Chapter 46: Antineoplastic Drugs: Preventing and Managing Extravasation

David R. Kohler

Irritant drugs may produce any of the following reactions: erythema along a vein or phlebitis, with sensations of tenderness, warmth, or burning, and pain, and, as a consequence of extravasation, inflammatory reactions, which may include local swelling, erythema, induration with sensations of itching, warmth, aching, tightness, or pain, but generally not tissue necrosis. Drugs categorized as irritants are more or less irritating to soft tissues owing to intrinsic differences in their physical and chemical properties and the properties of excipient products with which they are formulated. The manifestations and severity of reactions after extravasation with irritant drugs often correlate with the concentration of drug, the amount of drug and volume extravasated, and the duration of exposure; that is, some irritants exhibit properties characteristic of vesicants if the amount of drug extravasated is large or highly concentrated. However, except for local changes in pigmentation at an extravasation site (often hyperpigmentation), symptoms associated with irritant drug extravasations are typically of short duration (days to weeks), and there are no lasting sequelae

Vesicants

Vesicant drugs may cause severe tissue injury, usually resulting in necrosis; consequently, vesicant extravasation is a medical emergency requiring prompt situationally appropriate action. Vesicant extravasation injuries may be subtle with a delayed onset of morbidity, or immediately apparent with a rapid onset of symptoms. The severity of lesions, the time over which they develop, and the likelihood of spontaneous healing without intervention, also vary among vesicant drugs. DNA-binding agents (eg, anthracyclines, anthracenediones, mitomycin, dactinomycin) tend to produce more severe and persistent lesions than drugs that do not bind to DNA (eg, Vinca alkaloids, taxanes). Over a period of days to weeks, erythema, swelling, induration, and pain may increase and progress to brawny discoloration, blistering, or dry desquamation. Lesions may ulcerate and form eschars. Ulcers are characteristically painful with erythematous borders and necrotic bases. Spontaneous reepithelialization typically does not occur. Lesions caused by DNA-binding agents may continue to expand laterally and deepen for weeks to months after an extravasation event, involving adjacent structures after cytolytic release of active drug from necrotic tissues

What to Avoid in Placement of Vascular Access Devices (VADs)

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What to Avoid in Placement of Vascular Access Devices (VADs)

Peripheral VADs

Central VADs and Implanted Ports

Fragile, small, or low-flow vessels such as the dorsal aspect of the wrist
Vessels overlying areas with little subcutaneous tissue such as the dorsum of the hand and wrist, and areas of flexion, such as the wrist and antecubital fossa, particularly for administering irritants or vesicants
Areas of hematoma, edema, impaired lymphatic drainage, frank lymphedema, or distal to lymphatic dissection, phlebitis, inflammation, induration or obvious infection, and sites previously irradiated or treated with irritating or sclerosing drugs
Veins in extremities with decreased sensation, paresthesia, or neurologic weakness. Impaired tactile sensation may prevent a patient from feeling and promptly reporting discomfort associated with extravasation
Sites distal to former venipuncture sites, particularly within the previous 24 hours
Sites distal to sites of previous extravasation or a site affected by previous extravasation
Probing during VAD insertion
A site that does not allow for continuous visual inspection
Inadequately secured VADs or administration (giving) sets

Port placement in suboptimal locations, such as the groin or axillae
Areas where needle stability is compromised (eg, the side on which a patient prefers to sleep)
Deeply implanted ports

Assessing VADs

New Peripheral VADs

Preexisting Peripheral VADs

Central VADs and Implanted Ports

Obtain peripheral vascular access in a large vessel in the upper extremities. Peripheral venous access in a lower extremity is not recommended
Assess the length of percutaneously inserted VADs. A change in the length of the external portion of a catheter may indicate infiltration through a vein or migration (backing) out of a vein

A new access site should be obtained before administering vesicant drugs peripherally
Assess preexisting peripheral VADs for patency by verifying a brisk blood return and ease of flushing. Flush solutions should flow freely to gravity
Assess site for swelling, erythema, pain, drainage
Assess for signs or symptoms of venous obstruction
Assess the length of percutaneously inserted VADs. A change in the length of the external portion of a catheter may indicate infiltration through a vein or migration (backing) out of a vein

Radiographic confirmation of a central VAD catheter's tip location should be obtained immediately after device insertion and in the following clinical situations:
1. Pain or discomfort after catheter placement;
2. Inability to obtain positive aspiration of blood;
3. Inability to flush the catheter easily; or
4. After catheter migration is noted
Assess the length of percutaneously inserted VADs. A change in the length of the external portion of a catheter may indicate infiltration through a vein or migration (backing) out of a vein
Assess central VADs and ports for patency by verifying a substantial, free-flowing blood return (3–5 mL) and ease of flushing
- A flash of blood on aspiration or blood-tinged flush solution are not sufficient to confirm appropriate VAD placement or function
Use noncoring needles of appropriate lengths for accessing implanted ports

Note: A new peripheral VAD placed just before drug administration is strongly recommended for administering vesicant drugs

General Principles for Irritant and Vesicant Drug Administration

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General Principles for Irritant and Vesicant Drug Administration

