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Extravasation Management: Clinical Update
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Seminars in Oncology Nursing, Vol 27, No 1 (February), 2011: pp 82-90
Welcome to Clinical Update, a new addition to Seminars in Oncology Nursing. This Section has been designed to bring you up to date on topics that have proven to be the most popular in terms of online page views and downloads. In future issues, this section will be available online-only at http://www. nursingoncology.com, but it will always be listed on the Contents page to remind you to view it online.
EXTRAVASATION MANAGEMENT: CLINICAL UPDATE LISA SCHULMEISTER OBJECTIVE: To present a clinical update on the prevention, detection, and evidence-based management of vesicant chemotherapy extravasations.
DATA SOURCES: Journal articles, published and unpublished case reports, personal experience.
CONCLUSION: In the 4 years that have elapsed since the publication of the original article, much more is known about vesicant chemotherapy extravasation, and effective evidence-based treatments now are available. The antidotes sodium thiosulfate for mechlorethamine extravasations and hyaluronidase for plant alkaloid extravasations are recommended by the manufacturers of these vesicants and cited in nursing guidelines. The anthracycline extravasation treatment dexrazoxane for injection, the first and only extravasation treatment with proven effectiveness, is now available as Totect (dexrazoxane; TopoTarget USA, Rockaway, NJ, USA) in the US and Savene (SpePharm, Amsterdam, The Netherlands) in Europe.
IMPLICATIONS FOR NURSING PRACTICE: Nurses who administer vesicant chemotherapy agents need to be aware of the most current evidence (or lack of evidence) for various types of extravasation treatment. Well-informed nurses are patient advocates and instrumental in detecting, managing, and documenting extravasations. Most importantly, nurses play a key role in preventing vesicant chemotherapy extravasations. KEY WORDS: Antineoplastic therapy, vesicant extravasation, evidenced-based practice HEMOTHERAPY agents may be classified by their potential to cause tissue necrosis. Vesicants are agents that have the potential to cause blistering, sloughing of the skin, and varying degrees of
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localized tissue damage when they leak into, or are inadvertently administered into, the tissue. Non-vesicants do not impair or destroy the tissue when they infiltrate into the tissue. In oncology practice, the term extravasation is used to
Lisa Schulmeister, MN, APRN-BC, OCNÒ, FAAN: Oncology Nursing Consultant, New Orleans, LA. [This article is a clinical update of the previously published article ‘‘Extravasation Management,’’ which appeared in the August 2007 issue of Seminars in Oncology Nursing. Full citation: Schulmeister L. Extravasation management. Semin Oncol Nurs 2007;23:184-190.]
Address correspondence to Lisa Schulmeister, MN, APRN-BC, OCNÒ, FAAN, 282 Orchard Road, River Ridge, LA 70123-2648. e-mail: LisaSchulmeister@ hotmail.com Ó 2011 Elsevier Inc. All rights reserved. 0749-2081/2701-$36.00/0. doi:10.1016/j.soncn.2010.11.010
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describe the non-intentional administration of vesicant chemotherapy into areas outside of the venous system. Although vesicant extravasation injuries usually occur in the tissue, they may also occur in the mediastinum, lung, and other areas when central venous catheters rupture or migrate outside of a vein. Extravasations also may occur in the muscle when vesicants intended for intravenous (IV) administration are inadvertently given by injection.1,2 Vesicant chemotherapy extravasations have been called a dreaded complication of chemotherapy3 and a preventable catastrophe.4 Extravasations historically have been ineffectively treated and often required surgical intervention, such as debridement and skin grafting. Patients typically required prolonged wound care, often necessitating a delay or discontinuation of their cancer treatment.5 Fortunately, there is now greater knowledge about how vesicant extravasations occur and affect the tissue, and how they may be effectively treated.
TYPES OF VESICANTS Vesicant chemotherapy agents can be divided into two categories, DNA binding and DNA nonbinding (see Table 1). Vesicants that bind to nucleic acids in DNA (eg, anthracyclines) bind to the DNA in the cells of healthy tissue when they extravasate from the vein and promptly cause cell death. DNA-doxorubicin complexes are released from dead cells in the tissue and are taken
TABLE 1. Vesicant Chemotherapy Agents2 Classification DNA binding Alkylating agents Anthracycline antibiotics Other anticancer antibiotics Non-DNA binding Alkylators Plant alkaloids Taxanes a
Examples Mechlorethamine (nitrogen mustard) Bendamustinea Daunorubicin, doxorubicin, epirubicin, idarubicin Dactinomycin, mitomycin, mitoxantrone Amsacrine Vinblastine, vincristine, vindesine, vinorelbine Docetaxel, paclitaxela
Usually classified as irritants but reported to be mild vesicants.
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up by adjacent healthy cells by endocytosis. This process of cellular uptake of extracellular substances sets up a continuing cycle of tissue damage as the anthracycline is retained in the tissue for a long period of time and recirculated in the surrounding area.6,7 Consequently, these extravasation injuries become larger in size, deeper in depth, and more painful over time. Vesicants that do not bind to DNA (eg, plant alkaloids) have an indirect rather a direct effect on the cells in healthy tissue when they extravasate. Non-DNA binding vesicants are eventually metabolized in the tissue and are more easily neutralized than DNA binding agents.2 This type of extravasation injury generally remains localized, is mildly to moderately painful, and improves over time.
INCIDENCE DATA Vesicant extravasations are rare occurrences and no centralized reporting mechanism exists. Although published vesicant extravasation incidence rates range from a high of 6.5%8 (based on a small study conducted in 1979) to a low of 0.01%9 (based on 2002 data from MD Anderson Cancer Center), the true incidence rate is probably closer to the lower end of reported ranges. In order to better track and code extravasations, the Centers for Medicare and Medicaid Services created a new International Classification of Diseases (ICD-9) code, 999.81 extravasation of vesicant chemotherapy, which became effective on October 1, 2009.10 Every patient who receives a vesicant is at risk for extravasation. Because patients typically receive multiple courses of vesicant-containing chemotherapy, they are at risk for extravasation throughout their course of treatment. Although nurses do their best to prevent extravasations from occurring, they unfortunately still may occur.
