1. List those antineoplastic drugs that are vesicants.
2. Discuss the differentiation of extravasations from other venous reactions.
3. Recommend, in writing, treatment for extravasation of specific vesicant antineoplastic agents.
1. Larson DL: What is the appropriate management of tissue extravasation of antitumor agents?; Plastic and Reconstr Surg 75:397-402, 1985
2. Dorr RT: Discussion - What is the appropriate management of tissue extravasation of antitumor agents?; Plastic and Reconstr Surg 75:403-405, 1985
I. EXTRAVASATION = leakage of fluid outside of the vasculature into the perivascular and subcutaneous spaces; infiltration.
Some substances, upon leakage into subcutaneous tissue, have the potential to cause severe tissue damage and even necrosis. These substances are known as VESICANTS.
The following chemotherapeutic agents are vesicants:
Some chemotherapeutic agents can cause pain or burning on administration, even though they may remain in the vasculature:
- carmustine (BCNU)
- dacarbazine (DTIC)
Pain or burning can be minimized by infusing these drugs slowly, as dilute solutions (eg. 100-250ml over 30-60 minutes, as opposed to IV push injections)
II. OTHER VENOUS REACTIONS
MECHLORETHAMINE (nitrogen mustard) frequently causes phlebitis, irritating the vein independent of the possibility of extravasation. Some clinicians find that the use of hydrocortisone prior to or during (separated by saline flush) injection of mechlorethamine preserves the integrity of the vessel. This is a subjective finding.
5-FLUOROURACIL frequently causes darkening of the veins. This is referred to as "serpentine veins". It may be embarrassing for patients, although it is merely a discoloration. That is, the vein(s) can still be utilized for administration of chemotherapy, etc. This venous discoloration is particularly prominent in black patients.
DOXORUBICIN (as well as DAUNORUBICIN) can cause redness and itching along the distribution of the vein through which it has been administered. This is known as a "flare". Usually the flare is self-limited. It disappears in several minutes to half an hour with or without treatment (antihistamines, steroids). The cause is not known, although it has been suggested that the incidence is less when the diluent for doxorubicin is normal saline instead of water for injection. Rarely, the flare has been associated with systemic allergic symptoms. Management involves making sure a systemic allergic reaction is not present, and making sure the reaction does not represent an extravasation.
Several factors may influence the occurrence of or the severity of extravasation injuries. These factors include the location, size and fragility of the vessel, the age of the patient, site(s) of previous venipuncture, lymph node dissections, and the concentration of drug. These should be considered when selecting venous sites or ways to administer vesicant drugs. Practically speaking, however, one may have to use less than preferred sites in patients with poor or limited venous access.
Fragile, low flow, or small diameter vessels, or previously irradiated sites may all have relatively decreased vascularity. Thus, extravasated fluid is more likely to remain concentrated in a given area.
Use of vessels close to tendons or muscles can lead to greater functional loss in the event of extravasation of a vesicant agent.
Administration of drug distal to the site of a recent venipuncture can lead to leakage of the drug as it passes the venipuncture site.
The size of subsequent ulceration following extravasation of vesicant agents is related to the concentration and the total amount of drug that has extravasated. In an animal model, a critical concentration of doxorubicin was determined to be 0.01-0.02mg/ml. That is, when doxorubicin was diluted to this concentration, and volume of extravasated drug kept constant, the size of the subsequent ulcer was significantly decreased from that seen with more concentrated solutions.
Note that pain is not necessarily present at the time of extravasation. Thus absence of pain does not rule out an extravasation. When extravasation cannot be comfortably ruled out, drug administration should be discontinued and restarted in another vessel.
PATTERNS OF INJURY - The onset of injury is earlier with vinca alkaloids and mechlorethamine, and later with anthracyclines (eg. doxorubicin). The vinca alkaloids tend to produce blistering, not necessarily necrosis. Mechlorethamine leads to ulceration which reaches its maximum severity faster than that seen with anthracyclines. Tissue damage from anthracyclines is progressive over weeks to months. A full thickness ulcer can be seen and damage can extend to underlying structures like muscles and tendons.
IV. MANAGEMENT OF EXTRAVASATION
The goal of treatment is to prevent severe tissue damage and preserve function.
The majority of extravasations are suspected (eg. all of the sudden, blood return diminishes), when venous patency/blood return is checked frequently.
