Technical Tips for Collagenase Injection Treatment for Dupuytren Contracture

Technical Tips for Collagenase Injection Treatment for Dupuytren Contracture

SURGICAL TECHNIQUE Technical Tips for Collagenase Injection Treatment for Dupuytren Contracture Roy A. Meals, MD, Vincent R. Hentz, MD I N FEBRUARY...

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SURGICAL TECHNIQUE

Technical Tips for Collagenase Injection Treatment for Dupuytren Contracture Roy A. Meals, MD, Vincent R. Hentz, MD

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N FEBRUARY 2010, THE UNITED

States Food and Drug Administration approved collagenase clostridium histolyticum (CCH) (Xiaflex; Auxilium, Malvern, PA) injection for treatment of Dupuytren contracture. We participated in the Phase 2 and/or Phase 3 trials before United States Food and Drug Administration approval, and since approval, we have collectively injected approximately 275 doses of CCH in approximately 225 patients. The manufacturer’s full prescribing information for CCH injection is at https://www.xiaflex.com/_ assets/pdf/Xiaflex-PI-Med-Guide.pdf, and the obligatory training video is at http://xiaflexrems.dnsalias.net/. Full knowledge of these resources is paramount to the safe and effective use of CCH. Excerpts from the full prescribing information (accessed June 11, 2013) are included below in italics, followed in plain text by our From the Department of Orthopedic Surgery, University of California at Los Angeles; and the Department of Plastic Surgery, Stanford University, Stanford, CA. Received for publication October 22, 2013; accepted in revised form March 16, 2014. R.A.M. and V.R.H. have had research and consultancy positions with Auxilium in the past (none at the time of manuscript preparation). Corresponding author: Roy A. Meals, MD, Department of Orthopedic Surgery, University of California at Los Angeles, 1033 Gayley Avenue, #104, Los Angeles, CA 90024; e-mail: [email protected]. 0363-5023/14/3906-0031$36.00/0 http://dx.doi.org/10.1016/j.jhsa.2014.03.016

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We describe technical tips for injecting collagenase into Dupuytren cords based on experience acquired during the prerelease Food and Drug Administration clinical trials and with subsequent clinical practice. These tips include techniques for extracting the reconstituted enzyme efficiently from the vial, injecting the cord(s) with increased safety to the tendons, and anesthetizing the hand before manipulation. The tips are intended to supplement but by no means replace the manufacturer’s prescribing information and training video. (J Hand Surg Am. 2014;39(6):1195e1200. Copyright Ó 2014 by the American Society for Surgery of the Hand. All rights reserved.) Key words Dupuytren, injection, collagenase, technique.

tips for treatment that we have gained from experience. The technical tips are intended to supplement but by no means replace the manufacturer’s prescribing information and training video. INJECTION TECHNIQUE 2.2 d) Using a 1 mL syringe that contains 0.01 mL graduations with a 27-gauge 1/2-inch needle (not supplied), withdraw a volume of the diluent supplied, as follows:  0.39 mL for cords affecting an MCP [meta-

carpophalangeal] joint or  0.31 mL for cords affecting a PIP [proximal

interphalangeal] joint. 2.2 e) Inject the diluent slowly into the sides of the vial containing the lyophilized powder of XIAFLEX. Do not invert the vial or shake the solution. Slowly swirl the solution to ensure that all of the lyophilized powder has gone into solution. Because the drug is expensive and not immediately replaceable, be deliberate in the reconstitution and syringe loading steps. Because the needle is permanently fixed to the syringe (to minimize dead space caused by the hub), substitution for a contaminated needle is impossible. 2.2 g) Discard the syringe and needle used for reconstitution and the diluent vial.

