- Email: [email protected]
Extravasation Injuries
CURRENT CONCEPTS
Extravasation Injuries Michael G. Hannon, MD, Steve K. Lee, MD Extravasation injuries occur under a wide variety of circumstances in the inpatient setting. Prevention remains the ideal treatment for these iatrogenic injuries. When extravasation injuries do occur, they must be diagnosed and treated promptly to minimize the amount of soft tissue injury. Initial management is similar among vesicant extravasates. Although evidence is limited to guide management for specific extravasates, it is paramount to be aware of the described treatments and principles. (J Hand Surg 2011;36A:2060–2065. Copyright © 2011 by the American Society for Surgery of the Hand. All rights reserved.) Key words Extravasation, upper extremity.
NTRAVENOUS EXTRAVASATION INJURIES in the upper extremity are a frequent reason hand surgeons are consulted in the inpatient setting. A large body of case reports demonstrates that nearly any intravenous agent can and will extravasate. Common intravenous agents that have been reported to extravasate include total parental nutrition, phenytoin, arginine, vasopressors such as dopamine, radiographic contrast medium, and numerous chemotherapeutic agents, among others. The soft tissue injury that occurs as a result of the extravasate is related to 4 factors: the osmolarity of the extravasate, the inherent cytotoxicity of the extravasate, the infusion pressure, and possible vasoconstrictive properties of the extravasate.1 In general, extravasates are divided into irritants or vesicants based on their potential for local toxicity. An irritant can cause an inflammatory reaction, with warmth, erythema, and tenderness in the extravasated area; however, it is not directly toxic to the tissue. Vesicants are agents that have the potential to cause blistering, sloughing of the skin, and varying degrees of deep tissue damage because they are inherently toxic.2 Although prevention is
I
Current Concepts
From the Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, and the Hospital for Special Surgery, New York, NY. Received for publication August 19, 2011; accepted in revised form October 4, 2011. No benefits in any form have been received or will be received related directly or indirectly to the subject of this article. Corresponding author: Michael G. Hannon, MD, NYU Hospital for Joint Diseases, 301 East 17th Street, New York, NY 10003; e-mail: [email protected]. 0363-5023/11/36A12-0034$36.00/0 doi:10.1016/j.jhsa.2011.10.001
2060 䉬 © ASSH 䉬 Published by Elsevier, Inc. All rights reserved.
certainly the preferred treatment for these iatrogenic injuries, when extravasation injuries do occur, it is critically important that they be identified and treated promptly. Delayed management or mismanagement of extravasation injuries has led to debilitating and even devastating consequences including scarring, contracture, cellulitis, marked soft tissue loss requiring skin grafting or flap coverage, neurovascular injury, compartment syndrome, physeal injury, limb shortening, amputation, and death (Fig. 1). To date, there has been a paucity of literature on the principles of management of extravasation injuries, with no succinct guidelines with respect to specific treatment recommendations for certain extravasates. DIAGNOSIS AND MANAGEMENT Prevention is the ideal treatment for extravasation injuries. The nursing staff as well as other allied health professionals involved in intravenous therapies with commonly extravasated solutions should be well educated with regard to the proper preventative practices. Common sites for extravasation injury include the dorsum of the hand, the ulnar and radial aspects of the forearm about the basilic and cephalic veins, respectively, and the antecubital fossa, where peripheral intravenous access is typically obtained. At-risk patients should be identified. Neonates, the elderly, and the obtunded or unconscious are a particular concern given their relative inability to verbalize pain.3 It is recommended that the primary nurse responsible for administration of the intravenous agent of concern remain
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hypervigilant and continue to routinely check peripheral of the extravasation injury to further guide treatment. intravenous tubing on an hourly basis at the minimum. To that end, Loth and Eversmann5 proposed a classifiWhen extravasation injuries do occur, they must be cation system for extravasation injuries defined as mild, recognized promptly. Possible signs and symptoms of moderate, and severe based on clinical presentation, extravasation include swelling, pain at the infusion site, type of extravasate, and volume extravasated. Mild erythema, and blistering and or blanching of the overextravasations are characterized by minimal volumes of lying skin. It is important to stop the intravenous infuan irritant or vesicant, with minimal pain and swelling, sion as soon as an extravasaand no erythema or blisterEDUCATIONAL OBJECTIVES tion is recognized. Certain ing. These injuries respond specific details about the ex- ● List the common intravenous agents that have been reported to extrava- to elevation and the patient is sate. travasation injury should be often asymptomatic in 1 to 2 noted, including the concen- ● State the 4 factors of the extravasate that directly affect soft tissue injury. days. Moderate extravasatration of the agent, the vol- ● Discuss at-risk patients for extravasation injuries. tions are characterized by ume administered, and the ● Describe the saline flush-out technique for extravasation injuries. small volumes of approxiestimated duration of expo- ● mately 5 mL, a local inflamDiscuss the role of hyaluronidase in the treatment of extravasation injuries. sure to the tissue. The matory reaction less than 10 ● Summarize the difference between irritants and vesicants. method of intravenous thercm in diameter, moderate apy should also be noted (ie, Earn up to 2 hours of CME credit per JHS issue when you read the related tenderness with or without intravenous gravity drip, articles and take the online test. To pay the $20 fee and take this month’s erythema, and typically no manual bulb pump infusion test, visit http://www.jhandsurg.org/CME/home. blistering. There is no tissue system, or automated power necrosis and pain may be injection system such as is managed with non-narcotic used in radiographic contrast medium). Some authors pain medicines. Severe extravasations are characterized advocate initially leaving the intravenous catheter in by extreme pain, marked swelling, erythema, and often place and aspirating 5 mL blood to remove as much of blistering. These severe extravasations involve larger the drug as possible.4 Initial treatment includes elevavolumes, typically of vesicant extravasates. Among the tion of the involved extremity to the level of the heart, vesicant extravasates, there is a broad range of potential application of ice, and immobilization. Serial neurovasfor tissue necrosis. Mild to moderate extravasations will cular examinations as well as compartment examinabe amenable to observation, whereas severe extravasations are appropriate to monitor for impending comparttions will almost always require intervention. ment syndrome. The timing of any possible intervention is crucial After an extravasation injury has been identified and because earlier intervention appears to improve outinitially treated as above, the next step is to provide comes. Loth and Eversmann5 defined the term “necrodefinitive care. A spectrum of treatment options exist, sis interval” as the amount of time, measured from the including simple immobilization and continued obseronset of the extravasation, during which surgical intervation, injectable or topical antidotes, subcutaneous irvention may prevent further necrosis and improve the rigation techniques, early open surgical debridement, ultimate outcome. They went on to define the necrosis and upper extremity fasciotomies for compartment reinterval for certain common extravasates including valease. It is important to understand the individual nature sopressors (4 – 6 h), radiographic contrast (6 h), and chemotherapeutic agents (72 h). In the case of a patient presenting after the necrosis interval has elapsed for that particular extravasate, Loth and Eversmann recommended observation; if the patient is clinically stable, no further intervention is needed. Gault6 wrote an extensive retrospective review of extravasations injuries in 1993. He presented 96 cases of extravasation over a 5-year period at St. Thomas’ Hospital and the Hospital for Sick Children in London. Among the 96 cases, 44 of the extravasations received early treatment (less than 24 h) with a subcutaneous flush-out technique (37), a flush-out technique and liFIGURE 1: Tissue necrosis after extravasation of doxorubicin. posuction (6), and liposuction alone (1). Among this JHS 䉬 Vol A, December
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this could potentially cause an iatrogenic compartment syndrome. The wound is covered with a dry sterile dressing and monitored daily, with the incisions healing via secondary intention. In Gault’s original paper, he had 1 complication in 43 patients treated with this technique, a transient cellulitis that resolved with oral antibiotics.
