Acrylates are plastic materials that have numerous applications. They are formed by the polymerization of monomers that are derived from acrylic or methacrylic acid.1 They are well known to cause allergic contact dermatitis (ACD), and although the fully cured polymers are virtually inert, the acrylate monomers are highly allergenic.1 Cyanoacrylates are fast-acting glues, including 2-ethyl cyanoacrylate. They are often used as medical adhesives, and because they polymerize so rapidly, it was initially believed to be almost impossible for them to induce sensitization and ACD.2 This belief has since been refuted by many publications.1
Dermabond (Ethicon, Somerville, New Jersey) is a topical skin adhesive that contains 2-octyl cyanoacrylate that is used for superficial skin closure. The liquid compound is composed of monomer subunits that become polymerized when applied to tissue, providing a flexible, adherent skin barrier. Since this adhesive first achieved Food and Drug Administration approval in 1998, 37 cases of ACD been reported, 25 after elective orthopedic surgery.2–14
Ethicon later introduced the Dermabond Prineo skin closure system, which combines a liquid adhesive containing 2-octyl cyanoacrylate with a self-adhesive polyester mesh. The mesh is placed over the incision site with at least 1 cm mesh extending from each end. The liquid adhesive is then squeezed from the applicator bulb and brushed evenly over the length of the mesh in a single layer with the applicator tip. Benzalkonium chloride is present in the mesh, and it initiates and accelerates polymerization, a process that takes approximately 60 seconds. The nucleophile that drives the polymerization is water.14 Dermabond Prineo is increasingly being used for wound closure after elective orthopedic procedures. It is reported to be as strong as some sutures and staples, and it provides an effective microbial barrier. It also offers a water-tight seal to minimize wound drainage after total joint arthroplasty, thereby reducing one of the main risk factors for early periprosthetic joint infection.15,16 Since it first achieved Food and Drug Administration approval in 2014, there have been 41 reported cases of ACD to Dermabond Prineo.17–22 Of these, 33 occurred after elective orthopedic surgery; however, only 1 of these orthopedic cases was confirmed with patch testing.19
The authors describe the first case series of ACD to Dermabond Prineo where patch testing confirmed the diagnosis in all patients. The goal of this study was to increase awareness in the orthopedic community of the possibility of ACD to Dermabond Prineo, with particular focus on its prevention and management.
Materials and Methods
Study Design and Patients
A total of 6 patients who had suspected ACD to Dermabond Prineo were assessed and underwent patch testing by a single dermatologist in Perth, Western Australia. The patients had undergone elective surgery performed by 4 orthopedic surgeons between February 2018 and November 2018. Mean age of the patients was 51 years (range, 19–72 years; 4 women and 2 men). Clinical records and photographs were reviewed to support a working diagnosis of ACD to Dermabond Prineo. Additional information was collected, including patient demographic features, previous exposure to cyanoacrylates, management of the acute episode, and postoperative complications (Table 1).
Detailed information on the composition of Dermabond Prineo liquid adhesive was unavailable; however, the allergenic compound previously has been identified as 2-octyl cyanoacrylate.17–22 Because 2-octyl cyanoacrylate was not commercially available for patch testing, the patients were tested for reactions to the individual components of the Dermabond Prineo skin closure system “as is.” This testing included the Dermabond Prineo glue alone, the Dermabond Prineo mesh alone, and the Dermabond Prineo glue plus mesh together.
Patients also underwent patch testing to all other potentially allergenic perioperative exposures, including:
Their specific postoperative dressing (Table 1).
Chlorhexidine digluconate, which was used as a preoperative antiseptic for all patients and is a known cause of ACD.23
Benzalkonium chloride, which is present in the mesh of the Dermabond Prineo skin closure system and is known to cause both irritation and ACD.
Formaldehyde, which is released once cyanoacrylates polymerize and degrade. When cyanoacrylate ACD is suspected, ACD to formaldehyde must be excluded.3
An “acrylate screening series” because co-sensitization and cross-reactivity can occur with various acrylates.1 The acrylate series used contained ethyl cyanoacrylate.