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FIGURE 1: Removing reconstituted CCH from the vial. The hubless needle and syringe minimize dead space and maximize the volume injected. A The stem on the stopper has a longitudinal cutout. The maximum volume of the reconstituted CCH can be efficiently withdrawn from the vial if the needle tip is inserted into this longitudinal cutout. B With the vial tilted down and rotated so that the cutout on the stem is in the 6-o’clock position, the needle insertion starts at the 12-o’clock position on the circle on the stopper top and continues vertically into the longitudinal cutout.

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 An MCP joint contracture with a pretendinous cord

2.3 d) Reconfirm the cord to be injected. The site chosen for injection should be the area where the contracting cord is maximally separated from the underlying flexor tendons and where the skin is not intimately adhered to the cord. Because more than the recommended 0.25 mL of reconstituted CCH can be withdrawn from the vial and because larger doses of CCH injection are well tolerated,1 we consider using more than the manufacturer’s recommended dose to be a safe, although off-label procedure. 2.4 a) Using a new 1 mL hubless syringe that contains 0.01 mL graduations with a permanently fixed, 27-gauge 1/2-inch needle (not supplied), withdraw a volume of reconstituted solution (containing 0.58 mg of XIAFLEX) as follows:

associated with a natatory cord causing an adduction contracture between the primary targeted digit and the adjacent digit  First webspace and thumb contractures caused by more than 1 cord: for example, a distal commissural cord compromising the first webspace plus a radial cord restricting thumb MCP joint extension For ease of handling, we use the same hubless needle and syringe (Fig. 1) for reconstitution and injection. In this manner, the needle has passed through 2 rubber stoppers before injection rather than 1 if a separate syringe and needle are used for just the injection, but the sharpness of the needle seems to be unaffected. Therefore, using 1 syringe is appropriate unless the needle bends during the reconstitution phase or if there is any question whether the needle is still sterile. Withdrawing the correct volume of the reconstituted solution may be a source of technical error because of the small volume in the vial, the frequent presence of an air bubble around the stopper, the shape of the stopper, the possibility of the thin needle veering off a straight course as it traverses the stopper, and the poor visibility at the neck of the vial. If visualization of the needle tip is difficult, nearsighted individuals may find that it is better to remove their glasses. Farsighted individuals may benefit from the use of reading glasses or loupes. The stem on the stopper is 6 mm in diameter, with its central hollow channel measuring 3 mm. The stem is 7 mm long and has a longitudinal cutout traversing a 90 arc of the stem wall and extending from the end of the stem to within 2 mm of the undersurface of the stopper cap. The outer surface of the cap has a small, slightly raised central circle that axially aligns with the location of the hollow channel in the stem (Fig. 1).

 0.25 mL for cords affecting an MCP joint or  0.20 mL for cords affecting a PIP joint.

We have found that all but the thickest cords often respond completely to less than 0.58 mg of CCH and therefore consider using most of the injection volume in the most offending cord and using the remaining portion of the volume for a secondary cord. For a Y-cord that branches at the metacarpal head level into 2 adjacent fingers, injection of the CCH at the branch point often corrects the MCP joint contracture in both fingers. Other common opportunities to divide the dose include:  A PIP joint contracture caused by both radial and ulnar lateral digital cords. In this case, the dose to each cord is adjusted according to the relative thickness of the cord  A little finger PIP joint contracture caused by an abductor digit minimi cord (usually the prime cause of contraction but associated with a radial lateral digital cord) J Hand Surg Am.