FIGURE 2: The Gault technique. Drawing courtesy of Hugh Nachamie.
Current Concepts
early treatment group, 86% healed with no soft tissue loss. The other 52 patients all presented more than 24 hours after the onset of extravasation and were managed expectantly. Of these 52 patients, 15 ultimately required extensive reconstruction, including 6 split thickness skin grafts, 6 flaps, and 3 amputations. Khan and Holmes7 presented a series of 18 cytotoxic extravasations seen over a 2-year period at the Aberdeen Royal Infirmary in the United Kingdom. On all wards where chemotherapeutics were given, the staff was educated on how to use extravasation kits that included all the necessary materials to perform the flush-out technique as described by Gault.6 Of the 18 patients, 17 underwent the prescribed protocol using these kits. The mean time to institute treatment from the time the extravasation was noted to be just less than 20 minutes. All of the extravasation injuries healed well and required no further plastic surgery intervention. One patient did not have treatment according to the protocol and ultimately required a split-thickness skin graft. The saline flush-out technique as originally described by Gault6 is as follows (Fig. 2). The skin is prepared around the area of extravasation and 1% lidocaine is injected subcutaneously. Next, 1,500 U hyaluronidase is injected subcutaneously into the area of concern. The hyaluronidase hydrolyzes the hyaluronic acid in the subcutaneous tissues, making them more permeable to the pending lavage. Then, 4 small stab incisions are made about the periphery of the lesion. Next, a blunt tipped catheter or Veress needle attached to a saline-filled syringe is passed into the first stab incision and fluid is irrigated through the subcutaneous tissue, flowing out of the other 3 incisions. This procedure is repeated while injecting through the other incisions. A total of 500 mL fluid is recommended. Special care should be taken to ensure saline is actively flowing out the other incisions and not accumulating, because
EXTRAVASATES Total parenteral nutrition Total parenteral nutrition has been most commonly reported to extravasate in newborns in the intensive care unit setting; however, case reports also exist for adults.8 Parenteral nutrition is a complex mixture of substances including nitrogen, dextrose, lipids, electrolytes including potassium and calcium, vitamins, and trace elements. The solution is hyperosmolar, with some preparations averaging 650 mOsm/L compared with a serum osmolarity of approximately 285 mOsm/L. The proposed mechanism of local tissue toxicity is suggested to be a combination of toxic effects of the local ions, hyperosmolarity, and the acidic pH of the solution. Davies et al9 reported 2 cases of total parenteral nutrition extravasation in newborns treated in the neonatal intensive are unit. They used a saline flush-out technique as described by Gault6 in each case. Both infants healed with minimal scarring and no functional deficit (Table 1). Phenytoin Phenytoin is a widely used anticonvulsant commonly known as Dilantin (Parke-Davis, Morris Plains, NJ). There have been numerous case reports of extravasation of intravenous phenytoin, with variable clinical consequences ranging from cellulitis to frank necrosis requiring wrist disarticulation or below-elbow amputation.10 Hanna11 described the so-called purple glove syndrome that may be seen with phenytoin extravasation in the hand. Purple glove syndrome is characterized by edema, dark red or violet skin discoloration, and extreme pain. The exact etiology of purple glove syndrome remains unclear. Phenytoin toxicity is likely related to multiple factors including precipitation of the drug out of solution, blocking further intravenous flow, disruption of the vascular integrity of veins owing to high alkalinity (pH ⬃12), and subsequent binding of the drug to proteins in the subcutaneous tissues causing elevations in oncotic pressure and edema. Purple glove syndome is divided into 3 stages: appearance, progression, and resolution. In the appearance phase, during the first 2 to 12 hours after extravasation, there is edema and pain at the infusion site with localized blue or
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Common Extravasates
Extravasate (All Vesicants) Total parenteral nutrition (TPN)
Phenytoin
Arginine
Dopamine
Radiographic contrast medium
Contents Amino acids, dextrose, lipids, electrolytes, vitamins, trace elements Phenytoin, 40% propylene glycol, 10% ethanol in water, sodium bicarbonate
An essential amino acid, typically infused as 10% solution of arginine monohydrochloride A vasopressor, administered in 5% dextrose-in-water solution Ionic or nonionic formulations
Proposed Mechanism of Toxicity Combination of toxic effects of the local ions, hyperosmolarity, acidic pH Precipitation of the drug intravenously, disruption of vascular integrity of vein owing to high alkalinity (pH ⬃12), 90% protein bound in tissue, causing increase in oncotic pressure and edema Hyperosmolarity (950 mOsm/L) and local arginine-induced hyperkalemia
␣1-adreneregic receptor– mediated vasoconstriction causing ischemia Local edema to high osmolarity, pressure effect owing to large volumes
Mechlorethamine (nitrogen mustard)
DNA-binding vesicant
Binds and crosslinks DNA, preventing cell replication
Plant alkaloids (vinblastine/ vincristine)
Non-DNA binding vesicant
Binds tubulin, prevents formation of microtubules
Anthracyclines (daunorubicin, doxorubicin)
DNA-binding vesicant
Inhibits DNA/RNA synthesis by intercalating between base pairs, creates oxygen free radicals that damage DNA and cell membranes
purple discoloration. Next during the progression phase, 12 to 24 hours after extravasation, the pain worsens and is more generalized. Edema and discoloration may spread to involve the entire hand and forearm. It is typically during this time that the patient is at highest risk for a compartment syndrome. The resolution phase may last up to 4 weeks. Pain decreases and edema and discoloration gradually diminish. Pain may persist for weeks to months.
