A 3-year-old male Saint Bernard was treated with alternating doxorubicina and carboplatinb for osteosarcoma. For the first chemotherapy treatment, the dog was prescribed doxorubicin (30 mg/m2 [50 mg total]) diluted in 425 mL of saline (0.9% NaCl) solution. A catheter was placed in the right cephalic vein for administration. During the infusion, the IV catheter dislodged and approximately 30 mL of diluted doxorubicin was extravasated. Aspiration through the displaced catheter was attempted to remove as much drug as possible, the catheter was removed, and a cold compress was applied immediately. A central venous catheter was placed via the left jugular vein, and dexrazoxanec was administered at 500 mg/m2 (750 mg/dose) over 15 minutes. A total of 3 doses were administered at 3, 24, and 48 hours after extravasation. Tissue cooling was continued every 2 to 6 hours for 21 days. Additionally, 90% DMSO ointment was applied topically to the site every 8 hours for 14 days. Erythema developed at the site initially and resolved within 48 hours afterward. Erythema was noted again 6 days later but resolved. No additional lesions developed, and surgical intervention was not needed. Per the request of the owner, the chemotherapy protocol was discontinued after this event. The leg remained normal for 329 days following extravasation, at which time the dog was euthanized because of radiographic evidence of pulmonary metastases.
A 7-year-old neutered male mixed-breed dog was prescribed doxorubicin (30 mg/m2 [42 mg total]) diluted in 350 mL of saline solution for treatment of osteosarcoma. A catheter was placed in the right cephalic vein for administration. During the infusion, the IV catheter dislodged and an unknown but small amount of doxorubicin was extravasated. A cold compress was applied immediately, and a new peripheral catheter was placed in the left cephalic vein. One dose of dexrazoxane was administered IV 2 hours after extravasation at 354 mg/m2 (500 mg total) over 15 minutes. No additional doses of dexrazoxane were administered because of a nationwide drug shortage. Cold compresses were applied and 90% DMSO ointment was administered topically to the site every 8 hours for 14 days. Mild erythema, possibly secondary to DMSO application and tissue cooling, developed on the affected limb within 2 hours after extravasation. This resolved prior to the dog's recheck evaluation at the hospital the day following extravasation. No additional complications occurred, and no surgical intervention was required. Because this was the last scheduled dose in the protocol, chemotherapy was discontinued after this event. The leg remained normal for 249 days following extravasation, at which time the dog was euthanized because of radiographic evidence of pulmonary metastases.
A 12-year-old spayed female Bassett Hound was prescribed doxorubicin (30 mg/m2 [19 mg total]) diluted in 250 mL of lactated Ringer's solution for a high-grade sarcoma of the small intestine. A catheter was placed in the left lateral saphenous vein for administration. Midway through the infusion, the dog became restless, so the infusion was temporarily discontinued. Approximately 15 minutes after the infusion was restarted, a swelling was noted above the catheter. It was estimated that roughly half of the prescribed dose of doxorubicin (9.5 mg [125 mL]) was extravasated. Aspiration through the displaced catheter was attempted, and the catheter was removed. A new peripheral catheter was placed in the right cephalic vein, and 3 doses of dexrazoxane were administered IV at a dosage of 231 mg/m2 (250 mg/dose) at 1, 24, and 48 hours after extravasation. Cold compresses were applied for 15 minutes every 4 to 6 hours for 3 days. Topical administration of DMSO was not used in this patient. Erythema and discomfort developed at the site initially, and scabbing was noted 3 days after extravasation. All lesions resolved within 7 days, and no additional lesions developed. No further treatment was needed, and the chemotherapy protocol was continued without delay or further complications. The extravasation event occurred during the dog's first doxorubicin treatment, and the dog received another 5 doses after this event. The leg remained normal for 228 days following extravasation, at which time the dog was euthanized because of disseminated intravascular coagulopathy, likely related to underlying neoplasia.
