Extravasation of Drugs

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DESCRIPTION

Extravasation, or infiltration, is the leakage of intravenously infused fluids from the vein.

PATHOPHYSIOLOGY

Hyperosmolar Agents. Hypertonic cation-containing solutions (e.g., potassium chloride or calcium chloride), high-concentration dextrose solutions (10% or greater), hyperalimentation, and radiographic contrast media are thought to cause damage due to hyperosmolality.
Vasoconstriction. Vasopressors (e.g., dopamine or epinephrine) cause vasoconstriction-induced ischemic necrosis.
Direct Cytotoxicity. Chemotherapeutic drugs and some antibiotics (e.g., nafcillin, tetracycline) are directly cytotoxic to subcutaneous tissue.
Mechanical Compression. Large-volume extravasation of nontoxic solutions can cause mechanical compression.
pH. Tissue injury can result from the high pH of an infiltrate (e.g., acyclovir pH 10.5-11.6, aminophylline pH 9, phenytoin pH 10-12.3).
Infection. Tissue injury may predispose to infection and secondary tissue damage.

EPIDEMIOLOGY

Extravasation is common; the incidence ranges from 0.1% to 6%.
Extravasation incidence rates are higher for children and infants: 11% and 57% to 63%, respectively.
About 2% of patients with extravasation develop serious injury.
Extravasation occurs more often during surgery or cardiac resuscitation than in other settings.

CAUSES

The primary cause of extravasation injury is phlebitis.
Other causes of extravasation are mechanical: metal needles (e.g., butterfly needles), poor insertion technique, pressurized infusion pumps, or improper immobilization of the catheter or needle.

RISK FACTORS

Noncommunicative (very young or old, unconscious) patients are at risk for extravasation.
Severely debilitated or chronically ill patients (e.g., marked weight loss or extensive metastatic disease) are also at risk.
Patients with abnormal limb circulation (e.g., vascular disease, connective tissue disease, venous thrombosis or insufficiency, tourniquets, prior radiation to the limb or regional lymph node dissection) are at increased risk.
Multiple punctures of the same vein increase the risk for extravasation.
Injections on the ankle or the dorsum of the foot or hand also increase the extravasation risk.
Use of indwelling intravenous lines increases the risk for extravasation.
Injections through needles, as opposed to plastic catheters, increase extravasation risk.
Patients with underlying disease have greater risk of developing serious injury if extravasation occurs.

Section Outline:

DESCRIPTION
PATHOPHYSIOLOGY
EPIDEMIOLOGY
CAUSES
RISK FACTORS

Diagnosis ⬆ ⬇

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DIFFERENTIAL DIAGNOSIS

Further information on each poison is available in SECTION IV, CHEMICAL AND BIOLOGICAL AGENTS.

Antineoplastic agents that cause extravasation injury include aclacinomycin, amsacrine (M-AMSA), bisantrene, bleomycin, carmustine (BCNU), chlorzotocin, cyclophosphamide, cytarabine (Ara-C), dacarbazine (DTIC), dactinomycin (actinomycin D), daunorubicin (DNR), doxorubicin (ADR), etoposide (VP-16), fluorouracil (5-FU), mechlorethamine (nitrogen mustard), mitomycin (mitomycin-C), mitoxantrone, PALA, plicamycin (mithramycin), rubidazone, streptozocin, teniposide, vinblastine (VBL), vincristine (VCR), and vindesine (VDS).
Other agents that cause extravasation injury include acyclovir, aminophylline, hyperosmolar agents (urea 30%, dextrose solutions greater than 10%, mannitol, parenteral nutrition solutions), calcium salts, methylene blue, nafcillin, phenytoin, potassium salts, radiography contrast media, radiopharmaceuticals, sodium bicarbonate, sympathomimetic vasopressors (dopamine, dobutamine, epinephrine, metaraminol, methoxamine, norepinephrine, phenylephrine), tetracycline, thiopental, thrombolytic agents (streptokinase, urokinase, alteplase), heparin, and vasopressin.
Flares
- Local reactions called "flares" (pruritic, raised, red streaks 6-8 cm long along the course of the injected vein) should be differentiated from extravasation. Flares occur in the extremity through which an agent (doxorubicin, crotalid snake antivenom) is injected; these reactions develop within minutes and generally resolve in 30 to 90 minutes.
- Flares are distinguished from extravasation by lack of pain or swelling.
- If flares develop, the health-care provider should ensure that the catheter is functioning normally and extravasation has not occurred.

SIGNS AND SYMPTOMS

The patient may be minimally symptomatic if the extravasated fluid is isotonic, or if the total extravasated volume is small.
More severe symptoms include local irritation, erythema, edema, paresthesia, pain, altered tissue perfusion (e.g., change in skin color, decreased pulses, or capillary refill), change in sensation, skin ulceration, blistering, tissue necrosis, and damage to adjacent tendons, blood vessels, and nerves.
Necrosis may be the first sign that extravasation has occurred.

PROCEDURES AND LABORATORY TESTS

Appropriate laboratory studies for the drug involved should be obtained.

Section Outline:

DIFFERENTIAL DIAGNOSIS
SIGNS AND SYMPTOMS
PROCEDURES AND LABORATORY TESTS

Treatment ⬆ ⬇

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The severity of extravasation should be assessed.
Nonpharmacologic treatment should be initiated while the need for pharmacologic therapy is determined.

ANTIDOTES

Phentolamine, an alpha-receptor antagonist, is the specific antidote for vasopressor extravasation.

Therapeutic dose is 5 to 10 mg diluted in 10 ml of normal saline, infiltrated into the ischemic area within 12 hours of extravasation.
In infants, no more than 5 mg should be used.