Reported Treatment
Evidence
Gault flush-out technique
Case report9 Retrospective case series6
Subcutaneous hyaluronidase Nitroglycerin patch Gault flush-out technique
Case report13 Case report14 None
Gault flush-out technique
Case report16
Subcutaneous phentolamine Topical nitroglycerin ointment Squeeze maneuver Mixed technique (liposuction, modified Gault, Rhys-Davies exsanguinator) Sodium thiosulfate injection: mix 4 mL 10% sodium thiosulfate and 6 mL sterile water. Inject locally, 2 mL for each milligram of extravasate Hyaluronidase: inject 1–6 mL of 150 U/mL solution into affected area; 1 mL solution per milliliter extravasate Dexrazoxane intravenously in the opposite extremity, 1,000 U within 6 h of event, then 1,000 U on day 2 and 500 U on day 3
Case report17 Case report18 Case series23 Case report22
Oncology Nursing Society guidelines24
Oncology Nursing Society guidelines24
Oncology Nursing Society guidelines24
The initial management of phenytoin extravasation is similar to any vesicant extravasation as previously described, with a few special considerations. Seizure precautions must be initiated. A dry warm compress is also recommended, as opposed to cold compresses for most other vesicant extravasations.12 Sokol et al13 described using subcutaneous hyaluronidase injection alone for treatment of a mild phenytoin extravasation in a 14-month-old, child with good clinical results. Ed-
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TABLE 1.
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wards and Bosek14 reported using a nitroglycerin patch in a similar clinical situation, with good effect. Although there are no reported instances of use of the Gault technique in cases of phenytoin extravasation, it might be considered a treatment alternative. Arginine The arginine stress test is a provocative test used to assess growth hormone release in children and adolescents of short stature. Arginine, an amino acid, is a potent central stimulator of growth hormone release. Synthetic hyperosmolar arginine monohydrochloride in a 10% concentration solution diluted with normal saline is given via a rapid intravenous drip. Baker and Franklin15 first described arginine extravasation in 1991. Proposed mechanisms for arginine-mediated local tissue toxicity include hyperosmolar edema and local hyperkalemia leading to ischemia. More recently, Salameh and Shoufani16 described a case of arginine extravasation in the dorsal radial aspect of the forearm in a 3-year-old girl that required a groin flap and later splitthickness skin grafting. The patient presented 10 days after the extravasation injury with extensive necrosis about the intravenous site. During surgery she was found to have full-thickness skin necrosis, leaving exposed extensor tendons. The authors emphasized early recognition and treatment of arginine injuries and specifically recommended the Gault technique.
Current Concepts
Dopamine Dopamine is a commonly used vasopressor that increases cardiac output and renal perfusion. At low doses dopamine primarily acts on 1 receptors; however, at higher doses it stimulates ␣1 receptors. This stimulation of ␣1 receptors leads to peripheral vasoconstriction and ischemia. Subcutaneous injection of phentolamine, an ␣-adrenergic blocker, has been used to treat extravasation of ␣-adrenergic drugs such as dopamine, with good clinical effect.17 Wong et al18 reported 2 cases in which topical nitroglycerin ointment was used to reverse forearm ischemia after extravasation of dopamine in neonatal intensive care unit patients. Tran and Finlayson19 reported the technique of performing a stellate ganglion block to reverse hand ischemia resulting from vasopressors extravasation. Radiographic contrast medium Wang et al20 provided a retrospective review of nearly 70,000 intravenous contrast injections for computed tomography (CT) studies from 2000 to 2005. The incidence of contrast extravasation was 0.7% (475 of 69,657 injections). The frequency of upper extremity
extravasation injuries is almost certain to increase in association with increasing numbers of contrast studies. There have been numerous complications described after extravasation of radiographic contrast medium, ranging from superficial skin irritation and inflammation to forearm compartment syndrome requiring fasciotomy.21 Most institutions are now using non-iodinated contrast medium. Although extravasations of this nonionic contrast medium are said to be better tolerated than the older high-osmolarity ionic contrast, the nonionic contrast can still cause local tissue necrosis.22 Because automated power injectors are typically used for CT contrast studies, large-volume extravasations exceeding 150 mL have been reported. Proposed mechanisms for local tissue toxicity in contrast extravasations include hyperosmolarity causing local edema as well as pressure effects owing to large volumes of extravasate. There have been a limited number of reports to guide treatment in the case of contrast extravasation. Tsai et al23 described a technique they developed for treating high-volume (⬎50 mL) intravenous, contrast extravasations called the “squeeze maneuver.”23 Briefly, after the injection is ceased and the catheter is removed, an 18-gauge needle is used to make 5 to 8 stab incisions around the previous intravenous site. The extremity is then squeezed from the peripheral aspect of the swelling toward its center and the contrast is extruded out. The authors reported a case series of 8 patients with large extravasations with signs and symptoms of compromised perfusion of the fingers in the CT suite. All patients’ symptoms resolved after this squeeze maneuver technique. Schaverien et al recently described a surgical technique used to manage extravasation of approximately 100 mL nonionic contrast medium in the dorsal hand.22 After using a combination of liposuction, subcutaneous irrigation, and compression with a RhysDavies exsanguinator (Anetic Aid Limited, West Yorkshire, UK), the patient’s progressive median nerve symptoms resolved. The Rhys-Davies device is an inflatable cylindrical tube used by some in lieu of the Esmarch bandage to exsanguinate a limb. Ultimately this patient had no permanent sequelae. Chemotherapeutics Perhaps no other type of extravasate has been discussed and written about as much as chemotherapy. Chemotherapeutic agents, like all extravasates, can be divided into irritants and vesicants based on their potential to cause tissue necrosis. Vesicant chemotherapy extravasations have led to soft tissue loss requiring skin grafting or flap coverage, prolonged wound care, and loss of
