Vesicant chemotherapy

extravasation management
Lisa Schulmeister

and epirubicin) bind to the DNA in the cells of healthy

Abstract
Extravasation is a potentially harmful complication of vesicant
chemotherapy administration. Although nurses strive to prevent
extravasations from occurring, they cannot always be prevented.
Vesicant chemotherapy extravasations must be promptly detected
and appropriately treated in order to reduce the severity of tissue
destruction that occurs when vesicants inadvertently enter the
tissue. Recently approved treatments have demonstrated safety and
efficacy, and have enabled patients to maintain their skin integrity
and adhere to their planned chemotherapy treatment schedules.
Nurses need to be knowledgeable about advances in extravasation
management so that they can provide optimal care to patients
receiving vesicant chemotherapy.
Key words: Chemotherapy n Extravasation n Vesicant
tissue when they extravasate and promptly cause cell death.
The binding of the vesicant with the cellular DNA releases
complexes from the dead cells in the tissue, and these
complexes are taken up by adjacent healthy cells. This process
sets up a continuing cycle of tissue damage as the DNA-
binding vesicant is retained in the tissue for long periods of
time and recirculated in the surrounding area (Luedke et al,
1979). High dermal concentrations of DNA-binding vesicants
have been detected in patients 28 days post-extravasation, at
both the extravasation site and at a distance of 5 cms away
from the site (Sonneveld et al, 1984). When left untreated,
DNA-binding vesicant extravasation injuries become larger
in size, deeper in depth, and more painful over time.
Vesicants that do not bind to DNA (e.g. plant alkaloids,
such as vincristine and vinblastine) have an indirect rather
than a direct effect on the cells in healthy tissue when they

V
esicant chemotherapy extravasation has been called ‘a Figure 1. Three days post untreated doxorubicin extravasation.
dreaded complication of chemotherapy’ (Schrijvers, Copyright 2006 Lisa Schulmeister. Used with permission.
2003) and ‘a preventable catastrophe’ (Thakur el al,
2008). However, as nurses are aware, extravasations
cannot always be prevented. Patient movement may cause an
intravenous (IV) catheter to dislodge, central venous access
devices (CVADs) may break or malfunction, or other types of
device-related problems may occur and result in extravasation
of vesicant chemotherapy (Doellman et al, 2009; Goossens et
al, 2011).
Left untreated, vesicant chemotherapy extravasations have
the potential to cause tissue necrosis, sensory and functional
impairment, and permanent disfigurement (see Figure 1 and
Figure 2). Fortunately, over the past decade, new approaches
to extravasation management have been introduced that have
improved clinical outcomes for patients.

Severity factors
The potential severity of an extravasation injury is influenced
by the type of vesicant that has extravasated (DNA-binding
or non-DNA-binding), the concentration and amount of
the vesicant that has entered the tissue, and the location of
the IV device. Vesicants that bind to nucleic acids in DNA
(e.g. mechlorethamine, and the anthracyclines doxorubicin

