Review

Annals of Oncology 15: 858862, 2004 DOI: 10.1093/annonc/mdh214

Extravasation of systemic hemato-oncological therapies

R. A. Ener1*, S. B. Meglathery1 & M. Styler2
1

Albert Einstein Medical Center, Philadelphia, PA; 2Drexel University College of Medicine, Philadelphia, PA, USA

Received 1 September 2003; revised 5 December 2003; accepted 31 December 2003

Systemic intravenous chemotherapeutic agents can cause multiple emergency situations including acute and chronic local and systemic reactions. Amongst them, drug extravasation is one of the most devastating complications, as many drugs can cause varying degrees of local tissue injury when extravasated. Although it is difficult to give an accurate measurement, the incidence of extravasation of systemic infusional chemotherapeutic agents has been reported to occur in 0.16.5% of cases. Since most extravasations can be prevented with the systematic implementation of careful administration techniques, guidelines have been published for the administration of vesicant drugs. The proper maintenance of intravenous lines, application of local cooling or warming for certain extravasations, and the use of antidotes to prevent the local toxic action of the extravasated drugs are the basis of medical management. The specific antidotes for certain chemotherapeutic agents are also discussed in this article. Key words: antidotes, chemotherapy extravasation, irritant drugs, vesicant drugs

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Introduction
The extravasation of cancer chemotherapeutic agents is an unwanted and distressing situation that can easily occur and may cause severe and irreversible local injuries. The symptoms of extravasation reactions can range from pain and self-limited, localized tissue inflammation to full-thickness necrosis, ulceration and sloughing of skin and underlying structures. The extent of symptoms depends on the infusion site, condition of the tissue, concentration and volume of the vesicant, and the treatment that was applied. Most lesions heal poorly and slowly. They may expand in size over weeks to months. In conditions where extensive ulcerations develop, early plastic surgery consultation is needed in order to remove the trapped drug from the tissue, as well as skin grafting, if necessary. In terms of pain medicine, one of the best clinical indicators of the need for subsequent surgery is reported to be pain at the site of extravasation 12 weeks following the event. When surgery is indicated, a wide excision of the structures is necessary to completely remove non-viable tissues and any locally trapped drug early in the course so that prolonged evolution of anthracycline damage is prevented without allowing further extensive injury. If an open ulcer develops, the area of excision may need to be quite large and may involve deep structures, i.e. nerves and tendons. Although it is difficult to give an accurate measurement of its incidence, extravasation has been reported to occur in 0.16.5% of cases [14]. Most chemotherapy agents are not vesicants (ulcerogenic) if inadvertently extravasated or otherwise delivered outside the vas*Correspondence to: Dr R. A. Ener, 1829 Kater Street, Apt. No. 2, Philadelphia, PA 19146, USA. Tel: +1-215-732-3421; Fax: +1-215-732-3421; E-mail: enerr@einstein.edu
2004 European Society for Medical Oncology

cular compartment. Based on their potential to cause local tissue injury, drugs are classified as vesicant, irritant or non-vesicant [14]: 1 Vesicant drugs have the capability to induce the formation of blisters and/or cause tissue destruction. 2 Irritant drugs can cause pain at the injection site or along the vein, with or without an inflammatory reaction. Some of these agents have the potential to cause soft tissue ulcers only if a large amount of concentrated drug solution is inadvertently extravasated. 3 Non-vesicant drugs, if extravasated, rarely produce acute reactions or tissue necrosis. Tissue damage related to extravasation occurs by different mechanisms [5]: (a) Some chemotherapeutics that bind to nucleic acids in DNA, such as anthracyclines, are initially absorbed locally causing direct cell death. After endocytolysis, the additional death of surrounding cells can occur by the release of the drug from the nearby dead cells. The repetitive nature of this process impairs healing and may result in progressive and chronic tissue injury. With prolonged retention of doxorubicin in skin and underlying structures, significant levels of this drug can be detected in surrounding tissues many weeks to months after extravasation [1, 6, 7]. (b) The drugs which do not bind to DNA, such as vinca alkaloids or epipodophylotoxins, may undergo metabolism and clearance limiting the degree of tissue injury, and are therefore more easily neutralized [5]. Some of the vesicant and irritant drugs are outlined in Tables 1 and 2 [2, 3, 8].

