Inadvertent introduction of fluids or drugs meant for IV infusion may produce a variety of responses, varying from mild irritation of local tissues without inflammation to tissue necrosis. Vesicants are agents that can cause blistering, severe tissue injury, or progressive tissue necrosis when extravasated. The volume of the drug and its concentration affect the severity of tissue damage. Irritants are agents that cause aching, tightness, and phlebitis along the vein or at the injection site; irritation may occur with or without inflammation, and these symptoms resolve without causing tissue necrosis. A third type of reaction, flare, is a localized allergic reaction to an agent. Red blotches or streaks appear along the vein, usually without pain at the site.1 Accurately determining the type of reaction helps to determine the appropriate intervention.
Pathophysiology
Tissue damage caused by the extravasation of a vesicant is caused by 1 of 2 mechanisms.2 Infiltration of some vesicants, such as drugs, results in absorption by local tissues and binding to DNA within those cells. As the cells die, the drug is released into surrounding tissue and the destructive process continues widening the area of tissue damage. Non-DNA-binding agents interfere with mitosis, causing cell death. They may cause less tissue damage because they are cleared easier than DNA-binding agents (Table 1). Certain nonantineoplastic agents are also capable of causing extensive skin and soft tissue necrosis when extravasated (Table 1). Regardless of its underlying etiology, tissue necrosis associated with extravasation of a vesicant may require debridement, flap reconstruction, or skin grafting.
Epidemiology
Extravasation of vesicants is uncommon. Its estimated incidence is 0.1-6% of peripheral IV infusions and 0.3-4.7% of implanted venous access port infusions.3,4
Associated and Risk Factors
The risk of extravasation of a vesicant is clearly agent related, but the incidence is also affected by device-related, patient-related, and clinician-related factors.5 Patients at greatest risk for extravasation injuries include the very young or old, patients with impaired venous circulation or lymphatic drainage, impaired sensory perception, or difficulty understanding or communicating discomfort. Device-related factors include metal needles that tend to cause more trauma upon insertion. Similarly, large-gauge catheters are more traumatic to veins and may impede blood flow, slowing dilution of the infused fluid. Poorly secured IV cannulas or catheters may dislodge and traumatize tissue. IVs placed at the antecubital fossa, dorsum of the hand or wrist (rather than the forearm), increase the likelihood functional impairment when extravasation occurs because of tissue destruction and necrosis within the joint itself. Access sites that are surgically placed near a joint or area of movement present a challenge when attempting to secure needles or apply dressings. Short needles that do not reach the base of the port body may dislodge, leading to extravasation and tissue damage. Fibrin sheath formation at the tip of the catheter may impede flow and increase risk. Catheter dysfunction involving port separation, breakage, or dislodgement may allow leakage of drug into tissue. Flushing with a small-gauge syringe adds pressure to potentially weakened devices.
Clinicians must have the necessary knowledge and IV management skills to appropriately manage infusions and adverse reactions such as extravasation. Chemotherapy certification courses and periodic refresher training will maintain competency. Environmental stressors causing interruptions or distractions during vesicant drug administration should be minimized or eliminated.
Prevention
Vesicant extravasation is preventable in most cases. Effective prevention programs require an interdisciplinary approach involving nurses, physicians, and pharmacists. Labeling of vesicants by pharmacy alerts the administering nurse that the infusion contains a potential vesicant. Infusions of less than 60 minutes may be given via peripheral access. Ideally, an IV access site that is less than 24 hours old is selected and a confirmed blood return is demonstrated prior to beginning vesicant administration.5 The muscled area of the forearm is the preferable site for placement of a peripheral IV. If initial venipuncture is unsuccessful, a proximal site should be chosen because infused fluid may leak from holes in the vein that exist above the site of infusion, resulting in extravasation.6 Typically, the site should be assessed every 5 to 10 minutes by checking for blood return, appearance of the insertion site skin, and subjective patient assessment. However, blood return is checked after 2 to 5 mL of fluid is infused if bolus administration occurs via a peripheral IV. Infusions requiring 60 minutes or longer should not use a peripheral IV site.6
Central venous IV access is the preferred route for administration of vesicants. Appropriate placement must be confirmed by chest X-ray prior to usage. The needle must be correctly placed in the septum of an implanted venous access port. Transparent dressings allow visualization of the needle or cannula and the surrounding skin.7 Hourly assessments are recommended when using a central venous catheter.
Patients are informed of the risks of vesicant administration. They should be encouraged to notify the nurse of any change in sensation, leakage, pain, or burning and to try not to disturb the site. During continuous infusions patients can be taught to examine the needle site every 4-8 hours and to report any symptoms or concerns. Twenty-four hour access to a healthcare provider must be assured.8
Management of Extravasation
As noted previously, a variety of local reactions may occur during IV vesicant and extravasation, which must be distinguished from irritant or flare reactions. These latter reactions are usually self-limiting localized hypersensitivity responses. Flare and irritant reactions do not occur during central venous catheter infusions, as the infused fluid dilutes rapidly within the larger central veins. However, if there is any uncertainty as to type of reaction, the infusion should be immediately discontinued and managed as if it were an extravasation reaction.8
Signs and symptoms of extravasation at a peripheral IV site include: (1) sudden swelling; (2) palpable subcutaneous fluid; (3) pain, stinging, or burning at the injection site; (4) absent or minimal loss of blood return; (5) leakage of fluid from the needle insertion site; and (6) slowing or stoppage of the IV flow rate. Similar symptoms are seen with extravasation from tunneled central venous catheters or peripherally inserted central catheters. However, extravasation from a central catheter also may produce a cough, dyspnea, chest pain, or pleural effusion. Later signs and symptoms include localized erythema, inflammation, blanching, induration, vesicle formation, ulceration, and tissue sloughing. Tissue damage may progress for up to 6 months, resulting in impaired function of the affected extremity or even loss of the limb or breast.1,9,10
Once the infusion has been stopped, the IV tubing should be disconnected from the IV device.1 A 1- to 3-mL syringe is then attached to the device to attempt to aspirate residual drug and the physician is notified. If the vesicant is a vinca alkaloid, topoisomerase inhibitor, or micro tubular inhibiting agent, a warm pack is applied for 15 to 20 minutes 4 times daily over a period of 24 to 48 hours. Cold or ice packs should be used if the vesicant is a taxane or antitumor antibiotic following the same schedule. The affected extremity should be elevated to decrease swelling, but pressure should not be applied directly to the site because it may spread the vesicant into surrounding tissues, resulting in more extensive damage.
