MANAGEMENT OF DRUG EXTRAVASATIONS

 

Vesicant: An agent that causes tissue destruction.

Irritant: An agent that causes aching, tightness, and phlebitis with or without inflammation.

Extravasation: Unintentional leakage of fluid out of a blood vessel into surrounding tissue.

Vesicant extravasation: Leakage of a drug that causes pain, necrosis, or tissue sloughing.

Delayed extravasation: Symptoms occur 48 hours, or later, after drug administration.

Flare: Local, nonpainful, possibly allergic reaction often accompanied by reddening along the vein.

A potential, and potentially highly morbid, complication of drug therapy is soft tissue damage caused by leakage of the drug solution out of the vein. A variety of complications, including erythema, ulceration, pain, tissue sloughing, and necrosis are possible. This problem is not unique to antineoplastic therapy; a variety of drugs have been reported to cause tissue damage if extravasated. See table.

Vesicant Agents

 

Hyperosmotic Agents

(>280 mOsmol/L)

Ischemia Inducers

Direct Cellular Toxins

Nonantineoplastic Agents

Antineoplastic Agents

1In addition to the known vesicants, a number of other antineoplastic agents, not generally considered to be vesicants, have been associated with isolated reports of tissue damage following extravasation.

Calcium chloride (>10%)

Calcium gluconate

Calcium gluceptate

Contrast media

Crystalline amino acids (4.25%)

Dextrose (>10%)

Mannitol (>5%)

Potassium acetate (>2 mEq/mL)

Potassium chloride (>2 mEq/mL)

Sodium bicarbonate (≥8.4%)

Sodium chloride (>1%)

Thiopentone

Urea (30%)

Aminophylline

Dobutamine

Dopamine

Epinephrine

Esmolol

Metaraminol

Metoprolol

Norepinephrine

Phenylephrine

Vasopressin

Chlordiazepoxide

Diazepam

Digoxin

Ethanol

Nafcillin

Nitroglycerin

Phenytoin

Propylene glycol

Sodium thiopental

Tetracycline

Amsacrine1

Dactinomycin

Daunorubicin

Doxorubicin

Epirubicin

Esorubicin1

Idarubicin

Mechlorethamine

Mitomycin

Streptozocin (?)

Valrubicin

Vinblastine

Vincristine

Vindesine1

Vinorelbine

Agents Associated With Occasional Extravasation Reactions

Aclarubicin1

Arsenic trioxide

Bleomycin

Carboplatin ≥10 mg/mL

Carmustine

Cisplatin

Cyclophosphamide

Dacarbazine

Daunorubicin citrate (liposomal)

Dexrazoxane

Docetaxel

Doxorubicin (liposomal)

Etoposide

Floxuridine

Fluorouracil

Gemcitabine

Gemtuzumab

Ibritumomab

Ifosfamide

Irinotecan

Menogaril1

Mitoxantrone

Oxaliplatin

Paclitaxel

Promethazine

Teniposide

Topotecan

1Not commercially available in the U.S.

The actual incidence of drug extravasations is unknown. Some of the uncertainty stems from varying definitions of incidence. Incidence rates have been reported based on total number of drug doses administered, number of vesicant doses administered, number of treatments, number of patients treated with vesicants, and total number of patients treated. Most estimates place the incidence of extravasations with cytotoxic agents in the range of 1% to 7%.

The optimal treatment of drug extravasations is uncertain. A variety of antidotes have been proposed; however, objective clinical evidence to support these recommendations frequently is not available. There are no well done randomized prospective trials of potential treatments. Controlled clinical trials are not feasible, limiting efforts to identify optimal management of these reactions. Extant reports are based on animal models, anecdotal cases, and/or small uncontrolled series of patients. Many of the existing reports, both animal and human, used more than one therapeutic intervention simultaneously, adding to the difficulty of identifying the efficacy of any single approach.

