Management of Non-Chemo Drug Extravasation

(full update June 2024)

Some non-chemo vesicant drugs may be especially likely to harm soft tissue with infiltration or extravasation.21,22 They can be classified as:16,17,21,22,25

  • Hyperosmolar meds (e.g., hypertonic saline, parenteral nutrition, sodium bicarbonate) cause osmotic shifts leading to inflammation and cell death.
    • Common preventive strategies: Infuse through a central line. In particular, ≥600 mOsm/L may not be as well tolerated by peripheral veins.21,22 (For reference, the osmolarity of 0.9% sodium chloride is 308 mOsm/L and for 3% saline it’s 1,026 mOsm/L.)
  • Drugs with very high or low pH (e.g., acyclovir, amiodarone, phenytoin, vancomycin), which damage tissue and cause vasoconstriction.
    • Common preventive strategies: Dilute medication and infuse slowly. See detailed recommendations below.
  • Vasopressors (e.g., norepinephrine, phenylephrine, vasopressin), which cause ischemia and necrosis.
    • Common preventive strategies: Infuse through a central line, especially for longer durations and if a large peripheral vein is not available.25

General treatment for non-chemo extravasations includes these steps:1-3,15,17,18,21,22,24

  • Immediately stop the infusion.
  • Aspirate residual drug through the needle or catheter.
  • Elevate the affected limb to minimize swelling.
  • Apply a cold (to reduce swelling and localize the agent) OR a warm (for vasodilation and to disperse the agent) compress. Apply dry compresses for 20 minutes every 6 to 8 hours for up to 3 days.2,22,24 The choice of cold or warm will depend on the offending agent.
  • Administer an analgesic.

Drug treatments depend on the causative agent, and may include the following: (doses below have been cited in the literature):

  • To distribute the causative agent away from the site (commonly used for hyperosmolar and pH-related extravasation injury):
    • Hyaluronidase (US only) 150 units/mL. Dilute to 15 units/mL with 0.9% sodium chloride. Inject 0.2 mL intradermally, into five sites around the extravasation area.8,22 Administer within about one hour of extravasation.18,22 Note that warm compresses may complement the action of hyaluronidase, while cold compresses may theoretically act in opposition.21
  • To counteract local vasoconstriction (commonly used for vasopressor extravasation):
    • Phentolamine 5 to 10 mg, in 10 to 20 mL 0.9% sodium chloride, intradermal or subcutaneously, around the edges of the extravasation area as multiple small injections (e.g., 0.2 to 1 mL at a time [using a new needle for each injection]).21,22 Administer as soon as possible to prevent tissue necrosis (best outcomes within 12 hours of extravasation).22,27
    • Terbutaline (US only) 1 mg in 10 mL 0.9% sodium chloride (for larger areas) or 1 mL 0.9% sodium chloride (for localized ischemia). Administer subcutaneously at the edges of the extravasation area.22,24,25 Can repeat dose after 15 minutes.22
    • Nitroglycerin topical formulations used include patch or 2% ointment (US only), as a 1-inch strip, every 8 hours as needed.14,21,22,24

Silver sulfadiazine cream may help with extravasation of hyperosmolar drugs.21 Topical or systemic steroids have not been shown to be effective and can slow healing and promote infection.21 Severe cases may require surgical intervention.16,17,22 Note that treatments are often based on case reports and animal data.

The following chart contains non-chemo drugs that have some evidence for treatment of extravasation. Warm or cold compresses are included if data supporting use of one or the other are available. Some preventive strategies are also included. Additional sources of information for treating extravasations of drugs not listed may include drug manufacturers, poison control centers, or hospital protocols (consider developing protocols, if you don’t already have them).

Drug

Treatment Options

Comments

Calcium salts

Warm compress

Hyaluronidase22

Mechanism: hyperosmolarity22

Dilute calcium chloride to 3 mg/mL or less when administering via peripheral line.20,28

Contrast media

Cold or warm compress to alleviate symptoms22

Hyaluronidase (data are conflicting)22

Mechanism: hyperosmolarity3,6

Tissue damage is most likely with ionic agents.3,6,7

Dextrose (≥10%)

Hyaluronidase8

Mechanism: hyperosmolarity8

Mannitol

Warm compress22

Hyaluronidase9,22

Mechanism: hyperosmolarity9,21

Methylene blue

Topical nitroglycerin22

Phentolamine22

Mechanism: vasocontriction22

Nafcillin (US only)

