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Published on 1 July 2007

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A management algorithm for extravasation of cytotoxic agents

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Marta Lafuente González*
MPharmCare PhD

Hospital Pharmacist

Leonor Santos Morín**
MPharmCare PhD

Hospital Pharmacist

Alicia Díez del Pino*
MPharmCare PhD

Hospital Pharmacist/Director

*Pharmacy Department
**Oncology Pharmacy Department

Insular University Hospital of Gran Canaria
Las Palmas de Gran Canaria
Spain

E: marta_lafuente@hotmail.com

Extravasation of cytotoxic drugs is the unintentional instillation or leakage of these agents into the perivascular and subcutaneous spaces during their administration that is capable of causing pain, necrosis and/or sloughing of tissue. If it is left undiagnosed or if the treatment is inappropriate or delayed, necrosis and functional loss of the tissue and limb concerned may occur.(1)
Extravasation of medicinal drugs during intravenous therapy is a side-effect that can and must be avoided.

The incidence of extravasations is assessed in the literature in divergent ways, so is difficult to estimate. The incidence of extravasation of ­systemic infusional chemotherapeutic agents has been reported to occur in 0.1–6.5% of cases.(2) However, the actual percentage is unknown since ­extravasation often goes unnoticed and/or undocumented, especially if it is not severe.

Cytotoxic agents are classified as vesicants, irritants and nonvesicants, according to their potential to cause local toxicity.(3–7)

Nonvesicants do not generally cause a local ­reaction on administration (aldesleukin, ­alemtuzumab, amifostine, asparraginase, BCG, ­bevacizumab, bleomycin, carboplatin, cetuximab, cladribine, cyclophosphamide, cytarabine, fludarabine, fluorouracil, ifosfamide, interferon, irinotecan, ­leucovorin, ­mercaptopurine, methotrexate, pemetrexed, ­raltitrexed, rituximab, thiotepa, topotecan, ­trastuzumab).(5,6)

Irritants can produce pain, burning or inflammation without necrosis when extravasated (­bortezomib, busulfan, carmustine, cisplatin < 0.4 ­mg/ml, ­dacarbazine, daunorubicin liposomal, docetaxel, doxorubicin liposomal, etoposide, ­gemcitabine, ­melphalan, oxaliplatin, teniposide).(5–6,8)

Vesicants can result in progressive and severe tissue destruction, produce significant pain and ultimately interfere with the affected ­extremity’s function (amsacrine, cisplatin > 0.4 mg/ml), ­dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mechlorethamine, melphalan, ­mitomycin, ­mitoxantrone, paclitaxel, vinblastine, vincristine, vindesine, vinorelbine).(5–6,8)

Some variations may exist between classification of cytotoxic medicines according to their potential to cause serious necrosis when extravasation occurs.

An extravasation should be suspected if one or
more of the following symptoms have occurred: the patient complains of burning, stinging or any ­discomfort/pain at the injection site; observation of swelling, redness or blistering at the injection site; no blood return is obtained or the flow rate is reduced; resistance is felt to the plunger of the syringe of a bolus drug; there is absence of free flow of infusion. If in doubt about a case one should treat it as extravasation. Treatment of extravasation injuries includes pharmacological measures, ­physiological measures and surgery.

Extravasation of certain cytotoxic agents during peripheral intravenous administration may cause severe local injuries. Most extravasation can be ­prevented with systematic implementation of ­careful administration techniques. However, ­management of this complication, the aim of which is to ­prevent progression to tissue necrosis and ulceration, remains an important challenge in the care of cancer patients. Many antidotes have been evaluated experimentally and a few may be able to reduce the local toxicity of the more common ­vesicant cytotoxic drugs. Because no randomised trial on the management of cytotoxic drug extravasation in humans has ever been completed, recommendations must be based on the more consistent experimental evidence and on cumulative clinical experience from available case reports and uncontrolled studies.

Background
Our aim was to develop a management algorithm for extravasations of cytotoxic agents using available up-to-date information as hospital protocols.

Methods
All available original publications, textbooks, summaries of product characteristics and ­manufacturers’ brochures were reviewed.

Results
An algorithm for the treatment of extravasation of cytotoxic agents was developed (see Figure 1).(5–10)

[[HPE33_fig1_84USE]]

Evidence-based guidelines are required for ­managing extravasation. These should include ­management of extravasation involving more than one cytotoxic chemotherapeutic drug.