For treatments administered peripherally through vascular access placed in the upper extremities, secure administration set tubing to the arm with tape. Have patients rest the arm through which treatment is administered on an armrest, across their lap, or on a bed rather than allowing the extremity to hang over the side of a chair or bed
- Instruct patients to avoid moving a cannulated hand or arm during peripheral administration of irritant and vesicant drugs
Verify VAD patency by checking for a brisk blood return both before and after drug administration
- Instruct patients to immediately report an incident in which tubing is pulled or tugged, and reevaluate VAD patency
Review with patients signs and symptoms commonly associated with drug extravasation. Encourage patients to immediately report sensations of swelling, itching, pain, burning, stinging, or other discomfort they experience during and after parenteral drug administration
- Complaints of discomfort often occur during drug administration or promptly afterward, but may be delayed by ≥48 hours after completing drug administration. The onset of clinically apparent morbidity may be delayed by weeks after an extravasation incident
After drug administration is completed, flush the administration set with a compatible solution to ensure complete drug delivery

Intravenous Injection (Direct IV Injection or IV Push)

Peripheral VADs

Central VADs and Implanted Ports

Administer intravenously a freely flowing compatible solution before beginning chemotherapy administration
Introduce chemotherapy into an administration set at a Y-site or injection port most proximal to the patient
Check for a blood return before starting chemotherapy administration, check during drug administration after every 1–2 mL of drug administered, and check after drug administration is completed. DO NOT check for VAD patency with a chemotherapy drug
Flush the VAD and vein with the freely flowing compatible solution every 2–3 minutes when injecting large drug volumes, flush between different drugs, and flush after completing drug administration
Advise patients to immediately report sensations of swelling, itching, pain, burning, stinging, or other discomfort they experience during and after parenteral drug administration
Complaints of discomfort often occur during drug administration or promptly afterward, but may be delayed by ≥48 hours after completing drug administration. The onset of clinically apparent morbidity may be delayed by weeks after an extravasation incident
Observe the vascular access site continuously during drug administration

Intravenous Piggyback (Secondary Infusions)

Peripheral VADs

Central VADs and Implanted Ports

Administer a cytotoxic agent as a secondary infusion piggybacked into a primary line at a Y-site or injection port between the flush solution container and the infusion device (pump) used to control the rate of administration. If more than 1 injection port is available, use a port between the drug supply and a rate-controlling infusion device ("above the pump")
Secure administration set tubing using tape or a secure locking device

Secure administration set tubing using tape or a secure locking device
Administer as a secondary infusion piggybacked into a primary line at a Y-site or injection port
Every hour, observe the vascular access site for erythema or edema, and evaluate all fluid pathway connections
Advise ambulatory outpatients to monitor their VAD exit site or port entry site for redness and swelling, and sensations of warmth, tenderness, or discomfort, and instruct them whom to contact if complications arise

Irritant

Vesicant

Check for a brisk blood return before administering chemotherapy and after drug administration is completed
Observe the IV site every 15 minutes for erythema or edema until drug delivery is completed
An infusion pump should be used to administer irritant drugs through peripheral veins via continuous (prolonged) infusion

DO NOT use an infusion pump to administer vesicant drugs
Check for a brisk blood return before administering chemotherapy, check every 5 minutes during administration, and check after drug administration is completed
Observe the vascular access site continuously for erythema or edema
DO NOT administer large volumes of vesicant drugs into peripheral veins unless using a peripherally inserted central catheter

Continuous or Prolonged (Primary Infusions)

Peripheral VADs

Central VADs and Implanted Ports

Peripheral VADs should NOT be used to administer vesicant drugs

A low-pressure infusion pump or controller is required
Every 1–4 hours, observe the vascular access site for erythema or edema, and monitor the connections
Advise ambulatory outpatients to monitor their VAD exit site or port entry site for redness and swelling, and sensations of warmth, tenderness, or discomfort, and instruct them whom to contact if complications arise

Extravasation is suspected if:

A patient complains of swelling, pain, stinging, burning, or other discomfort at an injection site or in an area that is referable to the distal end of a catheter or implanted port
There is erythema or blanching in the epidermis overlying an injection site, and swelling or induration around the site
A blood return cannot be obtained from the VAD
Parenteral fluids used to "carry" or flush the drug no longer flow freely

Note: Extravasation from a tunneled VAD may produce discomfort and edema along the subcutaneous track or erythema where the VAD exits the skin. Patients with tunneled VADs or implanted ports may complain of tingling, burning, aching, or other types of pain over the chest wall, the infraclavicular area, neck, or shoulder (sites referable to the location of the port body) ± fever

Dermal reactions that must be distinguished from extravasation include:

Flare reactions: A local allergic reaction that occurs without pain or swelling, and blood return is unaffected. Flare reactions usually are characterized by red blotches along the vein through which a drug was administered, and typically subside within 30 minutes with or without treatment
Urticarial reactions: Associated with pruritus along the vein through which a drug was administered
Other nonextravasation reactions: Aching along the vein through which a drug was administered, supra- or perivascular hyperpigmentation, and wheals

If drug extravasation occurs or is suspected:

