cyanoacrylate topical skin adhesives are an important addition to our armamentarium of wound closure devices. Unlike other closure devices, they also function as a microbial barrier and as an occlusive dressing. Knowledge of their mechanical properties, advantages, and disadvan- tages will help the clinician determine their proper indica- tions and use. Although they are easy to use and offer many potential advantages over standard devices to both patients and practitioners, they are not appropriate for all wounds. Careful and meticulous wound evaluation, preparation, and closure are required regardless of wound closure device to achieve optimal results.

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