Extravasation injuries: A review

Abstract

Extravasation injuries are common emergencies in clinical practice. If they are not recognized and treated promptly, they can lead to deleterious functional and cosmetic outcomes. There is a vast range of agents involved in these injuries and marked paucity of evidence to support their specific management. Following an extensive literature review, we outline management principles for clinicians involved in the care of patients with extravasation injuries. Key parameters in deciding appropriate management plans include the volume/toxicity of the agent, the necrosis interval of the injury, patient-related factors, as well as the facilities and expertise available in the setting of individual cases of extravasation.

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The Journal of Hand Surgery
(European Volume)
2014, Vol. 39E(8) 808 –818
© The Author(s) 2014
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DOI: 10.1177/1753193413511921
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Introduction
Extravasation can be defined as the accidental infiltra-
tion of a medicinal product from a displaced intravas-
cular cannula into the perivascular/subcutaneous
tissues (Jones and Coe, 2004). The degree of tissue
damage depends on the volume, toxicity of the agent,
site of the cannula, and patient factors (Kumar et al.,
2001). The overwhelming majority of injuries relate to
peripheral intravenous catheters in the arm or hand,
but they can also occur in association with central
venous catheters. Extravasation rates of 0.01% to
6.5% have been reported in patients receiving chemo-
therapy, while rates up to 11% have been quoted in
children receiving intravenous fluids (Schulmeister,
2007; Sistrom et al., 1991). Clinical features of extrava-
sation include pain, oedema, and erythema around the
infusion site. Blistering, pain, and induration (persist-
ing more than 24 h) signify a severe extravasation
injury and potential for ulceration (Heckler, 1989;
TVCN, 2006). The swelling and erythema may subside
within 24 hours, but ulceration has a highly variable
timescale and may only appear weeks later (Heckler,
1989). Figures 1 and 2 depict common appearances of
extravasation within 48 h of injury. Histologically, fea-
tures of extravasation comprise primary vasodilation
and sludging of red blood cells as early as 2 to 4 h post
injury, followed by vascular endothelial degenerative
changes over the next 24 to 48 h. Later, necrotic
lesions appear with a marked lack of an inflammatory
infiltrate (Coleman et al., 1983; Heckler, 1989; Shenaq
et al., 1996).
It is important to differentiate extravasation from
simple tissue reactions, which can present in a simi-
lar manner. These include flare reactions due to his-
tamine release, skin discoloration due to coloured
infusions, and vessel spasm or phlebitis due to the
rapid injection of cold drugs. Lack of swelling around
the infusion site suggests tissue reaction as opposed
to extravasation. Early treatment of extravasation
injuries may prevent or minimize the development of
complications.
We performed a PubMed search in the English and
German literature using the keywords ‘extravasation’
and ‘treatment’ for the period between January 1965 to
the present time, and our strategy was approved by a
professional librarian. We identified 260 papers, the
abstracts of each were hand searched with the whole
paper being retrieved when the abstracts were
insufficient. Papers identified and selected had their
Extravasation injuries: a review
I. Goutos, L. K. Cogswell and H. Giele
Abstract
Extravasation injuries are common emergencies in clinical practice. If they are not recognized and treated
promptly, they can lead to deleterious functional and cosmetic outcomes. There is a vast range of agents
involved in these injuries and marked paucity of evidence to support their specific management. Following an
extensive literature review, we outline management principles for clinicians involved in the care of patients
with extravasation injuries. Key parameters in deciding appropriate management plans include the volume/
toxicity of the agent, the necrosis interval of the injury, patient-related factors, as well as the facilities and
expertise available in the setting of individual cases of extravasation.
Keywords
Extravasation, vesicant, exfoliant, irritant
Date received: 28th January 2013; revised 15th September 2013; accepted 16th October 2013
Department of Plastic and Reconstructive Surgery, John Radcliffe
Hospital, Headington, Oxford, UK
Corresponding author:
Ioannis Goutos, Department of Plastic and Reconstructive
Surgery, West Wing, John Radcliffe Hospital, Headley Way,
Headington, Oxford, OX3 9DU, UK.