STOP drug administration
Remove the syringe used to administer push doses or disconnect the administration set at the point closest to the VAD, but do not dislodge, reposition, or remove the VAD or a needle used to access an implanted port
With a fresh syringe, attempt to aspirate from the VAD (or a needle left in an implanted port) any drug it contains and any accessible drug that can be retrieved from the extravasation site
Aspirate gently. Aggressive aspiration may cause the catheter to collapse or tissue to occlude the catheter or needle tip
As a temporary VAD is removed, continue gentle aspiration until the cannula is removed from its insertion site
With a soft-tipped indelible marker, mark the outside border (circumference) of the area of extravasation and identify in the patient's medical record what the marking represents (eg, erythema, swelling, induration)
- If possible the area of extravasation should be photographed as soon as possible after an extravasation event, and serially, thereafter to record and facilitate comparison of gross and subtle changes. Photographs should be dated to facilitate comparisons through time
As appropriate for the situation, remove peripheral VADs (this does not include PICC, SICC, or midline catheters), or remove the needle from an implanted port before applying topical interventions
Thermal interventions—topical warming or cooling—are based on considerations of whether an extravasated drug should be localized by cooling or dispersed by applying heat
- Cooling produces local vasoconstriction which may limit perfusion of local or systemic antidotes into an extravasation site; therefore, DO NOT use topical cooling within 15–30 minutes before or after or during administration of pharmacologic antidotes
Implement appropriate pharmacologic and nondrug interventions as directed by a medically responsible care provider or as indicated by local policies, procedures, or standards of practice
- Note: If appropriate and practical, seek consultation with care providers experienced in managing extravasation of antineoplastic drugs. Nurses and pharmacists who are certified or experienced in oncology practice may be excellent resources for information about appropriate management
Apply a dressing if indicated, but protect an extravasation site from unnecessary compression
When extravasation occurs in an extremity, elevate the extremity
Instruct patients to avoid exposing an extravasation injury site to sunlight and to report episodes of fever or chills, skin blistering, peeling, or sloughing, and worsening discomfort or pain
Record in a patient's medical record details about the event and any interventions used in management

Note: Documentation should identify the date and time of extravasation, the dimensions of the injured site (perpendicular length and width at their greatest dimensions), relevant patient complaints, identify what drugs were extravasated, an estimate of the amount of extravasated drugs, all interventions used in management, instructions given to the patient, and a record of subsequent evaluations and consultations. When recording measurements, identify what was measured (eg, swelling, erythema, induration, blistering, ulceration), and the time it was measured with respect to when extravasation occurred
When vesicant extravasation occurs with a VAD placed in an extremity, the extremity should not be used for subsequent catheter placement. Treatment alternatives include discontinuation of therapy, use of the contralateral extremity, or use of a central VAD

VAD, vascular access device. In the present document, the term includes short peripherally inserted catheter (SICC); long-line, peripherally inserted, central catheter (PICC); and subcutaneously tunneled central catheter (CC)

The preceding recommendations are adapted from the following resources:

Camp-Sorrell D. Developing extravasation protocols and monitoring outcomes. J Intraven Nurs 1998;21:232–239

Extravasation. In: Polovich M, White JM, Olsen M, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice, 3rd ed. Pittsburgh, PA: Oncology Nursing Society (ONS), 2009:105–116, 360

Langer SW. Extravasation of chemotherapy. Curr Oncol Rep 2010;12:242–246

Schrijvers DL. Extravasation: A dreaded complication of chemotherapy. Ann Oncol 2003;14(Suppl 3):iii26–iii30

Schulmeister L, Camp-Sorrell D. Chemotherapy extravasation from implanted ports. Oncol Nurs Forum 2000;27:531–538

Society of Infusion Nursing. Infusion nursing standards of practice: infusion therapies: antineoplastic and biologic therapy. J Infus Nurs 2006;29(Suppl 1):S69–S71

Susser WS et al. Mucocutaneous reactions to chemotherapy. J Am Acad Dermatol 1999;40:367–398

The National Institutes of Health Clinical Center Nursing and Patient Care Services Department's Standard of Practice: Care of the Patient Receiving Intravenous Cytotoxic or Biologic Agents; revised, May 2010

Wengström Y, Margulies A. European Oncology Nursing Society extravasation guidelines. Eur J Oncol Nurs 2008;12:357–361

Table 42–1.Drug-Specific Extravasation Management Guidelines

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Table 42–1. Drug-Specific Extravasation Management Guidelines

Risk Category

Antidote Intervention and Preparation

Local Care

Comments

Actinomycin D

See guidelines for "Dactinomycin"

Adriamycin

See guidelines for "Doxorubicin HCl"

Alimta

See guidelines for "Pemetrexed disodium"

Alkeran

See guidelines for "Melphalan HCl"

BCNU

See guidelines for "Carmustine"

Bendamustine HCl (Treanda; distributed by Cephalon, Inc., Frazer, PA)

Irritant

No known antidotes

Aspirate back through the VAD to remove any accessible extravasated drug
No specific local therapy is indicated

Product labeling for Treanda (dated, July 2010) indicates extravasation has resulted in hospitalization with " . . . erythema, marked swelling, and pain. Precautions should be taken to avoid extravasation, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration . . ."

Camptosar

See guidelines for "Irinotecan HCl"

Carboplatin (available generically)

Unclassified^a

No known antidotes

No specific local therapy is indicated

Carmustine (also called BCNU, BiCNU; distributed by Bristol-Myers Squibb Company, Princeton, NJ)¹

Irritant

No known antidotes

Aspirate back through the VAD to remove any accessible extravasated drug
No specific local therapy is indicated

Patients may complain of irritation and stinging pain during administration—a result of ethanol used to reconstitute carmustine
- Carmustine should be diluted in at least 250 mL fluid
Topical sodium bicarbonate solution inactivates carmustine spilled or splashed on the skin, but MUST NOT be injected locally in the event of carmustine extravasation

Cisplatin (available generically)^2,3,4,5

Irritant

See Comments

No local therapy is indicated after extravasation with small volumes of dilute cisplatin solutions (see Comments)
Extravasation with large volumes or highly concentrated cisplatin solutions may be treated as an extravasation with mechlorethamine (see Comments)