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We recommend tilting the vial down at a 45 angle and rotating it so that the cutout on the stem is in the 6-o’clock position. Insert the needle at the 12-o’clock position of the circle, keep the needle and syringe vertical, and insert the needle obliquely through the stopper so that the fully inserted needle tip passes into the stem’s cutout at the deepest portion of the pooled fluid. Withdraw the needle so its tip is barely visible in the cutout. Tap the vial to move bubbles to the surface of the liquid in the vial. The liquid is too viscous to easily tap bubbles out of the syringe. Therefore, if there are excessive bubbles once the dose is in the syringe, the liquid should be reinjected into the vial and reaspirated without bubbles. Even with these tips, take care to ensure that fluid, not air, fills the syringe. (It is possible to withdraw and possibly inject only air if you are not extremely careful.) Taking these steps, it is usually possible to withdraw 0.35 mL (off-label dose) when 0.39 mL of diluent has been added to the lyophilized powder. 2.4 b) With your nondominant hand, secure the patient’s hand to be treated while simultaneously applying tension to the cord. With your dominant hand, place the needle into the cord, using caution to keep the needle within the cord. 2.4 c) If the needle is in the proper location, there will be some resistance noted during the injection procedure. The training video demonstrates injecting the cord by directing the needle in an anterior to posterior direction perpendicular to the volar surface of the palm or digit. We recommend approaching the cord somewhat obliquely so that if the needle tip extends to the far side of the cord, the injection is less likely to be in the immediate vicinity of the flexor tendons. The approach to a cord at the fifth metacarpal neck can further distance the needle tip from the flexor tendons by directing the needle from medial to lateral in the plane of the palm. For an abductor digiti minimi cord, however, a direct anteroposterior course of the needle directs the tip maximally away from the flexor tendon sheath. To keep appropriate tension on the cord, it is wise to have a nurse or an assistant gently pull the digit into extension so the cord is under tension. Then, the injector can use both hands to manipulate the syringe. Ideally, when the injection is occurring, one hand is holding the barrel firmly and still while the plunger is advanced with the other hand. This maneuver allows the injection to occur without the possibility of the needle slipping further into the cord during the administration of the dose. We recommend inserting the needle with the cord under tension, which can be achieved by an assistant J Hand Surg Am.

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pressing the finger into maximum extension or with the ulnar side of the injector’s nondominant hand. The tension helps define the exact dimensions of the cord and also causes the cord to bowstring away from the joint and tendons. Because the needle is sharp and fine, you may not be able to determine the needle tip’s location strictly by the resistance felt during needle insertion. If the initial resistance drops off, this implies that the needle tip has passed through the cord. In this case, the needle should be removed completely and replaced in a different location. The temptation to withdraw the needle slightly and then inject the dose should be avoided because the injectate will likely follow the established track and extrude from the cord. Experience gained from open surgery helps in anticipating the location of the needle tip when inserted percutaneously. The superficial aspect of most cords is within 2 to 4 mm of the skin surface, and cord (not nodule) thickness is rarely more than 4 to 5 mm. The needle bevel is approximately 1.2 mm long, which also helps estimate the depth of insertion. Once you sense that the needle is properly located, we recommend firmly stabilizing the barrel of the syringe with the dominant hand and using the thumb or index finger of the nondominant hand to push the plunger, all the while maintaining extension pressure on the digit. Using a syringe without a needle, practice this positioning on a volunteer to gain competence and confidence so that you can inject small aliquots of fluid into tissue that resists the flow of fluid (evidence that you are injecting into the cord) without allowing the needle to plunge deeper into the tissues. The ideal circumstance is when the resistance is great and the fluid flows slowly. Keep pressure on the plunger until fluid begins to flow, then ease the pressure a bit so that you can control the volume injected at the site (Fig. 2). 2.4 d) Next, withdraw the needle tip from the cord and reposition it in a slightly more distal location (approximately 2 to 3 mm) to the initial injection in the cord and inject another one-third of the dose. 2.4 e) Again withdraw the needle tip from the cord and reposition it a third time proximal to the initial injection (approximately 2 to 3 mm) and inject the final portion of the dose into the cord. The dose may be divided into 3 to 5 aliquots and administered by separate needle insertions, depending on the cord architecture. In general, aliquots are given longitudinally along the cord. However, when the cord is extremely thick, transverse alignment of the aliquots from medial to lateral or lateral to medial places enough enzyme at 1 level to disrupt a large, r