Lisa Schulmeister is Oncology Nursing Consultant (self-employed),

New Orleans, Louisiana, USA

Accepted for publication: September 2011

S6 British Journal of Nursing, 2011 (Intravenous Supplement), Vol 20, No 19


Figure 2. Ten months post untreated extravasation, after surgical debridement
of affected tissue.
Copyright 2006 Lisa Schulmeister. Used with permission.
extravasate into the tissue. Non-DNA binding vesicants
are eventually metabolized in the tissue and are more
easily neutralized than DNA-binding agents (Goolsby and
Lombardo, 2006). This type of extravasation injury generally
remains localized, is mildly to moderately painful, and
improves over time.
Vesicant chemotherapy extravasations in areas of flexion,
such as the wrist and elbow, or in areas with minimal
overlying tissue, such as the dorsum of the hand and wrist, are
likely to damage underlying structures and blood vessels (e.g.
tendons, nerves, veins, arteries). Extravasations in the forearm
are less likely to involve underlying structures because of
the greater amount of overlying tissue. Patient factors, such
as older age and comorbidity, also influence the severity of
extravasation injuries, and influence how patients respond to
extravasation treatment (Schulmeister, 2010).
Immediate management
Initial signs and symptoms of a vesicant extravasation include
redness, swelling, lack of a blood return from the IV device,
and a gravity infusion that slows or stops (if the vesicant
is administered as an IV bolus or ‘push’, resistance may be
encountered). Stinging, burning, and pain may or may not
be present (Polovich et al, 2009).
When an extravasation occurs or is suspected, the first
action is to stop the infusion or discontinue pushing
the syringe containing the vesicant. If the vesicant was
administered via an implanted port, the non-coring needle
should be assessed for correct placement. The affected area
should be inspected for skin discolouration and swelling,
and palpated for tenderness at rest and upon movement
(Schulmeister, 2010).
The residual vesicant in the IV device should be aspirated,
taking care to not apply direct manual pressure to the
extravasation site (European Oncology Nursing Society
(EONS), 2007; United Kingdom Oncology Nursing Society
(UKONS), 2008). Although Goolsby and Lombardo (2006)
recommend aspirating residual vesicant from the site, multiple
punctures in the area of the vesicant extravasation may be
S8
painful for the patient, disrupts the integrity of the skin, and
increases the patient's risk of infection. Further, unless the
extravasated vesicant forms a visible fluid pocket, it is likely
that it has been absorbed by and has spread throughout the
surrounding tissue area and cannot be aspirated from the tissue.
Local cooling (ice packs, cold gel packs) is widely
recommended for extravasations of DNA-binding vesicants
(e.g. anthracyclines and mechlorethamine). A cold pack is
applied to the affected area for 20 minutes four times daily
for 1-2 days (EONS, 2007; UKONS, 2008). Local warming
(dry heat) is indicated for non-DNA binding vesicant
extravasations (e.g. plant alkaloids) to disperse the vesicant so
that it can be metabolized by the tissue (EONS, 2007).
Antidotes
Vesicant extravasation antidotes and treatments must be
administered as soon as possible to mitigate tissue damage.
Although the European Oncology Nursing Society (EONS)
does not recommend the antidote sodium thiosulfate for
mechlorethamine extravasations, its use is recommended
by the Oncology Nursing Society (ONS) (Polovich et al,
2009). Sodium thiosulfate, with a pH of 11, neutralizes
mechlorethamine (pH=3) and reduces the production of
hydroxyl radicals that cause tissue injury (Dorr et al, 1988).
A 1/6 molar solution of sodium thiosulfate is prepared and
2 mls of the solution for each milligram of mechlorethamine
suspected to have extravasated are injected subcutaneously in
and around the extravasation site.
Local injection of hyaluronidase to treat plant alkaloid
extravasations is recommended by ONS but is not
recommended by EONS because of a lack of evidence
(EONS, 2007; Polovich et al, 2009). Hyaluronidase is an
enzyme that modifies the permeability of connective tissue
through hydrolysis of hyaluronic acid and helps disperse plant
alkaloid vesicants throughout the tissue and promotes their
absorption (Dorr, 1990). The ONS recommendation is to
subcutaneously inject 1 ml of a 150 units/ml hyaluronidase
solution into the plant alkaloid extravasation area.
Dexrazoxane is an IV drug that has been used for several
years to reduce doxorubicin cardiotoxicity and more recently
was found to have a protective effect against the development
of anthracycline extravasation injuries. In two prospective
clinical trials, 54 European patients with anthracycline
extravasations confirmed by fluorescence microscopy were
treated with a buffered dexrazoxane formulation, Savene®
(SpePharm). Patients had extravasations of doxorubicin or
epirubicin with a mean extravasation area of 23.6 cm2 in