Email: ioannisgoutos@hotmail.com
511921JHS0010.1177/1753193413511921The Journal of Hand SurgeryGoutos et al.
2014
Review article
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Goutos et al. 809
bibliographies searched. The overwhelming majority of
publications comprised case reports/series and man-
agement protocols presenting non-evidence−based
local or regional preferences. We identified one
Cochrane Database systematic review on saline irriga-
tion for neonatal extravasations. The review was incon-
clusive, given the lack of any eligible studies
(Gopalakrishnan et al., 2012). Four controlled animal
experiments were retrieved (Coleman et al., 1983; Dorr
et al., 1996; Laurie et al., 1984; Loth, 1986).
Only two comparative studies were identified in
humans (Gault, 1993; Loth and Eversmann, 1991).
Given the mixed nature of extravasants and patient
characteristics in the studies, it is impossible to draw
detailed conclusions regarding the efficacy of
different treatment options, but we identified some
widely accepted indications for surgical
management.
We have considered the review under the headings
of risk factors, classification, and management.
Risk factors
There are multiple risk factors for developing an
extravasation injury:
(i) Patient-related factors (Bellin et al., 2002; Cohan
et al., 1996; Schaverien et al., 2008).
a) At extremes of age, a number of factors
increase the risk of extravasation including:
skin/vessel fragility, low muscle-to-subcuta-
neous-tissue mass as well as decreased abil-
ity to report or detect pain at the infusion site.
b) Vascular compromise such as peripheral vas-
cular disease, venous insufficiency and lym-
phatic obstruction reduce tolerance to injury.
c) Peripheral neuropathy confers inability to
detect pain/discomfort associated with
extravasation.
(ii) Mechanism of injection/choice of infusion site
(Bellin et al., 2002; Gault, 1993; Göthlin, 1972).
a) The use of power injectors and metallic nee-
dles as opposed to plastic cannulae increases
the risk of extravasation.
b) Infusion sites including peri-articular areas
and the lower limb are more prone to dis-
lodgement due to movement; furthermore,
the risk of severe complications rises when
placing the cannula near tendons or nerves.
c) Multiple previous venepunctures especially
moving distally along a vein can compromise
venous wall integrity.
(iii) The injected drug (Ayre–Smith, 1982; Bellin et al.,
2002; Kumar, 2001; Upton et al., 1979). Apart from
the volume and concentration of the extravasant,
cytotoxicity, pH, osmolality, and vasoactive prop-
erties influence the severity of injuries.
a) Cytotoxicity: Medications are broadly divided
into vesicants, exfoliants, irritants, inflamma-
tory, and neutral agents in descending order
of cellular toxicity and type of reaction/tissue
damage they cause (Jones, 2004; TVCN, 2006).
Vesicants produce local tissue necrosis both within
and outside the venous system. Exfoliants cause
Figure 1. Deep dermal staining over the hand dorsum
appearing 4h following acyclovir extravasation.
Figure 2. Full thickness skin necrosis presenting 48h fol-
lowing chemotherapy extravasation.
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810 The Journal of Hand Surgery (Eur) 39(8)
inflammation and skin shedding, but are less likely to
cause subcutaneous tissue damage. Irritants cause
pain and inflammation at the administration site and
along the vein, but rarely result in necrosis.
Inflammatory agents produce a mild-to-moderate
inflammatory reaction. Neutral or inert agents cause
no inflammation or damage.
Table 1 lists agents involved in extravasation inju-
ries and their cytotoxic threat to tissues (TVCN, 2006).