RISK FACTORS Risk factors for vesicant chemotherapy extravasation have been identified, and patients are at high risk for extravasation when multiple risk factors are present. Prior to initiating a patient’s treatment regimen that contains one or more vesicants, the health care team should consider the planned duration of treatment and review patient
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factors, such as availability of peripheral veins and prior surgery that may limit peripheral venous access. Some patients may be candidates for placement of a central venous access device (VAD), such as an implanted port or Hickman catheter, or may require insertion of a central VAD at some point during treatment. Risk factors for extravasation from peripheral veins include the presence of small and/or fragile veins, obesity that obscures veins from view and palpation, multiple previous venipunctures, presence of disseminated skin diseases (eg, eczema or psoriasis), patient movement, and prior treatment with low pH and caustic drugs, such as chemotherapy. There also may be limited vein availability because of lymph node dissection, lymphedema, limb removal, or other conditions. Sensory deficits that impair the patient’s ability to detect a change in sensation at the site of chemotherapy administration (eg, post-cerebral vascular accident, paralysis) increase the risk that an extravasation, should it occur, may go unnoticed by the patient. Similarly, sedation, somnolence, impaired cognition, and altered mental status impair the patient’s ability to detect and report a change in sensation at the site of vesicant chemotherapy administration.11-14 Probing during IV catheter insertion into a peripheral vein may inadvertently puncture the vein wall, causing the vesicant to seep out into the tissue. The risk of extravasation is increased when vesicants are administered via rigid IV devices, such as steel-winged ‘‘scalp’’ or ‘‘butterfly’’ needles because they can easily puncture the vein on patient movement. Inadequately secured peripheral IV catheters and catheters with wet or loose dressings are at risk for backing out of the vein. When the tip of the catheter is no longer in the vein and a vesicant is administered, an extravasation will occur. Greater tissue damage occurs when vesicants extravasate on the dorsum of the hand, wrist, or antecubital area because there is minimal tissue in these areas and vesicant extravasation will likely cause damage to the underlying veins, arteries, nerve, tendons, and muscle.11-14 Risk factors for extravasation from central VADs include difficulty encountered during insertion of the device, such as probing and inability to advance the guidewire or catheter. Central VAD catheters also can be inadvertently sliced, pierced, or nicked before or during insertion. Device misplacement may occur, with the catheter tip being placed outside of the venous system (eg,
inadvertently placed in the pleural space) instead of the superior vena cava. Catheter migration may also occur, and the catheter tip may migrate from the vein into the tissue. Long dwell time (6 months or longer) increases the risk of extravasation; soft catheter materials are prone to weakening and fracture from ‘‘pinch-off’’ syndrome, which occurs when the catheter is compressed between the clavicle and first or second rib. The risk of extravasation also is increased when a fibrin sheath or thrombus is present at the catheter tip. The fibrin or thrombus may cause vesicant chemotherapy to back-track along the catheter and leak from the vein at the venotomy site.13-15 The risk of extravasation is increased when ports are deeply implanted. Non-coring needles need to be of sufficient length so that they may be securely inserted into the port septum. If a needle is too short or if patient movement causes ‘‘rocking’’ of the non-coring needle, the risk of vesicant extravasation is increased. Risk also is increased when implanted ports are inserted in locations where it is difficult to secure and stabilize the non-coring needle (eg, IV port placed in patient’s abdomen with catheter threaded to the inferior vena cava).15
INITIAL MANAGEMENT When an extravasation occurs or is suspected, the first action is to stop the infusion or discontinue pushing the syringe containing the vesicant. If the vesicant was administered via an implanted port, the non-coring needle should be assessed for correct placement. The affected area should be inspected for skin discoloration and swelling, and palpated for tenderness at rest and on movement. Assessment findings need to be documented in the patient’s medical record (see Table 2). If an extravasation is suspected to have occurred during vesicant administration, the concentration and amount of drug remaining in the syringe or infusion bag should be noted. The amount remaining in an infusion bag should be measured by withdrawing the drug into a syringe, rather than ‘‘eye balling’’ and estimating the amount remaining. Subtracting the amount remaining from the initial volume in the syringe or infusion bag provides a measurement of the maximum amount of vesicant that could have extravasated. Digital photographs are helpful to further document the injury and assess changes over time.12,13
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TABLE 2. Key Elements of Vesicant Extravasation Documentation20 Date and time that extravasation occurred or was suspected Type and size of peripheral venous access device or type of central venous access device and gauge/length of non-coring needle (implanted ports) Location and patency of peripheral or central venous access device Number and location(s) of venipuncture attempts (for peripheral vesicant administration) Description and quality of a blood return prior to and during vesicant administration Vesicant administration technique (eg, bolus, infusion) Concentration and estimated amount of extravasated vesicant Symptoms reported by patient (eg, burning, pain) Description of administration site appearance including measurement of edema and/or redness if present Photographs of administration site that include date and time in the photograph Assessment of extremity (if applicable) for range of motion and discomfort upon movement Immediate nursing interventions (eg, topical cooling or heating, physician notification) Follow-up recommendations (eg, referral to plastic surgery, return appointments) Patient teaching (eg, skin assessment, temperature monitoring, reporting pain)
Local cooling (ice packs) is recommended for extravasations involving DNA binding vesicants.13 Although ice has historically been applied to constrict blood vessels and help prevent the vesicant from spreading to adjacent tissues, it is now known that local cooling does not keep a DNA binding vesicant localized in the tissue, and more likely relieves some of the pain by serving as a nerve conduction block.16 Further, topical cooling should not be used in combination with the systemic anthracycline extravasation antidote dexrazoxane because vasoconstriction will counteract its beneficial effects.17 Local warming (dry heat) is indicated for non-DNA binding vesicants to increase blood flow to the area, which helps distribute the extravasated vesicant and promotes its absorption.13 Management Considerations Every vesicant extravasation is unique. Extravasations of small amounts of non-DNA binding vesicants usually heal without a break in skin integrity ever occurring. In contrast, extravasation of a small amount of a DNA binding vesicant is likely to cause blistering and tissue breakdown
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if it is left untreated. The severity of vesicant extravasation injuries generally is influenced by the type of vesicant that extravasates (eg, DNA binding or non-binding), the concentration and amount of the vesicant in the tissue, and the location of the injury. Vesicant extravasations in areas of flexion, such as the wrist and elbow, or in areas with minimal overlying tissue, such as the dorsum of the hand and wrist, tend to be greater in their severity when compared with extravasation injuries in other areas, such as the forearm. Further, patient factors, such as age, comorbidity (eg, diabetes), and immunocompetence may influence the severity of extravasation injuries and patients’ responses to treatment of these injuries.13,14 Historical Management Vesicant extravasations have historically been treated using various approaches, or combinations of approaches. One of the oldest ways of managing vesicant extravasations is a conservative, or ‘‘watch and wait,’’ approach with or without topical cooling/heating. This approach proved somewhat beneficial for patients with non-DNA binding vesicant extravasations, but for those with DNA binding extravasations, tissue necrosis frequently occurred and subsequently required surgical intervention.18,19 Early surgical intervention was once proposed as an effective treatment for anthracycline extravasations. Anthracyclines are DNA binding agents known to cause significant tissue damage, hence the logic behind early surgical intervention was to remove the involved tissue before it became necrotic or infected. However, not only was it difficult to determine the extent of the vesicant in the tissue in order to achieve clear margins, another issue was the large area of unprotected tissue that remained and required skin grafting or flap procedures. Whether surgical intervention was performed early or later when tissue necrosis occurred did not affect the outcome for these patients; most ultimately required wound management and skin grafting or flap procedures.20 A statement that has been perpetuated in the literature is that surgery is required for one third of all extravasation injuries.3 The original source of this estimate is David Larson, MD, who reviewed extravasation injuries that occurred at MD Anderson Hospital in Houston, TX in the 1980s. He recommended that when an extravasation is suspected, the IV line is removed, ice is intermittently
