What are current recommendations for treatment of drug extravasation?
Introduction
Extravasation is defined as the leakage or inadvertent administration of a vesicant drug or solution from a vein into the extravascular space.1 Infiltration, often used in reference to extravasation, refers to leakage of a non-vesicant drug or solution.2,3 Initial symptoms of extravasation are similar to infiltration and include persistent pain, burning, stinging, swelling, and either blanching or erythema at the site of injection or along the course of the vein. However, vesicants are differentiated from non-vesicants in that they can cause tissue necrosis, blistering, and ulceration. Damage from extravasation can progress to a significant degree, causing permanent disability and disfigurement, and necessitating surgical debridement or skin grafting.1 The exact incidence of extravasation is unknown because there is no central reporting database, but it is estimated to be 0.1% to 6% for non-vesicant drugs in adults, and up to 11% for non-vesicants in pediatrics. For vesicant drugs and chemotherapeutic agents, the incidence has been reported to range from 0.01% to 6%.2
This article summarizes the latest recommendations for treatment of extravasation, and updates a similar article prepared by our group in 2015.
Risk factors for extravasation
A variety of risk factors are associated with extravasation: mechanical (cannulation technique and line placement), patient-related (predisposition to infiltration injury, current infection, cognitive or other barriers to communicating pain), and pharmacologic (pH, osmolality, vasoactivity, and cytotoxicity of infusate).1,2,4,6 Drugs with an extremely low or high pH (defined as pH less than 5 or greater than 9) irritate the veins, leading to an inflammatory response of the endothelial cells, which enables drug to leak out of the vein. Osmolality is also a consideration, as differences in osmotic pressure can damage endothelial cells, leading to potential for drug leakage from vessels. Certain drugs cause vasospasms, which result in back pressure at the intravenous (IV) site and may expand the puncture site in the vein, allowing leakage to occur; drugs that act as vasoconstrictors can also cause tissue ischemia. Some drugs, including anti-cancer agents, are directly cytotoxic to cells. Cytotoxic agents can be further subdivided into DNA-binding and non–DNA-binding agents. Additionally, administration factors, including the experience of personnel administering the injection, the injection technique, and the number of venipuncture attempts to establish a line, contribute to the risk of extravasation, as does the fragility of the patient’s veins.
Interventions for extravasation
The best approach to extravasation injury is prevention.3-6 Preventive measures include appropriate dilution of medication, infusion of medication via the appropriate rate of administration, ensuring patency of the vascular access device, careful monitoring of infusions during administration, use of clear tape or dressings to allow for visual inspection of the infusion site, and immobilization of the extremity with the IV cannula.
Non-pharmacologic interventions for extravasation
For most medications, the treatment of extravasation is nonpharmacologic in nature; however, the efficacy of any specific approach has not been demonstrated in controlled studies.3 The recommended approach to the treatment of extravasation includes the following steps:1,3-9
- Immediately stop the IV push or infusion if the patient complains of pain or a burning sensation.
- Disconnect IV tubing from IV device. Do not remove the IV device or noncoring port needle.
- Leave the catheter or needle in place initially to attempt to aspirate fluid from the extravasated area. Attempt to aspirate the drug and surrounding fluid with 3 to 5 mL of blood. Aspiration of radiographic contrast media is not recommended.
- Remove the peripheral IV device or port needle.
- Assess the site of extravasation and the symptoms of the patient.
- Notify the healthcare provider.
- Elevate the affected limb to minimize swelling and encourage resorption of the drug via the lymphatic system.
- Apply dry warm or cold compresses as indicated depending on the drug extravasated.
- Generally cold compresses are recommended for extravasation of all irritant and vesicant drugs except vinca alkaloids (vincristine, vinblastine, vinorelbine), epipodophyllotoxins (etoposide), oxaliplatin, and vasopressors, as cold worsens tissue ulceration caused by these drugs. Cold compresses cause vasoconstriction, limiting the spread of the extravasated drug. Additionally, cold reduces local inflammation and pain.
- Warm compresses are preferred for extravasation of specific drugs including vinca alkaloids, etoposide, vasopressors, and oxaliplatin to increase local blood flow and enhance drug removal.
- Apply compresses for 20 to 60 minutes 3 or 4 times daily for the first 24 to 72 hours after extravasation occurs.
- Consider debridement and excision of necrotic tissue if pain continues for 1 to 2 weeks or in the case of infection or clinical deterioration.