the first study and 39 cm2 in the second study. All patients
received Savene as soon as possible and within 6 hours of
the extravasation for three consecutive days at a dose of
1000 mg/m2 on days one and two, and a dose of 500 mg/
m2 on day three. None of the 18 patients in the first study
and only one of the 36 patients in the second study had
tissue necrosis occur (overall efficacy was 98.2%). Mild pain
(19%) and mild sensory disturbances (17%) were the most
frequent treatment sequelae. Most of the patients (71%)
were able to continue chemotherapy treatment as scheduled
and the most common side effects of extravasation treatment
were nausea, injection site reactions, and myelosuppression.
British Journal of Nursing, 2011 (Intravenous Supplement), Vol 20, No 19
 However, all side effects were transient and reversible
(Mouridsen et al, 2006).
Anthracycline extravasations from CVADs and implanted
ports have been successfully treated with Savene. In a report
by Langer (2008), 6 of 7 patients treated with Savene did not
experience necrosis or require any surgical intervention, and
Savene was well tolerated by all of the patients. At 4 months
post-extravasation, this small area of necrosis was excised. It
was concluded that not only does Savene work for patients
who have suffered an anthracycline extravasation from a
peripheral line, but also for patients who have experienced
this accident from a central venous catheter, where this a high
risk of needing extensive surgical excision.
Uges et al (2006) reported a case of successful Savene
treatment of an intrapleural epirubicin extravasation. Before
the introduction of Savene, extravasations into the chest
wall tissue generally required repeated and extensive surgical
intervention, and in some cases, a mastectomy had to be
performed (Schulmeister and Camp-Sorrell, 2004).
Savene was approved by the European Commission in
2006. The drug binds to iron and prevents the formation
of free radicals, which are thought to play a major role in
the development of extravasation-induced tissue necrosis
(Hasinoff, 2008). Packaged as an emergency treatment kit for
single patient use, it is administered for three consecutive days
as a 1- to 2-hour IV infusion in a large vein in an area other
than the area affected by the extravasation.The recommended
dose is 1000 mg/m2 on days 1 and 2, and 500 mg/m2 on
day 3. Topical cooling should either not be applied or be
removed from the extravasation site 15 minutes prior to and
during administration of this treatment.
The equivalent of Savene, Totect® (dexrazoxane for
injection, TopoTarget USA), received United States Food
and Drug Administration approval in 2007, and is the ONS
recommended anthracycline extravasation treatment. EONS,
noting the efficacy of Savene in two clinical trials in which
anthracycline extravasations were confirmed by biopsy, advises
that Savene is administered in accordance with manufacturer’s
instructions (as soon as possible and within 6 hours of
an anthracycline extravasation). The UKONS Anthracycline
Extravasation Management Guidelines (UKONS, 2008)
suggested protocol for anthracycline extravasation is that no
action is required for extravasations of up to 1.5 ml and Savene
is administered for extravasations of 3 ml or greater. Clinical
decisions are made for anthracycline extravasations of 1.5-3 ml
and may include Savene, topical dimethyl sulfoxide, cooling,
and/or hydrocortisone. The UKONS guidelines note that
volumes are based on clinical judgment, and the concentration
of the anthracycline is not specified in the guidelines.
It is difficult to estimate the volume of extravasated
vesicants, especially if the extravasation is in a deep tissue
area, such as the chest wall/breast area. Because the window
of opportunity to treat an anthracycline extravasation is
short (within 6 hours) and safe, efficacious treatment is
now available, it may be prudent to treat all anthracycline
extravasations rather than potentially underestimate the
volume that has extravasated and not treat the area.
Dimethyl sulfoxide (DMSO) is a topically-applied liquid
solvent that increases skin permeability and promotes
S10
medication absorption (Schulmeister, 2011). Because it
also is a free radical scavenger, it has historically been used
as an extravasation antidote. In two studies, DMSO was
topically applied to DNA-binding and DNA non-binding
extravasations in rodents and humans. DMSO was applied
in various amounts, concentrations (50-100%), application
frequencies (every 2-8 hours), durations of treatment
(2-14 days), and in combination with other treatments (e.g.
ice, topical creams, and/or systemic antibiotics). Outcomes of
DMSO treatment varied, and some patients required surgical
intervention despite DMSO application (Bertelli et al, 1995;
Olver et al, 1988). The UKONS guidelines note that owing
to a lack of evidence, DMSO treatment of extravasations
needs to be further studied (UKONS, 2008).
Flush-out techniques
Scuderi and Onesti (1994) theorized that local injection of