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FIGURE 2: Injection techniques. Obscured by the safety shields, these syringes and needles are also hubless. A A radial digital cord is being injected. Note the oblique direction of the needle (inclined from medial to lateral) chosen to minimize risk of inadvertent injection into the flexor tendon sheath. The ulnar fingers of the surgeon’s left hand maintain tension on the cord. B An abductor digiti minimi cord is being injected. The needle is inclined away from the flexor tendons. Note that the barrel of the syringe is supported by fingers of both hands to ensure that the needle is not pushed deeper in the tissues as the plunger is depressed.

thick cord. When dealing with combined cords, such as a central cord and natatory cord, 4 aliquots should be placed equally at the junction, distal to the junction, proximal to the junction, and in the natatory cord. When there is a central cord with a natatory cord radially and a separate natatory cord ulnarly, divide the dose into 5 aliquots: 1 distally, 1 at the junction, 1 proximally, and 1 in each natatory cord.

extension procedure without local anesthesia can be extremely painful. One of us (R.A.M.) injects 6 to 8 mL 1% plain lidocaine subcutaneously in the midpalm (proximal to the area of swelling and ecchymosis) in the axis of the treated ray. The other of us (V.R.H.) inserts a long 27-gauge needle through the dorsal webspace skin on both sides of the digit to perform an intermetacarpal block. This may be less uncomfortable than the palmar injection, but it may not provide analgesia as far proximally as the palmar injection. A wrist block would also likely suffice, but in our experience the wrist block may require more time to set up. Buffering 9 mL lidocaine with 1 mL sodium bicarbonate reduces the acidity of the lidocaine and improves patient comfort. A supplemental field block injection on the back of the hand facilitates comfort if the anterior injection(s) prove inadequate. After 10 to 15 minutes, proceed with the extension procedure. Some patients will notice considerable pain over the dorsum of the hand during manipulation, in which case, inject some lidocaine dorsally and wait a few more minutes. 2.5 c) Care should be taken during rupture of the cord, as some patients may experience skin splitting. You should inform the patient of this possibility at the time of the initial consultation, on the day of injection, and immediately before the extension procedure. You should be prepared for a skin tear, which may emit several milliliters of old blood with considerable force,

MANIPULATION TECHNIQUE 2.5 a) At the follow-up visit the day after the injection, if a contracture remains, perform a passive finger extension procedure (as described below) to facilitate cord disruption. We and others have found that the finger extension procedure works as well 2 to 7 days after injection as it does on the first day after injection. This allows for scheduling the finger extension procedure on a day that is maximally convenient for the patient, surgeon, and hand therapist. At times, patients will rupture the cord spontaneously during daily activities before their day of manipulation appointment. We advise them nonetheless to return for evaluation and further extension maneuver if necessary and for splint fabrication and exercise instructions. 2.5 b) Local anesthesia may be used. We know from experience in the Phase III Food and Drug Administration trials that the finger J Hand Surg Am.