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Table 1. Vesicant drugs Group 1a Actinomycin D Amsacrine Bisantrene Daunorubicin Doxorubicin Epirubicine Idarubicin Mechlorethamine Mitomycin C Vinblastine Vincristine Vindesine Vinorelbine
a

lines, reduce but do not eliminate inadvertent drug extravasation. They may also leak as a result of:
Group 2b Aclacinomycin Cisplatinc Dacarbazine Docetaxel Etoposidec Esorubicin Fluorouracil Liposomal doxorubicin Menogaril Mitoxantrone Oxaliplatind Paclitaxel

(a) catheter separation from the port body; (b) a nick in the outflow catheter; (c) a rupture or tear in the port septum; (d) excessive back pressure around the needle due to a fibrin sheath at the catheter outflow tip; (e) incomplete or no penetration of the injection needle through the port septum; or (f) spontaneous retraction of the catheter tip from the subclavian vein. If a chemotherapeutic agent has to be given through a peripheral vein, one should keep in mind their potential toxicity and complications when extravasated. Peripheral lines should be used only for short infusions under direct, continuous monitoring of nursing staff and with a demonstrated good blood return. A peripheral intravenous (i.v.) catheter must be tested with i.v. fluids first at a high flow rate to determine the patency of the vessel to be used and to exclude extravasation prior to the administration of chemotherapy drugs. The dorsum of the hand and volar aspect of the wrist are not recommended for this purpose. If there is any doubt about the patency of the vessel, the infusion should not be attempted at all. Certain factors (i.e. fragile, small, sclerosed veins, superior vena cava syndrome, lymphedema, peripheral neuropathy, decreased local blood flow, recent venipuncture at the same vein, previous radiation therapy in the area, and medications capable of altering mental status) can increase the risk of extravasation and should be taken into account before starting chemotherapy. Guidelines which have been developed for administration of vesicant drugs have been published in the nursing literature and in oncology reviews, and are outlined below [3, 4]; 1 It is best to administer a vesicant drug through a recently started line in order to ensure the patency of the line. Avoidance of sites in the dorsum of the hand, or near joints, which can lead to more functional damage, is important. 2 Administration of vesicant agents should be carried out through a central line whenever possible, especially if it requires continuous infusion. 3 One should avoid limbs with impaired circulation or the side of lymph node dissection. 4 Place a suitable i.v. line of compatible fluids through a butterfly needle or plastic canula, securely taped in place without covering the entry site in order to allow visualization. Access vein using a single approach. 5 Side arm infusion technique can also be used if one is using a peripheral site. 6 The line should never be tested with cytotoxic drug initially. It should be observed for swelling, redness and pain. Its patency can be checked with gently withdrawing blood before starting cytotoxic chemotherapy. 7 Patients should be asked to report promptly any sensation of pain or burning. If there is any doubt, infusion should be stopped and changing the site should be considered.

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Group1 has high vesicant potential. Group 2 has low vesicant potential. c Especially in a large volume of concentrated solution. d Recently, oxaliplatin has been reported to have vesicant properties [26, 27], and is at least an irritant [28].
b

Table 2. Irritant drugs Bleomycine Carboplatin Cyclophosphamide Carmustine Gemcitabine Ifosfamide Irinotecan Melphalan Pentostatin Plicamycin Streptozocin Topotecan