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applied for 3 days, the wound is observed closely, and no drugs or antidotes are ever given locally. If the patient is asymptomatic by 10 days after the injury, he observed that no other care was usually required. However, if pain persisted or ulceration progressed, the area was debrided and a skin graft was applied 2 to 3 days later. Using this conservative approach, only a third of the patients he studied required surgery. Limitations of his studies include the variety of vesicants that extravasated (both DNA binding and non-binding agents), variations in the concentration and amounts of vesicants extravasated, differences in the sites of extravasation (eg, forearm vs dorsum of the hand), and confounding patient factors (eg, wide range in patient ages, and the presence or absence of comorbidity).21,22 In a study published in 2001 that compared early versus later surgical treatment, all of the 18 patients who were referred later (mean, 22 days after extravasation) required debridement, temporary wound covering, and skin grafting or coverage with a local flap.23 As increasing numbers of patients received vesicants, and new vesicants (eg, epirubicin24 and trabectedin25) were introduced in clinical practice, other approaches to vesicant extravasation treatment emerged. Among these approaches were saline and suction techniques. Scuderi and Onesti26 theorized that locally injecting normal saline solution into extravasation injuries would reduce the concentration of the extravasated drug and facilitate its reabsorption. The doxorubicin extravasation sites of 26 patients treated in Rome, Italy were injected with saline solution in varying amounts depending on the location of injury (20 mL on wrists, 40 mL on dorsum of hands, 60 to 90 mL for forearm and antecubital fossa areas) three to six times daily for 3 days. Pain and erythema resolved within 4 days and superficial ulcerations healed in 10 to 14 days. However, three patients with deep lesions required surgery. Slight variations in the sequencing and technique of combining saline lavage with suction have been reported. In one procedure, the area of doxorubicin extravasation injury is first suctioned and then flushed out with normal saline.27 In a variation of this procedure, a blunt needle is used to pierce the skin, followed by saline lavage and liposuction to remove the instilled saline. The subcutaneous ‘‘shower’’ is proposed to flush out the extravasated vesicant.28-31 The limited success of saline lavage/suction techniques has
been attributed to dilution and removal of extravasated vesicants in the tissues, and the procedure is ideally performed within 6 hours of extravasation injury.30 However, of note is that all of the extravasations in these studies were clinically diagnosed and not biopsy-confirmed. Langer et al18 also note that while repeated lavage and aspiration undoubtedly removes part of the extravasated vesicant, it is a time- and laborconsuming surgical intervention and there will still be the possibility that residual drug will remain in the tissue. Various medications and substances, including some referred to as ‘‘antidotes,’’ have been injected or topically applied to vesicant extravasation injuries. In animal and human studies, as well as anecdotal patient reports, there have been varying degrees of success in using these agents to treat extravasation injuries. Several drugs, such as glucocorticoids, hydrocortisone, antihistamines, sodium bicarbonate, heparin, and lidocaine, have been found to be ineffective in treating extravasation injuries19 The herb ginkgo biloba, alpha-tocopherol (vitamin E), and granulocytemacrophage colony stimulating factor (GM-CSF) were somewhat effective in treating extravasation injuries.12,19 However, in these studies, none of the extravasations were confirmed by biopsy and concurrent treatments were administered, such as systemic or topical antibiotics, which make it difficult to interpret and apply these findings in clinical practice. Dimethyl sulfoxide (DMSO) is a topically applied solvent that increases skin permeability, promotes absorption of extravasated vesicants, and scavenges free radicals. DMSO has been studied in rodents and humans in various amounts, concentrations (50% to 100%), application frequencies (every 2 to 8 hours), duration of treatment (2 to 14 days), and in combination with other treatments (eg, ice, topical creams, and/or systemic antibiotics). Side effects associated with DMSO include mild burning at the site of application and development of a garlic breath odor.32,33 The use of DMSO in the US is limited by its availability; medical-grade DMSO at concentrations greater than 50% are not available.20 Current Management Mechlorethamine and bendamustine extravasation. Mechlorethamine (nitrogen mustard) is a DNA binding vesicant. Sodium thiosulfate is
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indicated for the treatment of mechlorethamine extravasations and is available as a 10% or 25% solution. Although its exact mechanism of action is unknown, sodium thiosulfate is believed to chemically neutralize the reactive alkylating species of mechlorethamine and reduce the production of hydroxyl radicals that cause tissue injury.34 A 1/6 molar solution of thiosulfate is recommended, which can be obtained by mixing 4 mL of 10% sodium thiosulfate with 6 mL of sterile water for injection. Sodium thiosulfate is locally injected into the area of extravasation; 2 mL of the solution are injected for each milligram of mechlorethamine suspected to have extravasated.13 Bendamustine (Treanda; Cephalon, Frazer, PA) is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring that binds to DNA. Although bendamustine is usually classified as an irritant, its manufacturer has received postmarketing reports of bendamustine extravasations resulting in patients being hospitalized for erythema, marked swelling, and pain.35 Plant alkaloid extravasation. Hyaluronidase is a protein enzyme that degrades hyaluronic acid,promotes drug diffusion, and enhances drug absorption. It was found to be effective in preventing plant alkaloid-induced tissue necrosis in an experimental rabbit study and a study of seven patients with plant alkaloid extravasations.36,37 Although hyaluronidase was commercially unavailable from 2001 to 2004, several formulations of hyaluronidase are available. Three are animal-derived products (eg, hyaluronidase [Amphadase, Amphastar Pharmaceuticals, Rancho Cucamonga, CA, USA; Hydase, Akorn, Inc., Buffalo Grove, IL, USA; and Vitrase, ISTA Pharmaceuticals, Irvine, CA, USA]) and the fourth, Hyelenex (Baxter Healthcare Corp., Deerfield, IL, USA), is a purified preparation of the enzyme recombinant human hyaluronidase. Hyaluronidase product selection is based on prescriber preference; some prescribers prefer a recombinant human product over animal-derived products to lessen the likelihood of local injection reactions. Current recommendations are to subcutaneously inject 1 to 6 mL of a 150-U/mL solution into the area of extravasation in a clockwise manner. The usual dose is 1 mL of solution for 1 mL of extravasated drug.38 Liposomal anthracycline extravasation. The liposomal formulations of anthracyclines, such as
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doxorubicin liposome injection (doxorubicin HCl Liposome injection; Doxil, Ben Venue Laboratories, Bedford, OH, USA) and daunorubicin liposome injection (duanorubicin citrate injection, lipid complex; Duanoxome, Gilead Science Inc., San Dimas, CA, USA), are irritants. Their long half-life and liposomal encapsulation are thought to reduce their toxicity. In case reports, infiltration of these drugs caused swelling, skin discoloration, and mild tenderness. Extensive tissue necrosis has not been reported.39,40 If tissue necrosis occurs, a ‘‘mix-up’’ between doxorubicin or daunorubicin and their liposomal formulations should be suspected. Anthracycline extravasation. The anthracyclines daunorubicin, doxorubicin, epirubicin, and idarubicin are DNA binding agents known to cause significant tissue injury when they extravasate and are left untreated. In the past, patients with anthracycline extravasations typically required surgical intervention and wound management, and were sometimes left with permanent disfigurement.8,16 Fortunately, these extravasations can now be effectively treated with dexrazoxane. Dexrazoxane has been used for many years to minimize anthracycline cardiotoxicity and, in 2000, was found to have a protective effect against the development of anthracycline extravasation injuries as well.41 Dexrazoxane binds to iron and prevents the formation of free radicals, which are thought to play a major role in the development of extravasation-induced tissue necrosis. It also binds to DNA topoisomerase II at a different step in the catalytic cycle than anthracyclines and locks the enzyme in a form that is no longer affected by the anthracyclines.42 In animal studies and case reports, dexrazoxane was successful in reducing or eliminating tissue necrosis.41,43 From July 2001 to August 2005, 54 European patients with peripheral anthracycline extravasations verified by fluorescence microscopy were enrolled in two prospective, open-label clinical trials and treated with dexrazoxane. Patients experienced extravasations of doxorubicin or epirubicin and the mean extravasation area was 23.6 cm2 in the first study and 39 cm2 in the second study. All patients received dexrazoxane for 3 consecutive days, with a dose of 1,000 mg/m2 on days 1 and 2, and a dose of 500 mg/m2 on day 3. None of the 18 patients in the first study and only one of the 36 patients in the second study
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had tissue necrosis occur (overall efficacy, 98%) (see Fig. 1). Dexrazoxane must be administered intravenously within 6 hours of an anthracycline extravasation into a large vein in an area away from the extravasation site (eg, opposite arm). Side effects were mild and temporary and include nausea, infusion site reactions, and transient increases in liver enzyme levels.44 Marketing authorization of dexrazoxane (Savene) as a treatment of anthracycline extravasation in Europe was granted by the European Commission in July 2006,45 and Totect received US Food and Drug Administration approval in September 2007.46 Since the introduction of these new agents, clinical reports of the effectiveness of dexrazoxane in maintaining the skin integrity of patients experiencing anthracycline extravasations, including extravasations from central VADs, have been published.47-50
GUIDELINES AND RECOMMENDATIONS The third edition of the Oncology Nursing Society’s Chemotherapy and Biotherapy Guidelines and Recommendations for Practice,13 published in 2009, include the recommendations to treat anthracycline extravasations with Totect, administer the antidote sodium thiosulfate when mechlorethamine extravasations occur, and administer the antidote hyaluronidase when plant alkaloid extravasations occur. Use of topical DMSO as an extravasation antidote or treatment is not recommended.
FIGURE 1. Anthracycline extravasation before and after treatment with dexrazoxane. The small marks on the patient’s hand in the post-treatment photograph represent the sites where punch biopsies were obtained to verify that an extravasation had occurred. (Reprinted with permissions. Ó TopoTarget, Rockaway, NJ.)