Injury to soft tissues has been reported after extravasation of cisplatin solutions with concentrations >0.4 mg/mL³
Product labeling for Cisplatin Injection (dated, January 2008; APP Pharmaceuticals, LLC, Schaumberg, IL) indicates administration of solutions with a cisplatin concentration >0.5 mg/mL may result in local soft-tissue toxicity with cellulitis, fibrosis, and necrosis
Although sodium thiosulfate has been recommended to chemically neutralize cisplatin, the conditions under which cisplatin extravasation will produce severe morbidity and tissue necrosis remain undefined (with respect to a threshold concentration or volume extravasated); therefore, the most appropriate use of sodium thiosulfate is not known

Cosmegen

See guidelines for "Dactinomycin"

Dacarbazine (also called DTIC; available generically)^6,7

Irritant

No known antidotes

Aspirate back through the VAD to remove any accessible extravasated drug
No local therapy is indicated
Protect exposed tissues from light following extravasation
Elevate an involved extremity
Avoid applying pressure to the extravasation site

Increased skin toxicity was produced in some animal models when dacarbazine was administered intradermally followed by light exposure

Dactinomycin (also called actinomycin D; available generically)

Vesicant

No known antidotes

Conservative management^a
Product labeling for Dactinomycin for Injection recommends applying ice to the site for 15 minutes four times daily for 3 days (alternatively, substitute circulating ice water, an ice pack, or other cold compress)

Extravasation may occur with or without an accompanying burning or stinging sensation, even with a good blood return on aspiration from the injection site
Topical cooling has been inconsistently effective in animal studies
Blistering, ulceration, and persistent pain are indications for wide excision surgery, followed by skin grafting

Daunorubicin HCl (also called daunomycin. Cerubidine™; Bedford Laboratories, Bedford, OH; available generically)

Vesicant

Dexrazoxane (see Comments)

Aspirate back through the VAD to remove any accessible extravasated drug
Apply cold to an involved extremity with circulating ice water, an ice pack, or a cold compress for 15–60 minutes four times daily for at least 48 hours after extravasation^b
Elevate an involved extremity
Avoid applying pressure to the extravasation site

Administer dexrazoxane for anthracycline extravasation^c, ^8,9,10:

Dexrazoxane 1000 mg/m² per day (maximum daily dose is 2000 mg) intravenously, diluted in 1000 mL 0.9% sodium chloride injection (0.9% NS) over 1–2 hours for 2 consecutive days, on days 1 and 2, followed by:
Dexrazoxane 500 mg/m² (maximum dose is 1000 mg) intravenously, diluted in 1000 mL 0.9% NS over 1–2 hours on day 3 after extravasation
- Effectiveness is decreased if dexrazoxane administration is initiated more than 6 hours after extravasation
- Repeated doses (days 2 and 3) should be administered 24 ± 3 hours after a previously administered dose
- Decrease dexrazoxane dosage by 50% for patients whose creatinine clearance is <40 mL/min (<0.66 mL/s)

Daunorubicin citrate liposome injection (also called DaunoXome^®; Galen US Inc, Souderton, PA)^11,12,13

Irritant

No known antidotes

Aspirate back through the VAD to remove any accessible extravasated drug
Apply cold to an involved extremity with circulating ice water, an ice pack, or a cold compress for 15–60 minutes 4 times daily for at least 48 hours after extravasation^b
Elevate an involved extremity
Avoid applying pressure to the extravasation site

DaunoXome

See guidelines for "Daunorubicin citrate liposome injection"

Docetaxel (available generically)^14,15,16

Vesicant

No known antidotes

Aspirate back through the VAD to remove any accessible extravasated drug
Apply cold to an involved extremity with circulating ice water, an ice pack, or a cold compress for 15–20 minutes at least 4 times daily for 24–48 hours after extravasation^b
Elevate an involved extremity
Avoid applying pressure to the site

Extravasation often presents acutely with erythema, swelling, and tenderness of the involved site, but onset may be delayed by several days. Blistering and onset or exacerbation of pain may be delayed by several days. Erythema and edema may increase markedly during the first week. Skin desquamation characteristically occurs within 2–3 weeks
It is not yet clear whether application of either cold or heat provides benefit in managing extravasation with taxoid drugs. In one case report, erythema and hyperpigmentation may have been exacerbated by warming after extravasation with the related drug, paclitaxel¹⁷
Locally altered tactile sensation (dysesthesias or loss of sensation) may persist for months after an extravasation event^15,18

Doxil

See guidelines for "Doxorubicin HCl liposome injection"

Doxorubicin HCl (available generically)^19,20,21,22

Vesicant

Dexrazoxane (see Comments for Daunorubicin HCl)

Aspirate back through the VAD to remove any accessible extravasated drug
Apply cold to an involved extremity with circulating ice water, an ice pack, or a cold compress for 15–60 minutes 4 times daily for at least 48 hours after extravasation^b
Elevate an involved extremity
Avoid applying pressure to the extravasation site

Administer Dexrazoxane as for extravasation with Daunorubicin HCl (see "Daunorubicin HCl," Comments)^8,9,10
Seek surgical consultation, especially if a patient reports pain at the extravasation site within 10 days after the event. Surgical debridement or excision may be required to remove nonviable tissues, release trapped drug, and prevent more extensive prolonged tissue injury
Early surgical intervention should be reserved for patients with local uncontrolled pain, repeated infections, or limb restriction attributed to extravasation injury²³
Anecdotes and at least 1 prospective study suggest DMSO may mitigate local morbidity after extravasation with doxorubicin^d

Doxorubicin HCl liposome injection (Doxil; Centocor Ortho Biotech Products LP, Raritan, NJ)^24,25,26,27

