Non-Cytotoxic Drugs

Serious extravasation injury is less commonly seen with non-cytotoxic agents, cases associated with surgical debridement and skin grafting, prolonged hospitalization and increased morbidity have been reported. Most cases in the non-oncologic setting, however, usually occur without serious consequences. This types of injury is most often seen in regards to solution osmolality, vasoconstrictor properties of the offending agent, electrolyte concentration, infusion pressure, regional anatomical peculiarities, site of injection, amount of agent extravasated, duration of tissue exposure and other patient factors .
Consultation with a plastic surgeon should be considered when encountering severe skin and subcutaneous tissue injury, when vesicant is not removed within the first 24 hours of extravasation, when extravasated volume of conventional ionic contrast media exceeds 30 milliliters (mL), or extravasated volume of non-ionic contrast media exceeds 100 mL .

SPECIFIC AGENTS

Hyperosmolar Solutions

Hypertonic Solutions

Sympathomimetic agents

Parentaral Nutritition

Potassium Chloride

Dobutamine

Conventional Ionic Contrast Media

Calcium Chloride

Dopamine

Dextrose 10%

Epinephrine

Radiocontrast Media

Metaraminol

Norepinephrine

MANAGEMENT

1) Stop the infusion immediately. Do not flush the line, and avoid applying pressure to the extravasated site.
2) Elevate the affected extremity.
3) The catheter/needle should not be removed immediately. Instead, it should be left in place to attempt to aspirate fluid from the extravasated area and to facilitate the administration of an antidote to the local area, if appropriate.
4) If an antidote will not be injected into the extravasation site, the catheter/needle can be removed after attempted aspiration of the subcutaneous tissues.

CANNULA REMOVAL

Recommendations are equivocal. Guidelines exist for both immediate removal of the needle, as well as for its continued use as an access route to aspirate the extravasated solution before administering an antidote

ELEVATION AND SPLINTING

Elevation of the affected area may provide adequate treatment for minor injuries and may prevent serious complications. addition, early and proper splinting of the injured area will facilitate resolution of swelling and prevent long-term damage and disability of the extremity.

COMPRESSES

Topical application of ice or cold packs is recommended for extravasation of all vesicant or irritant drugs except the vinca alkaloids (Vincristine, Vinblastine, Vinorelbine) and epipodophyllotoxins (Etoposide), heat is reocmmended for these agents. THe subseqrnt vasodilation increased blood flow to area increasing the rate of drug removal. Intermittent cooling is thought to cause vasoconstriction, thereby diminishing the spread of the drug and the extent of the local injury. It is used for its anti-inflammation and analgesic effects as well. Ice packs can be applied for 15 to 60 minutes 3 to 4 times daily for 1 to 3 days, or until symptom resolution. Heat can increase drug distribution and absorption by inducing vasodilation. However, use of warm, moist compresses has resulted in maceration and subsequent tissue necrosis.

FLUSHING

The area of extravasation can be flushed with normal saline. One recommendation is to place 4 small scalpel punctures or stab incisions around the site. After inserting a blunt needle, flush with approximately 500 milliliters (mL) of saline as soon as extravasation occurs or within 24 hours. Make sure that saline and extravasate exit though the holes. Other variations can be to use a pediatric peritoneal dialysis tube for flushing or the use of a liposuction device. Liposuction and saline lavage dilutes has been used successfully in the management of significant extravasation injuries (stage III to IV).

SURGICAL DRAINAGE

If ionic contrast media extravasation exceeds 20 milliliters (mL) in volume, surgical drainage within 6 hours should be considered. Treatment should be individualized if the extravasated volume is between 5 mL and 20 mL

PREVENTION

Inject vesicants by reliable peripheral venous access, preferably on the forearm instead of the dorsum of the hand. Consider administration of vesicants through the most distal port if a central venous catheter is in place. Check all venous accesses regularly, and educate patients about abnormalities in connection with venous access cannulas. Prevention and early detection of extravasation are some of the best defense against tissue injury related to extravasation.

For peripheral infusions of chemotherapy, the IV line should be recently started, and the vein selected should be large and intact, with good blood return established prior to starting the infusion.

Infusion sites should be selected in the following order of preference: forearm (basilic, cephalic, and median antebrachial), dorsum of hand, wrist, and antecubital fossae.

The butterfly needle or plastic cannula should be secured to the skin with tape. Taping of the entry site itself should be avoided so that the area can be examined. Instead, once the hub of the cannula or butterfly needle is secured to the skin with tape, a clear dressing such as Tegaderm is usually applied to cover the skin entry site.