The European Oncology Nursing Society (EONS) published extravasation guidelines in four languages in 2007.51,52 Savene is recommended for anthracycline extravasation treatment. Sodium
TABLE 3. Vesicant Chemotherapy Extravasation Antidotes and Treatments* Agent Extravasated
Antidote/Treatment
Guidelines for Use
Mechlorethamine
Sodium thiosulfate
Plant alkaloids
Hyaluronidase
Anthracyclines
Dexrazoxane
To prepare a 1/6 molar solution, mix 4 mL of 10% sodium thiosulfate with 6 mL of sterile water for injection. Inject 2 mL of solution for each milligram of mechlorethamine suspected to have extravasated.13,34 Inject 1 to 6 mL of 150 U/mL solution through the existing IV line; if IV device has been removed, inject subcutaneously in a clockwise manner. Usual dose is 1 mL of solution for 1 mL of extravasated drug.13,37,38 Administer intravenously in a vein in an area away from the extravasation site (eg, opposite arm). Infuse 1,000 mg/m2 within 6 hours of extravasation on day 1, 1,000 mg/m2 on day 2, and 500 mg/m2 on day 3. Maximum daily dose is 2,000 mg. Dose should be reduced 50% in patients with creatinine clearance values <40 mL/min. DMSO should not be applied and topical cooling (eg, ice packs) should be removed 15 minutes before, and during, administration.44,46
*See package insert of each drug for full prescribing information.
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thiosulfate is not recommended for mechlorethamine extravasations ‘‘due to lack of evidence’’; however, further rationale for this recommendation is not discussed in the EONS guidelines. Hyaluronidase is ‘‘suggested as a possible antidote in many literature sources’’ and ‘‘due to lack of evidence it is recommended that this is further studied.’’ Topical DMSO (99% solution) is ‘‘suggested as a possible antidote for anthracycline and mitomycin C extravasations in many literature sources’’ and ‘‘due to lack of evidence it is recommended that it is further studied.’’ The United Kingdom Oncology Nursing Society adapted the EONS guidelines and published Anthracycline Extravasation Management Guidelines in January 2008.53 Savene is recommended for anthracycline extravasations exceeding 1.5 mL, with ‘‘volumes based on clinical judgment.’’ The American Society of Clinical Oncology (ASCO), European Society for Medical Oncology, Hematology/Oncology Pharmacy Association, International Society of Oncology Pharmacy Practitioners, Multinational Association of Supportive Care in Cancer, and National Comprehensive
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Cancer Network have, to date, not developed or published vesicant chemotherapy extravasation management guidelines or recommendations.54 However, extravasation management is now one of the ASCO/ONS chemotherapy administration safety standards.55
CONCLUSION This clinical update reviews the most current information on vesicant chemotherapy extravasation management available in October 2010 (see Table 3). Advances in treatment include the availability of hyaluronidase for treating plant alkaloid extravasations and the introduction and approval of dexrazoxane for anthracycline extravasation treatment. Updated guidelines from professional organizations have been published, and these can be used to guide the review and updating of institutional policies and procedures. Because nurses administer chemotherapy, they are on the forefront of detecting vesicant extravasations, and must be prepared to promptly implement evidence-based treatment.
REFERENCES 1. Bozkurt AK, Uzel B, Akman C, et al. Intrathoracic extravasation of antineoplastic agents: case report and systematic review. Am J Clin Oncol 2003;26:121-123. 2. Ener RA, Meglathery SB, Styler M. Extravasation of systemic hemato-oncological therapies. Ann Oncol 2004;15:858-862. 3. Schrijvers DL. Extravasation: a dreaded complication of chemotherapy. Ann Oncol 2003;14(suppl 3):26-30. 4. Thakur JS, Chauhan GS, Diwana VK, et al. Extravasational side effects of cytotoxic drugs: a preventable catastrophe. Indian J Plast Surg 2008;41:145-150. 5. Schulmeister L. Managing vesicant extravasations. The Oncologist 2008;13:284-288. 6. Cox RF. Managing skin damage induced by doxorubicin hydrochloride and daunorubicin hydrochloride. Am J Hosp Pharm 1984;41:2410-2414. 7. Luedke DW, Kennedy PS, Rietschel RL. Histopathogenesis of skin and subcutaneous injury induced by adriamycin. Plas Reconstr Surg 1979;63:463-465. 8. Barlock AL, Howser DM, Hubbard SM. Nursing management of adriamycin extravasation. Am J Nurs 1979;79: 94-96. 9. Langstein HN, Duman H, Seelig D, et al. Retrospective study of the management of chemotherapeutic extravasation injury. Ann Plast Surg 2002;49:369-374. 10. ICD-9-CM Index to diseases addenda (FY10). Available at: http://www.cdc.gov/nchs/data/icd9/icdidx10add (2).pdf. (accessed Sept 2, 2010). 11. Doellman D, Hadaway L, Bowe-Geddes LA, et al. Infiltration and extravasation: update on prevention and management. J Infus Nurs 2009;32:203-211.
12. Goolsby TV, Lombardo FA. Extravasation of chemotherapeutic agents: prevention and treatment. Semin Oncol 2006;33:139-143. 13. Polovich M, Whitford JM, Olsen M. Chemotherapy and biotherapy guidelines and recommendations for practice. Ed 3. Pittsburgh, PA: Oncology Nursing Society; 2009. 14. Sauerland C, Engelking C, Wickham R, et al. Vesicant extravasation part I: mechanisms, pathogenesis, and nursing care to reduce risk. Oncol Nurs Forum 2006;33: 1134-1141. 15. Schulmeister L, Camp-Sorrell D. Extravasations from implanted ports. Oncol Nurs Forum 2000;27:531-540. 16. Schulmeister L. Vesicant chemotherapy—the management of extravasation. Cancer Nurs Pract 2009;8:34-37. 17. Langer SW. Dexrazoxane for anthracycline extravasation. Expert Rev Anticancer Ther 2007;7:1081-1088. 18. Langer SW, Sehested M, Jensen PB. Anthracycline extravasation: a comprehensive review of experimental and clinical treatments. Tumori 2009;95:273-282. 19. Wickham R, Engelking C, Sauerland C, et al. Vesicant extravasation part II: evidence-based management and continuing controversies. Oncol Nurs Forum 2006;33:11431150. 20. Schulmeister L. Extravasation management. Semin Oncol Nurs 2007;23:184-190. 21. Larson DL. What is the appropriate management of tissue extravasation by antitumor agents? Plastic Reconstr Surg 1985;75:397-405. 22. Larson DL. Treatment of tissue extravasation by antitumor agents. Cancer 1982;49:1796-1799.