Pharmacologic interventions for extravasation
For some medications, nonpharmacologic management of extravasation is insufficient based on clinical presentation, and specific pharmacologic antidotes are used. The goal of antidote administration is to reverse the action of the extravasated agent, interfere with the process of cell destruction, prevent tissue necrosis, or limit the extent of tissue damage.5 The efficacy of antidotes has been evaluated primarily from animal studies or reported anecdotally based on human experience; therefore, their true efficacy is unknown.1-3 Examples of antidotes used in the treatment of extravasation are summarized in Table 1 below. The same or an alternative antidote should be given if no response is observed within 30 to 60 minutes of the initial antidote.6
| Table 1. Specific antidotes for extravasation.1,2,4-9 | ||
|---|---|---|
| Antidote | Preparation | Administration |
| Dexrazoxane MOA: Unknown, may reversibly inhibit topoisomerase II thereby protecting tissue from anthracycline cytotoxicity Used for anthracycline extravasation | Each vial of dexrazoxane must be mixed with the supplied diluent to a concentration of 10 mg/mL Dilute reconstituted solution in Lactated Ringers, 0.9% sodium chloride, or 5% dextrose to a final concentration of 1.3 to 5 mg/mL depending on specific manufacturer instructions | Withhold cold compress 15 minutes prior to infusion Begin infusion as soon as possible and within 6 hours of anthracycline extravasation Dose is based on patient’s body surface area Day 1: 1000 mg/m2 (max dose 2000 mg) Day 2: 1000 mg/m2 (max dose 2000 mg) Day 3: 500 mg/m2 (max dose 1000 mg) Treatment of day 2 and day 3 should start at the same hour (± 3 hours) as on day 1 Reduce dose by 50% in patients with creatinine clearance <40 mL/min Administer over 1 to 2 hours in a large vein in an area remote from the extravasation (ie, the opposite extremity) DMSO should not be used as it may diminish dexrazoxane efficacy |
| Hyaluronidase MOA: hydrolyzes hyaluronic acid in connective tissue, possibly leading to dilution and diffusion of extravasated drug Used for etoposide, vinca alkaloids, taxanes (eg, paclitaxel, docetaxel), ifosfamide, hyperosmolar agents, hypoosmolar agents, agents containing propylene glycol, acidic and alkaline agents, and agents that are refractory to absorption (eg, propofol, lipids) | Vial contains 150 units per 1 mL or 200 units per 1 mL depending on manufacturer To obtain a 15 unit/mL concentration, mix 0.1 mL (of 150 units/mL) with 0.9 mL of 0.9% sodium chloride in 1 mL syringe For extravasation of hyperosmolar solutions: 15 to 25 units intradermally over 5 injections For extravasation of acidic/basic agents: 15 units intradermally along injection site and edematous area | Inject from 15 to 150 units of the hyaluronidase solution as 5 separate injections, each containing 0.2 mL to 1 mL hyaluronidase Use a 25-gauge needle to inject SC to the affected area (change needle with each injection) Ideally administer within 1 hour of the event Doses up to 900 units have been suggested for cytotoxic drugs3 |
| Sodium thiosulfate MOA: neutralizes reactive species and reduces formation of hydroxyl radicals that can cause tissue injury Used for cisplatin, cyclophosphamide, mechlorethamine, dacarbazine, alternative for hyperosmolar agents, alternative for calcium | Prepare 1/6 molar solution: From 25% sodium thiosulfate solution: mix 1.6 mL with 8.4 mL sterile water for injection From 10% sodium thiosulfate solution: mix 4 mL with 6 mL sterile water for injection | Use 2 mL of the prepared solution for each 1 mg drug extravasated Use a 25-gauge needle to inject SC to the affected area (change needle with each injection) Hyperosmolar extravasations (severe): 12.5 g IV over 30 min, may increase to 25 g 3 times/week |
| DMSO MOA: scavenges free radicals and has anti-inflammatory, analgesic, and vasodilatory effects which promote systemic absorption of drug Used for mitomycin, dactinomycin, mitoxantrone and possible alternative for anthracyclines | 50% solution (99% solution reported in literature, but not available in US) | Apply topically to site for 7 to 14 days and allow to dry Do not cover application site with a dressing |
| Phentolamine MOA: α-adrenergic antagonist that promotes vasodilation and capillary blood flow Used for vasopressors | 5 to 10 mg in 10 to 20 mL of 0.9% sodium chloride 0.5 to 4.5 mg in 5 mL of 0.9% sodium chloride for epinephrine autoinjector-induced ischemia | Use a 25-gauge needle to inject at multiple sites within the affected area (change needle with each injection) Administer within 12 to 13 hours of the injury |
| Nitroglycerin topical MOA: increases nitric oxide, promoting vasodilation Used for vasopressors (alternative to phentolamine), hyperosmolar agents, methylene blue | 2% ointment 5 mg/day transdermal patch | 1-inch strip applied to site of ischemia, can redose every 8 hours as necessary 1 patch daily |
| Terbutaline MOA: α-adrenergic antagonist that promotes vasodilation and capillary blood flow Used for vasopressors (alternative to phentolamine) | 1 mg in 10 mL of 0.9% sodium chloride | Use a 25-gauge needle to inject locally across symptomatic sites (change needle with each injection) |
| Abbreviations: DMSO=dimethyl sulfoxide; IV=intravenous; MOA=mechanism of action; SC=subcutaneous(ly). |
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Management of extravasation of cytotoxic drugs
Management of extravasation of cytotoxic drugs consists of immediate application of either a cold or hot compress depending on the drug and administration of an antidote when available. Treatment is outlined in Table 2 below.