Irritant–Vesicant

No known antidotes

Product labeling for Doxil (dated, November 2010) advises application of ice over the site of extravasation for approximately 30 minutes may be helpful in alleviating the local reaction
Elevate an involved extremity
Avoid applying pressure to the extravasation site

Consider administering dexrazoxane^9,28 as for extravasation with daunorubicin HCl (see "Daunorubicin HCl," Comments)
The severity of tissue injury may be related to the volume and duration for which the extravasated drug remains in contact with the affected site²⁵

Ellence

See guidelines for "Epirubicin HCl"

Eloxatin

See guidelines for "Oxaliplatin"

Epirubicin HCl (Ellence; Pharmacia & Upjohn Company, Division of Pfizer Inc., New York, NY)²⁹

Vesicant

Dexrazoxane (see Comments for daunorubicin HCl)

Aspirate back through the VAD to remove any accessible extravasated drug
Apply cold to an involved extremity with circulating ice water, an ice pack, or a cold compress for 15–60 minutes 4 times daily for at least 48 hours after extravasation^b
Elevate an involved extremity
Avoid applying pressure to the extravasation site

Administer dexrazoxane as for extravasation with daunorubicin HCl (see "Daunorubicin HCl," Comments)^8,9,10,30
Anecdotes and at least one prospective study suggest DMSO may mitigate local morbidity following extravasation with epirubicin^d

Etoposide (available generically)³¹

Irritant (see Comments)

Treat as for vinblastine extravasation

Skin ulceration is unlikely when etoposide injection is diluted to concentrations used clinically

Fluorouracil (Adrucil; SICOR Pharmaceuticals, Inc, Irvine, CA)

Irritant

No specific local therapy is indicated

Gemcitabine HCl (Gemzar; Eli Lilly and Company, Indianapolis, IN)

Not well defined^a, but not a vesicant (see Comments)

No known antidotes

No specific local therapy

Product labeling for Gemzar (dated February 17, 2011) indicates gemcitabine is not a vesicant

Gemzar

See guidelines for "Gemcitabine HCl"

Hycamtin

See guidelines for "Topotecan HCl"

Idarubicin HCl (Idamycin; Pharmacia & Upjohn Company, Division of Pfizer Inc., New York, NY)³²

Vesicant

Dexrazoxane (see Comments for Daunorubicin HCl)

Aspirate back through the VAD to remove any accessible extravasated drug

Administer dexrazoxane as for extravasation with daunorubicin HCl (see "Daunorubicin HCl," Comments)^8,9,10

Irinotecan HCl (Camptosar; Pharmacia & Upjohn Company, Division of Pfizer Inc., New York, NY)

Unclassified^a

No known antidotes

Aspirate back through the VAD to remove any accessible extravasated drug
Apply cold to an involved extremity with circulating ice water, an ice pack, or a cold compress for 15–60 minutes at least 4 times daily for 24–48 hours after extravasation^b
Elevate an involved extremity
Avoid applying pressure to the site

The recommendations for local care are based on product labeling for Camptosar (dated August 2010), which specifies in the event of extravasation: ". . . flushing the site with sterile water [intradermally] and applications of ice [topically]. . . ." Healthcare providers should note subcutaneous infiltration and intradermal irrigation with solutions as a means of diluting and removing an extravasated drug are experimental techniques

Mechlorethamine HCl (also called nitrogen mustard, HN₂; Trituration of Mustargen; Lundbeck Inc., Deerfield, IL)^33,34,35,36

Vesicant

Isotonic sodium thiosulfate 0.167 mol/L (Na₂S₂O₃ 1/6 M) solution

Aspirate back through the VAD to remove any accessible extravasated drug
Inject 1/6 M Na₂S₂O₃ solution through IV access device: 2–5 mL for each milligram of mechlorethamine extravasated
Remove IV access device
With a 25G or smaller-gauge needle, inject subcutaneously 1/6 M Na₂S₂O₃ solution circumferentially around the perimeter of the involved site: 2 mL for each milligram of mechlorethamine extravasated
After sodium thiosulfate injection, apply an ice pack or cold compress for 6–12 hours to minimize the local reaction
Elevate an involved extremity
Avoid applying pressure to the site

Extravasation of the mechlorethamine into subcutaneous tissues results in painful inflammation
RAPID intervention is essential in treating mechlorethamine extravasation
Na₂S₂O₃ solution chemically neutralizes mechlorethamine
The intervention is clinically accepted, but reports confirming benefit are scant

Preparation of a 1/6 M sodium thiosulfate (Na₂S₂O₃) solution

Starting with 10% Na₂S₂O₃ solution (1 g/10 mL):
- In a syringe, mix 4 mL Na₂S₂O₃ with 6 mL water for injection, or
Starting with 25% Na₂S₂O₃ solution (2.5 g/10 mL):
- In a syringe, mix 1.6 mL Na₂S₂O₃ with 8.4 mL water for injection, or
Starting with anhydrous Na₂S₂O₃ dilute 2.64 g in 100 mL water for injection

Melphalan HCl (also called L-PAM, L-phenylalanine mustard; Alkeran; GlaxoSmithKline, Research Triangle Park, NC)

Vesicant

No known antidotes

Aspirate back through the VAD to remove any accessible extravasated drug
Apply cold to an involved extremity with circulating ice water, an ice pack, or a cold compress for 15–60 minutes at least 4 times daily for 24–48 hours after extravasation^b
Elevate an involved extremity
Avoid applying pressure to the site