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23. Cedidi C, Hierner R, Berger A. Plastic surgical management in tissue extravasation of cytotoxic agents in the upper extremity. Eur J Med Res 2001;6:309-314. 24. Vano-Galvan S, Jaen P. Extravasation of epirubicin. N Engl J Med 2009;360:2117. 25. Theman TA, Hartzell TL, Sinha I, et al. Recognition of a new chemotherapeutic vesicant: trabectedin (ecteinascidin743) extravasation with skin and soft tissue damage. J Clin Oncol 2009;27:e198-e200. 26. Scuderi N, Onesti MG. Antitumor agents: extravasation, management, and surgical treatment. Ann Plast Surg 1994;32:39-44. 27. Vandeweyer E, Deraemaecker R. Early surgical suction and washout for treatment of cytotoxic drug extravasations. Acta Chir Belg 1994;100:37-38. 28. Fleming A, Butler B, Gault D. Letter to the editor in response to ‘‘Surgical management after doxorubicin and epirubicin extravasation.’’ J Hand Surg [Br] 1998;24:390. 29. Gault DT. Extravasation injuries. Br J Plast Surg 1993;46:91-96. 30. Giunta R. Early subcutaneous wash-out in acute extravasations. Ann Oncol 2004;15:1146. 31. Van Wijck R. Liposuction to the radiologist’s rescue. Plast Reconstr Surg 1993;92:175. 32. Bertelli G, Gozza A, Forno GB, et al. Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: a prospective clinical study. J Clin Oncol 1995;13:2851-2855. 33. Olver IN, Aisner J, Hament A, et al. A prospective study of topical dimethyl sulfoxide for treating anthracycline extravasation. J Clin Oncol 1988;6:1732-1735. 34. Dorr RT, Soble M, Alberts DS. Efficacy of sodium thiosulfate as a local antidote to mechlorethamine skin toxicity. Cancer Chemother Pharmacol 1988;22:299-302. 35. Treanda (bendamustine HCl for injection) [package insert]. Cephalon, Frazer, PA. 2008. Available at: http://www.treanda.com/ docs/TREANDA_final_PI.pdf. (accessed Sept 7, 2010). 36. Bertelli G, Dini D, Forno BG, et al. Hyaluronidase as an antidote to extravasation of vinca alkaloids: clinical results. J Cancer Res Clin Oncol 1994;120:505-506. 37. Laurie SW, Wilson KL, Kernahan DA, et al. Intravenous extravasation injuries: the effectiveness of hyaluronidase in their treatment. Ann Plast Surg 1984;13:191-194. 38. Schulmeister L. Vesicant chemotherapy extravasation antidotes and treatments. Clin J Oncol Nurs 2009;13:395-398. 39. Madhavan S, Northfelt DW. Lack of vesicant injury following extravasation of liposomal doxorubicin. J Natl Cancer Inst 1995;87:1556-1557. 40. Laufman LR, Sickle-Santanello B, Paquelet J. Liposomal doxorubicin extravasation. Commun Oncol 2007;4:464-465.
41. Langer SW, Sehested M, Jensen PB. Treatment of anthracycline extravasation with dexrazoxane. Clin Cancer Res 2000;6:3680-3686. 42. Hasinoff BB. The use of dexrazoxane for the prevention of anthracycline extravasation injury. Expert Opin Investig Drugs 2008;17:217-223. 43. Langer SW, Sehested M, Jensen PB. Dexrazoxane is a potent and specific inhibitor of anthracycline induced subcutaneous lesions in mice. Ann Oncol 2000;12:405-410. 44. Mouridsen HT, Langer SW, Buter J, et al. Treatment of anthracycline extravasation with Savene (dexrazoxane). Results from two prospective clinical multicenter studies. Ann Oncol 2006;18:546-550. 45. Langer SW, Jensen PB, Sehested M. Other uses of dexrazoxane: Savene, the first proven antidote against anthracycline injuries. Cardiovasc Toxicol 2007;7:151-153. 46. Kane RC, McGuinn WDJ, Dagher R, et al. Dexrazoxane (Totect): FDA review and approval for the treatment of accidental extravasation following intravenous anthracycline chemotherapy. Oncologist 2008;13:445-450. 47. Frost A, Gmehling D, Azemar M, et al. Treatment of anthracycline extravasation with dexrazoxane—clinical experience. Onkologie 2006;29:314-318. 48. H€ unerlit€ urkoglou C, Tapprich C, Langer SW, et al. Successful use of dexrazoxane in two cases of extravasation of anthracycline containing polychemotherapy. Eur J Clin Med Oncol 2009;1:13-16. 49. Langer SW. Treatment of anthracycline extravasation from centrally inserted venous catheters. Oncol Rev 2008;2:114-116. 50. Uges JW, Vollaard AM, Wilms EB, et al. Intrapleural extravasation of epirubicin, 5-fluouracil, and cyclophosphamide, treated with dexrazoxane. Int J Clin Oncol 2006;11: 467-470. 51. Extravasation guidelines 2007. Available at: http://www. cancernurse.eu/documents/EONSClinicalGuidelinesPostSymp osiumReport.pdf. (accessed Sept 5, 2010). 52. Wengstr€ om Y, Margulies A. European Oncology Nursing Society extravasation guidelines. Eur J Oncol Nurs 2008;12:357-361. 53. UKONS anthracycline extravasation management guidelines. London, UK: United Kingdom Oncology Nursing Society; 2008. 54. Morganstern D, Held-Warmkessel J. Survey of practice guidelines for management of anthracycline extravasation (ae) [abstract]. Support Care Cancer 2008;16:755. 55. Jacobsen JO, Polovich M, McNiff KK, et al. American Society of Clinical Oncology/Oncology Nursing Society chemotherapy administration safety standards. Oncol Nurs Forum 2009;36:651-658.
Seminars in Oncology Nursing, Vol 27, No 1 (February), 2011: pp 82-90
Welcome to Clinical Update, a new addition to Seminars in Oncology Nursing. This Section has been designed to bring you up to date on topics that have proven to be the most popular in terms of online page views and downloads. In future issues, this section will be available online-only at http://www. nursingoncology.com, but it will always be listed on the Contents page to remind you to view it online.
EXTRAVASATION MANAGEMENT: CLINICAL UPDATE LISA SCHULMEISTER OBJECTIVE: To present a clinical update on the prevention, detection, and evidence-based management of vesicant chemotherapy extravasations.
DATA SOURCES: Journal articles, published and unpublished case reports, personal experience.
CONCLUSION: In the 4 years that have elapsed since the publication of the original article, much more is known about vesicant chemotherapy extravasation, and effective evidence-based treatments now are available. The antidotes sodium thiosulfate for mechlorethamine extravasations and hyaluronidase for plant alkaloid extravasations are recommended by the manufacturers of these vesicants and cited in nursing guidelines. The anthracycline extravasation treatment dexrazoxane for injection, the first and only extravasation treatment with proven effectiveness, is now available as Totect (dexrazoxane; TopoTarget USA, Rockaway, NJ, USA) in the US and Savene (SpePharm, Amsterdam, The Netherlands) in Europe.
IMPLICATIONS FOR NURSING PRACTICE: Nurses who administer vesicant chemotherapy agents need to be aware of the most current evidence (or lack of evidence) for various types of extravasation treatment. Well-informed nurses are patient advocates and instrumental in detecting, managing, and documenting extravasations. Most importantly, nurses play a key role in preventing vesicant chemotherapy extravasations. KEY WORDS: Antineoplastic therapy, vesicant extravasation, evidenced-based practice HEMOTHERAPY agents may be classified by their potential to cause tissue necrosis. Vesicants are agents that have the potential to cause blistering, sloughing of the skin, and varying degrees of
C
localized tissue damage when they leak into, or are inadvertently administered into, the tissue. Non-vesicants do not impair or destroy the tissue when they infiltrate into the tissue. In oncology practice, the term extravasation is used to
Lisa Schulmeister, MN, APRN-BC, OCNÒ, FAAN: Oncology Nursing Consultant, New Orleans, LA. [This article is a clinical update of the previously published article ‘‘Extravasation Management,’’ which appeared in the August 2007 issue of Seminars in Oncology Nursing. Full citation: Schulmeister L. Extravasation management. Semin Oncol Nurs 2007;23:184-190.]
Address correspondence to Lisa Schulmeister, MN, APRN-BC, OCNÒ, FAAN, 282 Orchard Road, River Ridge, LA 70123-2648. e-mail: LisaSchulmeister@ hotmail.com Ó 2011 Elsevier Inc. All rights reserved. 0749-2081/2701-$36.00/0. doi:10.1016/j.soncn.2010.11.010
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describe the non-intentional administration of vesicant chemotherapy into areas outside of the venous system. Although vesicant extravasation injuries usually occur in the tissue, they may also occur in the mediastinum, lung, and other areas when central venous catheters rupture or migrate outside of a vein. Extravasations also may occur in the muscle when vesicants intended for intravenous (IV) administration are inadvertently given by injection.1,2 Vesicant chemotherapy extravasations have been called a dreaded complication of chemotherapy3 and a preventable catastrophe.4 Extravasations historically have been ineffectively treated and often required surgical intervention, such as debridement and skin grafting. Patients typically required prolonged wound care, often necessitating a delay or discontinuation of their cancer treatment.5 Fortunately, there is now greater knowledge about how vesicant extravasations occur and affect the tissue, and how they may be effectively treated.