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by wearing gloves and covering the palm and base of the treated finger(s) with a gauze sponge. The great majority of skin tears are of the palmar skin where the contracture is greater than 45 or the skin is heavily calloused or when there is a great deal of ecchymosis at the site of injection. Sometimes, the cord clearly ruptures with the first effort at manipulation and the palmar skin shows signs of beginning to tear, but some resistance remains to full joint extension. A blood blister, perhaps occurring from inadvertent injection of collagenase into the skin, warns of an impending skin tear. Tearing can be minimized by not pulling vigorously on blistered areas and proceeding with a 4-step manipulation: Flex the proximal interphalangeal joint while extending the metacarpophalangeal joint; flex the metacarpophalangeal joint while extending the PIP joint; extend both joints together; and finally, by keeping the finger extended under moderate tension, press on and disrupt any residual intact cord fibers. The 4-step manipulation can be repeated several times if necessary while watching the skin and any disruption of capillary refill. Skin tears may extend only several millimeters, usually wider than long. Skin tears of over a centimeter can often be avoided by following the recommended manipulation technique previously described. If the skin does begin to tear, rather than continuing forceful manipulation, which will surely result in a large skin tear, we may choose to stop the manipulation at this point and instruct the patient to begin gentle progressive passive extension. The remaining resistance to joint extension is now primarily the result of skin tightness and the skin will respond to progressive stretch. 2.5 c) If this occurs, cover the area with gauze and apply gentle pressure until bleeding stops. Standard wound care with regular dressings should be applied. A skin tear may ooze slightly for several days, so advise the patient to change the gauze as needed. When it has stopped oozing, we advise having the patient wet the hand as desired and cover the area with an adhesive strip bandage until secondary intention has drawn the skin edges together. 2.5 d) If the first finger extension procedure does not result in disruption of the cord, a second and third attempt can be performed at 5- to 10-minute intervals. However, no more than 3 attempts are recommended to disrupt a cord. With the area fully anesthetized and the patient entirely comfortable, we proceed with repeat extension maneuvers immediately. It is often helpful to manipulate the adjacent, apparently unaffected fingers into extension individually, because further disruption of J Hand Surg Am.

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the contracture is often palpable and apparent by improved extension in the treated finger. We occasionally encounter a cord that does not fully rupture after manipulation and may offer this patient a needle aponeurotomy (or a second CCH injection) on another day when the swelling and ecchymosis have subsided and digital nerve sensation is normal. Doing the needle aponeurotomy on the day of Xiaflex manipulation would unduly risk injury to the blocked digital nerve, and oozing could be considerable, similar to what is encountered with a skin tear. Although the product literature indicates that up to 3 injections to achieve correction of a specific joint contracture may be performed, it has been our experience that few patients seek a second CCH injection if notable improvement has been obtained after the first injection, even if some residual contracture remains. POSTINJECTION MANAGEMENT 2.5 f) Following the finger extension procedure(s), fit patient with a splint and provide instructions for use at bedtime for up to 4 months to maintain finger extension. Also, instruct the patient to perform finger extension and flexion exercises several times a day for several months. The self-care instructions used by 1 of us (R.A.M.) are available in Appendix A (available on the Journal’s Web site at http://www.jhandsurg.org). Please feel free to download, amend as needed, and use the self-care instructions in your practice. It is helpful for the therapist to see the patient again a week after the extension procedure to ensure that the patient is maintaining the gains obtained by injection and manipulation; if not, the therapist can intensify the stretching regimen and see the patient at intervals. Simple MCP joint contractures caused by a thin cord often respond solely to self-therapy. Reverse knuckle bender splints for PIP joints stiff in flexion can be helpful in some cases. COMPLICATIONS 5.3) The efficacy and safety of XIAFLEX in patients receiving anticoagulant medications (other than lowdose aspirin, eg, up to 150 mg per day) within 7 days prior to XIAFLEX administration is not known. Therefore, XIAFLEX should be used with caution in patients with coagulation disorders including patients receiving concomitant anticoagulants (except for lowdose aspirin). Ecchymoses in the hand, forearm, and upper arm are common in patients not receiving anticoagulation r

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medications and may be more extensive in those taking nonsteroidal anti-inflammatory medication, clopidogrel, or warfarin. We do not believe, however, that anticoagulant therapy treatment is a rigid contraindication to CCH injection treatment, but anecdotal experience should yield to a systematic study. Similarly, skin tears ooze small quantities of old blood and exudate for several days in patients with normal clotting function and will ooze more in patients receiving anticoagulants. In the immediate postextension period, direct pressure and elevation are effective for clot formation as well as possible silver nitrate cauterization for small tears. A change to a new bandage before the patient leaves the office allows for CCH injection treatment in selected patients without altering their anticoagulation medication regimen. 17) Patient Counseling Information. Each vial of CCH comes with full prescribing information printed on white paper and a medication guide written in lay terms and printed on blue paper. We advise