ADJUNCTIVE TREATMENT

Nonpharmacologic Treatment

Needle aspiration of fluid from the site removes only minimal amounts; nonetheless, many clinicians recommend attempting fluid aspiration via the needle through which the extravasation occurred, before the needle is removed.
The affected extremity should be elevated above the level of the heart.
Heat or cold application. The use of either heat or cold packs remains debatable and some clinicians discourage their use. Heat is thought to enhance vasodilation and resorption; locally induced hyperthermia, however, could cause the chemical to spread and potentially increase tissue damage. Cold is thought to produce vasoconstriction, localizing the effect of extravasation.
Cold packs
- An ice pack may be applied for 15 to 60 minutes three to four times a day for 1 to 3 days or until symptoms resolve.
- Cold packs should be avoided in vinca alkaloid extravasation.
- Moist towels or soaks should be avoided because moisture may cause maceration of the skin.
Heat
- Specific protocols for heat application are not well described; application of dry, moderate heat has been used.
- Heat is recommended if extravasation involves vinca alkaloids, and it should be avoided with doxorubicin.

Pharmacologic Treatment

When blistering occurs, silver sulfadiazine has been recommended to prevent local superinfection.
- Silver sulfadiazine should be applied twice daily beneath a gauze dressing.
- The wound should be cleansed with soap and water to remove old silver sulfadiazine before reapplication.
Saline injection to dilute the extravasated fluid may decrease concentration and potentially reduce toxicity.
- A study involving saline injections of 20 to 90 ml between three and six times over several days into the sites of various chemotherapeutic drug extravasations found that the majority of patients healed without the need for surgery. (This study also used local cooling and systemic antiinflammatory drugs.)
- Local dilution is not uniformly recommended because of concern that administration of additional fluid could cause or worsen mechanical trauma.
Hyaluronidase hydrolyzes hyaluronic acid (a component of connective tissue).
- Subcutaneous administration decreases local tissue damage by allowing the irritant material to disperse through a larger area, facilitating absorption into the vascular and lymphatic systems.
- Hyaluronidase is most effective if given within 1 hour of extravasation, and works within minutes of injection; connective tissue returns to normal after 24 to 48 hours.
- Doses of 150 to 300 U diluted in 1.5 to 6.0 ml of fluid have been used in most studies.
- Hyaluronidase is potentially effective in treating extravasation injuries caused by hypertonic saline, calcium salts, nafcillin, penicillin, aminophylline, potassium salts, mannitol, sodium bicarbonate, many chemotherapeutic agents (doxorubicin, vincristine, vinblastine), and radiographic contrast material.
Dimethyl sulfoxide (DMSO) is a free oxygen radical scavenger and an excellent solvent (penetrates through tissue planes, conceivably carrying toxic agent with it); DMSO possibly produces antibacterial, vasodilatory, antiinflammatory, and analgesic effects.
- DMSO use is controversial, but the drug may have utility in the treatment of extravasation injury due to anthracycline chemotherapeutic agents (e.g., doxorubicin) because of its free radical scavenging activity.
- DMSO 15 ml (50% to 99% solution) has been used topically every 2 to 4 hours for about 3 days with or without concurrent use of alpha-tocopherol.
Topical proteolytic enzymes
- Fibrinolysin/deoxyribonuclease (Elase) ointment may be an alternative to surgical debridement of partial- or full-thickness skin damage due to extravasation injury; after removal of loose tissue, Elase is applied every 8 hours for about 1 week.
- Travase ointment also may have a role in this capacity, although further study is needed.
Vasodilators other than phentolamine. Nitroglycerin paste (2%) dilates vascular smooth muscle.
- Nitroglycerin paste has chiefly been studied in infants; good results were seen after application of nitroglycerin paste topically (4 mm/kg).
- Topical nitroglycerin exhibits effects for 3 to 6 hours after administration, which could be a theoretical advantage over the shorter acting phentolamine.
Corticosteroids (e.g., hydrocortisone or dexamethasone) have been used to blunt the inflammatory response of extravasation; although results are conflicting, most studies have failed to show that steroid injections are of value in treating extravasation injury.
Corticotropin releasing factor (CRF) has demonstrated effectiveness in decreasing the acute inflammatory reaction associated with experimental eyelid injection of doxorubicin.
- Doses of 75 to 150 µg reduced the acute influx of monocytes and macrophages and protected the skin overlying the injection site.
Sodium thiosulfate is used for the treatment of injury produced by nitrogen mustard agents.
- The dose is 6.2 ml of a 1 g/10 ml solution, diluted with sterile water to a volume of 15 ml, injected into the infiltration site.
- Sodium thiosulfate is thought to prevent tissue necrosis by inactivation of free radicals.
- Infiltration with 8.4% sodium bicarbonate solution may decrease toxicity by increasing local pH and possibly preventing drug/DNA complexing; sodium bicarbonate, however, is itself toxic when extravasated and should not be used routinely.
- N-acetylcysteine and granulocyte/macrophage colony-stimulating factor (GM-CSF) have been beneficial in treating extravasation injury due to chemotherapeutic agents in some studies but not in others.
- Ineffective agents. Published studies have failed to demonstrate benefit from locally injected alpha-tocopherol, cimetidine, diphenhydramine, heparin, lidocaine, or procaine in alleviating the severity of chemotherapeutic agent extravasation.

Surgical Treatment

Surgical treatment of an extravasation injury is generally effective.
Surgical drainage has been recommended when radiographic contrast material is involved.
Early excision may be of benefit for chemotherapeutic agents.
Saline flushout and liposuction have been used successfully in recent studies.

Section Outline:

ANTIDOTES
ADJUNCTIVE TREATMENT

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Basics ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pitfalls ⬆ ⬇

Miscellaneous ⬆