The best “treatment” for extravasation reactions is prevention. Although it is not possible to prevent all accidents, a few simple precautions can minimize the risk to the patient. The vein used should be a large, intact vessel with good blood flow. To minimize the risk of dislodging the catheter, veins in the hands and in the vicinity of joints (eg, antecubital) should be avoided. Veins in the forearm (ie, basilic, cephalic, and median antebrachial) are usually good options for peripheral infusions. Prior to drug administration, the patency of the I.V. line should be verified. The line should be flushed with 5-10 mL of a saline or dextrose solution and the drug(s) infused through the side of a free-flowing isotonic saline or dextrose infusion.

A frequently recommended precaution against drug extravasation is the use of a central venous catheter. Use of a central line has several advantages, including high patient satisfaction, reliable venous access, high flow rates, and rapid dilution of the drug. A wide variety of devices are readily available. Many institutions encourage or require use of a vascular access device for administration of vesicant agents.

Despite their benefit, central lines are not an absolute solution. Vascular access devices are subject to a number of complications. The catheter tip may not be properly positioned in the superior vena cava/right atrium, or may migrate out of position. Additionally, these catheters require routine care to maintain patency and avoid infections. Finally, extravasation of drugs from venous access devices is possible. Misplacement/migration of the catheter tip, improper placement of the needle in accessing injection ports, and cuts, punctures, or rupture of the catheter itself have all been reported. Reports of extravasation from central catheters range from 0.3% to 50% and are similar to extravasation rates reported from peripheral lines.

When a drug extravasation does occur, a variety of immediate actions have been recommended. Although there is considerable uncertainty regarding the value of some potential treatments, a few initial steps seem to be generally accepted.

  1. Stop the infusion. At the first suspicion of infiltration, the drug infusion should be stopped. If infiltration is not certain, the line can be tested by attempting to aspirate blood, and careful infusion of a few milliliters of saline or dextrose solution.
  2. Do NOT remove the catheter/needle. The infiltrated catheter should not be removed immediately. It should be left in place to facilitate aspiration of fluid from the extravasation site, and, if appropriate, administration of an antidote directly into the extravasation site.
  3. Aspirate fluid. To the extent possible, the extravasated drug solution should be removed from the subcutaneous tissues.
  4. Do NOT flush the line. Flooding the infiltration site with saline or dextrose in an attempt to dilute the drug solution generally is not recommended. Rather than minimizing damage, such a procedure may have the opposite effect by distributing the vesicant solution over a wider area.
  5. Remove the catheter/needle. If an antidote is not going to be injected into the extravasation site, the infiltrated catheter should be removed. If an antidote is to be injected into the area, it should be injected through the catheter to ensure delivery of the antidote to the infiltration site. When this has been accomplished, the catheter should then be removed.

Two issues for which there is less consensus are the application of heat or cold, and the use of various antidotes. A variety of recommendations exist for each of these concerns; however, there is no consensus concerning the proper approach.

Cold. Intermittent cooling of the area of infiltration results in vasoconstriction, which tends to restrict the spread of the drug. It may also inhibit the local effects of some drugs (eg, anthracyclines). Application of cold is usually recommended as immediate treatment for most drug extravasations, except the vinca alkaloids. In one report of antineoplastic drug extravasation treatment, almost 90% of the extravasations treated only with topical cold required no further therapy.

The largest single published series of antineoplastic drug extravasations was 175 patients reported by Larson in 1985. This series includes some of the more commonly used vesicants, including the anthracyclines, mechlorethamine, mitomycin, and the vinca alkaloids. For 119 patients, local application of cold (15 minutes four times a day for 3 days) and close observation was the sole treatment. The remaining 56 patients received a variety of antidotes. In 89% of the patients treated with cold alone, the extravasation resolved without further treatment. Of the patients treated by other methods, only 53% resolved without further treatment.

Helpful as it may be, Larson's report does have some limitations. Agents such as the epipodophyllotoxins and taxanes which are occasionally associated with soft tissue damage were not included, nor were extravasations of nonantineoplastic agents mentioned. The report included infiltrations of the vinca alkaloids, even though the literature recommends use of heat to treat these. Also, except for doxorubicin extravasations in the group treated with ice and observation, responses for the individual drugs were not indicated. In this group, 72% of the doxorubicin extravasations resolved completely.

