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vasation? | Drug Information Group | University of Illinois Chicago

Drug Information Group

UI H EALTH IS U IC’S ACAD EM IC HE ALTH ENT ER PR IS E
College of Pharmacy - Chicago | Rockford

Drug Information Group Monthly FAQs 2021 February 2021 FAQs

What are current recommendations for treatment of drug extravasation?

What are current

recommendations for treatment
of drug extravasation?

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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

1. Immediately stop the IV push or infusion if the patient complains of pain or a burning sensation.
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2. Disconnect IV tubing from IV device. Do not remove the IV device or noncoring port needle.

3. 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.

4. Remove the peripheral IV device or port needle.

5. Assess the site of extravasation and the symptoms of the patient.

6. Notify the healthcare provider.

7. Elevate the affected limb to minimize swelling and encourage resorption of the drug via the lymphatic
system.

8. 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.

9. 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

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Table 1. Specific antidotes for extravasation.1,2,4-9

Antidote Preparation Administration

Dexrazoxane Each vial of dexrazoxane must Withhold cold

be mixed with the supplied compress 15 minutes
MOA: Unknown, may reversibly inhibit diluent to a concentration of 10 prior to infusion
topoisomerase II thereby protecting tissue mg/mL
from anthracycline cytotoxicity Begin infusion as
Dilute reconstituted solution in soon as possible and
Used for anthracycline extravasation Lactated Ringers, 0.9% within 6 hours of
sodium chloride, or 5% anthracycline
dextrose to a final extravasation
concentration of 1.3 to 5
mg/mL depending on specific Dose is based on
manufacturer instructions 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

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Table 1. Specific antidotes for extravasation.1,2,4-9

Hyaluronidase Vial contains 150 units per 1 Inject from 15 to 150

mL or 200 units per 1 mL units of the
MOA: hydrolyzes hyaluronic acid in depending on manufacturer hyaluronidase
connective tissue, possibly leading to solution as 5
dilution and diffusion of extravasated drug To obtain a 15 unit/mL separate injections,
concentration, mix 0.1 mL (of each containing 0.2
Used for etoposide, vinca alkaloids, taxanes 150 units/mL) with 0.9 mL of mL to 1 mL
(eg, paclitaxel, docetaxel), ifosfamide, 0.9% sodium chloride in 1 mL hyaluronidase
hyperosmolar agents, hypoosmolar agents, syringe
agents containing propylene glycol, acidic Use a 25-gauge
and alkaline agents, and agents that are For extravasation of needle to inject SC to
refractory to absorption (eg, propofol, lipids) hyperosmolar solutions: 15 to the affected area
25 units intradermally over 5 (change needle with
injections each injection)

For extravasation of Ideally administer

acidic/basic agents: 15 units within 1 hour of the
intradermally along injection event
site and edematous area
Doses up to 900
units have been
suggested for
cytotoxic drugs3

Sodium thiosulfate Prepare 1/6 molar solution: Use 2 mL of the

prepared solution for
MOA: neutralizes reactive species and From 25% sodium thiosulfate each 1 mg drug
reduces formation of hydroxyl radicals that solution: mix 1.6 mL with 8.4 extravasated
can cause tissue injury mL sterile water for injection
Use a 25-gauge
Used for cisplatin, cyclophosphamide, From 10% sodium thiosulfate needle to inject SC to
mechlorethamine, dacarbazine, alternative solution: mix 4 mL with 6 mL the affected area
for hyperosmolar agents, alternative for sterile water for injection (change needle with
calcium each injection)

Hyperosmolar
extravasations
(severe): 12.5 g IV
over 30 min, may
increase to 25 g 3
times/week

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Table 1. Specific antidotes for extravasation.1,2,4-9

DMSO 50% solution (99% solution Apply topically to site

reported in literature, but not for 7 to 14 days and
MOA: scavenges free radicals and has anti- available in US) allow to dry
inflammatory, analgesic, and vasodilatory
effects which promote systemic absorption Do not cover
of drug application site with a
dressing
Used for mitomycin, dactinomycin,
mitoxantrone and possible alternative for
anthracyclines

Phentolamine 5 to 10 mg in 10 to 20 mL of Use a 25-gauge

0.9% sodium chloride needle to inject at
MOA: α-adrenergic antagonist that multiple sites within
promotes vasodilation and capillary blood 0.5 to 4.5 mg in 5 mL of 0.9% the affected area
flow sodium chloride for (change needle with
epinephrine autoinjector- each injection)
Used for vasopressors induced ischemia
Administer within 12
to 13 hours of the
injury

Nitroglycerin topical 2% ointment 1-inch strip applied

to site of ischemia,
MOA: increases nitric oxide, promoting 5 mg/day transdermal patch can redose every 8
vasodilation hours as necessary