Chemotherapeutic vesicants are further classified
into DNA binding and non-DNA binding. DNA binding
drugs set-up a continuous cycle of tissue damage by
cellular DNA–medication complexes, which are taken
up by adjacent healthy cells via endocytosis propagat-
ing tissue damage. Non-DNA−binding agents are
metabolized and neutralized more easily in the tis-
sues and result in less extensive injuries (Cox, 1984;
Ener et al., 2004; Luedke et al., 1979). Special refer-
ence should be made to liposomal anthracycline
preparations, which are considered irritants due to
their long half-life and ‘tissue protective’ encapsula-
tion. Extravasation with liposomal encapsulated
anthracyclines can be treated in a less aggressive
manner because no extensive tissue necrosis has yet
been recorded in the literature (Laufman et al., 2007;
Madhavan and Northfelt, 1995).
b) Extremes of pH. Agents with pH values outside
5.5–8.5 are particularly harmful to tissues
(National Extravasation Information Centre,
2005; Rao et al., 1988). Table 2 contains a list of
agents commonly involved in extravasations
and their pH (BasePortal, 2012).
c) Osmolality. Substances with osmolality different
from serum (281–289 mOsmol/L) may cause
significant tissue damage by cell implosion
(hypertonic solutions) or cell explosion (hypo-
tonic solutions). In clinical practice, injuries
from hyperosmolar agents are more common
with some agents involved including (National
Extravasation Information Centre, 2005):
1). Glucose solutions (10% or greater).
2). Sodium bicarbonate preparations (above 1.8%).
3). Potassium/sodium chloride, calcium gluconate,
magnesium sulphate, mannitol infusions.
4). Total parenteral nutrition preparations (with
osmolalities averaging 650 mOsm/L).
5). Ionic, high osmolality radiological contrast media.
Table 1. Classification of cytotoxic agents in descending toxicity order. The class of chemotherapeutic agents is indicated
in brackets for vesicants (Jones and Coe, 2004; TVCN, 2006).
Vesicants Exfoliants Irritants Inflammatory agents Neutral agents
Non classical alkylating
agent:
Amsacrine
Aclarubicin
Cisplatin
Docetaxel
Floxuridine
Oxaliplatin
Topotecan
Bortezomib
Carboplatin
Etoposide
Irinotecan
Liposomal
anthracyclines
Teniposide
Etoposide phosphate
Fluorouracil
Methotrexate
Pemetrexed
Raltitrexed
Asparaginase
Bleomycin
Cladribine
Cyclophosphamide
Cytarabine
Fludarabine
Gemcitabine
Isosfamide
Interferons
Interleukin 2
Melphalan
Pantostatin
Rituximab
Thiotepa
Trastuzumab
Alkylating agents:
Carmustine
Dacarbazine
Mechlorethamine
Streptozocin Treosulfan
Antitumour antibiotics:
Dactinomycin
Mitomycin
Mitoxantrone
Anthracyclines:
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin
Taxane:
Paclitaxel
Vinca alkaloids:
Vinblastine
Vincristine
Vindesine
Vinorelbine
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Goutos et al. 811
d) Vasoconstrictive/dilatory properties. Vascular
regulators pose a particular threat to tissues,
particularly vasoconstrictor agents (e.g.,
adrenaline/noradrenaline) (Hannon, 2011).
Classification
Loth and Eversmann (1991) classified the sever-
ity of extravasation injuries into the following
categories:
1) Mild: Minimal volume of an irritant or vesicant
causing little pain/swelling and no erythema or
blistering.
2) Moderate: Small volume (up to 5 ml) of extrava-
sation causing a local inflammatory reaction (less
than 10 cm diameter), moderate tenderness, with
or without erythema but no blistering.
3) Severe: Larger volume extravasation of typically
vesicant infusions resulting in extreme pain,
marked swelling, erythema and often blistering.
Table 2. Indicative list of agents commonly involved in extravasation injuries (in alphabetical order) and their corresponding
pH values (BasePortal, 2012).