The patch tests were applied to the upper back with allergEAZE Skin Patch Test Chambers (SmartPractice, Calgary, Alberta, Canada). Readings were performed on days 2 and 4, according to the International Contact Dermatitis Research Group recommendations (+=weak positive, ++=strong positive, +++=extreme reaction).
Of the 6 patients, 4 had previous exposure to Dermabond Prineo during earlier orthopedic surgery. Of these, 3 recalled mild peri-incisional itching and rash that occurred 10 days to 3 weeks postoperatively, and all cases resolved spontaneously. Of the 6 patients, 1 had previous exposure to Dermabond topical skin adhesive for a skin laceration, with no cutaneous reaction, and 1 patient had no previous exposure to any Dermabond product.
All patients had a history of uneventful exposure to other cyanoacrylates, including dental glue, cosmetic adhesive (ie, for eyelash extensions), acrylic nail glue, or craft and hobby glue. No patient reported a history of ACD to other materials, a documented drug allergy, or a history of atopy.
The predominant surgical site was the knee (5 knees, 1 hip). All patients applied ice every 2 hours and began routine range of movement exercises postoperatively, as advised.
The 5 patients who had previous Dermabond exposure had peri-incisional pruritus within 4 days of surgery and a visible rash within 5 days. The patient who had no previous Dermabond exposure presented later, with peri-incisional pruritus on day 10 and rash on day 14.
All patients progressed from an early eczematous eruption to a later vesiculobullous eruption (Figure 1). All patients had local extension of the rash beyond the contact site with the mesh. Of the patients, 3 had rash below the site of glue application, consistent with dripping of the Dermabond Prineo glue (Figure 2). In addition, 5 of the 6 patients had an itchy rash at distant skin sites, consistent with autoeczematization.
Clinical photographs of acute presentation. Patient 1 on day 3 after left knee patellar stabilization (A). Patient 2 on day 16 after right knee anterior cruciate ligament reconstruction with meniscal repair (B). Patient 3 on day 6 after right knee arthroscopy and removal of metal (C). Patient 4 on day 7 after left knee arthroplasty (D). Patient 5 on day 7 after revision of right knee arthroplasty (E). Patient 6 on day 5 after left hip arthroplasty (F).
Clinical photograph of patient 3 on day 7 showing a rash below the site of glue application (consistent with dripping of the Dermabond Prineo glue [Ethicon, Somerville, New Jersey]) as well as scattered perifollicular pustules and erosions.
All patients underwent removal of the Dermabond Prineo adhesive and mesh earlier than planned. In addition, 2 were treated with a short, high-dose, tapering course of systemic corticosteroids, 1 with both systemic corticosteroids and potent topical corticosteroids, 2 with potent topical corticosteroids, and 1 with weak topical corticosteroids. In addition, 4 were treated with systemic antibiotics. In 3 of these cases, treatment with antibiotics was initiated because of concern that the blistering represented postoperative surgical site infection. However, only 1 patient underwent swab testing, and the result was negative. The fourth patient was administered systemic antibiotics for perifollicular pustules and erosions at the ACD site (Figure 2). This patient had Staphylococcus aureus cultured on swab testing, and resolution occurred with oral antibiotics. No patient had signs or symptoms of deep or systemic infection.
For all patients, dermatitis resolved within 2 weeks of removal of the Dermabond Prineo dressing. No cutaneous scarring occurred. At the time of publication, all patients had a minimum of 12 months of follow-up, with no adverse effect on the orthopedic outcome. Specifically, they had no evidence of deep periprosthetic joint infection.
Results of Patch Testing
All patients had similar results, with either strong (++) or extreme (+++) positive reactions at the 2 sites where the Dermabond Prineo glue was applied. The result was negative for the patch containing the Dermabond Prineo mesh alone (Figure 3). Positive reactions were evident on day 2 and persisted on day 4. In addition, 2 patients had a weak (+) positive reaction to ethyl cyanoacrylate in the acrylate screening series. No other relevant reactions were noted on patch testing.
Clinical photograph of patient 6 on day 4 of patch testing showing no reaction at the site of mesh application alone (1) and extreme positive reactions at the sites of the application of Dermabond Prineo glue (Ethicon, Somerville, New Jersey) alone (2) and Dermabond Prineo glue plus mesh (3).