Prevention of extravasation
Extravasation into the subcutaneous tissues of vesicant cytotoxic agents is one of the most debilitating complications of the administration of chemotherapeutic agents that hematologists/oncologists have to face. Irritants generally do not cause permanent damage, but may cause pain and inflammation at the catheter site and vein. Therefore, all vesicant chemotherapy, especially if it requires continuous infusion, should be administered through a central line whenever possible for improved safety. As our case demonstrates, the central venous access devices, either subcutaneously implanted ports or peripherally inserted central catheter

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Table 3. Specific agent clinical picture Mechlorethamine Mitomycin C Anthracyclines Vinca alkaloids Oxaliplatin Results in phlebitis and immediate pain when extravasated. Lesions heal poorly Symptoms may sometimes be delayed months. Even though skin lesions rarely develop distal to injection site, lesions can expand over weeks Usually cause immediate pain. Lesions form slowly over weeks and expand locally over months given the fact that there is long tissue retention of unchanged drug Mostly painful ulceration with slow healing and local paresthesia Initial palpable swelling with discomfort on palpation, then erythematous painful lesions which may also be necrotic

8 The venous blood return and/or signs of redness and swelling during the administration should be checked frequently. Flushing the vein with i.v. fluids every 23 min between bolus injection of cytotoxic drugs and at the end of administration is also recommended.

Clinical presentation of extravasation

Despite the preventive guidelines, extravasation of hematooncological chemotherapeutic agents sometimes occurs. The diagnosis of extravasation is generally clinical, based on the appearance of local pain, burning sensation, swelling, erythema and lack of blood return. Extravasation generally causes immediate intense pain, but may on occasion be painless. The pain is usually followed by erythema and edema within a few hours and increasing induration within a few days time. Skin ulceration and skin necrosis may follow within the next 13 weeks, and can lead to necrosis of underlying fascia, tendon and periostium. If this is not recognized early, wide surgical resection and debridement may be required. Severe permanent disability or even amputation of the involved extremity may become necessary, particularly if this occurs on the dorsum of the hand or volar aspect of the wrist. However, a large number of patients are asymptomatic in whom extravasation is detected later in the hospital course, resulting in clinical signs of progressive tissue damage including loss of tissue function or even loss of a limb. Clinical scenarios related to specific agents are outlined in Table 3.

monly used vesicant cytotoxic drugs. The concept behind the administration of most antidotes is to disperse the chemotherapeutic agent and to facilitate its absorption from the subcutaneous tissues. Whenever an extravasation occurs, reference material or the package insert should be consulted since the type of specific intervention depends on the agent extravasated. Unfortunately, the lack of large scale comparative trials owing to the infrequent nature of these episodes and the unethical nature of placebo controlled trials make treatment mostly empirical, based on small uncontrolled trials, case reports and animal studies. In addition to pharmacological therapy, non-pharmacological management also needs consideration, which includes supportive local care [13, 11]. Based on the observation that hyperthermia enhances anthracycline cytotoxicity, it has been suggested that the application of warm compresses may enhance skin toxicity when anthracycline drug extravasation occurs [2, 12, 13]. Animal studies also support the protective effect of cold, and harmful effect of heat, in doxorubicin extravasation [13], whereas the contrary is the case in vinca alkaloid extravasation [5, 15]. Since clinical studies have shown a beneficial effect of topical cooling in the treatment of anthracycline extravasation [14], and topical warming in the treatment of vinca alkaloid extravasation, intermittent cooling or warming for 2448 h (as tolerated) is recommended for these scenarios, respectively [3, 14]. Antidotes which appear to be useful and safe are outlined below along with their mechanisms of action [13, 5, 1625]: 1 Hyaluronidase degrades hyaluronic acid, breaks down subcutaneous tissue bonds promoting drug diffusion through the interstitial space and enhances the absorption of injected substances. It appears to be effective and well tolerated in vinca alkaloid, epipodophylotoxin and paclitaxel extravasations [17, 18]. It should not be used in anthracycline extravasation, and is similarly contraindicated in infected and cancerous sites. 2 Sodium thiosulfate neutralizes the vesicant effect of mechlorethamine by providing an alternative target for alkylation (inactivation by alkalinization) to form non-toxic thioesters, which can be excreted into the urine [19, 20]. This can also be used in concentrated cisplatin extravasation. It prevents the expected necrosis of mechlorethamine when injected intramuscularly [21]. 3 Dimethyl sulfoxide (DMSO) is a common solvent, which penetrates tissues and enhances skin permeability that may facilitate absorption of an extravasated drug (especially in higher concentrations). When applied topically, it also has free-radical scavenging/antioxidant properties that may speed up the removal of