Medicine (A–K) pH Medicine (L–V) pH
Acetazolamide 9.2 Labetalol 3.5–4.2
Aciclovir 11 Lidocaine 5.0–7.0
Adenosine 6.3–7.3
Adrenaline (epinephrine) 2.5–3.6 Magnesium sulphate 50% 3.5–6.5
Allopurinol 10.8–11.8 Meropenem 7.3–8.3
Aminophylline 8.8–10 Metronidazole 5.5–5.7
Amiodarone hydrochloride 3.5–4.5 Midazolam 3.0
Atracurium 3.5 Morphine 2.5–4.5
Azathioprine 10–12
Naloxone 3.0–4.5
Buprenorphine 3.5–5.5 Noradrenaline 3.0–4.5
Cefotaxime 5.0–7.0 Omeprazole 9.0–10.0
Ceftazidime 5.0–8.0 Ondansetron 3.4–3.8
Ceftriaxone (1%) 6.7 Oxytocin 3.7–4.3
Cefuroxime 6.0–8.5
Clarithromycin 5.0 Pancuronium 3.8–4.2
Clindamycin 5.5–7.0 Phenobarbitone 9.0–10.5
Co-amoxiclav 8.0–8.9 Phenytoin 12
Cyclizine 3.3–3.7 Propofol 7.0–7.1
Propranolol 3
Diazepam 6.2–6.9 Protamine sulphate 6.0–7.0
Digoxin 6.7–7.3
Dobutamine 3.5–4.0 Quinine 2.0–3.0
Dopamine 2.5–4.5
Ranitidine 6.7–7.3
Erythromycin 6.5–7.5 Remifentanyl 2.5–3.5
Fentanyl 3.3–6.3 Salbutamol 3.5
Flucloxacillin 5.0–7.0 Sodium bicarbonate (4.2% and 8.4%) 7.0–8.5
Frusemide 8.7–9.3 Sodium valproate 6.8–8.5
Ganciclovir 10.0–11.0 Teicoplanin 7.5
Gentamycin 3.0–5.0 Thiamine 2.5–4.5
Glucagon 2.5–3.0 Thiopentone (2.5%) 10.5
Glucose 10%, 20%, 50% 3.5–6.5
Glyceryl trinitrate 3.5–6.5 Vancomycin 2.8–4.5
Verapamil 4.0–6.5
Haloperidol 3.0–3.6
Ketamine 3.5–5.5
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812 The Journal of Hand Surgery (Eur) 39(8)
The latter category of injuries almost always requires
active intervention. For mild/moderate injuries, the
authors advise conservative management/symptom
relief. They also introduced the important concept of
the ‘necrosis interval’ — the period of time from the
onset of extravasation to irretrievable injury during
which surgical intervention may prevent further tis-
sue necrosis. Typical values quoted range from 4–6 h
for vasopressors, 6 h for radiological contrasts, and
72 h for chemotherapeutic agents. The necrosis inter-
val gives an indication of the window of opportunity for
treatment after which active intervention is likely to
be of less value.
Management: general principles
Prevention
Staff should be trained in the insertion of cannulae,
and regional/national guidelines must be followed
for preparing, administering, and monitoring inject-
able medicines. Patients at increased risk of extrava-
sation require more intensive monitoring during
infusions. In terms of the choice of vein, sites liable
to dislodgement such as the dorsum of the hand,
antecubital fossa/other periarticular areas, and the
lower limb should be avoided. Multiple punctures in
a vein, especially moving more distally along the
same vein, risks extravasation. When a number of
drugs are to be injected, vesicants should be admin-
istered first and the patency of the cannula checked
regularly. Drug infusions should be monitored by
trained staff, and if infusion pumps are used, alarms
should be incorporated to monitor increased intralu-
minal pressure. New devices for the detection of
accidental infiltration into perivascular tissues such
as the extravasation detection accessory (EDA) show
a high sensitivity and specificity in detecting clini-
cally relevant extravasation (more than 10 ml)
(Birnbaum et al., 1999).
Immediate generic steps following
extravasation
If extravasation is suspected, prompt action is needed,
as shown in Figure 3 (Schulmeister, 2000; 2009; 2011;
Loth and Eversmann, 1991).
