RESPONSE

Extravasation, the accidental leakage of intravenous fluid into the interstitial tissue, can result in severe injury with subsequent functional impairment and residual cosmetic defects. While 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 ^[1][2][3]. Most cases in the non-oncologic setting, however, usually occur without serious consequences ^[1].
Extravasation injury can result from a combination of factors, such as 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 ^[1][3].
Populations at risk include infants and children who are too young to communicate the pain resulting from the pressure of extravasated fluid, the elderly, comatose patients, individuals under general anesthesia, and those receiving cardiac resuscitation. Other factors associated with the development of extravasation include the number of venipuncture attempts required to establish an intravenous line, the type of intravenous cannula employed, the specific site of injection, certain disease states (ie, peripheral vascular disease, patients with elevated venous pressure), the use of infusion pumps, and a history of radiation to the injection site. Patients with abnormal circulation in the limb to be injected, such as peripheral vascular disease, diabetic vascular disease, Raynaud phenomenon, venous thrombosis, ipsilateral regional lymph node dissection, or prior radiation to the injection limb, are also at risk of developing extravasation. Injection through metal needles is more likely to cause extravasation than plastic cannulae. The dorsum of the hand, and the dorsum of the foot or ankle are common sites of injury ^[4][5][3].
The degree of damage varies depending on the localization of the extravasation, the physicochemical characteristics of agent administered, duration and amount of exposure, and patient's general health. The initial presentation of pain, swelling, or local hyperthermia is not reliable predictors of the degree of tissue damage as late signs of extravasation, such as induration of the skin, ulcers, or paresthesia may appear days later. Thus, it is important to distinguish between local reaction and extravasation, and not to under-estimate the risk for subsequent tissue damage ^[1].
The treatment of extravasation injuries resulting from the infiltration of certain drugs and solutions involves the use of specific antidotes (see Table 1). The management of extravasation of chemotherapeutic agents has been published elsewhere ^{[1][4][6][7][8][9]}.
Drugs that have been reported to cause damage upon infiltration, but for which no specific medical treatment could be found, are not discussed in this article.
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 ^[1][3].
SPECIFIC AGENTS
Hyperosmolar solutions (eg, parenteral nutrition, conventional ionic contrast media) exert osmotic pressure, and may result in compartment syndrome if infiltration occurs ^[1][4][3].
Hypertonic solutions (eg, potassium chloride, calcium chloride, dextrose 10%, radiocontrast media) may cause prolonged depolarization and contraction of pre- and post-capillary smooth muscle sphincters, leading to tissue injury and ischemia ^[1][4][3](Lang, 1996)^{[10][11][2][12][12][13][14]}.
Ischemic necrosis secondary to local vasoconstriction can result from extravasation of sympathomimetic agents including dobutamine, dopamine, epinephrine, metaraminol, and norepinephrine ^{[1][11][15][16][10][17][2][18]}.
The irritant properties of nafcillin can be responsible for severe tissue injury following infiltration ^{[10][19][20][21]}.
MANAGEMENT
If extravasation occurs, the infusion should be immediately discontinued and, when available, a specific antidote administered.
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 ^[6].
ELEVATION AND SPLINTING: Elevation of the affected area may provide adequate treatment for minor injuries and may prevent serious complications ^{[4][3][2][11]}. In 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: Recommendations for application of heat or cold vary. Heat can increase drug distribution and absorption by inducing vasodilation. However, use of warm, moist compresses has resulted in maceration and subsequent tissue necrosis. Application of cold packs, through vasoconstriction and localization of the extravasated fluid, may be helpful if an antidote were to be locally injected; however, if no antidote is available, cold packs may result in more severe tissue damage at the site of infiltration ^[4][7]. For the treatment of contrast media extravasation, most studies recommend the application of cold compress. Ice packs can be applied for 15 to 60 minutes 3 to 4 times daily for 1 to 3 days, or until symptom resolution ^[3].
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 ^[1](Lang, 1996). Liposuction and saline lavage dilutes has been used successfully in the management of significant extravasation injuries (stage III to IV)^[22].
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 ^[3].
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 ^[1][3].
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 ^[7]. 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 ^[3].
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 ^[4][3].
HYALURONIDASE (Wydase(R) ): 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 ^[1][17]. The recommended concentration of hyaluronidase ranges from 15 to 250 units diluted in 1.5 to 6 milliliters (mL) of fluid ^[4]. 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 listed in Table 1 ^[3][17]. It also has been used successfully in the acute management of phenytoin extravasation in a 14-month-old boy ^[23]. Local subcutaneous injection of hyaluronidase could be used for the management of large extravasation of high or low osmolality contrast medium ^[4].
RECONSTITUTION/DILUTION:
IMPORTANT NOTE: Hyaluronidase injection is available as a lyophilized powder requiring reconstitution (Vitrase(R) lyophilized) and as a ready for use solution (Vitrase(R) 200 USP units/milliliter, Amphadase(R) 150 USP units/milliliter, and Hydase(TM) 150 USP units/milliliter) ^[24][25][26].
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 ^[24].
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 ^[24].
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. Afterwards, remove the filter needle and apply a needle appropriate for the intended injection ^[24]:

mL= milliliters
Reconstituted hyaluronidase should be used immediately or at least within 6 hours of reconstitution ^[24].
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 ^[27].
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 ^{[1][7][18][28]}(Prod Info, 1981).
SILVER SULFADIAZINE (Silvadene(R)): 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 ^{[4][3][11][28]}. 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 ^[5].

 CONCLUSION

Prevention of extravasation is preferable to treatment of the resultant tissue damage. Recommendations include: 1) appropriate dilution and rate of administration of drugs; 2) proper placement and location of intravenous sites (ie, avoidance of extremities with poor venous circulation); 3) proper splinting of the extremity while an intravenous cannula is in place to immobilize the extremity without constriction and prevent the cannula from tearing or eroding through the vessel; 4) careful and frequent monitoring of solutions administered by infusion pumps (at least hourly, and every few minutes during the infusion of irritating drugs) and; 5) use of transparent dressings and clear tape to allow inspection of the injection site^{[4][3][7][28][2][11]}.
When extravasation does occur, rapid administration of an appropriate antidote, elevation of the affected area, proper splinting of the extremity, use of silver sulfadiazine cream on areas of tissue necrosis, and surgical intervention as indicated can minimize tissue injury. The initial presentation often is not indicative of the extent of tissue damage, so the wait and see approach should be avoided, particularly with extravasation of vesicants, whether a typical antineoplastic agent or hyperosmolar solutions ^[1][4][3].

 Reference

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24. Product Information: Vitrase(R), hyaluronidase for injection. Cardinal Health, Albuquerque, NM, 2004.

25. Product Information: Amphadase(TM), hyaluronidase injection. Amphastar Pharmaceuticals, Inc., Rancho Cucamonga, CA, 2004.

26. Product Information: HYDASE(TM) injection, hyaluronidase injection. PrimaPharm Inc, San Diego, CA, 2005.

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28. Zenk KE: Management of intravenous extravasations. Infusion 1981; 5:77-79.

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