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Drug Extravasation: Management summary and update

Introduction

Extravasation is defined as the leakage of a drug or solution from a vein into the extravascular space. Early signs and symptoms suggesting extravasation are persistent pain, burning, stinging, and erythema at the injection site or along the course of the vein. Extravasation of intravenous fluids may result in skin sloughing, tissue necrosis, thrombophlebitis, venous thrombosis, or severe consequences including functional impairment, disability, residual cosmetic defects, prolonged hospital stays, and increased morbidity. Patients who experience extravasation may require surgical debridement or skin grafting. The incidence of extravasation is 0.1% to 0.7% for all drug infusions, and as high as 6% for chemotherapeutic drug administrations. There is a higher rate (11%) of extravasation from administration of intravenous (IV) fluid in children.

Risk factors for extravasation

There are multiple factors that play an important role in the potential development and outcome of extravasation, including:

• Experience of personnel administering injection;
• Injection technique;
• Fragility of a patient’s veins and the condition of the surrounding skin;
• Number of venipuncture attempts prior to establishing an operational intravenous line;
• Specific drug characteristics: hypertonicity, nonphysiologic pH, high concentration, drugs that produce vasoconstriction and tissue ischemia, and intrinsic or direct cytotoxic effects. Cytotoxic drugs often are classified as either irritants, non-irritants, vesicants or non-vesicants. Irritants produce local irritation and venous pain, usually with no permanent tissue damage. On the contrary, vesicants have the potential to cause severe tissue damage and necrosis on extravasation. Generally, extravasation from nonvesicants rarely causes tissue damage.
• The severity of tissue destruction from extravasation depends on:
  • Type of drugs that leaks into the surrounding tissues, whether they are nonvesicants (asparaginase, bleomycin, methotrexate, rituximab, gemtuzumab ozogamicin), irritants (dacarbazine, docetaxel, irinotecan, oxaliplatin, etoposide), or vesicants (daunorubicin, doxorubicin, mitomycin, paclitaxel, vinblastine, vincristine);
  • High local concentration of the extravasant;
  • Area of the body with little subcutaneous tissue;
  • Increased volume and length of contact with tissue.

The best approach to extravasation injury is prevention. Preventive measures, such as appropriate dilution of medication, infusion of medication via the appropriate rate of administration, careful monitoring of infusions as they are being administered, use of clear tape or dressings to allow for visual inspection of infusion site, and immobilization of the extremity with the intravenous cannula are all possible means to prevent extravasation and its serious outcomes.

Non-pharmacologic interventions

For most medications, the treatment of extravasation is nonpharmacologic in nature; the efficacy of any specific approach has not been demonstrated in controlled studies. The recommended approach to the treatment of extravasation includes the following steps:

1. Stop the intravenous push or infusion immediately if the patient admits to a burning sensation or complains of pain.
2. The catheter or needles should not be removed immediately, but should be left in place to attempt aspiration of fluid from the extravasated area. Aspiration of the drug and surrounding fluid should be attempted with three to five milliliters (mL) of blood.
3. Remove the needle.
4. Elevate the affected limb to minimize swelling.
5. Apply warm or cold compresses as indicated. This decision is usually based on physician preference and the type of drug extravasated.
   • In general, cold compression is recommended for extravasation of all vesicant or irritant drugs, EXCEPT the vinca alkaloids (vincristine, vinblastine, vinorelbine) and epipodophyllotoxins (etoposide), as cold worsens tissue ulceration caused by these drugs.
   • Cold compresses should be applied for 20 minutes three or four times daily for the first 48 to 72 hours after extravasation occurs. Cold compresses cause vasoconstriction resulting in diminished spread of the extravasate. It also reduces local inflammation and pain.
   • Hot compresses are sometimes preferred for specific drug extravasation (i.e. vinca alkaloids) to increase local blood flow and enhance drug removal.
6. Debridement and excision of necrotic tissue should be considered if pain continues for 1-2 weeks.

