Diffusion of injected collagenase clostridium histolyticum for dupuytren´s disease: an in-vivo study

INTRODUCTION

Dupuytren´s disease is a thickening of the palmar, digital fascia and adjacent soft tissues mainly affecting the ring finger and the little finger.¹

In 8 to 33% of cases the progressive nature of Du-puytren´s contracture (DC) may form progressive fixed flexion contracture (FFC), that inhibit normal function of the hand.^2-4 The mainstay treatment for DC is surgical fasciectomy or fasciotomy.⁵ Collagenase Clostridium Histolyticum (CCH) was introduced in 2009 as an alternative nonsurgical, minimally invasive treatment for DC and the efficacy and safety of CCH has been confirmed in clinical studies subsequently. ^6-10 It relies on enzymatic cleavage of the pathologic cords via local injection of collagenase, followed by delayed manual manipulation.¹¹ The most common adverse events of CCH injection are swelling, ecchymosis, blisters, lymphadenopathy  and skin tears that usually resolve without further surgical therapies;^5-9 on the other hand, severe complication is tendon rupture requiring technically demanding surgical procedures. ¹²

The technical instruction leaflet for CCH injection (Auxilium Pharmaceuticals, Inc., Malvern, PA, USA) recommends a “2–3mm depth” of injection but gives no further guidance.¹³ We hypothesized that the injected CCH does not only concentrate inside the cord but also dissipates both along the cord and into the adjacent tissues. Povidone-iodine (PI) is a widely used water-soluble antiseptic solution consisting of polyvinylpyrrolidone with water, iodide and 1% available iodine introduced by Shelanki in 1956.¹⁴ It has bactericidal ability against a large array of pathogens.¹⁵ This study investigated our hypothesis by visual intraoperative findings after injecting PI into the cord demanding surgical procedures¹².

MATERIALS AND METHODS

This study enrolled five male and one female patient with DC (four little fingers and two ring fingers) with a mean age of 71 (range; 60–78 years old) on whom we performed partial fasciectomies due to FFC of the metacarpo-phalangeal (MP) and proximal interphalangeal (PIP) joints (Table 1). Before the surgical procedure, we marked three hypothetical collagenase injection points at 2 mm intervals on the skin above the cord around the MP joint and measured the distance from the skin surface to the middle of the cord as hypothetical injection depth by ultrasonography (US) with long axis images (SNiBLE; Konica Minolta, Tokyo, Japan). We then dispensed a total amount of 0.25 ml of PI, which is a commonly used antiseptic solution used to reduce the risk of surgical site infection before the skin incision or to irrigate infected tissues ^16,17 (Mylan Inc., Tokyo, Japan), into the three points after adjusting the needle length to the hypothetical injection depth by our silicone tube method.¹⁸ The silicone tube method involves placing a precut, measured and sterilized silicone tube (Phycon tube SH No. 1, inner diameter-outer diameter; 1.0-2.0mm, Fuji Systems, Tokyo, Japan) prepared for us by BEAR Medic Corporation’s factory (Ibaraki, Japan) over the 13 mm non-removable needle of VA syringes (Nipro, Osaka, Japan) which effectively adjusts the needle length (Figure 1). The restricted depth provides not only precise injection into the middle of the cords but also avoids needle tip migration. Stabilizing the tube with sterilized forceps while depressing the plunger simplifies the procedure. Soon after the injection of PI, we performed a careful dissection and visually examined the extent of the PI diffusion checking A) the longitudinal extent in the cord central to the injected sites and B) the infiltration into the adjacent tissues located inside the subcutaneous structures i.e. fat tissue, neurovascular bundles and the space underneath the cord structure. After completing the partial fasciectomies, the remaining PI was irrigated with saline thoroughly and skin was closed.

RESULTS

The hypothetical injection depth averaged 2.6 mm. In detail it was equivalent to 2.1 mm (Case 1), 3 mm (Case 2), 2.5 mm (Case 3), 3 mm (Case 4), 2.8 mm (Case5) and 2.1 mm (Case 6).

