EFFICACY OF ADCON-T/N AFTER PRIMARY FLEXOR TENDON REPAIR IN ZONE II: A CONTROLLED CLINICAL TRIAL

A. GOLASH, A. KAY, J. G. WARNER, F. PECK, J. S. WATSON and V. C. LEES From the Department of Plastic Surgery, Wythenshawe Hospital, Wythenshawe, Manchester, UK

A prospective double-blind, randomized, controlled clinical trial was conducted to assess the use of ADCON-T/N after exor tendon repair in Zone II. Forty-ve patients with 82 exor tendon repairs in 50 digits completed the study. ADCON-T/N was injected into the tendon sheath after tenorrhaphy in the experimental group while the control group was not treated with ADCON-T/N. ADCON-T/N had no statistically signicant effect on total active motion at 3, 6 and 12 months but the time taken to achieve the nal range of motion was signicantly shorter in treated patients. ADCON-treated patients had a higher rupture rate but this was not signicant. Journal of Hand Surgery (British and European Volume, 2003) 28B: 2: 113115

INTRODUCTION The inammatory response following trauma and surgery results in the formation of peritendinous adhesions that limit the range of movement of tendon repairs undertaken within the conned space of the digital exor sheath. Adhesion formation has long been recognized as a particular problem for Zone II exor tendon injuries and inhibition of adhesion formation could potentially improve the outcome in respect of range of motion. A number of materials have been used as a mechanical barrier between the tendons and the surrounding tissues to minimize adhesion formation after primary tendon repair (Ashley et al., 1959, 1962; Douglas et al., 1967; Hagberg, 1992; Lane et al., 1975; Peacock and Madden, 1969). However, none of these have been shown to be effective. ADCON-T/N (Gliatech, Cleveland, USA) is a bioresorbable gel that acts as a physical barrier. It has been shown to be safe and effective in inhibiting adhesions in experimental and clinical studies (Palatinsky et al., 1997; Petersen et al., 1996). It is composed of porcine gelatin and a polyglycan ester in phosphate buffered saline. In order to test the efcacy of ADCON-T/N in reducing adhesion formation after primary exor tendon repair in Zone II, a randomized, double-blind, controlled clinical trial was conducted over an 18-month period. The null hypothesis tested was that ADCON-T/ N would make no difference to the rate of healing and rehabilitation following Zone II exor tendon repairs.

PATIENTS AND METHODS Adult patients (over the age of 18) with complete division of exor digitorum profundus (FDP) in Zone II, with or without exor digitorum supercialis (FDS) division were included in the trial after obtaining informed consent. Multiple digit injuries and associated digital nerve injuries were not exclusion criteria but
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children, pregnant women, and patients presenting with injuries sustained more than 1 week previously were excluded. Further exclusions were injuries with associated soft-tissue loss, severe crush, fracture, palmar plate injury and devascularization. Patients judged preoperatively as unlikely to comply with the requirements of the trial were not recruited. Ethical approval was obtained from the hospital and university ethics committee prior to commencement of the study. All tendon repairs were performed by the Specialist Registrars and Consultants of the department. The patients arm was exsanguinated and a pneumatic tourniquet used to provide a bloodless eld. The exor tendons were repaired using a 4/0 Prolene modied Kessler core suture and a 6/0 Prolene epitendinous stitch through a Bruner or midlateral approach. Pulleys were vented as necessary and good passive gliding of the repair was ensured. The tourniquet was deated and meticulous haemostasis was obtained at the end of the procedure (this is necessary to prevent potential leaching out of the ADCON). Patients were randomly allocated following completion of the tendon repair into two groups. ADCON-T/N was used in the ADCON group, but not in the control group. A small amount of ADCON-T/N was squirted proximally and distally along the exor sheath using a 22 g Venon in the ADCON group. The nger was then passively moved through its full range several times. Any excess ADCON was wiped off before closure of the wound in accordance with the manufacturers recommendations. All the patients were tted with a plaster of Paris dorsal blocking splint. The randomization code, but not the allocated group, was written in the operation notes but the therapists who undertook the formal assessments were unaware if ADCON-T/N had been used, thus ensuring the doubleblind nature of the trial. The surgeons took no further part in the assessment procedure. All patients were assessed by therapists within 24 h of surgery and controlled active mobilization was then started in a lightweight orthoplastic splint. Patients were

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counselled in detail regarding the physiotherapy programme and were also given written information before discharge from hospital. They were seen by a senior member of the medical team and a dedicated hand therapist in the hand clinics twice a week during the rst 4 weeks, once a week during the next 4 weeks and then at 10 weeks and 3, 6 and 12 months after surgery. At each visit, active and passive range of movement at the distal interphalangeal, proximal interphalangeal and metacarpophalangeal joints of the affected digits were measured by the therapist, using a goniometer. Range of movement in other digits was measured at 3 and 6 weeks and all the subsequent visits. Any problems with wound healing were noted and adverse events like rupture of the repair were recorded and analysed. Statistical analysis was undertaken on the data set. The following variables were compared between the treatment and control groups for signicant differences: nal total active motion (TAM) of the treated digit (active proximal and distal interphalangeal joint exion extension decit) (Strickland and Glogovac, 1980); time taken to achieve nal TAM; rupture rate. Rupture rate in the two groups was compared using the chi-square test, whereas nal TAM and the time taken to achieve this were compared with two sample t tests. In performing this analysis, hands and not individual ngers were used as independent observations (ve patients had more than one involved digit).