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mount to be aware of the described treatments and principles. REFERENCES 1. Kumar RJ, Pegg SP, Kimble RM. Management of extravasation injuries. ANZ J Surg 2001;71:285–289. 2. Schulmeister L. Extravasation management: clinical update. Semin Oncol Nurs 2011;27:82–90. 3. Tong R. Preventing extravasation injuries in neonates. Paediatr Nurs 2007;19:22–25. 4. Khan MS, Holmes JD. Reducing the morbidity from extravasation injuries. Ann Plast Surg 2002;48:628 – 632. 5. Loth TS, Eversmann WW Jr. Extravasation injuries in the upper extremity. Clin Orthop Relat Res 1991;272:248 –254. 6. Gault DT. Extravasation injuries. Br J Plast Surg 1993;46:91–96. 7. Khan MS, Holmes JD. Reducing the morbidity from extravasation injuries. Ann Plast Surg 2002;48:628 – 632. 8. Gil ME, Mateu J. Treatment of extravasation from parenteral nutrition solution. Ann Pharmacother 1998;32:51–55. 9. Davies J, Gault D, Buchdahl N. Preventing the scars of neonatal intensive care. Arch Dis Child Fetal Neonatal Ed 1994;70:F50 –F51. 10. Rao VK, Feldman PD, Dibbell DG. Extravasation injury to the hand by intravenous phenytoin. Report of three cases. J Neurosurg 1988; 68:967–969. 11. Hanna, DR. Purple glove syndrome: a complication of intravenous phenytoin. J Neurosci Nurs 1992;24:340 –345. 12. Snelson C, Dieckman B. Recognizing and managing purple glove syndrome. Crit Care Nurse 2000;20:54 – 61. 13. Sokol DK, Dahlmann A, Dunn DW. Hyaluronidase treatment for intravenous phenytoin extravasation. J Child Neurol 1998;13:246 – 247. 14. Edwards JJ, Bosek V. Extravasation injury of the upper extremity by intravenous phenytoin. Anesth Analg 2002;94:672– 673. 15. Baker GL, Franklin JD. Management of arginine monohydrochloride extravasation in the forearm. South Med J 1991;84:381–384. 16. Salameh Y, Shoufani A. Full-thickness skin necrosis after arginine extravasation—a case report and review of literature. J Pediatr Surg 2004;39:e9 – e11. 17. Siwy BK, Sadove AM. Acute management of dopamine infiltration injury with Regitine. Plast Reconstr Surg 1987;80:610 – 612. 18. Wong AF, McCulloch LM, Sola A. Treatment of peripheral tissue ischemia with topical nitroglycerin ointment in neonates. J Pediatr 1992;121:980 –983. 19. Tran DQ, Finlayson RJ. Use of stellate ganglion block to salvage an ischemic hand caused by the extravasation of vasopressors. Reg Anesth Pain Med 2005;30:405– 408. 20. Wang CL, Cohan RH, Ellis JH, Adusumilli S, Dunnick, NR. Frequency, management, and outcome of extravasation of nonionic iodinated contrast medium in 69,657 intravenous injections. Radiology 2007;243:80 – 87. 21. Benson LS, Sathy MJ, Port RB. Forearm compartment syndrome due to automated injection of computed tomography contrast material. J Orthop Trauma 1996;10:433– 436. 22. Schaverien MV, Evison D, McCulley SJ. Management of large volume CT contrast medium extravasation injury: technical refinement and literature review. J Plast Reconstr Aesthet Surg 2008;61: 562–565. 23. Tsai YS, Cheng SM, Ng SP, Yang FS, Shih SL, Sheu CY, et al. Squeeze maneuver: an easy way to manage radiological contrastmedium extravasation. Acta Radiol 2007;48:605– 607. 24. Schulmeister L. Extravasation management: clinical update. Semin Oncol Nurs 2011;27:82–90.
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limb function. Partly because of the well-documented complications associated with vesicant chemotherapy extravasation, steps have been taken to minimize the incidence of these iatrogenic injuries. Although increased awareness of the problem as well as development of central venous access devices has certainly decreased the incidence of these injuries, they still occur. Vesicant chemotherapeutics may be further subdivided into 2 categories: DNA binding and non-DNA binding. DNA-binding agents bind to the DNA in healthy tissue and cause cell death. Complexes of DNA bound to the drug are then released and taken up by adjacent cells via endocytosis. This process repeats in a vicious cycle that can lead to prolonged tissue damage. Examples of DNA-binding chemotherapeutic agents include mechlorethamine, doxorubicin, and mitomycin. Non-DNA– binding drugs, on the other hand, are more easily metabolized and neutralized. Examples of non-DNA– binding chemotherapeutics include amsacrine, vinblastine, vincristine, and paclitaxel. As previously noted, Khan and Holmes4 demonstrated that early subcutaneous washout of vesicant extravasations using extravasation kits led to wound healing in all cases, with no further surgical intervention required. In addition, the Oncologic Nursing Society recommends several specific treatment protocols for certain extravasates. Many of these treatment guidelines are based on animal studies or human case series with small numbers. Mechlorethamine, a DNA-binding vesicant, may be treated with sodium thiosulfate. Sodium thiosulfate is thought to neutralize the reactive alkylating species of mechlorethamine and reduce production of hydroxyl radicals that cause tissue injury.24 It is recommended that plant alkaloid extravasation be treated with hyaluronidase. Anthracycline extravasation may be treated with intravenous dexrazoxane. Dexrazoxane binds to iron and prevents the formation of free oxygen radicals. Extravasation injuries occur under a wide variety of circumstances in the inpatient setting. Prevention remains the ideal treatment for these iatrogenic injuries. When extravasation injuries occur, they must be diagnosed and treated promptly to minimize the amount of soft tissue injury. Initial management is similar among vesicant extravasates. Although evidence is limited to guide management for specific extravasates, it is para-
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Extravasation Injuries Michael G. Hannon, MD, Steve K. Lee, MD Extravasation injuries occur under a wide variety of circumstances in the inpatient setting. Prevention remains the ideal treatment for these iatrogenic injuries. When extravasation injuries do occur, they must be diagnosed and treated promptly to minimize the amount of soft tissue injury. Initial management is similar among vesicant extravasates. Although evidence is limited to guide management for specific extravasates, it is paramount to be aware of the described treatments and principles. (J Hand Surg 2011;36A:2060–2065. Copyright © 2011 by the American Society for Surgery of the Hand. All rights reserved.) Key words Extravasation, upper extremity.