A) The longitudinal extent in the cord central to the injected sites

In all cases the cord was homogeneously stained with PI to the following extents; 10 mm (Case 1), 6 mm (Case 2), 
10 mm (Case 3), 8 mm (Case 4), 15 mm (Case 5) and 13 mm (Case 6) with an average of 10 mm.

B) The infiltration into the adjacent tissues

The infiltration of PI into the subcutaneous structure underneath the injection sites and into the bilateral fat tissue was seen in all cases (Figure 2a). In addition, Case 1, 3 and 6 showed the infiltration into the neurovascular bundles (Figure 2b). Furthermore, Case 1 and 6 showed the infiltration of PI underneath the cord structure (Figure 2c).

DISCUSSION

Although CCH injection treatment is reported to have a high rate of both clinical success with FFC ≤5 degree and patients’ satisfaction, there is a persistent rate of adverse events, such as oedema, injection site swelling, blood blisters, skin laceration and pain in extremity. ^6-10 The incidence of the severe complication of tendon rupture is low ^6,7,10,13 and it is postulated that this should be prevented by avoiding injection too deeply. For this reason, physicians may be tempted to inject CCH shallowly. We suggest this likely exacerbates the occurrence of the adverse events. Therefore, we consider it is important to inject CCH in the centre of the cord in an effort to minimize those complications and maximize CCH efficacy. Verheyden also recommended a direct CCH injection into the centre of the cord by feeling the firm pressure at plunging of the syringe.¹⁹ However, swelling (40%) and skin lacerations (35%) which were noted were comparable to previous reports. ^6-10 This implies that even if CCH is injected into the centre of the cord, the liquid does not only concentrate inside the cord but also dissipates along the cord and infiltrates into the adjacent tissues. This may explain why CCH injection at the MP joint improved the FFC of the PIP joints⁹ but with the occurrence of adverse events. ^6-10 In fact, as direct visual inspection of injected CCH is impossible, we designed this study to simulate an in vivo condition by injecting PI into the cord of the cases that were due to have partial fasciotomies. Although CCH and PI are different agents, they are soluble liquid substrate mixtures. The diffusion of PI inside and outside of the cord implies that CCH would behave similarly. Crivello et. al.²¹ reported the inflammatory changes about the flexor tendons (60%) and around the cord (100%) by slightly increased signal intensity on the MRI one month after CCH injection. Those findings were attributed to a reaction to CCH because there was no sign of inflammation on the MRI taken before CCH injection. They commented about the importance of understanding the effect of CCH on the neighbouring soft tissues, for example, the possible spread of CCH to nearby flexor tendons and pulleys. Our study confirms their comments showing the infiltration of PI into the subcutaneous structure underneath the injection sites and the bilateral fat tissue in all six cases, into the neurovascular bundles in three cases, and underneath the cord structure in two cases.

The limitations of this study were firstly, PI and CCH are different agents and secondly, the case numbers are small. However, we believe this study demonstrates the likelihood of CCH dissipation inside the cord and infiltration into the adjacent tissues.

CONCLUSIONS

This study simulated the likely diffusion outcomes of injected CCH around the cord.

Even if CCH is injected into the centre of the cord, CCH may not concentrate inside the cord only but also may dissipate along the cord and infiltrates into the adjacent tissues with potential secondary damages.

Role of authors: All authors have been actively involved in the planning, preparation, analysis and interpretation of the findings, enactment and processing of the article with the same contribution.

Declaration: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study. Some data from this paper were presented at the 73^rd Annual Meeting of the American Society for Surgery of the Hand, September 15–18, 2018, Boston.

Conflict of interest: None.

Funding : This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Corresponding author:

Stefano Lucchina, MD

Locarno Hand Center,

Via Ramogna 16, 6600 Locarno

Switzerland

E-mail: info@drlucchina.com