Allergic contact dermatitis is a type IV delayed-type hypersensitivity reaction that occurs when skin comes in contact with a chemical to which the individual has been previously sensitized. Once sensitization occurs, any future exposure to the allergen will result in ACD, often with increasingly rapid onset and more severe reactions. The risk of sensitization to a particular agent is dependent on individual, chemical, and environmental factors. The authors propose risk factors for sensitization to Dermabond Prineo in the orthopedic cohort (Table 2). These factors may account for the overrepresentation of orthopedic surgery in published reports of ACD to Dermabond products.
Risk Factors for Sensitization to Dermabond Prineo in the Orthopedic Cohort
A history of allergen exposure increases the likelihood of sensitization and the risk of ACD. In this case series, 4 of the 6 patients had previous orthopedic surgery in which Dermabond Prineo was used and 1 had previous exposure to Dermabond topical skin adhesive (Table 1). In these 5 cases, initial exposure to the Dermabond product likely resulted in primary sensitization. Elicitation of ACD with subsequent exposure to Dermabond Prineo then followed, consistent with the early postoperative onset of severe itching and rash.19,21 The first exposure to an allergenic product also can result in active sensitization followed by ACD in the same episode. Only 1 current patient reported no previous exposure to Dermabond products, and the authors suspect that her acute episode of ACD also represented active sensitization, consistent with later onset of symptoms and signs.
It is generally agreed that cyanoacrylates and methacrylates do not cross-react.1 This was true of the current patients and can provide some reassurance to orthopedic surgeons, given that methacrylates are commonly present in bone cement.6 However, cyanoacrylates occasionally cross-react with each other. Of the 6 current patients, 2 had a positive patch test result for ethyl cyanoacrylate, which is found in medical, dental, nail, and cosmetic adhesives as well as in craft and hobby glues. In 3 other reported cases, patch testing has suggested cross-reactivity between 2-octyl cyanoacrylate and ethyl cyanoacrylate.4,7,12
The quantity of the adhesive used also may increase the risk of ACD to Dermabond products.7 Elective orthopedic surgery often results in long cutaneous incisions or multiple smaller cutaneous incisions, as with arthroscopic procedures. Large volumes of Dermabond glue are required, increasing cutaneous exposure. Extreme care should be taken to ensure that the glue is applied directly to the mesh in a single layer, according to the Dermabond Prineo package insert, avoiding spillage beyond this site. Glue that drips elsewhere should be immediately washed off of the affected skin. Those applying the glue also should be careful to avoid skin exposure themselves, and the authors recommend double gloving when using Dermabond Prineo glue.
Occlusion of an allergen enhances its absorption and can increase the risk of sensitization. Postoperative occlusive dressings have been reported to contribute to cyanoacrylate sensitization.5 In the current case series, a variety of occlusive and nonocclusive dressings were used. Ethicon recommends covering Dermabond Prineo with a dry protective dressing, such as gauze, which is highly permeable and relatively nonocclusive. However, many orthopedic surgeons favor an occlusive waterproof dressing, which acts as a barrier to contamination and enables ease of showering because dressings typically are left untouched for 2 weeks.
Sensitization is more likely to occur when the skin has prolonged contact with the adhesive.6,7,14 Once the surgical wound has healed, the Dermabond Prineo mesh and adhesive can be actively removed or left to slough off naturally with the desquamating epidermis. Although Ethicon reports that sloughing occurs within 7 to 14 days, residual adhesive can persist on the skin for much longer. In 1 case, ACD occurred 4 weeks after application, suggesting that the adhesive was still present.6 To reduce the risk of sensitization, the current authors concur with McDonald and Buckley6 in recommending complete removal of the mesh and adhesive no later than 14 days postoperatively.
Extensor surfaces appear to be at highest risk for ACD to Dermabond products, reflected in the current series in which 5 cases involved the knee.21 Tension on the adhesive may cause microfracturing of the adhesive, potentially releasing more allergen and causing more skin irritation, again predisposing to sensitization.21 Ethicon recommends that patients avoid “activity that may cause tension on the wound”; however, this recommendation is not practical after knee surgery.