NTRAVENOUS EXTRAVASATION INJURIES in the upper extremity are a frequent reason hand surgeons are consulted in the inpatient setting. A large body of case reports demonstrates that nearly any intravenous agent can and will extravasate. Common intravenous agents that have been reported to extravasate include total parental nutrition, phenytoin, arginine, vasopressors such as dopamine, radiographic contrast medium, and numerous chemotherapeutic agents, among others. The soft tissue injury that occurs as a result of the extravasate is related to 4 factors: the osmolarity of the extravasate, the inherent cytotoxicity of the extravasate, the infusion pressure, and possible vasoconstrictive properties of the extravasate.1 In general, extravasates are divided into irritants or vesicants based on their potential for local toxicity. An irritant can cause an inflammatory reaction, with warmth, erythema, and tenderness in the extravasated area; however, it is not directly toxic to the tissue. Vesicants are agents that have the potential to cause blistering, sloughing of the skin, and varying degrees of deep tissue damage because they are inherently toxic.2 Although prevention is
I
Current Concepts
From the Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, and the Hospital for Special Surgery, New York, NY. Received for publication August 19, 2011; accepted in revised form October 4, 2011. No benefits in any form have been received or will be received related directly or indirectly to the subject of this article. Corresponding author: Michael G. Hannon, MD, NYU Hospital for Joint Diseases, 301 East 17th Street, New York, NY 10003; e-mail: [email protected]. 0363-5023/11/36A12-0034$36.00/0 doi:10.1016/j.jhsa.2011.10.001
2060 䉬 © ASSH 䉬 Published by Elsevier, Inc. All rights reserved.
certainly the preferred treatment for these iatrogenic injuries, when extravasation injuries do occur, it is critically important that they be identified and treated promptly. Delayed management or mismanagement of extravasation injuries has led to debilitating and even devastating consequences including scarring, contracture, cellulitis, marked soft tissue loss requiring skin grafting or flap coverage, neurovascular injury, compartment syndrome, physeal injury, limb shortening, amputation, and death (Fig. 1). To date, there has been a paucity of literature on the principles of management of extravasation injuries, with no succinct guidelines with respect to specific treatment recommendations for certain extravasates. DIAGNOSIS AND MANAGEMENT Prevention is the ideal treatment for extravasation injuries. The nursing staff as well as other allied health professionals involved in intravenous therapies with commonly extravasated solutions should be well educated with regard to the proper preventative practices. Common sites for extravasation injury include the dorsum of the hand, the ulnar and radial aspects of the forearm about the basilic and cephalic veins, respectively, and the antecubital fossa, where peripheral intravenous access is typically obtained. At-risk patients should be identified. Neonates, the elderly, and the obtunded or unconscious are a particular concern given their relative inability to verbalize pain.3 It is recommended that the primary nurse responsible for administration of the intravenous agent of concern remain
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hypervigilant and continue to routinely check peripheral of the extravasation injury to further guide treatment. intravenous tubing on an hourly basis at the minimum. To that end, Loth and Eversmann5 proposed a classifiWhen extravasation injuries do occur, they must be cation system for extravasation injuries defined as mild, recognized promptly. Possible signs and symptoms of moderate, and severe based on clinical presentation, extravasation include swelling, pain at the infusion site, type of extravasate, and volume extravasated. Mild erythema, and blistering and or blanching of the overextravasations are characterized by minimal volumes of lying skin. It is important to stop the intravenous infuan irritant or vesicant, with minimal pain and swelling, sion as soon as an extravasaand no erythema or blisterEDUCATIONAL OBJECTIVES tion is recognized. Certain ing. These injuries respond specific details about the ex- ● List the common intravenous agents that have been reported to extrava- to elevation and the patient is sate. travasation injury should be often asymptomatic in 1 to 2 noted, including the concen- ● State the 4 factors of the extravasate that directly affect soft tissue injury. days. Moderate extravasatration of the agent, the vol- ● Discuss at-risk patients for extravasation injuries. tions are characterized by ume administered, and the ● Describe the saline flush-out technique for extravasation injuries. small volumes of approxiestimated duration of expo- ● mately 5 mL, a local inflamDiscuss the role of hyaluronidase in the treatment of extravasation injuries. sure to the tissue. The matory reaction less than 10 ● Summarize the difference between irritants and vesicants. method of intravenous thercm in diameter, moderate apy should also be noted (ie, Earn up to 2 hours of CME credit per JHS issue when you read the related tenderness with or without intravenous gravity drip, articles and take the online test. To pay the $20 fee and take this month’s erythema, and typically no manual bulb pump infusion test, visit http://www.jhandsurg.org/CME/home. blistering. There is no tissue system, or automated power necrosis and pain may be injection system such as is managed with non-narcotic used in radiographic contrast medium). Some authors pain medicines. Severe extravasations are characterized advocate initially leaving the intravenous catheter in by extreme pain, marked swelling, erythema, and often place and aspirating 5 mL blood to remove as much of blistering. These severe extravasations involve larger the drug as possible.4 Initial treatment includes elevavolumes, typically of vesicant extravasates. Among the tion of the involved extremity to the level of the heart, vesicant extravasates, there is a broad range of potential application of ice, and immobilization. Serial neurovasfor tissue necrosis. Mild to moderate extravasations will cular examinations as well as compartment examinabe amenable to observation, whereas severe extravasations are appropriate to monitor for impending comparttions will almost always require intervention. ment syndrome. The timing of any possible intervention is crucial After an extravasation injury has been identified and because earlier intervention appears to improve outinitially treated as above, the next step is to provide comes. Loth and Eversmann5 defined the term “necrodefinitive care. A spectrum of treatment options exist, sis interval” as the amount of time, measured from the including simple immobilization and continued obseronset of the extravasation, during which surgical intervation, injectable or topical antidotes, subcutaneous irvention may prevent further necrosis and improve the rigation techniques, early open surgical debridement, ultimate outcome. They went on to define the necrosis and upper extremity fasciotomies for compartment reinterval for certain common extravasates including valease. It is important to understand the individual nature sopressors (4 – 6 h), radiographic contrast (6 h), and chemotherapeutic agents (72 h). In the case of a patient presenting after the necrosis interval has elapsed for that particular extravasate, Loth and Eversmann recommended observation; if the patient is clinically stable, no further intervention is needed. Gault6 wrote an extensive retrospective review of extravasations injuries in 1993. He presented 96 cases of extravasation over a 5-year period at St. Thomas’ Hospital and the Hospital for Sick Children in London. Among the 96 cases, 44 of the extravasations received early treatment (less than 24 h) with a subcutaneous flush-out technique (37), a flush-out technique and liFIGURE 1: Tissue necrosis after extravasation of doxorubicin. posuction (6), and liposuction alone (1). Among this JHS 䉬 Vol A, December
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this could potentially cause an iatrogenic compartment syndrome. The wound is covered with a dry sterile dressing and monitored daily, with the incisions healing via secondary intention. In Gault’s original paper, he had 1 complication in 43 patients treated with this technique, a transient cellulitis that resolved with oral antibiotics.