Table 1Summary of data set ADCON group Control group Number of patients 26 Number of digits 30 Mean age (years) 34 FDP only 13 FDP+FDS 17 Mean active DIPJ ROM (deg) 47 Mean active PIPJ ROM (deg) 72 Mean TAM (FDP repair) (deg) 112 Mean TAM (FDP+FDS repair) (deg) 127 Mean nal TAM (all digits) (deg) 119 Mean nal TPM (deg) 155 Mean time to nal TAM (weeks) 10 Rupture rate 10/30 Mean time to rupture (weeks) 4 19 20 36 5 15 49 65 110 116 114 149 14 4/20 2

RESULTS Fifty-one patients were included in the trial, 27 in the ADCON group and 24 in the control group. Approximately as many patients again declined to participate following counselling. A further group of similar size were excluded because of the complex nature of their injury or because of late presentation. Six patients defaulted from follow-up, thus leaving a total of 45 patients, 26 in the ADCON group and 19 in the control group. There were 50 digits involved in total, 30 in the ADCON group and 20 in the control group. The mean age of the patients was similar in both groups. The ADCON group had 13 ngers with FDP injury alone and 17 ngers with injury to both tendons. The control group had ve ngers with FDP injury alone and 15 with injury to both tendons. The clinical results are summarized in Table 1. The mean nal TAM of the digits was 1191 in the ADCON group compared to 1141 in the control group (normal=1751). This difference is not statistically signicant (P=0.763). Further, when the results of FDP injuries alone and both tendon injuries were analysed separately there was still no signicant difference between the two groups. The combined FDP and FDS injuries did not have worse outcomes than isolated FDP injuries. The mean total passive

motion (TPM) was 1551 in the ADCON group and 1491 in the control group. Though there was no signicant difference in the mean TAM of the two groups, the ADCON group of patients took signicantly less time (P=0.02) to achieve the nal TAM (10 weeks compared with 14 weeks in the control group). One patient in each group had problems with wound healing due to a wound infection and several patients in the ADCON group had erythema around the wound margin that persisted for 10 days. One nger in each group subsequently required tenolysis. The rupture rate was high, occurring in ten out of 30 digits (33%) in the ADCON group and four out of 20 digits (20%) in the control group. Only three of ten ruptures in the ADCON group and one out of the four ruptures in the control group were due to a specic incident or surgical error. No denite reason could be found for the remaining ten ruptures in the trial although some failed to attend clinic as scheduled and were therefore not fully compliant with the therapy regime. The difference in rupture rate between the two groups was not statistically signicant. The mean time to rupture in the ADCON group was 4 weeks, compared to 2 weeks in the control group (P=0.016) when tested by two sample t tests. After analysing the initial results it was decided that the study should be discontinued early. The reasons for this are detailed in the next section.

DISCUSSION ADCON-T/N works as an absorbable barrier to scar formation and has been shown to be both safe and effective in reducing extraneural scarring (Palatinsky et al., 1997; Petersen et al., 1996). In unpublished studies, it has also been shown to be effective in minimizing postoperative adhesions following tenolysis. The results of this study demonstrate that ADCONT/N does not affect the healing of exor tendons, as the rupture rates and ranges of active motion were not

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different in the treated and untreated groups. However, ADCON-T/N seemed to limit adhesion formation in the early stages of healing, as treated ngers achieved their nal TAM in a signicantly shorter time. It is conceivable that ADCON is eliminated from the repair site and exor sheath earlier than the 4 weeks time period suggested by the promotional literature. Postoperative bleeding, early active mobilization and the activity of macrophages could all cause the dispersal and early breakdown of ADCON. Our study showed a higher rate of late rupture in the ADCON group of patients, which might suggest that ADCON does cause some inhibition of wound healing. The time to achieve TAM was also quicker in the ADCON group, suggesting suppression of adhesion formation. The signicance of this is that ADCON-T/N appears to affect the intrinsic as well as the extrinsic healing system. A tendon repair is weakest during the rst 10 days, with a nadir around the 5th day (Ketchum, 1985). The majority of ruptures occur during the rst 10 days and this pattern was observed within our control group. The increased delayed rupture rate in the ADCON group (most occurred between 3 and 5 weeks) suggests that ADCON-T/N interferes with tendon healing in some way. Formation of 14 mm gaps (known as gapping) is known to occur following tendon repair and controlled mobilization (Seradge, 1983; Silverskiod et al., 1992). It is conceivable that when this happens, ADCON-T/N gel enters the gap and acts as a barrier to healing between the two tendon ends. It is possible that the use of a method of exor tendon repair which prevented gapping (such as a multistrand repair) could prevent the ingress of ADCON-T/N between the tendon ends and eliminate the excess rupture rate and eliminate delayed ruptures. Alternatively, there may be some biological effect of the ADCON-T/N that delays tendon healing. The limitations of this study include the relatively small numbers in each of the trial groups and the overall high rupture rate in the control group. This may have masked a higher rate of rupture in the ADCON group. It is not the purpose of this study to address the issues surrounding the relatively high underlying rupture rate of 20%, although this is the subject of ongoing review. ADCON-TN is marketed as a device and not as a drug. However, it appears biologically active and therefore would be more appropriately designated as a drug which has implications for its licensing requirements. We noticed inammatory changes in skin wounds when ADCON gel was used and a tendency towards late rupture of exor tendon repairs in a pattern not normally observed. This raises the suspicion that there is biological activity associated with ADCON-TN and that it is not functioning solely as a mechanical barrier to adhesions. This study showed that the use of ADCON-T/N resulted in patients achieving their nal range of motion 4 weeks earlier. However, the ranges of motion were the