| Table 2. Pharmacologic therapy for extravasation of cytotoxic drugs.3,7,8 | ||
|---|---|---|
| Medication extravasated | Immediate topical therapy | Antidote |
| Cabazitaxel Docetaxel Nab-paclitaxel Paclitaxel | Apply cold compress for 15 to 20 minutes at least 4 times/day for the first 24 hours | None or hyaluronidase |
| Cisplatin ˃0.4 mg/mL Cyclophosphamide | Apply cold compress for 15 to 20 minutes at least 4 times/day for the first 24 to 48 hours | Sodium thiosulfate |
| Daunorubicin Doxorubicin Epirubicin Idarubicin | Apply cold compress (but remove at least 15 minutes prior to dexrazoxane) | Dexrazoxanea |
| Etoposide | Apply dry warm compress for 60 minutes every 8 hours for 3 days | Hyaluronidase |
| Mechlorethamine | Apply cold compress for 6 to 72 hours following sodium thiosulfate injection or for 20 minutes 4 times/day for 24 to 48 hours | Sodium thiosulfate |
| Mitomycin Dactinomycin Mitoxantrone | Apply cold compress for 15 to 20 minutes at least 4 times/day for 24 to 48 hours | None or topical DMSO |
| Oxaliplatin | Apply warm compress (ice increases risk of cold-induced peripheral neuropathy) for 15 to 20 minutes at least 4 times/day for the first 24 hours | None or dexamethasone 8 mg twice daily for 14 days |
| Vinblastine Vincristine Vinorelbine | Elevate extremity and apply dry warm compress for 15 to 60 minutes at least 3 times/day for the first 24 to 72 hours | Hyaluronidase |
| Abbreviation: DMSO=dimethyl sulfoxide. a DMSO may be an option when dexrazoxane is not available; however, it should not be used once dexrazoxane has been given.3,7 |
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Management of extravasation of non-cytotoxic drugs
The management of non-cytotoxic drugs is largely supportive and non-pharmacological, except where antidotes exist, such as for vasopressors. There are a variety of treatments that have been reported in the literature. Treatment considerations are outlined in Table 3 below.
| Table 3. Extravasation of non-cytotoxic drugs.1,2,6,7,10-12 | ||
|---|---|---|
| Medication extravasated | Immediate topical therapya | Antidote/treatment considerations |
| Vasopressors Dobutamine Dopamine Epinephrine Methylene blue Norepinephrine Phenylephrine Vasopressin | Consider use of warm compress | Preferred: Phentolamine for most agents; topical nitroglycerin ointment for vasopressin and methylene blue Alternative: Topical nitroglycerin ointment, terbutaline |
| Hyperosmolar agents Ampicillin Arginineb Calcium chloride 10% Calcium disodium edetate (EDTA) Calcium gluconate Dextrose 10% to 50% Diazepam Digoxin Etomidate Immune globulin Lorazepam Mannitol ≥20% Nafcillin Parenteral nutrition Phosphate salts Potassium ≥60 mEq/L Radiographic contrast mediac Sodium bicarbonate 8.4% Sodium chloride ≥3% | Consider use of warm or cold compress | Preferred: Hyaluronidase Alternative for calcium: Sodium thiosulfate Alternative for total parenteral nutrition: some authors suggest topical nitroglycerin ointment |
| Hypo-osmolar agents Aminophylline | Consider use of warm or cold compress | Hyaluronidase |
| Substances containing propylene glycol Diazepam Digoxin Etomidate Lorazepam Nitroglycerin Phenobarbital | Consider use of warm or cold compress | Hyaluronidase |
| Acidic and alkaline agents Acyclovir Amiodarone Arginineb Conivaptan Dantrolene Doxycycline Esmolol Gentamicin Pentamidine Pentobarbital Phenobarbital Phenytoind Promethazine Vancomycin | Dry heat and elevation | Hyaluronidase |
| Refractory to absorption Lipids Propofol | Consider use of warm compress | Hyaluronidase |
| Other Amphotericin Metronidazole Penicillin Valproate | Consider use of cold compress (valproate) Consider use of warm compress (metronidazole) Consider use of either warm or cold compress (amphotericin, penicillin) | Hyaluronidase |