TYPES OF VESICANTS Vesicant chemotherapy agents can be divided into two categories, DNA binding and DNA nonbinding (see Table 1). Vesicants that bind to nucleic acids in DNA (eg, anthracyclines) bind to the DNA in the cells of healthy tissue when they extravasate from the vein and promptly cause cell death. DNA-doxorubicin complexes are released from dead cells in the tissue and are taken
TABLE 1. Vesicant Chemotherapy Agents2 Classification DNA binding Alkylating agents Anthracycline antibiotics Other anticancer antibiotics Non-DNA binding Alkylators Plant alkaloids Taxanes a
Examples Mechlorethamine (nitrogen mustard) Bendamustinea Daunorubicin, doxorubicin, epirubicin, idarubicin Dactinomycin, mitomycin, mitoxantrone Amsacrine Vinblastine, vincristine, vindesine, vinorelbine Docetaxel, paclitaxela
Usually classified as irritants but reported to be mild vesicants.
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up by adjacent healthy cells by endocytosis. This process of cellular uptake of extracellular substances sets up a continuing cycle of tissue damage as the anthracycline is retained in the tissue for a long period of time and recirculated in the surrounding area.6,7 Consequently, these extravasation injuries become larger in size, deeper in depth, and more painful over time. Vesicants that do not bind to DNA (eg, plant alkaloids) have an indirect rather a direct effect on the cells in healthy tissue when they extravasate. Non-DNA binding vesicants are eventually metabolized in the tissue and are more easily neutralized than DNA binding agents.2 This type of extravasation injury generally remains localized, is mildly to moderately painful, and improves over time.
INCIDENCE DATA Vesicant extravasations are rare occurrences and no centralized reporting mechanism exists. Although published vesicant extravasation incidence rates range from a high of 6.5%8 (based on a small study conducted in 1979) to a low of 0.01%9 (based on 2002 data from MD Anderson Cancer Center), the true incidence rate is probably closer to the lower end of reported ranges. In order to better track and code extravasations, the Centers for Medicare and Medicaid Services created a new International Classification of Diseases (ICD-9) code, 999.81 extravasation of vesicant chemotherapy, which became effective on October 1, 2009.10 Every patient who receives a vesicant is at risk for extravasation. Because patients typically receive multiple courses of vesicant-containing chemotherapy, they are at risk for extravasation throughout their course of treatment. Although nurses do their best to prevent extravasations from occurring, they unfortunately still may occur.
RISK FACTORS Risk factors for vesicant chemotherapy extravasation have been identified, and patients are at high risk for extravasation when multiple risk factors are present. Prior to initiating a patient’s treatment regimen that contains one or more vesicants, the health care team should consider the planned duration of treatment and review patient
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factors, such as availability of peripheral veins and prior surgery that may limit peripheral venous access. Some patients may be candidates for placement of a central venous access device (VAD), such as an implanted port or Hickman catheter, or may require insertion of a central VAD at some point during treatment. Risk factors for extravasation from peripheral veins include the presence of small and/or fragile veins, obesity that obscures veins from view and palpation, multiple previous venipunctures, presence of disseminated skin diseases (eg, eczema or psoriasis), patient movement, and prior treatment with low pH and caustic drugs, such as chemotherapy. There also may be limited vein availability because of lymph node dissection, lymphedema, limb removal, or other conditions. Sensory deficits that impair the patient’s ability to detect a change in sensation at the site of chemotherapy administration (eg, post-cerebral vascular accident, paralysis) increase the risk that an extravasation, should it occur, may go unnoticed by the patient. Similarly, sedation, somnolence, impaired cognition, and altered mental status impair the patient’s ability to detect and report a change in sensation at the site of vesicant chemotherapy administration.11-14 Probing during IV catheter insertion into a peripheral vein may inadvertently puncture the vein wall, causing the vesicant to seep out into the tissue. The risk of extravasation is increased when vesicants are administered via rigid IV devices, such as steel-winged ‘‘scalp’’ or ‘‘butterfly’’ needles because they can easily puncture the vein on patient movement. Inadequately secured peripheral IV catheters and catheters with wet or loose dressings are at risk for backing out of the vein. When the tip of the catheter is no longer in the vein and a vesicant is administered, an extravasation will occur. Greater tissue damage occurs when vesicants extravasate on the dorsum of the hand, wrist, or antecubital area because there is minimal tissue in these areas and vesicant extravasation will likely cause damage to the underlying veins, arteries, nerve, tendons, and muscle.11-14 Risk factors for extravasation from central VADs include difficulty encountered during insertion of the device, such as probing and inability to advance the guidewire or catheter. Central VAD catheters also can be inadvertently sliced, pierced, or nicked before or during insertion. Device misplacement may occur, with the catheter tip being placed outside of the venous system (eg,
inadvertently placed in the pleural space) instead of the superior vena cava. Catheter migration may also occur, and the catheter tip may migrate from the vein into the tissue. Long dwell time (6 months or longer) increases the risk of extravasation; soft catheter materials are prone to weakening and fracture from ‘‘pinch-off’’ syndrome, which occurs when the catheter is compressed between the clavicle and first or second rib. The risk of extravasation also is increased when a fibrin sheath or thrombus is present at the catheter tip. The fibrin or thrombus may cause vesicant chemotherapy to back-track along the catheter and leak from the vein at the venotomy site.13-15 The risk of extravasation is increased when ports are deeply implanted. Non-coring needles need to be of sufficient length so that they may be securely inserted into the port septum. If a needle is too short or if patient movement causes ‘‘rocking’’ of the non-coring needle, the risk of vesicant extravasation is increased. Risk also is increased when implanted ports are inserted in locations where it is difficult to secure and stabilize the non-coring needle (eg, IV port placed in patient’s abdomen with catheter threaded to the inferior vena cava).15
INITIAL MANAGEMENT When an extravasation occurs or is suspected, the first action is to stop the infusion or discontinue pushing the syringe containing the vesicant. If the vesicant was administered via an implanted port, the non-coring needle should be assessed for correct placement. The affected area should be inspected for skin discoloration and swelling, and palpated for tenderness at rest and on movement. Assessment findings need to be documented in the patient’s medical record (see Table 2). If an extravasation is suspected to have occurred during vesicant administration, the concentration and amount of drug remaining in the syringe or infusion bag should be noted. The amount remaining in an infusion bag should be measured by withdrawing the drug into a syringe, rather than ‘‘eye balling’’ and estimating the amount remaining. Subtracting the amount remaining from the initial volume in the syringe or infusion bag provides a measurement of the maximum amount of vesicant that could have extravasated. Digital photographs are helpful to further document the injury and assess changes over time.12,13
EXTRAVASATION MANAGEMENT: CLINICAL UPDATE
TABLE 2. Key Elements of Vesicant Extravasation Documentation20 Date and time that extravasation occurred or was suspected Type and size of peripheral venous access device or type of central venous access device and gauge/length of non-coring needle (implanted ports) Location and patency of peripheral or central venous access device Number and location(s) of venipuncture attempts (for peripheral vesicant administration) Description and quality of a blood return prior to and during vesicant administration Vesicant administration technique (eg, bolus, infusion) Concentration and estimated amount of extravasated vesicant Symptoms reported by patient (eg, burning, pain) Description of administration site appearance including measurement of edema and/or redness if present Photographs of administration site that include date and time in the photograph Assessment of extremity (if applicable) for range of motion and discomfort upon movement Immediate nursing interventions (eg, topical cooling or heating, physician notification) Follow-up recommendations (eg, referral to plastic surgery, return appointments) Patient teaching (eg, skin assessment, temperature monitoring, reporting pain)