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Management of extravasation
Documentation and close follow-up with appropriate consultations are highly recommended. Proper documentation of extravasation should include the time, line insertion site and needle size, number of venipuncture attempts and location, drugs administered and their sequence, estimated amount of extravasated drug, techniques used to manage extravasation, appearance of site, action taken to treat extravasation and patient comments. Photographic documentation of the lesion is also encouraged whenever possible [1, 3, 9]. It is estimated that approximately one-third of all vesicant extravasations will produce ulceration in the absence of therapy. This rate is historically used for indirect comparison with the results of non-randomized studies when evaluating specific measures or antidotes. Only a few antidotes may be able to reduce local toxicity of the com-

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Table 4. Drug antidote comments Anthracyclines DMSO Apply topically 12 ml 1 mM 5099% (w/ v) DMSO (typically apply 1.5 ml topically to the skin twice the size of infiltration with a cotton swab) and allow it to dry (do not cover), repeating every 68 h for 714 days

Ice packs Mitomycin C Meclorethamine or concentrated cisplatin DMSO Sodium thiosulfate Same as for anthracyclines Prepare either a 170 mM or 333 mM solution by mixing isotonic sodium thiosulfate (1 g/10 ml) (4 or 8 ml of 10% sodium thiosulfate with 6 ml sterile water for injection) and inject 2 ml into site for each milligram of mechlorethamine or for each 100 mg cisplatin extravasated through an existing i.v. line. Then consider injecting 1 ml s.c. (0.1 ml doses clockwise around the area of extravasation) as described. s.c. injections can be repeated several times over the next 34 h Reconstitute with normal saline (hyaluronidase 150 U/ml) and inject 16 ml (150900 U) into the extravasation site through the existing i.v. line and/or, if the line has been removed, in a clockwise manner s.c. Typical dose used is 1 ml for 1 ml infiltrated drug.This can be repeated several times over the next 34 h

Vinca alkaloids or concentrated epipodophylotoxins

Hyaluronidase

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Warm packs Paclitaxel Hyaluronidase Ice packs DMSO, dimethyl sulfoxide (Sol Rinso-50R); s.c., subcutaneously. Same as for vinca alkaloids

extravasated drugs. Experimental studies suggest that topical DMSO has antidotal activity against anthracycline-induced skin ulceration [22, 23]. Therefore, it can be used in concentrations listed below. DMSO toxicity may involve a transient burning sensation with urticaria, and erythema during application. The use of corticosteroids has been proposed for different drug extravasations because of their anti-inflammatory properties, but has been shown to be ineffective in most trials [1, 2, 5]. In the case of doxorubicin extravasation, the majority of soft tissue damage appears to be related to direct tissue necrosis, and only a delayed acute inflammatory response 1 week following subcutaneous administration (without significant acute inflammation) has been described. Therefore, since acute inflammation is not a prominent histopathological feature of doxorubicin extravasation, the pharmacological rationale for glucocorticosteroid use is unclear. If we look at the experimental studies, most reports do not describe any antidotal effect, although some show a moderate reduction in ulcer size. When very high doses are used or multiple injections are given, glucocorticosteroids may even be deleterious. Despite these observations, low dose hydrocortisone given by a single injection is still suggested as a local remedy in doxorubicin extravasation by some authors. In addition, hydrocortisone is also recommended for the treatment of doxorubicin-induced venous flare reactions, which are more common than extravasations. In small case series with oxaliplatin extravasation [28], early hydrocortisone administration along with non-steroid anti-inflammatory drug use for pain management appeared to be useful in treating these patients. Some patients who develop necrosis may require plastic surgery [26] in addition to conventional measures. Sodium bicarbonate has also been proposed as a potential antidote, based on its effect on local pH and related cellular uptake and

