Extravasation Injuries from Chemotherapy

 Updated 3/2017-- photos and all links (except to my own posts) removed as many no longer active.

Recently Buckeye Surgeon wrote about a complication of chemotherapy (severe neutropenic enterocolitis) that necessitated removal of some dead bowel. It recalled for me the skin injuries I have been called to see over the years. Fortunately, I haven't seen any in several years. Still, I thought I would review the injuries and share them with you.

Extravasation injury is a well-known adverse event associated with intravenous chemotherapy administration and occurs when drugs escape from the veins or intravenous catheters into subcutaneous tissues. Accidental extravasation occurs in approximately 0.1 to 6% of patients receiving intravenous chemotherapy. Cancer patients are inherently at high risk of extravasation for several reasons. These patients often require multiple venipuncture sites and have thin and fragile veins, concomitant peripheral vascular disease, and malnutrition. In addition, the number of optimal intravenous sites may be reduced due to previous chemotherapy, cutaneous radiation therapy changes, and lymphedema secondary to surgery.

The cutaneous manifestations of extravasation may range from discomfort and mild erythema to severely painful skin necrosis, ulcerations, and invasion and damage of deep tissue structures. The extent of tissue damage in extravasation largely depends on the concentration, volume, and vesicant nature of the extravasated agent.

Extravasated cytotoxic agents generally cause two types of local cutaneous reactions:
Irritant Reaction

• Irritants cause a short-lived and self-limited phlebitis and tender, warm, erythematous reaction along the vein or at the site of intravenous administration.
• A variant of this local irritation is an erythematous and urticarial hypersensitivity “flare reaction” that has been associated with the anthracyclines (Daunorubicin, doxorubicin, and epirubicin).

While almost all vesicants exhibit some degree of irritation on a spectrum of injury, carboplatin, cyclophosphamide, docetaxel, ifosfamide, menogaril, and thiotepa are known to produce irritation, but have not been reported to cause chemical cellulitis. If these agents do have vesicant activity, it is likely to be very minimal and rare.

Vesicant Reaction

• Chemical cellulitis which initially presents in a similar way to irritation but may worsen, depending on the amount of drug that has extravasated. The erythema associated with small-volume extravastions will usually resolve over a few weeks. Chemical cellulitis is rare with fluorouracil and less severe with vinblastine and vincristine.
• Necrosis--Large-volume extravasations may induce necrosis within a matter of days. Eschars generally follow with subsequent development of painful ulcerations with red, raised edges. It has been estimated that about one-third of all vesicant extravasations will develop into ulcerations. (photo credit)
• Extravasation recall reaction--This is a reaction at a previous extravasation site that happens when there is an extravasation at a new site. This reaction can range from erythema to ulcerations. It has been seen with Paclitaxel.

Chemical cellulitis displays poor healing activity and often continues to worsen and progress, necessitating surgical intervention. Rudolph and Larson have reported that vesicant-induced damage to the skin delays fibroblastic wound contraction. The ability of these vesicants to bind to DNA may allow them to be recycled and retained in the tissue, thereby inducing damage for a longer duration.

Management
Vigilance in the proper and timely recognition and management of extravasation plays a major role in limiting tissue injury. When extravasation is suspected:

• Prompt discontinuation of the infusion is recommended
• Aspirate any residual drug and removal of the catheter.
• Apply local cold application--Intermittent local cooling (for 20 minutes QID x 3 days) alone has an 89.1% success rate in preventing ulceration. For the vinca alkaloids, heat application (apply heat packs for 20 minutes QID x 3 days) is recommended instead, as cold application may actually induce ulceration.
• Elevate the affected extremity

The use of antidotes is controversial. Some antidotes such as sodium bicarbonate may be harmful or ulcerative.

• On September 6, 2007, the U.S. Food and Drug Administration approved dexrazoxane hydrochloride for injection (Totect™ made by TopoTarget USA, Inc.), equivalent to 500 mg dexrazoxane, for the treatment of extravasation resulting from IV anthracycline chemotherapy. The first dexrazoxane hydrochloride dose should be given as soon as possible and within six hours following extravasation. After the first dose, treatment is repeated 24 and 48 hours later for a total of three doses. Dexrazoxane hydrochloride is administered as a 1-2 hour IV infusion through a different venous access location.
• Sodium thiosulfate has been recommended for mechlorethamine. Use 4ml 10% sodium thiosulfate + 6ml water and instill via multiple injections in and around the area of extravasation (ie. SQ/ID) using a small gauge needle (eg. 25g).
• Hyaluronidase had been recommended for vinca alkaloids (Vincristine, Vinblastine, and Vinorelbine). Use 150U (1ml) and instill via multiple injections in and around the area of extravasation (ie. SQ/ID) using a small gauge needle (eg. 25g).
• Locally injected corticosteroids --the results have been variable. As few inflammatory cells are involved in extravasation reactions, these reactions may not be inflammatory and would not, hypothetically, benefit from locally injected corticosteroids.
• Locally injected granulocyte macrophage colony-stimulating factor (GM-CSF) has been used to promote healing of doxorubicin ulcerations. It needs more study.
• Pyridoxine has been used to treat mitomycin extravasation, This also needs further study.
• Locally injected saline alone has proven successful in resolving extravasation reactions and preventing ulceration.

While conservative treatment is preferable for most vesicant extravasations, early excision is sometimes favored, especially when the most potent vesicants are involved. Surgical consultation for wide local excision and flap reconstruction is invariably necessary when ulcerations become evident, or if extravasation lesions prove unresponsive to therapy.

For topical therapy, the free-radical scavenger (DMSO) has shown consistent therapeutic success. Use 50-70% solution (1.5ml) and apply topically (ie. "paint" on the skin) QID x 14 days. Leave uncovered. DMSO has been recommended as an antidote for extravasation of Doxorubicin and Daunorubicin as well as Mitomycin. In 1995, an analysis of 96 cumulative patients from multiple studies showed that DMSO protected 98.3% of extravasation cases from ulceration.

Prevention is always the most effective measure in managing extravasation and includes use of a central line or a carefully chosen site of administration.

• The use of a central venous catheter (CVC) or port is recommended for continuous infusion therapies. However, the use of CVC administration does not prevent extravasation injury, since devices may be dislodged, or venous vessels may be perforated with potentially disastrous consequences, including mediastinitis. Thus, central extravasation should be considered in the differential in the presentation of fever, severe pleuritic pain, upper extremity and neck swelling, and a widened mediastinum.
• In the case of peripheral intravenous administration, the selection of sites should be in the order of forearm, dorsal hand, wrist, and antecubital fossae (inner elbow), on the basis of the presence of vital underlying structures. Optimally, vesicants should not be given in areas of recent administration, irradiation, or lymphedema. It is also wise to avoid sites, which are distal to a recent site of venipuncture, as leakage could occur at these sites.

References
Cancer Medicine e.5; by BC Decker Inc. First published 1981. Fifth Edition 2000
Preventing and Managing Peripheral Extravasation; Nursing, May 2004 by Hadaway, Lynn C
What is the appropriate management of tissue extravasation of antitumor agents?; Plastic and Reconstr Surg 75:397-402, 1985 ; Larson DL
Discussion - What is the appropriate management of tissue extravasation of antitumor agents?; Plastic and Reconstr Surg 75:403-405, 1985: Dorr RT