The patency of the IV line should be verified just prior to drug infusion by flushing with 5 to 10 mL of isotonic saline or a 5 percent dextrose solution.

The chemotherapeutic agent, appropriately diluted, should be infused through the side arm of the freely-flowing IV with isotonic saline or 5 percent dextrose. During the infusion, patients should be closely monitored for pain (often described as mild to severe burning radiating along the vein), and the site inspected for erythema or swelling.

Use of a central venous catheter for infusion of vesicant drugs provides reliable venous access, high flow rates and rapid drug dilution. However, these vascular access devices are subject to a number of complications, including drug extravasation. The catheter tip may not be properly positioned in the superior vena cava or right atrium, it may migrate out of position, the needle may be improperly inserted into the injection port, or the catheter itself may be punctured or rupture. One report found a 6.5 percent rate of extravasation from subcutaneous ports, a value that is similar to that reported for peripheral lines.

SPECIFIC AGENTS FOR TREATMENT OF NON-CYTOTOXIC EXTRAVASATIONS

CORTICOSTEROIDS

The use of corticosteroids as anti-inflammatory agents in extravasation injuries is based upon recommendations for the treatment of infiltrations of cancer chemotherapeutic agents. Hydrocortisone sodium succinate and dexamethasone sodium phosphate are most frequently utilized.Conflicting results exist regarding the use of local or systemic corticosteroids after extravasation of radiographic contrast media. If used, the beneficial effect is expected to be mild.

DIMETHYL SULFOXIDE (DMSO)

While DSMO may offer antibacterial, vasodilatory, anti-inflammatory, and analgesic effects, it has not been proven for treating extravasation of radiographic contrast media.

HYALURONIDASE

Hyaluronidase is an enzyme that temporarily decreases the viscosity of hyaluronic acid, the ground substance or intracellular cement of the tissues. Subcutaneous administration of hyaluronidase increases permeability into the tissues and facilitates absorption of the infiltrated solution by allowing diffusion of extravasated fluid over a larger area. This minimizes tissue injury through rapid absorption and dilution in tissue fluids. The enzyme has an almost immediate onset of action and a 24 to 48 hour duration of effect on the "tissue cement." Allergic reactions, usually manifested as urticaria, occur rarely; otherwise, clinical reports emphasize minimal or lack of toxicity. The enzyme should not be injected into cancerous or acutely inflamed areas since there is a potential for disseminating infection or increasing the invasiveness or metastasis of neoplasms.

The recommended concentration of hyaluronidase ranges from 15 to 250 units diluted in 1.5 to 6 milliliters (mL) of fluid. After cleansing the infiltration site and surrounding area with povidone-iodine, approximately five 0.2-mL injections (of 15 units/mL) are administered subcutaneously or intradermally into the leading edge of the extravasation site, using a 25-gauge needle. The needle should be changed after each injection. A dose of 30 units has been used for severe, large infiltrates. Doses less than 15 units have been employed in preterm infants weighing less than one kg. Swelling is usually significantly decreased within 15 to 30 minutes following hyaluronidase administration. The enzyme must be used promptly, ie, within 60 minutes of the infiltration, since the potential for tissue damage increases with the duration of exposure to extravasated fluid.
Hyaluronidase has been used successfully to prevent tissue injury due to infiltration of both nafcillin and the hyperosmotic agents. It also has been used successfully in the acute management of phenytoin extravasation in a 14-month-old boy.Local subcutaneous injection of hyaluronidase could be used for the management of large
extravasation of high or low osmolality contrast medium.

NITRATES

Transdermal application of nitroglycerin patch 5 milligrams per day (mg/d) daily close to the infusion site have demonstrated a reduction in infusion failure rate, including phlebitis, extravasation, and/or an irregular infusion rate in 2 prospective, double-blind, randomized clinical trials. While the mechanism is unknown, it has been theorized that vasodilation and increased capillary blood flow may help reverse tissue ischemia due to phlebitis- or extravasation-related injuries. Prophylactic use of transdermal nitroglycerin, therefore, may be considered for patients requiring long-term intravenous therapy for at least 50 hours in duration to prevent infusion failures associated with phlebitis or extravasation. Headache has been the most commonly reported adverse effect with such use.