Hyaluronidase10

Mechanism: not clear; possibly hyperosmolarity22

Parenteral nutrition

Warm compress22

Hyaluronidase1

Topical nitroglycerin1,22

Mechanism: hyperosmolarity1

Formulations with up to 900 mOsm/L are considered safe for peripheral administration.23

Phenytoin

Warm compress11,22

Hyaluronidase12

Topical nitroglycerin11

Mechanism: high pHa,11 (vehicle composition and formation of precipitates may also contribute)

Extravasation may result in “purple glove syndrome.”11

Potassium salts

Hyaluronidase22

Mechanism: hyperosmolarity22

Adult recommended infusion rate is 10 mEq/hour.20

Concentration limits for peripheral administration may vary by institution. Most allow 0.1 mEq/mL to be infused peripherally, and some may allow
0.2 mEq/mL to be infused via peripheral line.20

Promethazine

No proven treatment.4 Sympathetic blockade (i.e., nerve block) and systemic heparin therapy have been used to manage inadvertent intra-arterial administration and extravasation of promethazine based on animal data.4,19,22

Mechanism: low pH,a chemical irritant19

Suggested preventive strategies include:5

  • Dilute doses in 0.9% sodium chloride to allow for slower administration.
  • Start with smaller doses such as 6.25 to 12.5 mg.
  • Infuse doses through a large vein over 10 to
    15 minutes.

ISMP recommends removing promethazine from formulary and all areas of the hospital.29

Saline (3%)

Hyaluronidase22

Mechanism: hyperosmolarity22

Vasopressors

  • Dobutamine
  • Dopamine
  • Epinephrine
  • Norepinephrine
  • Phenylephrine
  • Vasopressin

Warm compress21,22,24

Phentolamine13

Terbutaline24

Topical nitroglycerin14,22,24

Mechanism: vasoconstriction, low pHa,13,21,22

Infusing pressors through central lines is usually recommended, but some data suggest the risk of extravasation injuries from infusing vasopressors through peripheral lines may be lower than thought.26

Hyaluronidase or cold compresses can extend/worsen vasoconstriction.21c

Topical nitroglycerin is preferred over phentolamine for extravasation due to vasopressin.24
  1. Do not attempt to neutralize acidic or basic extravasations due to the potential for heat and gas formation.21,22

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

Level

Definition

Study Quality

A

Good-quality patient-oriented evidence.*
  1. High-quality randomized controlled trial (RCT)
  2. Systematic review (SR)/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*
  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

C

Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. https://www.aafp.org/pubs/afp/issues/2004/0201/p548.html.]