Definitive management options
There are a variety of strategies for treating extrava-
sation injuries described in the literature based solely
on experience. The controlled animal experiments
identified in the literature search (Coleman et al.,
1983; Dorr et al., 1996; Laurie et al., 1984; Loth, 1986)
helped draw the following conclusions: early excision
in chemotherapy extravasation is a valid option for
management; steroid injection is ineffective in pre-
venting ulcer formation in adriamycin injuries, and
prompt subcutaneous injection of hyaluronidase is
key in reducing necrosis caused by common extrava-
sation agents: calcium chloride, hyperalimentation
solution, adriamycin, and paclitaxel.
A) Conservative management
This is the first and often only step needed for extrava-
sation injury management and it includes: (Kumar
et al., 2009; Langstein et al., 2002; Larson, 1982;
Pitkänen et al., 1983; Shenaq et al., 1996):
a) Pain relief.
b) Application of ice: Commonly 15 min sessions
four times daily for 3 days to decrease the spread
of drugs into adjacent tissues (via vasoconstric-
tion), slow down the cellular metabolic rate, and
deactivate the extravasated agent.
c) Dressings with serial assessment in the outpa-
tient clinic.
The rationale for conservative treatment is that only
11–21% of extravasation injuries require surgery (Loth
and Eversmann, 1991). A conservative approach can
most importantly prevent inaccurate and insufficient
tissue excision given the slow evolution of clinical signs
in many injuries (Kumar et al., 2001). Corticosteroid
Stop the infusion and disconnect from drip set
Aspirate any extravasated drug using a small syringe before
removing the cannula.
Elevate the limb and summon help from plastic or hand surgery
colleagues
Mark the extravasation area and start monitoring for neurovascular
compromise and skin changes
(blistering, induration, deep dermal staining)
Take digital photographs and estimate the volume, concentration and
duration of exposure to extravasated drug
Provide analgesia and apply topical compresses
(cold for non-vesicant drugs and DNA binding vesicants; warm for
phenytoin and non DNA binding vesicants)
Complete extravasation documentation and ill out a clinical incident
form as per trust guidelines
Figure 3. Immediate generic steps in the management of
extravasation injuries.
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Goutos et al. 813
preparations (topical creams and subcutaneous injec-
tions) feature in some protocols for chemotherapy
extravasations (Tsavaris et al., 1990), but their use is not
supported either by controlled clinical studies or by
existing histological evidence (lack of florid inflamma-
tion in tissues affected by extravasation) (Coleman
et al., 1983; Heckler, 1989; Shenaq, 1996).
In radiological contrast media extravasations, the
recent switch to low osmolality, non-ionic contrast
media has resulted in a marked reduction in soft-
tissue complications (Sbitany et al., 2010; Schaverien
et al., 2008). Magnetic resonance agents are less
likely to produce significant extravasation injuries,
given the markedly lower osmotic loads and admin-
istered volumes compared with X-ray and computed
tomography contrast agents (Bellin et al., 2002). The
majority of extravasations involve small volumes
and symptoms tend to resolve without treatment
within 24 h (Cohan et al., 1996; 1997; Federle et al.,
1998; Jacobs et al., 1998; Sistrom et al., 1991). In a
large 6-year retrospective study of 40 000 CT scans,
102 extravasation injuries were treated successfully
with conservative therapy (Sbitany et al., 2010).
Based on data analysis, the authors proposed an
extravasation volume of 150 ml as a cut-off to define
a high volume injury. A number of other studies have
agreed that extravasation of up to 150 ml of contrast
can be treated conservatively (Cohan et al., 1990;
1997; Sistrom et al., 1991). However, the critical vol-
ume of extravasant should be correlated to the posi-
tion of the affected site with sites below the elbow,
evidence of skin or neural compromise, large vol-
umes and possible compartment syndrome qualify-
ing for a plastic/hand surgery consultation (Sbitany
et al., 2010).