FIGURE 2: The Gault technique. Drawing courtesy of Hugh Nachamie.
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early treatment group, 86% healed with no soft tissue loss. The other 52 patients all presented more than 24 hours after the onset of extravasation and were managed expectantly. Of these 52 patients, 15 ultimately required extensive reconstruction, including 6 split thickness skin grafts, 6 flaps, and 3 amputations. Khan and Holmes7 presented a series of 18 cytotoxic extravasations seen over a 2-year period at the Aberdeen Royal Infirmary in the United Kingdom. On all wards where chemotherapeutics were given, the staff was educated on how to use extravasation kits that included all the necessary materials to perform the flush-out technique as described by Gault.6 Of the 18 patients, 17 underwent the prescribed protocol using these kits. The mean time to institute treatment from the time the extravasation was noted to be just less than 20 minutes. All of the extravasation injuries healed well and required no further plastic surgery intervention. One patient did not have treatment according to the protocol and ultimately required a split-thickness skin graft. The saline flush-out technique as originally described by Gault6 is as follows (Fig. 2). The skin is prepared around the area of extravasation and 1% lidocaine is injected subcutaneously. Next, 1,500 U hyaluronidase is injected subcutaneously into the area of concern. The hyaluronidase hydrolyzes the hyaluronic acid in the subcutaneous tissues, making them more permeable to the pending lavage. Then, 4 small stab incisions are made about the periphery of the lesion. Next, a blunt tipped catheter or Veress needle attached to a saline-filled syringe is passed into the first stab incision and fluid is irrigated through the subcutaneous tissue, flowing out of the other 3 incisions. This procedure is repeated while injecting through the other incisions. A total of 500 mL fluid is recommended. Special care should be taken to ensure saline is actively flowing out the other incisions and not accumulating, because
EXTRAVASATES Total parenteral nutrition Total parenteral nutrition has been most commonly reported to extravasate in newborns in the intensive care unit setting; however, case reports also exist for adults.8 Parenteral nutrition is a complex mixture of substances including nitrogen, dextrose, lipids, electrolytes including potassium and calcium, vitamins, and trace elements. The solution is hyperosmolar, with some preparations averaging 650 mOsm/L compared with a serum osmolarity of approximately 285 mOsm/L. The proposed mechanism of local tissue toxicity is suggested to be a combination of toxic effects of the local ions, hyperosmolarity, and the acidic pH of the solution. Davies et al9 reported 2 cases of total parenteral nutrition extravasation in newborns treated in the neonatal intensive are unit. They used a saline flush-out technique as described by Gault6 in each case. Both infants healed with minimal scarring and no functional deficit (Table 1). Phenytoin Phenytoin is a widely used anticonvulsant commonly known as Dilantin (Parke-Davis, Morris Plains, NJ). There have been numerous case reports of extravasation of intravenous phenytoin, with variable clinical consequences ranging from cellulitis to frank necrosis requiring wrist disarticulation or below-elbow amputation.10 Hanna11 described the so-called purple glove syndrome that may be seen with phenytoin extravasation in the hand. Purple glove syndrome is characterized by edema, dark red or violet skin discoloration, and extreme pain. The exact etiology of purple glove syndrome remains unclear. Phenytoin toxicity is likely related to multiple factors including precipitation of the drug out of solution, blocking further intravenous flow, disruption of the vascular integrity of veins owing to high alkalinity (pH ⬃12), and subsequent binding of the drug to proteins in the subcutaneous tissues causing elevations in oncotic pressure and edema. Purple glove syndome is divided into 3 stages: appearance, progression, and resolution. In the appearance phase, during the first 2 to 12 hours after extravasation, there is edema and pain at the infusion site with localized blue or
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Common Extravasates
Extravasate (All Vesicants) Total parenteral nutrition (TPN)
Phenytoin
Arginine
Dopamine
Radiographic contrast medium
Contents Amino acids, dextrose, lipids, electrolytes, vitamins, trace elements Phenytoin, 40% propylene glycol, 10% ethanol in water, sodium bicarbonate
An essential amino acid, typically infused as 10% solution of arginine monohydrochloride A vasopressor, administered in 5% dextrose-in-water solution Ionic or nonionic formulations
Proposed Mechanism of Toxicity Combination of toxic effects of the local ions, hyperosmolarity, acidic pH Precipitation of the drug intravenously, disruption of vascular integrity of vein owing to high alkalinity (pH ⬃12), 90% protein bound in tissue, causing increase in oncotic pressure and edema Hyperosmolarity (950 mOsm/L) and local arginine-induced hyperkalemia
␣1-adreneregic receptor– mediated vasoconstriction causing ischemia Local edema to high osmolarity, pressure effect owing to large volumes
Mechlorethamine (nitrogen mustard)
DNA-binding vesicant
Binds and crosslinks DNA, preventing cell replication
Plant alkaloids (vinblastine/ vincristine)
Non-DNA binding vesicant
Binds tubulin, prevents formation of microtubules
Anthracyclines (daunorubicin, doxorubicin)
DNA-binding vesicant
Inhibits DNA/RNA synthesis by intercalating between base pairs, creates oxygen free radicals that damage DNA and cell membranes
purple discoloration. Next during the progression phase, 12 to 24 hours after extravasation, the pain worsens and is more generalized. Edema and discoloration may spread to involve the entire hand and forearm. It is typically during this time that the patient is at highest risk for a compartment syndrome. The resolution phase may last up to 4 weeks. Pain decreases and edema and discoloration gradually diminish. Pain may persist for weeks to months.