Used for vasopressors (alternative to 1 patch daily

phentolamine), hyperosmolar agents,
methylene blue

Terbutaline 1 mg in 10 mL of 0.9% sodium Use a 25-gauge

chloride needle to inject
MOA: α-adrenergic antagonist that locally across
promotes vasodilation and capillary blood symptomatic sites
flow (change needle with
each injection)
Used for vasopressors (alternative to
phentolamine)

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 Immediate topical therapy Antidote

extravasated

Cabazitaxel Apply cold compress for 15 to 20 minutes at least 4 None or

Docetaxel times/day for the first 24 hours hyaluronidase
Nab-paclitaxel
Paclitaxel

Cisplatin ˃0.4 Apply cold compress for 15 to 20 minutes at least 4 Sodium thiosulfate
mg/mL times/day for the first 24 to 48 hours
Cyclophosphamide

Daunorubicin Apply cold compress (but remove at least 15 minutes Dexrazoxanea

Doxorubicin prior to dexrazoxane)
Epirubicin
Idarubicin

Etoposide Apply dry warm compress for 60 minutes every 8 hours Hyaluronidase
for 3 days

Mechlorethamine Apply cold compress for 6 to 72 hours following sodium Sodium thiosulfate
thiosulfate injection or for 20 minutes 4 times/day for 24
to 48 hours

Mitomycin Apply cold compress for 15 to 20 minutes at least 4 None or topical

Dactinomycin times/day for 24 to 48 hours DMSO
Mitoxantrone

Oxaliplatin Apply warm compress (ice increases risk of cold-induced None or

peripheral neuropathy) for 15 to 20 minutes at least 4 dexamethasone 8
times/day for the first 24 hours mg twice daily for
14 days

Vinblastine Elevate extremity and apply dry warm compress for 15 to Hyaluronidase
Vincristine 60 minutes at least 3 times/day for the first 24 to 72
Vinorelbine hours

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.

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Table 3. Extravasation of non-cytotoxic drugs.1,2,6,7,10-12

Medication Immediate topical therapya Antidote/treatment considerations

extravasated

Vasopressors Consider use of warm Preferred: Phentolamine for most agents;

Dobutamine compress topical nitroglycerin ointment for vasopressin
Dopamine and methylene blue
Epinephrine
Methylene blue Alternative: Topical nitroglycerin ointment,
Norepinephrine terbutaline
Phenylephrine
Vasopressin

Hyperosmolar Consider use of warm or cold Preferred: Hyaluronidase

agents compress
Ampicillin Alternative for calcium: Sodium thiosulfate
Arginineb
Calcium chloride Alternative for total parenteral nutrition: some
10% authors suggest topical nitroglycerin ointment
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%

Hypo-osmolar Consider use of warm or cold Hyaluronidase

agents compress
Aminophylline

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Table 3. Extravasation of non-cytotoxic drugs.1,2,6,7,10-12

Substances Consider use of warm or cold Hyaluronidase

containing compress
propylene glycol
Diazepam
Digoxin
Etomidate
Lorazepam
Nitroglycerin
Phenobarbital

Acidic and Dry heat and elevation Hyaluronidase

alkaline agents
Acyclovir
Amiodarone
Arginineb
Conivaptan
Dantrolene
Doxycycline
Esmolol
Gentamicin
Pentamidine
Pentobarbital
Phenobarbital
Phenytoind
Promethazine
Vancomycin

Refractory to Consider use of warm Hyaluronidase

absorption compress
Lipids
Propofol

Other Consider use of cold compress Hyaluronidase

Amphotericin (valproate)
Metronidazole Consider use of warm
Penicillin compress (metronidazole)
Valproate Consider use of either warm or
cold compress (amphotericin,
penicillin)

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Table 3. Extravasation of non-cytotoxic drugs.1,2,6,7,10-12

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

1. 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

2. Le A, Patel S. Extravasation of noncytotoxic drugs: a review of the literature. Ann Pharmacother.

2014;48(7):870-886. doi:10.1177/1060028014527820

3. 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

4. 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

5. 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.

6. 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

7. Management of drug extravasations. Lexicomp [database online]. Hudson, OH: Wolters Kluwer
Health; 2021. http://onlinelexi.com. Accessed January 13, 2021.

8. 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

9. 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&sectionid=40199442&jumpsectionID=40215299&Resultclick=2. Accessed January
13, 2021.

10. David V, Christou N, Etienne P, et al. Extravasation of noncytotoxic drugs. Ann Pharmacother.
2020;54(8):804-814. doi:10.1177/1060028020903406

11. 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

12. American College of Radiology. ACR Manual on Contrast Media 2020. https://www.acr.org/Clinical-
Resources/Contrast-Manual[https://www.acr.org/Clinical-Resources/Contrast-Manual]. Accessed
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5/15/22, 12:05 PM What are current recommendations for treatment of drug extravasation? | Drug Information Group | University of Illinois Chicago

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.

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