A 12-year-old spayed female mixed-breed dog was prescribed undiluted liposome-encapsulatedd doxorubicin (35 mg/m2 [33.6 mg total]) for splenic histiocytic sarcoma. A catheter was placed in the left cephalic vein for administration, and no complications with the catheter were noted during treatment. Forty-eight hours after treatment, the dog developed severe swelling and erythema in the limb where the doxorubicin had been administered. On the basis of clinical signs, doxorubicin extravasation was suspected. A new peripheral catheter was placed in the right cephalic vein, and 2 doses of dexrazoxane were administered IV at 359 mg/m2 (350 mg/dose) 48 and 72 hours after the suspected extravasation. Cold compresses were applied and 90% DMSO ointment was administered topically every 8 hours and piroxicam (0.3 mg/kg [0.14 mg/lb], PO) was prescribed for 14 days. Extensive limb necrosis, requiring amputation, developed in the affected limb 21 days after extravasation (Figure 1). Deep localized tissue necrosis with cellulitis and granulation tissue suggestive of doxorubicin extravasation were noted on histologic assessment of the limb. Following amputation, the incision site became infected. Two months elapsed before the site was completely healed. The chemotherapy protocol was discontinued after this event. The dog was euthanized 422 days following extravasation for suspected liver metastases.
Photograph of the lateral aspect of the left forelimb of a 12-year-old spayed female mixed-breed dog 21 days after receiving undiluted liposome-encapsulatedd doxorubicin (35 mg/m2 [33.6 mg total]) for treatment of splenic histiocytic sarcoma. Clinical signs of extravasation were evident 48 hours after doxorubicin administration, and extensive limb necrosis developed in the affected limb, requiring amputation, 21 days later. (Photo courtesy of Dr. David Vail.)
Citation: Journal of the American Veterinary Medical Association 240, 3; 10.2460/javma.240.3.304
Discussion
Extravasation has been defined as the inadvertent leakage of a drug or solution from the vascular space into surrounding healthy tissues.1 For many drugs, such an event is associated with minimal risk of local tissue injury, but this can be a devastating complication of administration of certain chemotherapeutic agents. The extent of resultant injury is dictated by the vesicant potential of the extravasated drug and its volume and concentration.1 Anthracyclines, such as doxorubicin, are potent vesicants, resulting in severe tissue ulceration and necrosis after extravasation. Lesions typically progress over weeks to months and are difficult to treat. Extravasation of a known vesicant is considered a medical emergency.1–6 Chemotherapeutics with vesicant potential that are used in veterinary medicine include actinomycin D, docetaxel, doxorubicin, epirubicin, mechlorethamine, paclitaxel, vinblastine, vincristine, and vinorelbine. Although injury appears to be concentration and volume dependent, cisplatin may also result in tissue vesication and necrosis.
In people, symptoms of extravasation injury are mild initially and include pain, erythema, pruritis, and swelling at the extravasation site. Progression to infection, joint destruction, nerve damage, and permanent cosmetic changes occur over days to weeks.1,3,4,6,7 That said, not all extravasations require surgical intervention. In a retrospective review8 of 44 extravasation events in 42 human patients, doxorubicin and paclitaxel were identified as the most common drugs involved. Of all patients, 24% required surgical treatment by a plastic surgeon. Injuries in the remainder of patients healed spontaneously.8
In veterinary patients, initial clinical signs of extravasation may go unnoticed, in part because signs of local tissue pain may be easily confused with restlessness during prolonged restraint for chemotherapy administration. Clinical signs such as swelling, inflammation, desquamation, and signs of pain may develop within hours or up to 10 days after extravasation. Tissue damage progresses over 1 to 3 weeks, leading to deep ulceration and exposure of muscle, tendons, and bone.9
Research regarding treatment of anthracycline (eg, doxorubicin) extravasation injuries is limited in both human and veterinary oncology. Most of the literature consists of experimental animal studies10–13 and case reports.3,14,15 Recommendations regarding treatment strategies are often anecdotal and controversial.