Reported Treatment
Evidence
Gault flush-out technique
Case report9 Retrospective case series6
Subcutaneous hyaluronidase Nitroglycerin patch Gault flush-out technique
Case report13 Case report14 None
Gault flush-out technique
Case report16
Subcutaneous phentolamine Topical nitroglycerin ointment Squeeze maneuver Mixed technique (liposuction, modified Gault, Rhys-Davies exsanguinator) Sodium thiosulfate injection: mix 4 mL 10% sodium thiosulfate and 6 mL sterile water. Inject locally, 2 mL for each milligram of extravasate Hyaluronidase: inject 1–6 mL of 150 U/mL solution into affected area; 1 mL solution per milliliter extravasate Dexrazoxane intravenously in the opposite extremity, 1,000 U within 6 h of event, then 1,000 U on day 2 and 500 U on day 3
Case report17 Case report18 Case series23 Case report22
Oncology Nursing Society guidelines24
Oncology Nursing Society guidelines24
Oncology Nursing Society guidelines24
The initial management of phenytoin extravasation is similar to any vesicant extravasation as previously described, with a few special considerations. Seizure precautions must be initiated. A dry warm compress is also recommended, as opposed to cold compresses for most other vesicant extravasations.12 Sokol et al13 described using subcutaneous hyaluronidase injection alone for treatment of a mild phenytoin extravasation in a 14-month-old, child with good clinical results. Ed-
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wards and Bosek14 reported using a nitroglycerin patch in a similar clinical situation, with good effect. Although there are no reported instances of use of the Gault technique in cases of phenytoin extravasation, it might be considered a treatment alternative. Arginine The arginine stress test is a provocative test used to assess growth hormone release in children and adolescents of short stature. Arginine, an amino acid, is a potent central stimulator of growth hormone release. Synthetic hyperosmolar arginine monohydrochloride in a 10% concentration solution diluted with normal saline is given via a rapid intravenous drip. Baker and Franklin15 first described arginine extravasation in 1991. Proposed mechanisms for arginine-mediated local tissue toxicity include hyperosmolar edema and local hyperkalemia leading to ischemia. More recently, Salameh and Shoufani16 described a case of arginine extravasation in the dorsal radial aspect of the forearm in a 3-year-old girl that required a groin flap and later splitthickness skin grafting. The patient presented 10 days after the extravasation injury with extensive necrosis about the intravenous site. During surgery she was found to have full-thickness skin necrosis, leaving exposed extensor tendons. The authors emphasized early recognition and treatment of arginine injuries and specifically recommended the Gault technique.
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Dopamine Dopamine is a commonly used vasopressor that increases cardiac output and renal perfusion. At low doses dopamine primarily acts on 1 receptors; however, at higher doses it stimulates ␣1 receptors. This stimulation of ␣1 receptors leads to peripheral vasoconstriction and ischemia. Subcutaneous injection of phentolamine, an ␣-adrenergic blocker, has been used to treat extravasation of ␣-adrenergic drugs such as dopamine, with good clinical effect.17 Wong et al18 reported 2 cases in which topical nitroglycerin ointment was used to reverse forearm ischemia after extravasation of dopamine in neonatal intensive care unit patients. Tran and Finlayson19 reported the technique of performing a stellate ganglion block to reverse hand ischemia resulting from vasopressors extravasation. Radiographic contrast medium Wang et al20 provided a retrospective review of nearly 70,000 intravenous contrast injections for computed tomography (CT) studies from 2000 to 2005. The incidence of contrast extravasation was 0.7% (475 of 69,657 injections). The frequency of upper extremity
extravasation injuries is almost certain to increase in association with increasing numbers of contrast studies. There have been numerous complications described after extravasation of radiographic contrast medium, ranging from superficial skin irritation and inflammation to forearm compartment syndrome requiring fasciotomy.21 Most institutions are now using non-iodinated contrast medium. Although extravasations of this nonionic contrast medium are said to be better tolerated than the older high-osmolarity ionic contrast, the nonionic contrast can still cause local tissue necrosis.22 Because automated power injectors are typically used for CT contrast studies, large-volume extravasations exceeding 150 mL have been reported. Proposed mechanisms for local tissue toxicity in contrast extravasations include hyperosmolarity causing local edema as well as pressure effects owing to large volumes of extravasate. There have been a limited number of reports to guide treatment in the case of contrast extravasation. Tsai et al23 described a technique they developed for treating high-volume (⬎50 mL) intravenous, contrast extravasations called the “squeeze maneuver.”23 Briefly, after the injection is ceased and the catheter is removed, an 18-gauge needle is used to make 5 to 8 stab incisions around the previous intravenous site. The extremity is then squeezed from the peripheral aspect of the swelling toward its center and the contrast is extruded out. The authors reported a case series of 8 patients with large extravasations with signs and symptoms of compromised perfusion of the fingers in the CT suite. All patients’ symptoms resolved after this squeeze maneuver technique. Schaverien et al recently described a surgical technique used to manage extravasation of approximately 100 mL nonionic contrast medium in the dorsal hand.22 After using a combination of liposuction, subcutaneous irrigation, and compression with a RhysDavies exsanguinator (Anetic Aid Limited, West Yorkshire, UK), the patient’s progressive median nerve symptoms resolved. The Rhys-Davies device is an inflatable cylindrical tube used by some in lieu of the Esmarch bandage to exsanguinate a limb. Ultimately this patient had no permanent sequelae. Chemotherapeutics Perhaps no other type of extravasate has been discussed and written about as much as chemotherapy. Chemotherapeutic agents, like all extravasates, can be divided into irritants and vesicants based on their potential to cause tissue necrosis. Vesicant chemotherapy extravasations have led to soft tissue loss requiring skin grafting or flap coverage, prolonged wound care, and loss of