References

  1. Gil ME, Mateu J. Treatment of extravasation from parenteral nutrition solution. Ann Pharmacother. 1998 Jan;32(1):51-5.
  2. Wang RY. Extravasation of xenobiotics. In: Nelson LS, Howland M, Lewin NA, et al, Eds. Goldfrank's Toxicologic Emergencies. 11th ed. New York, NY: McGraw-Hill Education, 2019.
  3. Belzunegui T, Louis CJ, Torrededia L, Oteiza J. Extravasation of radiographic contrast material and compartment syndrome in the hand: a case report. Scand J Trauma Resusc Emerg Med. 2011 Feb 4;19:9.
  4. Cross MB, Warner K, Young K, Weiland AJ. Peripheral sympathectomy as a novel treatment option for distal digital necrosis following parenteral administration of promethazine. HSS J. 2012 Oct;8(3):309-12.
  5. Grissinger M. Preventing serious tissue injury with intravenous promethazine (phenergan). P T. 2009 Apr;34(4):175-6.
  6. Maddox TG. Adverse reactions to contrast material: recognition, prevention, and treatment. Am Fam Physician. 2002 Oct 1;66(7):1229-34.
  7. Schwartz DT. Principles of diagnostic imaging. In: Nelson LS, Howland M, Lewin NA, et al, Eds. Goldfrank's Toxicologic Emergencies. 11th ed. New York, NY: McGraw-Hill Education, 2019.
  8. Wiegand R, Brown J. Hyaluronidase for the management of dextrose extravasation. Am J Emerg Med. 2010 Feb;28(2):257.e1-2.
  9. Kumar MM, Sprung J. The use of hyaluronidase to treat mannitol extravasation. Anesth Analg. 2003 Oct;97(4):1199-1200.
  10. Zenk KE, Dungy CI, Greene GR. Nafcillin extravasation injury. Use of hyaluronidase as an antidote. Am J Dis Child. 1981 Dec;135(12):1113-4.
  11. Edwards JJ, Bosek V. Extravasation injury of the upper extremity by intravenous phenytoin. Anesth Analg. 2002 Mar;94(3):672-3; table of contents.
  12. Sokol DK, Dahlmann A, Dunn DW. Hyaluronidase treatment for intravenous phenytoin extravasation. J Child Neurol. 1998 May;13(5):246-7.
  13. Bey D, El-Chaar GM, Bierman F, Valderrama E. The use of phentolamine in the prevention of dopamine-induced tissue extravasation. J Crit Care. 1998 Mar;13(1):13-20.
  14. Denkler KA, Cohen BE. Reversal of dopamine extravasation injury with topical nitroglycerin ointment. Plast Reconstr Surg. 1989 Nov;84(5):811-3.
  15. Wickham R, Engelking C, Sauerland C, Corbi D. Vesicant extravasation part II: Evidence-based management and continuing controversies. Oncol Nurs Forum. 2006 Nov 27;33(6):1143-50.
  16. Khan MS, Holmes JD. Reducing the morbidity from extravasation injuries. Ann Plast Surg. 2002 Jun;48(6):628-32; discussion 632.
  17. Rosenthal K. Reducing the risks of infiltration and extravasation. Nursing. 2007 Fall;37 Suppl Med:4-8.
  18. Dougherty L. Extravasation: prevention, recognition and management. Nurs Stand. 2010 Sep 1-7;24(52):48-55; quiz 56, 60.
  19. Product information for Phenergan. Hikma Pharmaceuticals. Berkeley Heights, NJ 07922. May 2020.
  20. Clinical Pharmacology powered by ClinicalKey. Tampa, FL: Elsevier 2024. http://www.clinicalkey.com. (Accessed May 15, 2024).
  21. David V, Christou N, Etienne P, et al.Extravasation of Noncytotoxic Drugs. Ann Pharmacother. 2020 Aug;54(8):804-814.
  22. Stefanos SS, Kiser TH, MacLaren R, Mueller SW, Reynolds PM. Management of noncytotoxic extravasation injuries: A focused update on medications, treatment strategies, and peripheral administration of vasopressors and hypertonic saline. Pharmacotherapy. 2023 Apr;43(4):321-337.
  23. Boullata JI, Gilbert K, Sacks G, et al.A.S.P.E.N. clinical guidelines: parenteral nutrition ordering, order review, compounding, labeling, and dispensing. JPEN J Parenter Enteral Nutr. 2014 Mar-Apr;38(3):334-77.
  24. University of Illinois Chicago. What are current recommendations for treatment of drug extravasation? February 2021. https://dig.pharmacy.uic.edu/faqs/2021-2/february-2021-faqs/what-are-current-recommendations-for-treatment-of-drug-extravasation/. (Accessed May 29, 2024).
  25. Cardenas-Garcia J, Schaub KF, Belchikov YG, et al. Safety of peripheral intravenous administration of vasoactive medication. J Hosp Med. 2015 Sep;10(9):581-5.
  26. Lewis T, Merchan C, Altshuler D, Papadopoulos J. Safety of the Peripheral Administration of Vasopressor Agents. J Intensive Care Med. 2019 Jan;34(1):26-33.
  27. Product information for phentolamine. Hikma Pharmaceuticals. Berkeley Heights, NJ 07922. May 2022.
  28. Anger KE, Belisle C, Colwell MB, et al. Safety of compounded calcium chloride admixtures for peripheral intravenous administration in the setting of a calcium gluconate shortage. J Pharm Pract. 2014 Oct;27(5):474-7.
  29. ISMP. ISMP targeted medication safety best practices for hospitals. 2024-2025. https://www.cfpr.org/files/ISMP_TargetedMedicationSafetyBestPractices_Hospitals_021524_MS5818.pdf. (Accessed May 29, 2024).

Cite this document as follows: Clinical Resource, Management of Non-Chemo Extravasation. Pharmacist’s Letter/Pharmacy Technician’s Letter/Prescriber Insights. June 2024. [400660]

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