Product labeling for Alkeran for Injection (dated June 9, 2011) stipulates extravasation may cause local tissue damage, and reports among adverse reactions, skin ulceration at injection site, and skin necrosis rarely requiring skin grafting
An experimental study in mice inconsistently produced ulceration after intradermal injection of melphalan; doses, but not drug concentration were specified⁵

Mithramycin

See guidelines for "Plicamycin"

Mitomycin (mitomycin-C, Mutamycin; Bristol-Myers Squibb Oncology, Bristol-Myers Squibb Company, Princeton, NJ. available generically)^{37,38,39,40,41,42}

Vesicant

No known antidotes

Conservative management^a
Aspirate back through the VAD to remove any accessible extravasated drug
Apply cold to an involved extremity with circulating ice water, an ice pack, or a cold compress for 15–60 minutes at least 4 times daily for 24–48 hours after extravasation^b
Elevate an involved extremity
Avoid applying pressure to the extravasation site

Extravasation is typically accompanied by pain and swelling, but initially may be painless
Mitomycin is associated with ulceration at areas of recent vascular damage, including venipuncture sites that are distant from the site of extravasation
Dermal injury after mitomycin extravasation may be delayed from 1 to 29 weeks after administration
Mitomycin extravasation injury may occur, may be exacerbated, or may recur after the affected area is exposed to sunlight³⁷
Anecdotes and at least one prospective study suggest that topically applied DMSO may mitigate local morbidity after extravasation with mitomycin^d

Mitoxantrone HCl (Novantrone; marketed by (osi)™ oncology, OSI Pharmaceuticals, Inc, Melville, NY)^5,43,44

Vesicant

Dexrazoxane (see Comments for Daunorubicin HCl)

Aspirate back through the VAD to remove any accessible extravasated drug
Apply cold to an involved extremity with circulating ice water, an ice pack, or a cold compress for 15–60 minutes 4 times daily for at least 48 hours after extravasation^b
Elevate an involved extremity
Avoid applying pressure to the extravasation site

Consider administering dexrazoxane²⁸ as for extravasation with daunorubicin HCl (see "Daunorubicin HCl," Comments)
- Dexrazoxane did not prevent ulceration after experimental mitoxantrone extravasation in a mouse model, but the size and duration of lesions was significantly decreased in comparison with controls²⁸
May cause blue discoloration in soft tissues where infiltration occurs
Inconsistently produces tissue necrosis after extravasation
When ulceration occurs, lesions may spontaneously resolve with conservative management

Navelbine

See guidelines for "Vinorelbine tartrate"

Nitrogen mustard

See guidelines for "Mechlorethamine HCl"

Novantrone

See guidelines for "Mitoxantrone HCl"

Oncovin

See guidelines for "Vincristine sulfate"

Oxaliplatin (Eloxatin; Sanofi-Synthelabo Inc, New York, NY)^45,46,47

Irritant–Vesicant (see Comments)

No known antidotes

Aspirate back through the VAD to remove any accessible extravasated drug
Apply cold to an involved extremity with circulating ice water, an ice pack, or a cold compress for 15–60 minutes at least 4 times daily for 24–48 hours after extravasation^b
Elevate an involved extremity
Avoid applying pressure to the site
Orally administered nonsteroidal analgesics may be useful in managing pain and inflammation

Product labeling for Eloxatin (dated March 2009) indicates necrosis associated with extravasation has been reported
Inflammatory reactions were reported after oxaliplatin extravasation (approximate amount extravasated: 40–104 mg)⁴⁷
Clinical appearance within 2–3 days after extravasation is described as resembling erysipelas, with swelling, pain, induration, erythema, local heat, and impaired movement when joints are involved
Although there is concern that cold compresses may trigger the cold temperature-induced neuropathy associated with oxaliplatin,⁴⁶ both cold and warm compresses have been used to manage oxaliplatin extravasation without reports of deleterious effects from either intervention^47,48
Induration, inflammation, and paresthesias may persist for weeks after an extravasation event⁴⁶

Paclitaxel (available generically) ^49,50,51,52

Vesicant (see Comments)

No known antidotes

Aspirate back through the VAD to remove any accessible extravasated drug
Apply cold to an involved extremity with circulating ice water, an ice pack, or a cold compress for 15–20 minutes at least 4 times daily for 24–48 hours after extravasation^b
Elevate an involved extremity
Avoid applying pressure to the site

Onset of an injection site reaction may be delayed by up to 10 days
Paclitaxel administration after paclitaxel extravasation at a different site has been associated with recurrence of skin reactions at the site of prior extravasation, ie, a "recall" reaction
It is not yet clear whether application of either cold or heat provides benefit in managing paclitaxel extravasation. In 1 case report, blisters, erythema, and hyperpigmentation may have been exacerbated by warming¹⁷
Gross and microscopic examination of biopsied and excised tissues from paclitaxel extravasation injuries reveals tissue necrosis.^52,53 Anecdotal reports support product labeling which indicates extravasation reactions are usually mild, consisting of erythema, tenderness, skin discoloration, or swelling at the injection site. In general, administration procedures and extravasation management follow procedures developed for irritant (not vesicant) hazardous drugs
Skin overlying the extravasation site may become inflamed (mimicking a first-degree thermal burn) and desquamate
In 2 reported cases, subcutaneous perilesional infiltration with hyaluronidase after paclitaxel extravasation may have delayed healing⁵⁴
Involved site dysesthesias or sensory loss are common sequelae; motor weakness also has been reported

Paraplatin

See guidelines for "Carboplatin"

Pemetrexed disodium (Alimta; Eli Lilly and Company, Indianapolis, IN)