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mount to be aware of the described treatments and principles. REFERENCES 1. Kumar RJ, Pegg SP, Kimble RM. Management of extravasation injuries. ANZ J Surg 2001;71:285–289. 2. Schulmeister L. Extravasation management: clinical update. Semin Oncol Nurs 2011;27:82–90. 3. Tong R. Preventing extravasation injuries in neonates. Paediatr Nurs 2007;19:22–25. 4. Khan MS, Holmes JD. Reducing the morbidity from extravasation injuries. Ann Plast Surg 2002;48:628 – 632. 5. Loth TS, Eversmann WW Jr. Extravasation injuries in the upper extremity. Clin Orthop Relat Res 1991;272:248 –254. 6. Gault DT. Extravasation injuries. Br J Plast Surg 1993;46:91–96. 7. Khan MS, Holmes JD. Reducing the morbidity from extravasation injuries. Ann Plast Surg 2002;48:628 – 632. 8. Gil ME, Mateu J. Treatment of extravasation from parenteral nutrition solution. Ann Pharmacother 1998;32:51–55. 9. Davies J, Gault D, Buchdahl N. Preventing the scars of neonatal intensive care. Arch Dis Child Fetal Neonatal Ed 1994;70:F50 –F51. 10. Rao VK, Feldman PD, Dibbell DG. Extravasation injury to the hand by intravenous phenytoin. Report of three cases. J Neurosurg 1988; 68:967–969. 11. Hanna, DR. Purple glove syndrome: a complication of intravenous phenytoin. J Neurosci Nurs 1992;24:340 –345. 12. Snelson C, Dieckman B. Recognizing and managing purple glove syndrome. Crit Care Nurse 2000;20:54 – 61. 13. Sokol DK, Dahlmann A, Dunn DW. Hyaluronidase treatment for intravenous phenytoin extravasation. J Child Neurol 1998;13:246 – 247. 14. Edwards JJ, Bosek V. Extravasation injury of the upper extremity by intravenous phenytoin. Anesth Analg 2002;94:672– 673. 15. Baker GL, Franklin JD. Management of arginine monohydrochloride extravasation in the forearm. South Med J 1991;84:381–384. 16. Salameh Y, Shoufani A. Full-thickness skin necrosis after arginine extravasation—a case report and review of literature. J Pediatr Surg 2004;39:e9 – e11. 17. Siwy BK, Sadove AM. Acute management of dopamine infiltration injury with Regitine. Plast Reconstr Surg 1987;80:610 – 612. 18. Wong AF, McCulloch LM, Sola A. Treatment of peripheral tissue ischemia with topical nitroglycerin ointment in neonates. J Pediatr 1992;121:980 –983. 19. Tran DQ, Finlayson RJ. Use of stellate ganglion block to salvage an ischemic hand caused by the extravasation of vasopressors. Reg Anesth Pain Med 2005;30:405– 408. 20. Wang CL, Cohan RH, Ellis JH, Adusumilli S, Dunnick, NR. Frequency, management, and outcome of extravasation of nonionic iodinated contrast medium in 69,657 intravenous injections. Radiology 2007;243:80 – 87. 21. Benson LS, Sathy MJ, Port RB. Forearm compartment syndrome due to automated injection of computed tomography contrast material. J Orthop Trauma 1996;10:433– 436. 22. Schaverien MV, Evison D, McCulley SJ. Management of large volume CT contrast medium extravasation injury: technical refinement and literature review. J Plast Reconstr Aesthet Surg 2008;61: 562–565. 23. Tsai YS, Cheng SM, Ng SP, Yang FS, Shih SL, Sheu CY, et al. Squeeze maneuver: an easy way to manage radiological contrastmedium extravasation. Acta Radiol 2007;48:605– 607. 24. Schulmeister L. Extravasation management: clinical update. Semin Oncol Nurs 2011;27:82–90.
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limb function. Partly because of the well-documented complications associated with vesicant chemotherapy extravasation, steps have been taken to minimize the incidence of these iatrogenic injuries. Although increased awareness of the problem as well as development of central venous access devices has certainly decreased the incidence of these injuries, they still occur. Vesicant chemotherapeutics may be further subdivided into 2 categories: DNA binding and non-DNA binding. DNA-binding agents bind to the DNA in healthy tissue and cause cell death. Complexes of DNA bound to the drug are then released and taken up by adjacent cells via endocytosis. This process repeats in a vicious cycle that can lead to prolonged tissue damage. Examples of DNA-binding chemotherapeutic agents include mechlorethamine, doxorubicin, and mitomycin. Non-DNA– binding drugs, on the other hand, are more easily metabolized and neutralized. Examples of non-DNA– binding chemotherapeutics include amsacrine, vinblastine, vincristine, and paclitaxel. As previously noted, Khan and Holmes4 demonstrated that early subcutaneous washout of vesicant extravasations using extravasation kits led to wound healing in all cases, with no further surgical intervention required. In addition, the Oncologic Nursing Society recommends several specific treatment protocols for certain extravasates. Many of these treatment guidelines are based on animal studies or human case series with small numbers. Mechlorethamine, a DNA-binding vesicant, may be treated with sodium thiosulfate. Sodium thiosulfate is thought to neutralize the reactive alkylating species of mechlorethamine and reduce production of hydroxyl radicals that cause tissue injury.24 It is recommended that plant alkaloid extravasation be treated with hyaluronidase. Anthracycline extravasation may be treated with intravenous dexrazoxane. Dexrazoxane binds to iron and prevents the formation of free oxygen radicals. Extravasation injuries occur under a wide variety of circumstances in the inpatient setting. Prevention remains the ideal treatment for these iatrogenic injuries. When extravasation injuries occur, they must be diagnosed and treated promptly to minimize the amount of soft tissue injury. Initial management is similar among vesicant extravasates. Although evidence is limited to guide management for specific extravasates, it is para-
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