Cyanoacrylates may be susceptible to degradation after contact with water.24 Such degradation can cause the polymer chains to undergo retropolymerization to reform monomers, which are strong sensitizers. Ethicon advises keeping the Dermabond Prineo skin closure dry until it is removed. Therefore, ice should not be applied directly to the wound postoperatively. A preferable option may be the use of a cold therapy unit or an icing device.25
A low-humidity environment is a possible factor in the increased rates of ACD to Dermabond glue reported in arid locations.2,5 Low humidity may deprive cyanoacrylate polymerization of water, which is its principal nucleophile, slowing polymerization and prolonging exposure to the allergenic monomer. Bitterman and Sandhu13 extended this theory to home heaters and air conditioners. All patients in the current case series underwent surgery in Perth, Australia, which has a Mediterranean climate. Further, 4 of the 6 patients underwent surgery during the month of Perth's highest August rainfall in 50 years.26 Hence, a low-humidity environment does not appear to be a factor in the current cohort.
The classic picture of ACD is a well-demarcated pruritic eczematous eruption, which in the acute phase may show blistering, weeping, and edema. Although the clinical appearance of the rash may mimic a postoperative surgical site infection, ACD to Dermabond Prineo should be suspected in any systemically well patient who has a well-defined itchy rash at the site of application, typically within 2 weeks. Once a reaction is identified, removal of the mesh and residual adhesive is paramount. Additional treatment recommendations are summarized in Table 3.
Management of Allergic Contact Dermatitis to Dermabond Prineo
Although the history and the findings on examination may strongly suggest a diagnosis of ACD, patch testing is the gold standard to confirm the diagnosis. The authors propose the addition of 2-octyl cyanoacrylate to the acrylate screening series for routine testing.13,19 Until then, they recommend patch testing with Dermabond Prineo glue “as is.” Patients who have a confirmed ACD to Dermabond Prineo glue should be counseled to avoid all products containing 2-octyl cyanoacrylate (Table 3).
To date, 2 articles have estimated the incidence of ACD to Dermabond products in the orthopedic cohort. In the first series of 912 orthopedic patients, published in 2014, the incidence of ACD to Dermabond was 1.7% (n=15).9 In the second series of 6008 orthopedic patients, published in 2017, the incidence of ACD to Dermabond Prineo was 0.5% (n=29).21 These figures likely underestimate the true incidence of ACD because many initial exposures cause only mild itching and rash that may resolve spontaneously with adhesive removal. In addition, the authors suspect that the incidence will increase with more widespread use of Dermabond Prineo, leading to more patient exposures and therefore more opportunities for sensitization. Interestingly, in more than 4 years of routine use of Dermabond Prineo by the 4 contributing surgeons, no case of ACD was seen until February 2018. Patients may be presenting for their second surgery with re-exposure to Dermabond Prineo, resulting in increased prevalence of ACD in this cohort of patients who have had more than 1 exposure.
On the basis of the current findings, the surgeons now routinely use 2 simple screening questions during the preoperative consultation to help to identify high-risk patients (Table 4). The major difficulty is for patients who have a history of exposure to Dermabond Prineo without a skin reaction. Should these patients be re-exposed to Dermabond Prineo, given the increased risk of ACD? To date, no studies have been published that estimate the incidence of ACD in this cohort of patients with previous exposure. Therefore, it is difficult to quantify the risk. One suggestion has been to perform patch testing to Dermabond Prineo liquid before the second exposure. Although there is no evidence yet to support this practice, it seems to be a reasonable course of action, based on current knowledge. A positive patch test result implies that the surgeon should choose an alternative method of skin closure. A negative patch test result provides reassurance that the patient has not yet been sensitized and thus it is currently safe to use Dermabond Prineo.
Screening Questions Before the Use of Dermabond Prineo
The main limitations of this study are the small sample size and the short sampling period. Based on the results of this study, a rigorous multicenter study would be useful to determine the incidence of ACD in orthopedic patients after their first, second, third, or later exposure to Dermabond Prineo. Patient selection for the Dermabond Prineo skin closure system also requires clarification, in particular, the role of preoperative patch testing for patients with previous exposure without a skin reaction. Finally, a larger sample size would help to confirm the significance of the authors' proposed risk factors for Dermabond Prineo ACD in orthopedic patients.