Local cooling (ice packs) is recommended for extravasations involving DNA binding vesicants.13 Although ice has historically been applied to constrict blood vessels and help prevent the vesicant from spreading to adjacent tissues, it is now known that local cooling does not keep a DNA binding vesicant localized in the tissue, and more likely relieves some of the pain by serving as a nerve conduction block.16 Further, topical cooling should not be used in combination with the systemic anthracycline extravasation antidote dexrazoxane because vasoconstriction will counteract its beneficial effects.17 Local warming (dry heat) is indicated for non-DNA binding vesicants to increase blood flow to the area, which helps distribute the extravasated vesicant and promotes its absorption.13 Management Considerations Every vesicant extravasation is unique. Extravasations of small amounts of non-DNA binding vesicants usually heal without a break in skin integrity ever occurring. In contrast, extravasation of a small amount of a DNA binding vesicant is likely to cause blistering and tissue breakdown
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if it is left untreated. The severity of vesicant extravasation injuries generally is influenced by the type of vesicant that extravasates (eg, DNA binding or non-binding), the concentration and amount of the vesicant in the tissue, and the location of the injury. Vesicant extravasations in areas of flexion, such as the wrist and elbow, or in areas with minimal overlying tissue, such as the dorsum of the hand and wrist, tend to be greater in their severity when compared with extravasation injuries in other areas, such as the forearm. Further, patient factors, such as age, comorbidity (eg, diabetes), and immunocompetence may influence the severity of extravasation injuries and patients’ responses to treatment of these injuries.13,14 Historical Management Vesicant extravasations have historically been treated using various approaches, or combinations of approaches. One of the oldest ways of managing vesicant extravasations is a conservative, or ‘‘watch and wait,’’ approach with or without topical cooling/heating. This approach proved somewhat beneficial for patients with non-DNA binding vesicant extravasations, but for those with DNA binding extravasations, tissue necrosis frequently occurred and subsequently required surgical intervention.18,19 Early surgical intervention was once proposed as an effective treatment for anthracycline extravasations. Anthracyclines are DNA binding agents known to cause significant tissue damage, hence the logic behind early surgical intervention was to remove the involved tissue before it became necrotic or infected. However, not only was it difficult to determine the extent of the vesicant in the tissue in order to achieve clear margins, another issue was the large area of unprotected tissue that remained and required skin grafting or flap procedures. Whether surgical intervention was performed early or later when tissue necrosis occurred did not affect the outcome for these patients; most ultimately required wound management and skin grafting or flap procedures.20 A statement that has been perpetuated in the literature is that surgery is required for one third of all extravasation injuries.3 The original source of this estimate is David Larson, MD, who reviewed extravasation injuries that occurred at MD Anderson Hospital in Houston, TX in the 1980s. He recommended that when an extravasation is suspected, the IV line is removed, ice is intermittently
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applied for 3 days, the wound is observed closely, and no drugs or antidotes are ever given locally. If the patient is asymptomatic by 10 days after the injury, he observed that no other care was usually required. However, if pain persisted or ulceration progressed, the area was debrided and a skin graft was applied 2 to 3 days later. Using this conservative approach, only a third of the patients he studied required surgery. Limitations of his studies include the variety of vesicants that extravasated (both DNA binding and non-binding agents), variations in the concentration and amounts of vesicants extravasated, differences in the sites of extravasation (eg, forearm vs dorsum of the hand), and confounding patient factors (eg, wide range in patient ages, and the presence or absence of comorbidity).21,22 In a study published in 2001 that compared early versus later surgical treatment, all of the 18 patients who were referred later (mean, 22 days after extravasation) required debridement, temporary wound covering, and skin grafting or coverage with a local flap.23 As increasing numbers of patients received vesicants, and new vesicants (eg, epirubicin24 and trabectedin25) were introduced in clinical practice, other approaches to vesicant extravasation treatment emerged. Among these approaches were saline and suction techniques. Scuderi and Onesti26 theorized that locally injecting normal saline solution into extravasation injuries would reduce the concentration of the extravasated drug and facilitate its reabsorption. The doxorubicin extravasation sites of 26 patients treated in Rome, Italy were injected with saline solution in varying amounts depending on the location of injury (20 mL on wrists, 40 mL on dorsum of hands, 60 to 90 mL for forearm and antecubital fossa areas) three to six times daily for 3 days. Pain and erythema resolved within 4 days and superficial ulcerations healed in 10 to 14 days. However, three patients with deep lesions required surgery. Slight variations in the sequencing and technique of combining saline lavage with suction have been reported. In one procedure, the area of doxorubicin extravasation injury is first suctioned and then flushed out with normal saline.27 In a variation of this procedure, a blunt needle is used to pierce the skin, followed by saline lavage and liposuction to remove the instilled saline. The subcutaneous ‘‘shower’’ is proposed to flush out the extravasated vesicant.28-31 The limited success of saline lavage/suction techniques has
been attributed to dilution and removal of extravasated vesicants in the tissues, and the procedure is ideally performed within 6 hours of extravasation injury.30 However, of note is that all of the extravasations in these studies were clinically diagnosed and not biopsy-confirmed. Langer et al18 also note that while repeated lavage and aspiration undoubtedly removes part of the extravasated vesicant, it is a time- and laborconsuming surgical intervention and there will still be the possibility that residual drug will remain in the tissue. Various medications and substances, including some referred to as ‘‘antidotes,’’ have been injected or topically applied to vesicant extravasation injuries. In animal and human studies, as well as anecdotal patient reports, there have been varying degrees of success in using these agents to treat extravasation injuries. Several drugs, such as glucocorticoids, hydrocortisone, antihistamines, sodium bicarbonate, heparin, and lidocaine, have been found to be ineffective in treating extravasation injuries19 The herb ginkgo biloba, alpha-tocopherol (vitamin E), and granulocytemacrophage colony stimulating factor (GM-CSF) were somewhat effective in treating extravasation injuries.12,19 However, in these studies, none of the extravasations were confirmed by biopsy and concurrent treatments were administered, such as systemic or topical antibiotics, which make it difficult to interpret and apply these findings in clinical practice. Dimethyl sulfoxide (DMSO) is a topically applied solvent that increases skin permeability, promotes absorption of extravasated vesicants, and scavenges free radicals. DMSO has been studied in rodents and humans in various amounts, concentrations (50% to 100%), application frequencies (every 2 to 8 hours), duration of treatment (2 to 14 days), and in combination with other treatments (eg, ice, topical creams, and/or systemic antibiotics). Side effects associated with DMSO include mild burning at the site of application and development of a garlic breath odor.32,33 The use of DMSO in the US is limited by its availability; medical-grade DMSO at concentrations greater than 50% are not available.20 Current Management Mechlorethamine and bendamustine extravasation. Mechlorethamine (nitrogen mustard) is a DNA binding vesicant. Sodium thiosulfate is
EXTRAVASATION MANAGEMENT: CLINICAL UPDATE