Antidote administration for extravasations

For some medications, nonpharmacologic management of extravasation is insufficient based on clinical presentation and specific pharmacologic antidotes are used. The goal of antidote administration is to reverse the action of the extravasated agent, interfere with process of cell destruction, prevent tissue necrosis, or limit the extent of tissue damage. The efficacy of antidotes has been evaluated primarily from animal studies or reported anecdotally based on human experience; therefore, their true efficacy is unknown. Examples of antidotes used in the treatment of extravasation are briefly summarized in the section below:

• Sodium thiosulfate. This is an accepted antidote for mechlorethamine (nitrogen mustard) extravasation. Sodium thiosulfate 1/6 molar (0.16 M) solution, injected subcutaneously, is the only antidote currently recommended by the Oncology Nursing Society for extravasation of mechlorethamine. The recommendations are based largely on in-vitro data demonstrating a chemically neutralizing interaction of thiosulfate with mechlorethamine, and in animal data demonstrating the ability of thiosulfate to inactivate mechlorethamine.
• Hyaluronidase. This agent is an enzyme that degrades hyaluronic acid. It modifies connective tissue permeability and enhances drug resorption from subcutaneous tissues. Animal and human studies supported the efficacy of hyaluronidase as an antidote of extravasation from vinca alkaloids.
• Dimethyl sulfoxide (DMSO) is believed to exert its antioxidant action via free radical scavenging, causing potent vasodilation, pain reduction, anti-inflammatory action, and stabilization of the cell membrane. Topical application of DMSO may be effective against anthracycline-induced tissue damage because of its ability to scavenge anthracycline-generated free radicals. Various applications have been used with DMSO concentrations of 50% to 99% solutions applied topically every 3, 4, 6, or 8 hours for 7 to 14 days. The side effects of topical DMSO are mild, including mild burning and skin scaling, and unpleasant garlic-like odor.
• Dexrazoxane is used to prevent anthracycline-induced cardiotoxicity. The mechanism responsible for its cardio-protection is unclear, possibly via the attenuation of free radical formation and intracellular chelation. Dexrazoxane is a topoisomearse II catalytic inhibitor with potential use after extravasation of anthracyclines. Systemic use (IV or intraperitoneal) in mice was found effective in decreasing the incidence and duration of lesions produced after anthracycline extravasation.
• Discredited antidote. Topical corticosteroids were advocated for anthracycline extravasation in the past, due to its anti-inflammatory action. However, only few inflammatory cells are found in tissues damaged by extravasation. Therefore, topical steroids are currently considered ineffective and may be harmful, as it can lead to greater skin ulceration after anthracycline or vinca alkaloid extravasation.

Treatment recommendations for extravasation

The treatment of extravasation due to cytotoxic agents and non-cytotoxic agents are summarized below in Tables 1 and 2; this information is based on published literature and tertiary drug information databases.

Table 1. Pharmacologic Therapy for Extravasation of Cytotoxic Drugs

^aPrepare a 0.16 Molar (mole/liter ) solution by mixing 4 mL sodium thiosulfate 10% solution with 6 mL sterile water for injection.

^bHyaluronidase injection is available as lyophilized powder requiring reconstitution and as a ready for use solution. After reconstitution with normal saline, hyaluronidase should be further diluted with normal saline to the desired concentration, commonly 150 units/mL. Reconstitued hyaluronidase should be used immediately or at least within 6 hours of reconstitution.

^cReported dose of dexrazoxane used for anthracyclines extravasation is 1000 mg/square meter (m²)as an IV infusion within 6 hrs, 1000 mg/m² on the second day, and 500 mg/m² on the third day.

Table 2. Pharmacologic Therapy for Extravasation of Non-cytotoxic Drugs

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Yosowitz P, Ekland DA, Sharw RD. Peripheral intravenous infiltration necrosis. Ann Surg 1975; 182:553-6.

Brown AS, Hoelzer DJ, Piercy Sa. Skin necrosis from extravasation of intravenous fluids in children. Plastic & Reconstructive Surgery 1979;64:145-150.

Wang RS: Antineoplastics. In: Goldfrank LR, Flomenbaum N, Hoffman RS, et al, eds. Goldfrank's Toxicologic Emergencies. 8th ed. McGraw Hill, New York, NY, 2006.

Jensen JN, Lock-Andersen J, Langer SW, et al: Dexrazoxane -- a promising antidote in the treatment of accidental extravasation of anthracyclines. Scand J Plast Reconstr Surg Hand Surg. 2003;37:174-5.

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By: Kwanta Na-Thalang, PharmD