Heat. Application of heat results in a localized vasodilation and increased blood flow. Increased circulation is believed to facilitate removal of the drug from the area of infiltration. The data supporting use of heat are less convincing than for cold. One report of the application of heat for nonantineoplastic drug extravasations suggested application of heat increased the risk of skin maceration and necrosis. Most data are from animal studies with relatively few human case reports. Animal models indicate application of heat exacerbates the damage from anthracycline extravasations. No large series of extravasations managed with the application of heat has been published. Heat is generally recommended for treatment for vinca alkaloid extravasations; a few reports recommend it for treatment of amino acid solutions, aminophylline, calcium, contrast media, dextrose, mannitol, nafcillin, paclitaxel, phenytoin, podophyllotoxin, potassium and vinca alkaloid infiltrations. There are conflicting reports on the initial management of paclitaxel infiltrations.

For some agents, such as cisplatin, epipodophyllotoxins, mechlorethamine, and paclitaxel, there are conflicting recommendations. Some reports recommend application of cold, others recommend heat. At least one report suggests neither cold nor heat is effective for paclitaxel extravasations.

ANTIDOTES

A very wide variety of agents have been reported as possible antidotes for extravasated drugs, with no consensus on their proper use. For a number of reasons, evaluation of the various reports is difficult.

  1. Mechanism of action. For many drugs, the underlying mechanism responsible for the tissue damage is not certain. For some of the antidotes, the purported mechanism of action of the antidote is also unclear.
  2. Controlled trials. Prospective, randomized controlled trials are not practical. Information concerning treatment of extravasations is based almost exclusively on animal models, anecdotal reports, and small, uncontrolled studies.
  3. Outcome definitions. Published reports use a number of different end-points and outcomes to define efficacy of a given treatment.
  4. Confounding factors. A number of confounding factors exist which make assessment of various antidotes difficult. Among these are:
    1. Response to nonpharmacologic therapy. Application of heat or cold alone, especially the latter, appears to have a significant protective effect.
    2. Multiple therapies. A number of reports used more than one therapeutic modality to treat drug extravasations. In many cases, cold or heat is applied along with the antidote. In some cases, more than one antidote is used, sometimes in conjunction with heat or cold. Use of multiple approaches further complicates the determination of the possible effect of a particular antidote, or the additive effect of various combinations.
    3. Variable applications. For some proposed antidotes, a wide variety of different doses, concentrations, methods of application, and duration of therapy have been reported, making determination of the optimal treatment regimen difficult.

Agents Used as Antidotes

Albumin

Antihistamines

Antioxidants

Beta-adrenergics

Carnitine

Corticosteroids1

Dexrazoxane

Dextranomer

Dimethyl sulfoxide

Dopamine

Fluorescein

Hyaluronidase1

Iron dextran

Isoproterenol

Nitroglycerin paste

Phentolamine

Radical dimer

Saline

Sodium bicarbonate

Sodium hypochlorite

Sodium thiosulfate1

Terbutaline

Vitamin E

1Listed in the package insert of at least one agent.

Sodium bicarbonate. An 8.4% solution of sodium bicarbonate was briefly recommended for treatment of anthracycline extravasations. The recommendation was based on a case report of its use in a single patient. The proposed mechanism of action was that the high pH of the bicarbonate solution would break the glycosidic bond of the anthracycline, thereby inactivating it. Follow-up studies in a variety of animal models failed to confirm the original report. Also, the concentrated sodium bicarbonate may itself be a vesicant. See the Vesicant Agents table. At present, most reviews and guidelines discourage its use for treating extravasations.