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giving the medication guide to patients to read when they arrive on the day of injection, at the same time when the CCH is removed from the freezer. Then, before injection, we ask the patients whether they have questions about the medication guide, which thoroughly details the potential complications. We then note in the chart that the patient read the medication guide and had all questions answered. We hope that these technical tips facilitate the effective use of CCH injections for the treatment of Dupuytren contracture. We reiterate that these tips may supplement but certainly not replace a full understanding of the manufacturer’s full prescribing information and training video. REFERENCE 1. Coleman S, Gilpin D, Tursi J, Jones N, Cohen B. Multiple concurrent collagenase clostridium histolyticum injections to Dupuytren’s cords: an exploratory study. BMC Musculoskelet Disord. 2012 Apr 27;13:61. http://dx.doi.org/10.1186/1471-2474-13-61.

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Start by massaging the hand form fingertips to wrist. (If you have a skin tear, wait until the skin is sealed before doing this step).

APPENDIX A Instructions for Care and Therapy for Your Hand After Xiaflex Injection for Dupuytren Disease Day of injection: Use hand for light activities only. Use over the counter acetaminophen as needed for pain relief. Elevate the hand higher than the heart if the hand is throbbing. Remove all bandages before bedtime. OK to get hand wet. The hand will be tender and swollen. Bruising may extend from the hand onto the forearm. You may have tenderness and swelling of a lymph node at your elbow and armpit. Day of manipulation: You can expect the tenderness, swelling, and bruising to gradually resolve over the next 7 to 10 days. If you note throbbing in your hand, rest it on your opposite shoulder or on top of your head during the day and elevate it in on several pillows at night. If you have a skin tear (and about a third of Xiaflex-treated patients do), the tear requires minimal care and will heal in 1 to 2 weeks.

1. Start with the wrist, hand, and fingers in the policeman “stop” position. 2. Then make the best fist you can. When you think you have done your best, try a little harder. 3. Then use your opposite hand to gently push the treated fingers towards the palm. The goal is to touch your treated fingers to your palm without any help from your untreated hand.

4. Bend your wrist slightly and straighten your fingers. 5. Now, use the opposite hand to gently and persistently push the fingers straight, first one finger at a time, then all 4 fingers at once.

 Remove the bandage and begin wetting your



  



hand in tap water and shower water the day following manipulation. If the gauze bandage is stuck to your hand, just get it wet under water and swirl your hand around until the bandage releases easily. Keep a dry gauze on the tear until it stops oozing—usually several days. Then keep the tear covered with an adhesive strip bandage until the skin is sealed. Although the tear looks drastic, it is almost impossible to keep it from healing or to get it infected. You will probably be surprised how quickly and completely it heals. Do not expose your hand to chemicals or garden soil until the skin is sealed.

6. Place the treated hand on a tabletop palm down and use the untreated hand to gently push the treated hand into a flat position. Keep your wrist straight while pushing. Move your thumb out away from your palm.

Wear the brace at night for 4 months. This helps maintain your correction. The brace should not make your fingers numb. To minimize the risk of tendon rupture, do not forcefully close the treated finger against resistance for 6 weeks. This means avoiding finger tug of war and lifting heavy objects (for example, gallon milk jugs, furniture, suitcases) with your treated finger(s). Perform the following exercise 3 to 4 times daily for 4 months.

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7. Lay the hand flat on table. Raise each finger up one at a time. Hold for 5 seconds. Repeat 10 times. Move each finger from side to side (like a windshield wiper) one finger at a time. Repeat 10 times.

9. Hold your treated finger with your opposite hand. Bend and straighten your fingertip. Repeat these exercise 3 to 4 times daily. Contact the hand therapist (phone number __________________) for splint adjustment as soon as the splint is not pushing your finger(s) straight.

8. Bend only the top 2 joints of the fingers keeping the large knuckles straight. Arch the large knuckles back. Repeat 10 times.

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