Primary prevention (see above):
- choice of vessel
- IV push injections may be preferred when possible. Infusions may be more likely to be left unattended, allowing for leakage of a greater amount of fluid before the extravasation is detected.
Aspirate back fluid, to avoid extravasation of any more fluid remaining in the needle/catheter. Then remove the needle.
Aspirate any bleb if possible.
Follow up. Continued pain or ulceration after 1-2 weeks is an indication for surgery/skin grafting. (Plastic) surgery should be consulted at this point.
1. SODIUM THIOSULFATE 1/6M (4ml 10% sodium thiosulfate + 6ml water = 1/6M). Instill via multiple injections in and around the area of extravasation (ie. SQ/ID) using a small gauge needle (eg. 25g).
Sodium thiosulfate is recommended as an antidote for extravasation of MECHLORETHAMINE. It provides a substrate for alkylation by mechlorethamine, preventing the alkylation and subsequent destruction in subcutaneous tissue.
2. HYALURONIDASE 150U (1ml). Instill via multiple injections in and around the area of extravasation (ie. SQ/ID) using a small gauge needle (eg. 25g).
Hyaluronidase is recommended as an antidote for extravasation of VINCRISTINE, VINBLASTINE, and VINORELBINE. It breaks down hyaluronic acid ("cement") in connective/soft tissue, allowing for dispersion of the extravasated drug.
3. DIMETHYLSULFOXIDE (DMSO) 50-70% solution 1.5ml. Apply topically (ie. "paint" on the skin) QID x 14 days. Leave uncovered.
DMSO has been recommended as an antidote for extravasation of DOXORUBICIN and DAUNORUBICIN as well as MITOMYCIN. There is conflicting data in animals regarding its effectiveness. Some reports of prevention/decreased ulcer formation were obtained when DMSO was used in conjunction with Vitamin E. There is one series of patients reported in whom topical application of 99% DMSO was thought to have prevented ulceration. Little other information is presented (eg. amount of drug extravasated, whether or not cold was used). Note that the only commercially available concentration of DMSO is 50%. DMSO may work by virtue of its free radical scavenging property.
4. COLD - Apply cold packs for 20 minutes QID x 3 days.
Cold is recommended as an antidote for extravasation of DOXORUBICIN and DAUNORUBICIN. Initially, cold was suggested as a general measure for extravasation of a variety of drugs. The rationale for cold was vasoconstriction, thereby "containing" the drug at the site of extravasation and minimizing the size of the subsequent ulceration. Studies in animal models, however, have shown that the concentration of doxorubicin at the site of extravasation was not different from that at a distal site following the application of cold. But ulceration was still not seen. Thus it appears that cold prevents ulceration from doxorubicin or daunorubicin by a mechanism other than vasoconstriction and "containing" the drug. This mechanism has been suggested to be decreased cellular uptake of drug at lower temperatures - the same rationale as that for the use of scalp cooling to prevent alopecia.
5. HEAT - Apply heat packs for 20 minutes QID x 3 days.
Heat is recommended, in conjunction with hyaluronidase, as an antidote for extravasation of VINCRISTINE and VINBLASTINE. Initially, heat was suggested as a general measure for extravasation of a variety of drugs. The rationale for heat was vasodilation, thereby "diluting" the drug and minimizing the size of the subsequent ulcer. It seems unlikely that heat can result in a change in concentration of the magnitude noted above to decrease ulcer size. Yet, in the mouse model heat did decrease ulceration due to extravasation of vinca alkaloids, and not that due to anthracyclines.
6. SUMMARY - Although several drugs have been well studied in animals (eg. doxorubicin), there is less data available on the management of extravasation of some of the other agents. The following represents my recommendations for acute treatment of extravasation of vesicant antineoplastic agents:
- doxorubicin, daunorubicin, idarubicin, mitomycin, actinomycin - cold " DMSO
- vincristine, vinblastine, vinorelbine - hyaluronidase and heat
- mechlorethamine - sodium thiosulfate
- streptozocin - cold
paclitaxel - recent reports indicate that paclitaxel is a vesicant, although there are also reports of extravasation without resulting necrosis; there is as yet no universally recommended treatment for paclitaxel extravasation; my recommendation would be to treat it like extravasation of the vinca alkaloids
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