Unclassified^a (see Comments)

No known antidotes

No specific recommendations for local therapy

Product labeling for Alimta (dated March 2011) indicates pemetrexed disodium is not a vesicant

Platinol

See guidelines for "Cisplatin"

Plicamycin (not currently marketed in the United States)

Irritant

No known antidotes

Aspirate back through the VAD to remove any accessible extravasated drug
No specific local therapy is indicated
Elevate an involved extremity
Avoid applying pressure to the site

Taxol

See guidelines for "Paclitaxel"

Taxotere

See guidelines for "Docetaxel"

Teniposide (Vumon; Bristol Laboratories Oncology products, a Bristol-Myers Squibb Company, Princeton, NJ)

Irritant–Vesicant (see Comments)

Treat as for vinblastine extravasation

Product labeling for Vumon (dated December 2010) indicates extravasation may result in local tissue necrosis

Topotecan HCl (Hycamtin; GlaxoSmithKline, Research Triangle Park, NC)

Irritant

No known antidotes

Aspirate back through the VAD to remove any accessible extravasated drug
Apply cold to an involved extremity with circulating ice water, an ice pack, or a cold compress for 15–20 minutes 4 times daily for 24 hours after extravasation^b
Elevate an involved extremity
Avoid applying pressure to the site

Product labeling for Hycamtin (dated April 2010) indicates ". . . most [extravasation] reactions have been mild but severe cases have been reported"
In 2 cases, extravasation was accompanied by pain, which resolved soon after discontinuing drug administration, and swelling that resolved within 24 hours without evidence of redness or ulceration. In one case, topical cooling was applied to mitigate swelling. There were no sequelae in either case. One patient received topotecan on the day after extravasation without adverse effects related to extravasation, and both patients received one or more additional courses of topotecan without morbidity related to the extravasation events⁵⁵

Treanda

See guidelines for "Bendamustine HCl"

Velban

See guidelines for "Vinblastine sulfate"

Vinblastine sulfate (available generically)^56,57,58,59

Vesicant

No known antidotes

Aspirate back through the VAD to remove any accessible extravasated drug
Consider dispersing the drug by administering hyaluronidase injection (150–300 units diluted in 1–6 mL 0.9% sodium chloride injection injected either into the VAD through which the extravasated drug was administered), by subcutaneous injection with a fine-gauge needle circumferentially around the perimeter of the involved site, or a combination of both techniques

Note: Hyaluronidase is marketed in the United States in several formulations: solutions containing 150 USP units or 200 USP units/mL, and a lyophilized powder for reconstitution for injection
Apply warm packs for 15–20 minutes at least 4 times daily for 24–48 hours after extravasation^b
Elevate an involved extremity
Avoid applying pressure to the site

Warmth increases local blood flow, enhancing drug dispersal from the site
Hyaluronidase may further aid dispersing the drug from the site of extravasation
- Hyaluronidase injection currently marketed in the United States includes products from ovine and bovine sources, and recombinant (human) DNA technology. All products have received FDA approval for use as adjuvants to increase the absorption and dispersion of other injected drugs
DO NOT apply topical steroid products. Topical steroids have exacerbated extravasation injury associated with Vinca alkaloids in animal models

Vincristine sulfate (available generically)^59,60

Vesicant

No known antidotes

Treat as for extravasation with vinblastine sulfate

Vindesine sulfate (not currently marketed in the USA)^61,62

Vesicant

No known antidotes

Treat as for extravasation with vinblastine sulfate

Vinorelbine tartrate (available generically)^59,63,64,65

Vesicant

No known antidotes

Treat as for extravasation with vinblastine sulfate

VM-26

See guidelines for Teniposide

VP-16, VP-16-213 See guidelines for Etoposide

^aConservative management

When it is not known whether a drug is an irritant or a vesicant, and specific antidotes and other remedies have not been identified for mitigating toxicity after extravasation:

Aspirate back through the infiltrated VAD to remove any accessible extravasated drug
Apply topical cooling to an involved extremity with circulating ice water, an ice pack, or a cold compress for 15–60 minutes at least 4 times daily for 24–48 hours after extravasation^b
When the site of extravasation is located on an extremity, elevate the involved extremity
Avoid applying pressure to an extravasation site
Closely monitor the site of extravasation serially (watchful waiting). The appearance of tissue injury related to extravasation becomes less likely with the passage of time
- With the exception of mitomycin, for which the onset of acute extravasation injury may appear late, or after repeated exposure to the drug or after exposure of the injured site to ionizing or solar radiation^{37,39,41,42,66}
Seek surgical consultation, especially if a patient reports pain at the extravasation site within 10 days after the event. Although recommendations for surgical treatment of tissue injury from extravasated drugs are not uniform with respect to standard techniques or interventional timing, surgical debridement or excision may be required to remove nonviable tissues and lesions complicated by secondary infection, remove active vesicant drug that remains sequestered in tissues to prevent more extensive prolonged tissue injury, and in skin grafting
- Early surgical intervention should be reserved for patients with uncontrolled local pain, repeated infections, or limb restriction attributed to extravasation injury
- Severe pain, blistering, and ulceration, at a site of extravasation have generally been considered indications for surgical excision¹⁰
- If surgical excision is used to remove anthracycline drugs remaining in tissues after extravasation, the procedure may be guided intraoperatively by fluorescence microscopy. Fluorescence-positivity in tissue biopsies is indicative of the presence of anthracycline drugs, and facilitates differentiating between affected and drug-free tissues^{67,68,69,70,71,72}