indicated for the treatment of mechlorethamine extravasations and is available as a 10% or 25% solution. Although its exact mechanism of action is unknown, sodium thiosulfate is believed to chemically neutralize the reactive alkylating species of mechlorethamine and reduce the production of hydroxyl radicals that cause tissue injury.34 A 1/6 molar solution of thiosulfate is recommended, which can be obtained by mixing 4 mL of 10% sodium thiosulfate with 6 mL of sterile water for injection. Sodium thiosulfate is locally injected into the area of extravasation; 2 mL of the solution are injected for each milligram of mechlorethamine suspected to have extravasated.13 Bendamustine (Treanda; Cephalon, Frazer, PA) is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring that binds to DNA. Although bendamustine is usually classified as an irritant, its manufacturer has received postmarketing reports of bendamustine extravasations resulting in patients being hospitalized for erythema, marked swelling, and pain.35 Plant alkaloid extravasation. Hyaluronidase is a protein enzyme that degrades hyaluronic acid,promotes drug diffusion, and enhances drug absorption. It was found to be effective in preventing plant alkaloid-induced tissue necrosis in an experimental rabbit study and a study of seven patients with plant alkaloid extravasations.36,37 Although hyaluronidase was commercially unavailable from 2001 to 2004, several formulations of hyaluronidase are available. Three are animal-derived products (eg, hyaluronidase [Amphadase, Amphastar Pharmaceuticals, Rancho Cucamonga, CA, USA; Hydase, Akorn, Inc., Buffalo Grove, IL, USA; and Vitrase, ISTA Pharmaceuticals, Irvine, CA, USA]) and the fourth, Hyelenex (Baxter Healthcare Corp., Deerfield, IL, USA), is a purified preparation of the enzyme recombinant human hyaluronidase. Hyaluronidase product selection is based on prescriber preference; some prescribers prefer a recombinant human product over animal-derived products to lessen the likelihood of local injection reactions. Current recommendations are to subcutaneously inject 1 to 6 mL of a 150-U/mL solution into the area of extravasation in a clockwise manner. The usual dose is 1 mL of solution for 1 mL of extravasated drug.38 Liposomal anthracycline extravasation. The liposomal formulations of anthracyclines, such as
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doxorubicin liposome injection (doxorubicin HCl Liposome injection; Doxil, Ben Venue Laboratories, Bedford, OH, USA) and daunorubicin liposome injection (duanorubicin citrate injection, lipid complex; Duanoxome, Gilead Science Inc., San Dimas, CA, USA), are irritants. Their long half-life and liposomal encapsulation are thought to reduce their toxicity. In case reports, infiltration of these drugs caused swelling, skin discoloration, and mild tenderness. Extensive tissue necrosis has not been reported.39,40 If tissue necrosis occurs, a ‘‘mix-up’’ between doxorubicin or daunorubicin and their liposomal formulations should be suspected. Anthracycline extravasation. The anthracyclines daunorubicin, doxorubicin, epirubicin, and idarubicin are DNA binding agents known to cause significant tissue injury when they extravasate and are left untreated. In the past, patients with anthracycline extravasations typically required surgical intervention and wound management, and were sometimes left with permanent disfigurement.8,16 Fortunately, these extravasations can now be effectively treated with dexrazoxane. Dexrazoxane has been used for many years to minimize anthracycline cardiotoxicity and, in 2000, was found to have a protective effect against the development of anthracycline extravasation injuries as well.41 Dexrazoxane binds to iron and prevents the formation of free radicals, which are thought to play a major role in the development of extravasation-induced tissue necrosis. It also binds to DNA topoisomerase II at a different step in the catalytic cycle than anthracyclines and locks the enzyme in a form that is no longer affected by the anthracyclines.42 In animal studies and case reports, dexrazoxane was successful in reducing or eliminating tissue necrosis.41,43 From July 2001 to August 2005, 54 European patients with peripheral anthracycline extravasations verified by fluorescence microscopy were enrolled in two prospective, open-label clinical trials and treated with dexrazoxane. Patients experienced extravasations of doxorubicin or epirubicin and the mean extravasation area was 23.6 cm2 in the first study and 39 cm2 in the second study. All patients received dexrazoxane for 3 consecutive days, with a dose of 1,000 mg/m2 on days 1 and 2, and a dose of 500 mg/m2 on day 3. None of the 18 patients in the first study and only one of the 36 patients in the second study
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had tissue necrosis occur (overall efficacy, 98%) (see Fig. 1). Dexrazoxane must be administered intravenously within 6 hours of an anthracycline extravasation into a large vein in an area away from the extravasation site (eg, opposite arm). Side effects were mild and temporary and include nausea, infusion site reactions, and transient increases in liver enzyme levels.44 Marketing authorization of dexrazoxane (Savene) as a treatment of anthracycline extravasation in Europe was granted by the European Commission in July 2006,45 and Totect received US Food and Drug Administration approval in September 2007.46 Since the introduction of these new agents, clinical reports of the effectiveness of dexrazoxane in maintaining the skin integrity of patients experiencing anthracycline extravasations, including extravasations from central VADs, have been published.47-50
GUIDELINES AND RECOMMENDATIONS The third edition of the Oncology Nursing Society’s Chemotherapy and Biotherapy Guidelines and Recommendations for Practice,13 published in 2009, include the recommendations to treat anthracycline extravasations with Totect, administer the antidote sodium thiosulfate when mechlorethamine extravasations occur, and administer the antidote hyaluronidase when plant alkaloid extravasations occur. Use of topical DMSO as an extravasation antidote or treatment is not recommended.
FIGURE 1. Anthracycline extravasation before and after treatment with dexrazoxane. The small marks on the patient’s hand in the post-treatment photograph represent the sites where punch biopsies were obtained to verify that an extravasation had occurred. (Reprinted with permissions. Ó TopoTarget, Rockaway, NJ.)
The European Oncology Nursing Society (EONS) published extravasation guidelines in four languages in 2007.51,52 Savene is recommended for anthracycline extravasation treatment. Sodium
TABLE 3. Vesicant Chemotherapy Extravasation Antidotes and Treatments* Agent Extravasated
Antidote/Treatment
Guidelines for Use
Mechlorethamine
Sodium thiosulfate
Plant alkaloids
Hyaluronidase
Anthracyclines
Dexrazoxane
To prepare a 1/6 molar solution, mix 4 mL of 10% sodium thiosulfate with 6 mL of sterile water for injection. Inject 2 mL of solution for each milligram of mechlorethamine suspected to have extravasated.13,34 Inject 1 to 6 mL of 150 U/mL solution through the existing IV line; if IV device has been removed, inject subcutaneously in a clockwise manner. Usual dose is 1 mL of solution for 1 mL of extravasated drug.13,37,38 Administer intravenously in a vein in an area away from the extravasation site (eg, opposite arm). Infuse 1,000 mg/m2 within 6 hours of extravasation on day 1, 1,000 mg/m2 on day 2, and 500 mg/m2 on day 3. Maximum daily dose is 2,000 mg. Dose should be reduced 50% in patients with creatinine clearance values <40 mL/min. DMSO should not be applied and topical cooling (eg, ice packs) should be removed 15 minutes before, and during, administration.44,46
*See package insert of each drug for full prescribing information.
EXTRAVASATION MANAGEMENT: CLINICAL UPDATE
thiosulfate is not recommended for mechlorethamine extravasations ‘‘due to lack of evidence’’; however, further rationale for this recommendation is not discussed in the EONS guidelines. Hyaluronidase is ‘‘suggested as a possible antidote in many literature sources’’ and ‘‘due to lack of evidence it is recommended that this is further studied.’’ Topical DMSO (99% solution) is ‘‘suggested as a possible antidote for anthracycline and mitomycin C extravasations in many literature sources’’ and ‘‘due to lack of evidence it is recommended that it is further studied.’’ The United Kingdom Oncology Nursing Society adapted the EONS guidelines and published Anthracycline Extravasation Management Guidelines in January 2008.53 Savene is recommended for anthracycline extravasations exceeding 1.5 mL, with ‘‘volumes based on clinical judgment.’’ The American Society of Clinical Oncology (ASCO), European Society for Medical Oncology, Hematology/Oncology Pharmacy Association, International Society of Oncology Pharmacy Practitioners, Multinational Association of Supportive Care in Cancer, and National Comprehensive
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Cancer Network have, to date, not developed or published vesicant chemotherapy extravasation management guidelines or recommendations.54 However, extravasation management is now one of the ASCO/ONS chemotherapy administration safety standards.55
CONCLUSION This clinical update reviews the most current information on vesicant chemotherapy extravasation management available in October 2010 (see Table 3). Advances in treatment include the availability of hyaluronidase for treating plant alkaloid extravasations and the introduction and approval of dexrazoxane for anthracycline extravasation treatment. Updated guidelines from professional organizations have been published, and these can be used to guide the review and updating of institutional policies and procedures. Because nurses administer chemotherapy, they are on the forefront of detecting vesicant extravasations, and must be prepared to promptly implement evidence-based treatment.
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