Corticosteroids. Steroids are most commonly used to treat anthracycline extravasations. Hydrocortisone is the steroid most frequently recommended, although dexamethasone has also been used. It is suggested that steroids reduce local inflammation from the extravasated drug. Such activity has not been confirmed, nor has it been demonstrated that the tissue damage from drug infiltrations is the result of an inflammatory process. Interpretation of steroid efficacy is complicated by the multiple doses, routes of administration, duration of therapy, and outcome measurements used. Reports of animal trials offer little additional information, being plagued by many of the limitations of the clinical case reports. The official labeling of only one of the three suppliers of doxorubicin includes a steroid as part of the treatment for drug extravasations. The product labeling from two doxorubicin suppliers (as well as the suppliers of daunorubicin, idarubicin, and liposome-encapsulated daunorubicin and doxorubicin) do not mention corticosteroids to treat drug infiltrations. Most reports question the efficacy of steroids for treatment of drug extravasations; they are not recommended by most guidelines.

Dexrazoxane. Dexrazoxane, a derivative of EDTA, is an intracellular chelating agent often used as a cardioprotective agent in patients receiving anthracycline therapy. It is believed that the cardioprotective effect of dexrazoxane is a result by chelating iron following intracellular hydrolysis. Dexrazoxane is not an effective chelator itself, but is hydrolyzed intracellularly to an open-ring chelator form, which complexes with iron, other heavy metals, and doxorubicin complexes to inhibit the generation of free radicals. It has been postulated that dexrazoxane's chelating effect, or its ability to inhibit topoisomerase II may be useful in preventing tissue damage from anthracycline infiltrations. Several case reports and two small (N = 23, N = 57), uncontrolled, open-labeled studies report dexrazoxane effective in preventing tissue damage following anthracycline extravasation.

Although localized cooling was permitted (except within 15 minutes of dexrazoxane infusion) in the trials, the number of patients in which this was used was not reported. Dexrazoxane was required to start within 6 hours of the drug extravasation. In two small (N = 23, N = 57) studies, 54 of the 80 patients were assessed for efficacy. In 53 patients, dexrazoxane appeared to be effective. One-third of the patients in the two studies were not assessed for efficacy, leaving the actual efficacy rate of dexrazoxane uncertain. Use of dexrazoxane was also associated with a variety of side effects, including fever, fatigue, reactions at the dexrazoxane injection site, nausea, vomiting, diarrhea, mucositis, myelosuppression, increased bilirubin and hepatic transaminases, and increased serum creatinine. What proportion of these toxicities were attributable to the dexrazoxane, and what was a result of the primary antineoplastic therapy was not clear. Dexrazoxane received approval by the Food and Drug Administration (FDA) in 2007 for treatment of anthracycline extravasations.

Dimethyl sulfoxide (DMSO). A number of reports have suggested application of DMSO is an effective treatment for infiltrations of a number of different drugs. It is believed DMSO's protective effect is due to its ability to act as a free radical scavenger (one theory suggests tissue damage from vesicants, particularly anthracyclines, is due to formation of hydroxyl free radicals). Results in animal models have been equivocal, with some reports indicating DMSO is beneficial, and some showing little or no effect. Clinical reports of its use are extremely difficult to interpret due to variations in DMSO concentration, number of applications/day, duration of therapy, and concomitant treatments. A number of different treatments, including cold, steroids, vitamin E, and sodium bicarbonate have been used in conjunction with DMSO. Also, most reports that suggest DMSO is effective in preventing tissue damage used DMSO concentrations >90% which is not available for clinical use in the United States.

A further complication to interpretation of DMSO's efficacy is that some series included infiltrations of agents not generally considered to be vesicants. The largest clinical series included infiltrations in 75 patients, but only 31 of the extravasations involved vesicants (doxorubicin, epirubicin, or mitomycin). The remaining incidents involved drugs not usually associated with tissue damage (cisplatin, ifosfamide, and mitoxantrone). Application of 99% DMSO for 7 days and cold for 3 days resulted in a 93.5% success rate in the patients with vesicant extravasations. Only two patients (6.5%) had complications requiring further therapy. Whether the addition of DMSO represented a real improvement over cold alone is difficult to assess.