removal of doxorubicin, but it has failed to show clinical benefit [1]. Furthermore, sodium bicarbonate is itself a vesicant if extravasated. The antioxidant butylated hydroxy toluene (BHT) has been shown to have some efficacy in experimental studies, although it did not completely prevent skin ulceration. The radical dimer bis-3,5-dimethyl-5-hydroxymethyl-2-oxomorpholin-3-yl (DHM3) has been shown to have antidotal efficacy by reducing anthracyclines to insoluble and inactive 7-deoxyaglycone metabolites in experimental studies. Since this appears to be a promising agent, it should be tested further in clinical trials. Some general measures for treatment of extravasation are outlined below: 1 If there is any sign of extravasation, or a suspicion of extravasation, it should be assumed to have occurred and the infusion should be stopped. 2 i.v. line management: i.v. lines should be left in place initially. 3 If extravasation occurs from a peripheral i.v. line, after stopping the infusion, aspiration of some of the extravasated fluids should be attempted before the needle is withdrawn, even though this is generally not productive owing to tissue blockage at the needle terminus. If a known antidote exists, it is recommended that it be administered i.v. using the original line (especially relevant in mechlorethamine and vinca alkaloid extravasation), in addition to subcutaneously (s.c.), before discontinuing the line, since it is very important to deliver the antidote directly into the extravasated area or in close proximity to this area for maximum efficacy. 4 If extravasation occurs from a central line, it should be stopped if its rate decreases, or if the patient complains of changes in sensation, pain, burning, swelling at the central venous catheter site,

862 or in the ipsilateral chest [3, 10]. If the patient has an implanted port, it should be assessed for proper needle placement. The residual drug should be aspirated from the area of suspected infiltration at the port pocket or at the exit site of the tunneled catheter. If an antidote is indicated, it should be injected into subcutaneous tissue along with local care. If the antidote is administered intravenously, an adequate amount has to be instilled while avoiding excess pressure on the central venous catheter site. If the patient has an implanted port, it has to be deaccessed after instilling the antidote. 5 Administration of specific antidote as indicated (Table 4). Antidote should be given within 1 h through the needle and/or in a clockwise order s.c. around the site of extravasation. A 25 or 27 gauge needle should be used via pincushion technique intradermally and changed with each injection. 6 Resting and elevating the affected site for 48 h may aid in the normal absorption and drainage of loculated extravasated fluids. The area should be checked every 24 h. 7 Local cooling or warming for at least 1530 min four times a day for 2448 h. Alternatively, this can be applied immediately for 3060 min, alternating on and off every 15 min, for 1 day. Avoid applying direct pressure on the site, as this can spread the extravasated drug to a much broader area, although it can be covered lightly with a dressing. 8 Local cooling (ice packs) for anthracycline extravasation. This causes vasoconstriction and tends to restrict the spread of the drug. 9 Local warming (dry heat) for vinca alkaloid extravasation. It causes local vasodilatation and increased blood flow in the area. 10 Document the extravasation as noted. 11 Photograph when possible and arrange early plastic/ reconstructive surgery and/or physical therapy and rehabilitation consultations. 12 Systemic analgesics and/or local pain medications administered for pain. 13 If skin becomes open, blistered or necrotic, silver sulfadiazine (Silvadene) can be applied every 12 h until healing occurs. Empirical treatment guidelines and their mechanism of action are listed in Table 4.
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Acknowledgements
We dedicate this article to our mentors.

References
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