same in both groups by 6 months and although not signicant, the higher rupture rate in the ADCON group raises concerns about its effect on tendon healing. There was thus no major advantage to the use of ADCON-TN in Zone II exor tendon repair and there appeared to be the potential for real disadvantages. Thus, the decision was taken to conclude the study early. Further controlled laboratory studies with special reference to elimination rate, effect on tendon healing and the need for stronger multistrand repairs to avoid gap formation are suggested before further clinical trials are performed.

Acknowledgements
ADCON-T/N was supplied free of charge by Gliatech Inc. for this trial. We express our thanks to Mr Mark Mellor of Surgicraft for his help in arranging the timely supply of ADCON-T/N for the study and for supply of measuring equipment to the Hand Clinic.

References
Ashley GL, Stone RS, Alonso-Artieda JM, Syverud JM, Edwards JW, Sloan RF, Mooney SA (1959). Experimental and clinical studies on the application of monomolecular cellulose lter tubes to create articial tendon sheath in digits. Plastic and Reconstructive Surgery, 23: 526534. Ashley GL, Polack T, Stone RS, Marmor L (1962). An evaluation of the healing process in avian and mammalian digitalexor tendons following the application of an articial tendon sheath (silastic). Journal of Bone and Joint Surgery, 44A(5): 1038. Douglas LG, Jackson SH, Lindsay WK (1967). The effects of dexamethasone, norethandrolone, promethazine and tension relieving procedure on collagen synthesis in healing exor tendons as estimated by tritiated proline uptake studies. Canadian Journal of Surgery, 10: 3646. Hagberg L (1992). Exogenous hyaluronate as an adjunct in the prevention of adhesions after exor tendon surgery: a controlled clinical trial. Journal of Hand Surgery, 17A: 132136. Ketchum LD. Suture materials, and suture techniques used in tendon repair. In: Strickland (Ed.): Hand Clinics. Philadelphia, WB Saunders, 1985, 1: 4353. Lane JM, Bora FW, Black J (1975). Cis-hydroxyproline limits work necessary to ex a digit after tendon injury. Clinical Orthopaedics and Related Research, 109: 193200. Palatinsky EA, Maier KH, Touhalisky DK, Mock JL, Hingson MT, Cocker GT (1997). ADCON-T/N reduces in vivo perineural adhesions in a rat sciatic nerve reoperation model. Journal of Hand Surgery, 22B: 331335. Peacock EE, Madden JW (1969). Some studies on the effect of b-aminopropionitrile in patients with injured exor tendons. Surgery, 66: 215223. Peterson J, Russel L, Andrus K, MacKinnon M, Silver J, Kliot M (1996). Reduction of extraneural scarring by ADCON-T/N after surgical intervention. Neurosurgery, 38: 976983. Seradge H (1983). Elongation of the repair conguration following exor tendon repair. Journal of Hand Surgery, 8: 182185. Silfverskiold KL, May EJ, Tornvall AH (1992). Gap formation during controlled motion after exor tendon repair in zone II: a prospective clinical study. Journal of Hand Surgery, 17A: 539546. Strickland JW, Glogovac SV (1980). Digital function following exor tendon repair in Zone II: A comparison of immobilisation and controlled passive motion techniques. Journal of Hand Surgery, 5: 537543.

Received: 29 March 2001 Accepted: 29 July 2002 Ms V. C. Lees, Department of Plastic Surgery, Acute Block, Wythenshawe Hospital, Southmoor Road, Wythenshawe, Manchester M23 9LT, UK. Tel.: +44 161 291 6648; Fax: +44 161 291 6381; E-mail: v.lees@virgin.net. r 2003 The British Society for Surgery of the Hand. Published by Elsevier Science Ltd. All rights reserved. doi:10.1016/S0266-7681(02)00249-8/jhsb.2003.0851, available online at http://www.sciencedir ect.com