Hyaluronidase. Hyaluronidase is an enzyme that destroys hyaluronic acid, an essential component of connective tissue. This results in increased permeability of the tissue, facilitating diffusion and absorption of fluids. It is postulated that increasing the diffusion of extravasated fluids results in more rapid absorption, thereby limiting tissue damage. In individual case reports, hyaluronidase has been reported effective in preventing tissue damage from a wide variety of agents, including amino acid solutions, aminophylline, calcium, contrast media, dextrose, mannitol, nafcillin, phenytoin, potassium and vinca alkaloids. Other reports suggest it might also be useful in managing extravasations of epipodophyllotoxins and taxanes, although not all guidelines recommend its use for these agents.

Phentolamine. Phentolamine is an alpha1-adrenergic antagonist which produces peripheral vasodilation. It has been reported to reduce tissue necrosis following extravasation of pressor (vasoconstrictor) agents such as dobutamine, dopamine, epinephrine, and norepinephrine.

Sodium thiosulfate. A freshly prepared 1/6M (∼4%) solution of sodium thiosulfate has been recommended for treatment of mechlorethamine and cisplatin infiltrations. A 2% solution has been recommended for doxorubicin, epirubicin, mitomycin, and vinblastine extravasations. This recommendation is based on in vitro data demonstrating an interaction between sodium thiosulfate and cisplatin, dacarbazine, and mechlorethamine and very limited animal data on thiosulfate's ability to inactivate dacarbazine and mechlorethamine. At present, no clinical reports of its efficacy for treating cisplatin or dacarbazine extravasations have been published. Since cisplatin and dacarbazine are generally not considered to be vesicants, the use of thiosulfate to treat infiltrations of these drugs may not be required.

The use of sodium thiosulfate to treat mechlorethamine infiltrations is based almost exclusively on the in vitro and animal data. A single case report of successful thiosulfate treatment of an accidental intramuscular mechlorethamine injection has been published. Thus far, no reports of thiosulfate treatment of mechlorethamine infiltrations have been published.

One study of thiosulfate therapy of antineoplastic drug extravasations has been published. In a series of 63 patients with extravasation of doxorubicin, epirubicin, mitomycin, or vinblastine, 31 were treated with subcutaneous hydrocortisone and topical dexamethasone. The remaining 32 patients received subcutaneous injection of a 2% thiosulfate solution in addition to the subcutaneous and topical steroids. No patient in either group developed skin ulceration or required surgery, but the patients who received the thiosulfate healed in about half the time as the patients who received only the steroid therapy.


Reported Treatment Regimens for Drug Extravasations

 

Treatment

Dose

Route

Duration

Concomitant Therapy

Used to Treat

Preparation

Administration

N/A = Not applicable; NS = Not specified; I.V. = Intravenous; SubQ = Subcutaneous; I.D. = Intradermal.

1Listed in the package insert of at least one product.

2Most guidelines discourage application of cold to treat infiltrations of vinca alkaloids. Some reports discourage its use to treat infiltrations of epipodophyllotoxins and/or taxanes.

3There are conflicting data on the efficacy of heat or cold for infiltrations of epipodophyllotoxins and taxanes. Each approach has been reported to be effective, harmful, and of no discernable effect.

4Remove cooling 15 minutes prior to dexrazoxane infusion.

5DMSO concentrations >50% are not available for human use in the U.S.

6Large extravasations only.

Cold1

15 min qid

Topical

3-4 days

None

All agents2

N/A

N/A

Heat1

15 min on;

15 min off

Topical

1 day

None

Vinca alkaloids

N/A

N/A

Heat

NS

Topical

NS

None

Epipodophyllotoxins, taxanes3

N/A

N/A

Dexrazoxane

1000 mg/m2

500 mg/m2

I.V.

Days 1 and 2

Day 3

Cold6

Daunorubicin, doxorubicin, epirubicin, idarubicin

NS

NS

Dexamethasone

4 mg

SubQ, I.D.

One time

Cold

Daunorubicin, doxorubicin

NS

Inject into several sites surrounding the area of extravasation.

Dimethyl sulfoxide5

50%-99% q2-4h

Topical

3 days

Dexamethasone 8 mg I.D.