B) Antidote administration
Sodium thiosulfate is the first-line agent for the treat-
ment of extravasations with mechlorethamine, a
nitrogen mustard DNA binding vesicant. Its mecha-
nism of action is thought to rely on reduced produc-
tion of reactive alkylating species and hydroxyl
radicals (Dorr et al., 1988). It is administered as a 1/6
molar solution (4 ml of 10% agent diluted with 6 ml
sterile water) injected into the injured area in 2 ml ali-
quots for each ml of agent extravasated (Schulmeister,
2011). Mouse skin toxicity experiments have con-
firmed the need for urgent administration of the agent
with delays of more than 4 hours resulting in loss of
antidotal action (Dorr et al., 1988).
Dexrazoxane is an antidote used in anthracycline
extravasations and it prevents the formation of free
radicals by binding DNA topoisomerase II (Hasinoff,
2008). Its effectiveness has been confirmed in two
clinical trials. It must be administered intravenously
within 6 hours of the injury in an area away from the
extravasation with the following regimen: 1000 mg/
m2 on day 1 and 2, and 500 mg/m2 on day 3. The maxi-
mum daily dose is 2000 mg. This is reduced by 50% in
patients with creatinine clearance <40ml/min (Kane
et al., 2008; Mouridsen et al., 2007).
A number of early experimental animal studies have
shown encouraging results with topical antidotes in
cytotoxic extravasations including n-acetylcysteine,
vitamin C, basic fibroblast growth factor, and granulo-
cyte macrophage colony stimulating factor (Hajarizadeh
et al., 1994; Shamseddine et al., 1998; Vasilev et al.,
1992). These agents have not undergone evaluation in
human studies, so cannot be recommended for inclu-
sion in therapeutic protocols at present.
C) Bedside intervention/ Surgical
management
Bedside/surgical intervention can be categorized
according to the timescale following injury into:
a) Emergency: Compromise to the neurovascular
status of the limb or suspected compartment
syndrome.
b) Acute: Signs of imminent tissue necrosis, blister-
ing, induration, and intractable pain.
c) Time-independent intervention including sepsis,
established ulceration, patient’s desire not to
undergo dressings or delayed secondary healing,
and interference with planned adjuvant therapy
(Fallscheer et al., 2007; Heckler, 1989; Larson,
1982; Loth, 1986; Pitkänen et al., 1983; Rudolph
and Larson, 1985; 1987; Shenaq et al., 1996).
Subcutaneous hyaluronidase injection
Hyaluronidase breaks down hyaluronic acid, a normal
component of the interstitial fluid barrier and its use
aims to aid agent dispersion into the surrounding tis-
sues. (Laurie et al., 1984). Current recommendations
suggest subcutaneous injection of 1 ml of hyaluroni-
dase (150 U/ml solution) per ml of extravasated agent
in a clockwise manner to the affected area
(Schulmeister, 2009). The effectiveness of hyaluroni-
dase in reducing necrosis caused by calcium chloride,
hyperalimentation solution, and adriamycin was inves-
tigated in a rabbit experiment. Immediate subcutane-
ous injection with hyaluronidase produced a statistically
significant reduction in the area of necrosis (p = 0.01),
but only when used in the first hour from injury (p =
0.01) (Laurie, 1984). In a similar mouse model
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814 The Journal of Hand Surgery (Eur) 39(8)
employing paclitaxel, hyaluronidase reduced ulcer size
by 50% (p <0.05) (Dorr et al., 1996). In a cohort of 148
patients with antineoplastic extravasations, hyaluroni-
dase prevented ulceration in all cases (Heckler, 1989).