Treatment
Evidenced-based management strategies are limited to two antidotes that have been utilized for peripheral extravasation.11,12 Sodium thiosulfate in a (0.16 M) solution has been used for the extravasation of mechlorethamine or concentrated cisplatin (>20 mL of 0.5 mg/ml).6 Two milliliters of solution for each 1 mL of mechlorethamine or 100 mg cisplatin should be injected subcutaneously as soon as possible. Hyaluronidase has been shown to be effective for vinca alkaloid or taxane extravasations in animal and human studies.13,14 It modifies connective tissue permeability, enhancing drug resorption from tissue. Lyophilized ovine hyaluronidase is commercially available for the treatment of extravasation.6
Other potentially useful antidotes include dimethyl sulfoxide (DMSO 70-90% solution), dexrazoxane, and growth factors (GM-CSF, G-CSF). Oral dexamethasone has been administrated over a period of 10 to 14 days in an attempt to reduce inflammation caused by oxaliplatin extravasation.15 Topical corticosteroids have been tried, but they have been shown to have no value and may paradoxically cause skin breakdown.16
Savane is a detoxifying agent currently available in Europe that protects tissues from accidental exposure to anthracyclines. The drug acts as a catalytic inhibitor of topoisomerase II, an enzyme found in the nucleus of the cell. Totect is the proposed brand name to be used in the United States; at the time this article was written, the agent is undergoing review for safety and efficacy by the Food and Drug Administration (http://www.pipelinereview.com).
Additional techniques minimize toxicity have been described.17-19 For example, injection of large amounts of sterile normal saline (NS) into extravasation, owing to doxorubicin or vinca alkaloids, has been advocated.18 The NS will dilute the drug and induce localized edema, activation reabsorption, and drug uptake into the bloodstream. A similar "washout" technique has been described by Giunta,19 following vinca alkaloid or anthracycline extravasation. Two or 3 incisions were made in the affected area. Using a large catheter, 300-500 mL of NS was infiltrated into the site. The NS flushed out of the incisions or was withdrawn using a smaller catheter. In the instance of a confirmed norepinephrine extravasation, a similar washout technique was performed via stab incisions and insertion of surgical drains.17
Wound Management
A conservative approach is often best, since only a third of all vesicant extravasations will ulcerate.20 Routine excisional debridement is not warranted. Prompt consultation with the WOC nurse is strongly encouraged at initial evaluation. Serial photography is a useful adjunct to supplement carefully written documentation of wound bed progress from injury to wound healing.
Gentle cleansing and protection from shear or trauma is essential. Intact skin may be protected with a transparent film, and the wound will require a dressing that promotes moist wound healing. Application of sterile amorphous hydrogel applied to the affected area will promote autolytic debridement of slough and necrotic tissue. The gel may also rehydrate damaged or desiccated tissue. Silver sulfadiazine may be applied 1-2 times daily to open or closed bullae (Kusiak JF, personal communication, May 1999.). Frequent monitoring of the wound site should be coordinated with assessment of blood counts on a weekly basis at minimum, especially as the patient approaches drug nadir. If the patient develops neutropenia, topical or systemic antibiotics are begun whenever signs or symptom of infection occur.8
Even though routine debridement is not necessary, prompt consultation with plastic surgery is advised. Early assessment allows the clinician to establish a baseline description of the injury and facilitates planning and timely intervention as the condition of the injury evolves. Physical therapy also may be consulted, especially when joint or limb function is compromised.
Persistent pain, swelling, erythema, blistering, or early necrosis warrants surgical intervention. Extravasation of doxorubicin may cause progressive necrosis as cellular DNA in peripheral layers of tissue continues to take up the drug. Excision of all damaged tissue is necessary and should be considered within 24 hours of extravasation.8 Analysis of frozen section by fluorescence microscopy is a reliable method to delineate doxorubicin extravasation.21 Early debridement with delayed closure using negative pressure wound therapy, biologic dressings, or skin grafting will promote closure of the wound over time.
Summary
The WOC nurse's expertise in assessment and long-term management of extravasation wounds is an essential component of a facility-wide interdisciplinary approach to preventing and managing extravasation of vesicants. Knowledge of the risks and preventive measures provides the foundation for thorough assessment of factors that contribute to an extravasation injury and for the review essential elements of an effective plan for treatment. Knowledge of the detrimental sequelae of extravasation also helps the WOC nurse to influence education and training standards, procedural development, and risk assessment.
In the brief case report provided, Maslovsky describes a 65-year-old male with an extravasation injury caused by a combination of vincristine and doxorubicin infused through peripheral IV access. Management of this case was complicated by the conflicting interventions associated with extravasation of a vinca alkaloid and anthracycline. They approached this complicated situation using a combination of topical dimethylsulfoxide and local cooling. Identifying and incorporating the latest knowledge of alternative treatment options for detoxifying complex extravasation wounds is an essential component to an evidence-based program for preventing and treating extravasation injuries in your facility.
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