^bHeating and cooling

Optimal temperatures and the frequency and duration for applying warm and cold compresses over areas of extravasation injury are not known. Heat produces vasodilation with local hyperemia, which facilitates drug absorption and dispersion,¹⁰ but may also increase the cytotoxic effect of some drugs (eg, anthracyclines).^73,74 Cooling produces local vasoconstriction, which inhibits dispersion of a drug through extravascular tissues, thus, in an acute setting, potentially decreasing the extent of cytotoxic injury. Topical cooling also may decrease local swelling and provide an analgesic effect;¹⁰ however, topical cooling should be used with caution around the time local or systemic antidotes are administered to avoid decreasing the distribution of antidote to tissues involved in an extravasation. When thermal interventions are utilized, caregivers should instruct patients to apply heat or cold intermittently for as long as possible during each application, but not with extremes of temperature or for durations that may compromise a patient's comfort or quality of life

^cDexrazoxane (ICRF-187)

Administer dexrazoxane in a large vein over 1–2 hours at a site remote from the site of anthracycline extravasation (eg, a contralateral extremity)

Adverse effects commonly associated with dexrazoxane use, include decreased leukocyte, neutrophil, and platelet counts; decreased hemoglobin; and increased serum alanine and aspartate aminotransferases and bilirubin; injection site pain; fever; nausea; vomiting; diarrhea; and constipation

After dexrazoxane use, monitor a patient's complete blood cell and leukocyte differential counts and hepatic transaminases in blood or serum

DO NOT apply topical cooling to a site of extravasation within 15 minutes before or after, or during dexrazoxane administration

DO NOT apply topical DMSO concurrently with dexrazoxane use

^dDimethyl sulfoxide (DMSO, CAS 67-68-5, NSC 763)

Topical application and intradermal injection of DMSO to treat extravasation injuries are controversial. Appropriate application settings and optimal strategies for utilizing DMSO after extravasation with particular antineoplastic drugs have not been defined

Clinical anecdotes and at least 1 prospective study suggest dimethyl sulfoxide may prevent ulceration and mitigate local morbidity after extravasation of anthracyclines, mitomycin, and perhaps other drugs. However, in the majority of reports in which benefit was suggested, drug extravasation was suspected based on clinical observations but not confirmed (eg, by fluorescence microscopy-guided biopsy for anthracyclines); thus, neither extravasation nor clear attribution of benefit from DMSO use can be confirmed. In at least 2 anecdotal reports, a single application of DMSO and application 3-times-daily, respectively, were ineffective in preventing vesicant reactions^{75, 76}

DMSO should NOT be used concomitantly with dexrazoxane for anthracycline extravasation^9,77,78

Note: The following regimens are not ordered or ranked by either preference or effectiveness

Regimen 1. Dimethyl sulfoxide 50% (w/w) 1–2 mL applied topically over the involved site once, followed by cold compresses applied topically for 15–20 minutes every hour for 12–24 hours⁴²

Regimen 2. Dimethyl sulfoxide 99% 4 drops/10 cm² of involved skin surface area, applied topically over an area 2-fold greater than the affected area (including the involved site) every 8 hours for 1 week. The solution is left to dry in air without a dressing, and its administration is followed by local cooling with a cold pack applied topically to the involved site for 60 minutes every 8 hours for the first 3 days after an extravasation event⁷⁹

Treatment continued for up to 6 weeks in 29.3% of cases as a result of persistent symptoms
Fourteen of 127 evaluable patients sustained residual mild induration of perivascular tissues without functional impairment after a median follow-up duration of 18.5 months

Regimen 3. Dimethyl sulfoxide 99% applied topically over an area 2-fold greater than the affected area (including the involved site) every 6 hours for 14 days. The solution is left to dry in air without a dressing⁸⁰

Regimen 4. Dimethyl sulfoxide 99% or 50% 15 mL or dimethylsulfoxide 75% volume not specified, applied topically over the involved site every 2–4 hours (at least every 6 hours) for at least 3 days after the extravasation event with topical cooling⁸¹

Among 4 patients treated, all received intradermal steroids injected into or around the site of suspected extravasation and topical cooling. One patient also received local injection of sodium bicarbonate
Note: The U.S. Food and Drug Administration has approved dimethyl sulfoxide 50% (w/w) for administration to human subjects only for the symptomatic relief of interstitial cystitis. Dimethyl sulfoxide 99.0% is commercially marketed for cryopreservation, and is also available in various concentrations and purity grades for veterinary and laboratory use and as an industrial solvent. Dimethyl sulfoxide or particular product concentrations may not be commercially available in all countries. Healthcare providers are urged not to use DMSO products other than those labeled for clinical use. Although chemically equivalent, DMSO not formulated for use in human subjects may contain and facilitate systemic absorption of chemical impurities and contaminants during topical or parenteral use

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Adverse Reactions From Dimethyl Sulfoxide

DMSO 50%

DMSO 99%

Reference

Unpleasant taste, halitosis, and body odor (often described as garlic-like)

79–81

Tingling, stinging, or burning sensation

Histamine release with itching, erythema, rash, and urticaria

DMSO is hygroscopic. Application to moist or wet skin produces an exothermic reaction (heat)

Erythema, itching, and scaling

Blistering; severe if a dressing was applied over the site of DMSO application

Local tingling, stinging, or burning

79, 80, 83–85

Severe pain

86, 87

Burning, swelling, and erythema

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Chapter 46: Antineoplastic Drugs: Preventing and Managing Extravasation

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INTRODUCTION

GENERAL REFERENCES

DRUG-SPECIFIC REFERENCES

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