normal saline solution into an area of vesicant extravasation
would reduce the concentration of the vesicant and facilitate
its reabsorption. The doxorubicin extravasation sites of
26 patients treated in Rome, Italy were injected with saline
solution in varying amounts depending on the location of
injury (20 ml on wrists, 40 m on dorsum of hands, 60-90 ml
for forearm and antecubital fossa areas) three to six times
daily for 3 days. Pain and erythema resolved within 4 days and
superficial ulcerations healed in 10-14 days for most patients.
However, three patients still required surgical debridement
and skin grafting despite saline flushing.
Variations in the sequencing and technique of combining
saline lavage with suction have been reported, with varying
results (Gault, 1993; Vandeweyer et al, 2000; Giunta, 2004).
However, the extravasations were not confirmed by biopsy
and details about them are lacking. It is unclear how many
of the treated extravasations were non-DNA-binding agents,
which historically do not cause tissue destruction, and how
many were anthracycline extravasations, which are well
documented to cause tissue destruction when they bind to
the DNA in healthy tissue. Based on the conflicting results,
Langer et al (2009) concluded that despite flushing, not all of
the vesicant is removed and some remains behind in the tissue
and causes necrosis.
Dougherty and Oakley (2011) reported that the flush-out
technique is the treatment of choice for vesicant extravasations
in the South East and South West London Cancer Networks.
They described the development of a nurse-led flush-out
service and their flush-out procedure. After cleansing the
area and marking the area of extravasation, lidocaine is first
intradermally injected and then subdermally injected. Next,
a syringe is used to inject hyaluronidase into the anesthetized
area. At least four incisions are then made using a scalpel, the
area is gently pressed, and 0.9% sodium chloride is infused
through a cannula via an IV administration set.The area swells
from the saline flush solution and after massaging and milking
the area, the flush solution (and presumably the vesicant)
exits the area via the incisions that were made. Although the
authors note that the nurse-led flush-out technique resulted
in successful treatment in all cases, there is no information
about the number of patients treated, the types of vesicants
that extravasated (e.g. DNA-binding or non-binding), and
British Journal of Nursing, 2011 (Intravenous Supplement), Vol 20, No 19
 the concentration and estimated volume of the extravasated
vesicants. The authors recommend the flush-out technique
for small extravasations where a flush-out service is accessible
within 24 hours of extravasation occurring, and stated
that dexrazoxane may be of most use for large peripheral
extravasations, extravasations from CVADs, or in places where
a flush-out service is not available.
Follow up
Vesicant antidotes and treatments that are promptly and
properly administered help keep skin integrity intact and
prevent the development of tissue necrosis. Patients need
to be instructed to observe their extravasation sites, keep
them clean and dry, and avoid sun exposure to the area.
Patients with vesicant extravasations that go untreated, or
are under-treated, are likely to develop tissue necrosis that
may require surgical intervention, such as debridement, and
in some cases may require skin grafting. Now that approved
extravasation treatments with demonstrated efficacy are
available and recommended by professional oncology
organizations, no patient with a vesicant extravasation
should ever go untreated. Failure to treat also exposes the
oncology staff to potential litigation.
Conclusion
Not all extravasations can be prevented; therefore,
extravasations need to be promptly detected. Whenever an
extravasation occurs or is suspected, vesicant administration
must immediately cease and the appropriate antidote or
treatment should be promptly administered. Nurses are
in the forefront of vesicant chemotherapy extravasation
detection and management, and need to collect data on
patient outcomes so that more is known about how different
Key points
n Left untreated, vesicant chemotherapy extravasations can cause tissue
necrosis, sensory and functional impairment, and permanent disfigurement
n The potential severity of an extravasation injury is influenced by the type of
vesicant that has extravasated, the concentration and amount of the vesicant
that has entered the tissue, and the location of the intravenous device
n Vesicant extravasation antidotes and treatments must be administered as
soon as possible to mitigate tissue damage
S12
approaches, such as antidote administration and the flush-out
technique, compare in clinical practice. BJN
Conflict of interest: none
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Copyright of British Journal of Nursing (BJN) is the property of Mark Allen Publishing Ltd and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.