| a In some cases in which only warm or cold compresses are listed, published recommendations are available to support use of the other type of compress. Clinical judgement should be used and the therapeutic goals of the individual patient should be considered. b Arginine is both hyperosmolar and is highly alkaline (pH 5.6). c There are rare reports of using hyaluronidase for radiographic contrast media extravasation, but this is recommended against by the American College of Radiology due to the lack of data.12 d The propylene glycol component of phenytoin injection may also play a role in extravasation injuries, but animal studies suggest that the major causative factor is alkaline pH.1 |
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Conclusion
Extravasation is a potentially serious unintended event associated with IV drug administration. Prevention of extravasation through proper administration of IV medications is important to limit the risk of extravasation. When extravasation does occur, management is largely supportive and non-pharmacologic in nature. Evidence supporting the use of specific antidotes is limited and largely limited to case reports.
References
- Reynolds PM, MacLaren R, Mueller SW, Fish DN, Kiser TH. Management of extravasation injuries: a focused evaluation of noncytotoxic medications. Pharmacotherapy. 2014;34(6):617-632. doi:10.1002/phar.13962
- Le A, Patel S. Extravasation of noncytotoxic drugs: a review of the literature. Ann Pharmacother. 2014;48(7):870-886. doi:10.1177/1060028014527820
- Pérez Fidalgo JA, García Fabregat L, Cervantes A, et al. Management of chemotherapy extravasation: ESMO-EONS clinical practice guidelines. Ann Oncol. 2012;23 Suppl 7:vii167-vii173. doi:10.1093/annonc/mds294
- Gorski LA, Hadaway L, Hagle ME, et al. Infusion Therapy Standards of Practice, 8th edition. J Infus Nurs. 2021;44(1S Suppl 1):S1-S224. doi:10.1097/NAN.0000000000000396
- Buter J, Steele KT, Chung KC, Elzinga K. Extravasation injury from chemotherapy and other non-antineoplastic vesicants. In: Post TW, ed. UpToDate. Waltham, MA: Wolters Kluwer Health, 2020. http://www.uptodate.com. Accessed January 13, 2021.
- Ong J, Van Gerpen R. Recommendations for management of noncytotoxic vesicant extravasations. J Infus Nurs. 2020;43(6):319-343. doi:10.1097/NAN.0000000000000392
- Management of drug extravasations. Lexicomp [database online]. Hudson, OH: Wolters Kluwer Health; 2021. http://onlinelexi.com. Accessed January 13, 2021.
- Kimmel J, Fleming P, Cuellar S, Anderson J, Haaf CM. Pharmacological management of anticancer agent extravasation: A single institutional guideline. J Oncol Pharm Pract. 2018;24(2):129-138. doi:10.1177/1078155217690924
- Wang RY. Extravasation of xenobiotics. In: Nelson LS, Howland MA, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS, eds. Goldfrank’s Toxicologic Emergencies. 11th New York, NY: McGraw-Hill; 2019. http://accessemergencymedicine.mhmedical.com/content.aspx?bookid=454§ionid=40199442&jumpsectionID=40215299&Resultclick=2. Accessed January 13, 2021.
- David V, Christou N, Etienne P, et al. Extravasation of noncytotoxic drugs. Ann Pharmacother. 2020;54(8):804-814. doi:10.1177/1060028020903406
- Gorski LA, Stranz M, Cook LS, et al. Development of an evidence-based list of noncytotoxic vesicant medications and solutions. J Infus Nurs. 2017;40(1):26-40. doi:10.1097/NAN.0000000000000202
- American College of Radiology. ACR Manual on Contrast Media 2020. https://www.acr.org/Clinical-Resources/Contrast-Manual. Accessed January 13, 2021.
Prepared by:
Heather Ipema, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
Jennifer Anderson, PharmD
University of Illinois at Chicago College of Pharmacy
February 2021
The information presented is current as of January 13, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.