Dexrazoxane is currently the only FDA-approved treatment for anthracycline extravasation in people.16 It was first developed as a cardioprotective agent for anthra-cycline-induced cardiotoxicity.17 The mechanism of action supporting its use for extravasation is unknown, but at least 2 mechanisms have been proposed. As an analogue of EDTA, dexrazoxane is a strong metal ion chelator that protects against free radical damage induced by anthracy-clines. Dexrazoxane penetrates cell membranes and complexes with iron, copper, and other metal ions, thereby removing them and preventing free radical generation. As a reversible inhibitor of the catalytic cycle of topoisomerase II, dexrazoxane can block effects of topoisomerase II poisons, including doxorubicin, thus protecting cells from formation of lethal DNA double strand breaks.11,13,18 Although these mechanisms are plausible in theory, studies13 in mice have failed to confirm either of these mechanisms.
Clinical trials investigating the efficacy of dexrazoxane for treatment of anthracycline extravasation injuries are difficult to conduct and to justify. However, research in mice and clinical reports in people have supported its use for this purpose. Mouse studies10,11 have demonstrated that dexrazoxane administration prevents wound development after SC administration of doxorubicin and have provided information about the dosage required for adequate protection. On the basis of these studies11,19 as well as prospective clinical trials in human patients, it is recommended that the first dose is administered within 3 to 6 hours after the extravasation event, followed by subsequent dosing at 24 and 48 hours after extravasation. Recommended doses in human patients are 1,000 and 500 mg/m2.7,19 In most cases, such dosing appears to prevent symptoms of injury and allows patients to continue chemotherapy without further delay.19
The authors are unaware of any published data on use of dexrazoxane for the prevention of anthracycline extravasation injury in dogs. Successful treatment has been reported in a cat.14 Dexrazoxane was administered as an IV bolus at a dose that was 10 times the prescribed doxorubicin dose. One month after extravasation, a 0.6-cm firm callus was noted over the site. This lesion healed without further treatment, and no additional adverse effects were noted.14
Because of the lack of information regarding the use of dexrazoxane in veterinary medicine, recommended doses are variable and range from approximately 300 (or 10 times the doxorubicin dose) to 1,000 mg/m2.20 In many cases, prescribed doses are likely selected on the basis of vial size or recommendations for human patients. Dexrazoxane is available in single use vials of 250 and 500 mg, and in the Saint Bernard and Bassett Hound described in the present report, doses were chosen on the basis of vial size. In the male mixed-breed dog, only one 500-mg vial was available in the hospital. The dose chosen in the female mixed-breed dog was 10 times the doxorubicin dose, the cardioprotective dose used in people. Timing of dexrazoxane administration in the Saint Bernard, male mixed-breed dog, and Bassett Hound was chosen on the basis of recommendations for people. In the female mixed-breed dog, complications were not noted during the doxorubicin infusion, so dexrazoxane was not administered until 48 hours later when the dog was evaluated because of clinical signs suggestive of extravasation injury. Interestingly, this was the only dog in which lesions did not resolve and that ultimately required amputation. We believe that the outcome in this patient further indicates that treatment within 6 hours after the event is beneficial; nonetheless, exact dosing requirements remain uncertain.
Overall, dexrazoxane appears well tolerated in human patients. Observed adverse effects are uncommon and seemingly mild but have included transient elevation of liver enzyme activities, sensory disturbances, nausea, vomiting, wound infection, and pain at the injection site. Hematologic abnormalities have also been observed. However, it is difficult to attribute hematologic abnormalities solely to dexrazoxane because patients receiving this drug are typically undergoing chemotherapy concurrently.19
Although dexrazoxane appears to be the most efficacious treatment in the prevention of anthracycline extravasation injury, other recommendations have been made. The first step in addressing anthracycline extravasation involves stopping the infusion and immediate aspiration through the displaced IV catheter to remove as much extravasated drug as possible.1,2,4 Additionally, clear documentation of the event and appropriate consultations with oncologists and possibly surgeons are recommended.4,6
Historically, application of heat to the site was recommended, but this has actually been shown to cause further tissue damage.2,21 Instead, tissue cooling is recommended to induce vasoconstriction and decrease diffusion of the drug into adjacent tissues.21,22 However, 1 study10 in mice reported no beneficial effect of topical cooling after SC doxorubicin extravasation.