PHENTOLAMINE

Phentolamine, an alpha-adrenergic blocking agent, is used to treat extravasation of sympathomimetic agents. Competitive inhibition of the alpha effects of these drugs decreases local vasoconstriction and the resultant ischemia. The recommended dose of phentolamine is 5 to 10 mg, diluted in 10- to 15-ml sodium chloride 0.9%, injected with a fine hypodermic needle into the area of extravasation (defined by its cold, hard and pale appearance). Phentolamine should be administered within 12 hours of the infiltration; however, it is preferable to treat the injury as soon as possible. Phentolamine has been used successfully to prevent tissue injury due to infiltration of vasoconstricting agents listed in Table 1.

SILVER SULFADIAZINE

Surgical evaluation and management should be considered when there is evidence of tissue necrosis or blistering. Application of silver sulfadiazine cream could prevent wound infections resulting from bacterial colonization of these areas. Topical use of silver sulfadiazine with chlorhexidine 0.2% to 0.5% cream dressings has been shown to be effective in managing extravasation injuries from isotonic dextrose 4%-saline 0.18%, calcium gluconate , parenteral nutrition containing 20% lipid, sodium bicarbonate, human immunoglobulin, gentamicin and penicillin, and flucloxacillin in a case series.

RECONSTITUTION/DILUTION

Hyaluronidase (Vitrase(R)) is reconstituted by adding 6.2 milliliters (mL) of sodium chloride injection to the vial of lyophilized hyaluronidase, yielding a concentration of hyaluronidase 1000 units/mL. After reconstitution, hyaluronidase should be further diluted to the desired concentration, commonly 150 units/milliliter. The following table shows amounts of hyaluronidase and sodium chloride injection needed for various concentrations. A 1-milliliter (mL) syringe and a 5 micron filter needle are supplied with hyaluronidase. Following reconstitution of Vitrase(R), apply the 5-micron filter needle to the 1-mL syringe. Draw the desired amount of reconstituted hyaluronidase into the syringe and dilute according to the table below.

Desired Concentration

Hyaluronidase Reconstituted Solution (1000 units/mL)

Additional Sodium Chloride Injection

15 units/mL

0.015 mL

0.985 mL

50 units/mL

0.05 mL

0.95 mL

75 units/mL

0.075 mL

0.925 mL

150 units/mL

0.15 mL

0.85 mL

300 units/mL

0.3 mL

0.7 mL

**Reconstituted hyaluronidase should be used immediately or at least within 6 hours of reconstitution

Table 1.

Specific Agents Used to Treat Extravasation

Extravasated Drug

Drug Treatment

Dose

Hyperosmotic Solutions:

Calcium

Hyaluronidase

15 units/mL in normal saline (5 injections of 0.2 mL each)

Dextrose 10%

Parenteral Nutrition: Potassium

Radiocontrast media

Nafcillin, Penicillin, Aminophylline

Hyaluronidase

15 units/mL in normal saline (5 injections of 0.2 mL each)

Sympathomimetics:

dobutamine

Phentolamine

5 to 10 mg in 10 to 15 mL normal saline

dopamine

epinephrine

metaraminol

norepinephrine

Table 2

Recommended treatment regimens for cytotoxic drug extravasations

Drug

Treatment

Route

Frequency

Vinca alkaloids (vinblastine, vincristine, vinorelbine)

Heat

Topical

15 min on, 15 min off

Epidophyllotoxins (eg, etoposide)

Hyaluronidase

SC

1 mL (150 units) once

Anthracyclines (daunorubicin, doxorubicin, epirubicin, idarubicin)

Cold

Topical

30 to 60 mins, then every 15 min

DMSO* 50 percent

Topical

Dexrazoxane

IV

1000 mg/m² within six hours, 1000 mg/m² after 24 hours, and 500 mg/m² after 48 hours

Liposomal anthracyclines (daunorubicin, doxorubicin)

Cold

Topical

Mitomycin

Cold

Topical

30 to 60 mins, then every 15 min

DMSO* 50 percent

SC and Topical

Taxanes (docetaxel, paclitaxel)

Cold

Topical

30 to 60 mins, then every 15 min

Hyaluronidase

SC

1 mL (150 units) once

Mechlorethamine

Cold

Topical

30 to 60 mins initially, then every 15 min

Cisplatin

Dacarbazine

SC

One time dose

Other agents

Cold

Topical

30 to 60 mins initially, then every 15 min

* Specific benefit of this concentration of DMSO unclear.

**  Optimal duration of DMSO application uniknown; some authors recommend 7 to 14 days (American Society of Health-System Pharmacists), while others recommend "at least a few days") (Albanell, J, Semin Oncol 2000; 27:347).