The extravasation management algorithm devised was sent to the supervisors of the hospital for distribution to the appropriate staff. Clinical services have implemented the algorithm and found it very useful. The algorithm should be updated periodically.

Discussion
Extravasation is a rare but recognised complication of intravenous chemotherapy. The pathogenesis and mechanism of chemotherapy drug extravasations are not precisely understood. Tissue damage ­secondary to drug infiltration occurs as a result of one of two major mechanisms: (1) the drug is absorbed by local cells in the tissue and binds to critical structures, causing cell death; and (2) the drug does not bind to cellular DNA.

Damage to immediately adjacent tissue is more readily neutralised than is damage to surrounding tissue.(11) The type and extent of damage to local tissues depend on the properties of the cytotoxic agent, the excipients, and the amount extravasated.(12) The rate of healing after extravasation of cytostatic drugs is proportional to the size of the lesion and to the time at which therapy is started.(13) It is impossible to prevent this even though we take all possible precautions. Forethought, planning and improved prevention measures can minimise the risk of extravasation. The most important approach to extravasation is prevention, because the efficacy of local treatments after extravasation has not been established. Because no randomised trial on the management of cytotoxic drug extravasation in humans has been completed, recommendations must be based on the more consistent experimental evidence and on cumulative clinical experience from available case reports and uncontrolled studies.

Available data are often contradictory or ­cannot be reproduced; for this reason, prevention is a major goal. Early detection and urgent initiation of treatment is vital for the prevention of complications ­associated with the extravasation of cytotoxic agents. The more recent publications were used to develop the ­management algorithm. Most importantly:

  • It is vital to act promptly, acting in a manner that will not aggravate the injury but that offers prompt first-aid treatment.
  • If an extravasation is suspected, take immediate action as set out in the flow chart (see Figure 1).
  • Staff responsible for administering cytotoxic drugs should be informed and educated about the drugs, the problems they may cause in cases of extravasation, and the procedures to follow if this happens.
  • Extravasation kits should be standardised to meet the requirements and must be available within all areas where cytotoxic chemotherapy drugs are administered.
  • The patient’s cooperation should be solicited. All patients receiving the drug should be individually counselled and educated by nurses and pharmacists.

The authors would like to express their gratitude to the staff at the Oncology Day Hospital and Pharmacy Service of the Insular Hospital of Gran Canaria

References
1. Cox K, Stuart-Harris R, Abdini G, et al. The management of cytotoxic-drug extravasation: guidelines drawn up by a working party for the Clinical Oncological Society of Australia. Med J Aust 1988;148:185-9.
2. Ener RA, Meglathery SB, Styler M. Extravasation of systemic hemato-oncological therapies. Ann Oncol 2004;15(6):858-62.
3. Bertelli G. Prevention and management of extravasation of cytotoxic drugs. Drug Saf 1995;12(4):245-55.
4. Medical University of South Carolina. Work practice policy for personnel dealing with cytotoxic drugs. Charleston SC: MUSC; 2005.
5. Mader I, et al. Extravasation of cytotoxic agents: compendium for prevention and management. Vienna/NewYork: Springer; 2003.
6. British Columbia Cancer Agency. Extravasation of chemotherapy. Vancouver BC: BCCA; 2006.
7. Apisarnthanarax N, Duvic MM. Dermatologic complications of cancer chemotherapy. In: Kufe DW, Pollock RE, Weichselbaum RR, et al (eds). Cancer Medicine. Hamilton ONT: BC Decker; 2003: 2469-76.
8. Avon, Somerset and Wiltshire Cancer Services. ASWCS chemotherapy handbook. Bristol: ASWCS; 2005: 24-52.
9. 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;13:2851-5.
10. Cajaraville G, Tamés MJ. Guía de manejo de medicamentos citostáticos. Madrid: SANED; 2002.
11. Goolsby TV, Lombardo FA. Extravasation of chemotherapeutic agents. Semin Oncol 2006;33:139-43.
12. Martin VR, Walker FE, Goodman M. Delivery of cancer chemotherapy. In: McCorkle R, Grant M, Frank-Stromborg M, Baird SB (eds). Cancer Nursing. Philadelphia: WB Saunders; 1996: 395-433.
13. Tsavaris NB, Komitsopoulou P, Karagiaouris P,
et al. Prevention of tissue necrosis due to accidental extravasation of cytostatic drugs by a conservative approach. Cancer Chemother Pharmacol 1992;30:330-3.



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