Use of DMSO is also commonly suggested, but data on the effects have been conflicting. Dimethyl sulfoxide is a free radical scavenger and topical application can potentially reduce local tissue damage by increasing systemic absorption of extravasated drug. It also has vasodilatory, analgesic, and anti-inflammatory properties. Data from early clinical case studies2,6 suggested that human patients treated with DMSO were less likely to develop ulcerations after anthracycline extravasation. However, studies11,12 in rabbits, pigs, and mice have reported a marginal benefit at best. Furthermore, in mice treated with dexrazoxane in combination with topical DMSO, dexrazoxane efficacy appeared decreased, compared with those treated with dexrazoxane alone. Findings from that study6,12 suggest that perhaps the use of dexrazoxane and DMSO in combination should be discouraged. The combination did not appear harmful in the dogs treated in the present report, but again, definitive conclusions cannot be made with this small set of patients.
Other suggested treatments have included corticosteroids, bicarbonate, topical and intralesional hyaluronidase, hyperbaric oxygen, and granulocyte-macrophage colony stimulating factor.4,6,19,23 All of these appear to be of little or no benefit in people, and because of the lack of convincing data, none of these treatments are routinely recommended.4,6,19 Of these treatments, the only one reported in the veterinary literature is intralesional hyaluronidase. Two dogs were reportedly treated with hyaluronidase after doxorubicin extravasation. Normal limb function was preserved despite development of fibrosis at the extravasation site.24
Clinicians may initially be tempted to treat potential extravasation events conservatively and to monitor for lesion development. Unfortunately, once ulceration and necrosis develop, radical surgery is generally required to stop lesion spread. If injury is allowed to progress proximally on the limb toward and onto the trunk, even amputation may be ineffective. In such patients, euthanasia is the only humane option.
In addition to understanding the treatment of anthracy-cline extravasation, prevention is prudent and begins with education of the staff administering chemotherapy. Written guidelines about chemotherapy safety and proper administration should be posted, and extravasation kits including necessary drugs (eg, dexrazoxane) and equipment (eg, cold compresses and extra catheters and supplies) should be readily accessible to manage extravasation incidents. Identified risk factors include improperly secured catheters and use of metal needles or large-gauge catheters. Metal needles are more damaging to tissues during placement and are not flexible within the vessel. Large-gauge catheters also cause more vessel trauma and can impede blood flow. Once blood flow is impeded, intraluminal pressure is increased, leading to leakage from the puncture site. Ideally, cytotoxic agents should not be administered through a butterfly needle, and a clean-stick indwelling catheter should be placed by experienced personnel.1,3,23,25
In the present report, the female mixed-breed dog was the only dog treated with liposome-encapsulated doxorubicin. Liposomal encapsulation of chemotherapeutic drugs appears to alter toxicity profiles. Specific to doxorubicin, liposomal encapsulation reportedly reduces the vesicant potential, compared with the unencapsulated drug.4 In this series of dogs, this did not prove to be true. However, definitive conclusions cannot be made on the basis of this single patient.
Limitations of the present case series include its small numbers and the unknown factor of whether ulceration and necrosis would have developed without dexrazoxane treatment. The role of other treatments instituted, specifically DMSO ointment and tissue cooling, remains unclear. Conclusions about the appropriate management of anthra-cycline extravasations cannot be made on the basis of this small series of dogs. However, based on results from mouse studies, case reports, and clinical trials in people and the fact that dexrazoxane is the only FDA-approved treatment for anthracycline extravasation for people, we believe its use should be strongly considered in veterinary patients that develop this potentially devastating complication of anthracycline administration. Because of the importance of timely administration, veterinarians treating patients with doxorubicin should have dexrazoxane readily available.
ABBREVIATION
| DMSO | Dimethyl sulfoxide |
Doxorubicin, Doxorubicin HCl, Bedford Laboratories, Bedford, Ohio.
Carboplatin, Hospira, Lake Forest, Ill.
Zinecard, Pfizer, New York, NY.
250 mg phosphatidylserine and phosphatidylcholine (molar ratio, 7:3), provided by Ciba-Geigy Ltd, Basel, Switzerland.
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