Doxorubicin

N/A

N/A

Dimethyl sulfoxide5

70% q3-4h

Topical

10 days

Sodium bicarbonate SubQ, dexamethasone 4 mg SubQ

Daunorubicin

N/A

N/A

Dimethyl sulfoxide5

90% q12h

Topical

2 days

Vitamin E 10% topical

Doxorubicin, esorubicin, mitomycin

N/A

N/A

Dimethyl sulfoxide5

99% q8h for up to 1 week

Topical

1 week

Cold for 3 days

Doxorubicin, mitomycin, mitoxantrone

N/A

Apply 4 drops/10 cm2 of skin surface over an area twice the size of the extravasation; allow to air dry without dressings.

Dimethyl sulfoxide5

99% q2-4h

Topical

3 days

None

Doxorubicin

N/A

N/A

Dimethyl sulfoxide5

99% q6-24h

Topical

14 days

None

Doxorubicin, daunorubicin

N/A

N/A

Dimethyl sulfoxide5

99% q6-12h

Topical

1-5 weeks

None

Mitomycin

N/A

N/A

Hyaluronidase1

15 units

SubQ

One time

Heat

Amino acid solutions, aminophylline, calcium, contrast media6, dextrose, mannitol, nafcillin, phenytoin, potassium, vinca alkaloids

Reconstitute vial with NS to a concentration of 150 units/mL. Dilute 0.1 mL (15 units) with 0.9 mL NS for a final concentration of 15 units/mL

4-5 injections (0.2 mL) into area of extravasation

Hyaluronidase1

150 units

SubQ

One time

Heat

Amino acid solutions, aminophylline, calcium, contrast media6, dextrose, mannitol, nafcillin, phenytoin, potassium, vinca alkaloids

Reconstitute with 1 mL NS

5-10 injections (0.5-1 mL) into area of extravasation

Hyaluronidase1

250 units

SubQ

One time

None

Amino acid solutions, aminophylline, calcium, contrast media6, dextrose, mannitol, nafcillin, phenytoin, potassium, vinca alkaloids

Reconstitute with 6 mL NS

Inject directly through the original needle; OR 6 SubQ injections into area of extravasation.

Hydrocortisone

50-200 mg

I.V., SubQ, I.D.

NS

Cold

All agents except vinca alkaloids

NS

Inject into several sites surrounding the area of extravasation.

Hydrocortisone

500 mg

SubQ

One time

Betamethasone and gentamicin ointment q12h for 2 days, then qd

Doxorubicin, epirubicin, vinblastine, mitomycin

500 mg in 10 mL NS

Inject at 1 cm intervals around the area of extravasation.

Nitroglycerin paste

NS

Topical

NS

NS

Vasopressors (dobutamine, dopamine, epinephrine, norepinephrine, phenylephrine)

N/A

N/A

Phentolamine

5 mg

SubQ

1 day

None

Vasopressors (dobutamine, dopamine, epinephrine, norepinephrine, phenylephrine)

Mix 5 mg with 9 mL NS

Inject a small amount into area of extravasation. Blanching should reverse immediately. If blanching should recur, additional injections may be needed.

Sodium thiosulfate1,6

2%

SubQ

One time

Hydrocortisone 500 mg SubQ, betamethasone and gentamicin ointment q12h for 2 days, then qd

Doxorubicin, epirubicin, vinblastine, mitomycin

NS

Inject at 1 cm intervals around the area of extravasation.

Sodium thiosulfate1

1/6 M (∼4%)

I.V., SubQ

One time

Ice or heat

Mechlorethamine, cisplatin

Mix 4 mL of 10% sodium thiosulfate with 6 mL sterile water

Inject 2 mL for each 1 mg of mechlorethamine; inject locally for cisplatin infiltrates (>20 mL and >0.5 mg/mL)

Terbutaline

1 mg

SubQ

NS

NS

Vasopressors (dobutamine, dopamine, epinephrine, norepinephrine, phenylephrine)

NS

NS

 

 

 

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