Saline flush out
This method relies on dispersion of the noxious agent
via flushing saline into the extravasation area and the
egress of irrigation fluid out through stab wounds in
the surrounding skin. It is often used in conjunction
with hyaluronidase and is ideally performed within 1–2
hours of the injury. This technique was used by Gault in
37 patients with subcutaneous infiltration of 1500 IU of
hyaluronidase after local anaesthetic infiltration with
1% lidocaine. Four stab incisions were then made
around the periphery of the extravasation and a blunt-
tipped catheter or needle was used via one of the inci-
sions to flush 500 ml of saline through the subcutaneous
tissue and out via the other three incisions (Gault,
1993). Eighty-six percent of patients receiving treatment
within 24 h of injury healed with no soft tissue loss; 15
out of 52 patients presenting more than 24 h post-
extravasation required extensive reconstruction (6
flaps, 6 split thickness grafts, and 3 amputations)
(Gault, 1993). In a series of 18 cytotoxic extravasations
treated with hyaluronidase and saline flush out more
than 20 min after injury, 17 patients recovered sponta-
neously (Khan, 2002). This treatment was also suc-
cessful in infants who had extravasation of parenteral
nutrition (Davies et al., 1994). A variation of saline
washout was described in a case series using a single
stab incision outside the affected area, infiltration of
saline to produce swelling and induration beyond the
extravasation area, and fluid aspiration using a 2 mm
cannula. No evidence of skin necrosis was noted in 13
patients undergoing this treatment at an average 345
(range 140–795) min post-chemotherapy extravasation
(Steiert et al., 2011). D’Andrea et al. (2004) successfully
used repeated saline infiltration into the extravasation
area (without flushing or aspirating) to dilute chemo-
therapeutic agents with only three out of 229 patients
Figure 4. Illustration of hyaluronidase infiltration and saline flush out technique. (a) The extravasation site is cleaned with
chlorhexidine solution and anaesthetized with 1% lidocaine (field block technique). (b) Using a sterile technique, hyaluroni-
dase is infiltrated into the affected subcutaneous tissues in a clockwise manner using a 23 gauge needle. The dose is 1 ml
of 150 U/ml solution of hyaluronidase per ml extravasation. (c) A 20 gauge cannula is inserted across the extravasation site
through the subcutaneous tissue to exit on the other side. (d) The needle is removed from around the plastic sheath of the
cannula and a 20 ml syringe filled with saline is attached; the cannula is slowly withdrawn through the area whilst flush-
ing the saline solution. (e) Steps c and d are repeated using a different angle through the area until six entry/exit sites are
present for further flushing. The 20 gauge cannula (without the needle) is inserted into any of the holes in the skin and the
washout proceeds in 20 ml aliquots to allow the solution to flush out through the other holes. The recommended volume
of flush out is 20–60 ml for neonates, 60–240 ml for children, and up to 500 ml for adults. The site is dressed with a non-
adherent dressing and the limb is elevated.
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Goutos et al. 815
developing ulceration. Late washout may be effective,
so could still be considered even after days have passed
after the injury (Dionyssiou et al., 2011). Figure 4a-e
shows the steps employed for hyaluronidase infiltra-
tion and saline flushout in our institution.
Squeeze technique
In a series of eight patients with digital vascular com-
promise due to extravasation of a high-volume (>50
ml) radiological contrast, the intravenous catheter
was removed and an 18 gauge needle used to create
five to eight openings near the catheter insertion site.
The extremity was then squeezed in a distal-to-proxi-
mal direction. Treatment was successful with imme-
diate resolution of the vascular compromise in all
cases (Tsai et al., 2007). This technique was modified
using a combination of liposuction, subcutaneous
irrigation, and compression with a Rhys–Davies
exsanguinator to successfully treat a 100 ml contrast
medium injury causing median nerve compromise
(Schaverien et al, 2008).
Surgical excision of the extravasation
area and direct closure
A controlled animal experiment with adriamycin
extravasation in rats compared the effect of the fol-
lowing three interventions: immediate excision and
closure, delayed (48hrs) excision and closure and
treatment with hydrocortisone injection. The results
revealed that all five rats treated with immediate exci-
sion and 4 out of 5 treated with delayed excision and
closure healed with no necrosis at 7 days. The rats
treated with steroid injection developed ulcers, which
remained static at 16 days post extravasation (Coleman
et al., 1983). Another rat experiment examined early
minimal debridement in doxorubicin-induced skin
ulcers. The debrided sites developed significantly
smaller ulcers than those in the control animals.
Re-debridement of necrotic skin 1 week after the ini-
tial minimal debridement procedure produced a fur-
ther significant decrease in ulcer size (Loth, 1986).
A clinical series examined direct excision of vesicant
chemotherapy extravasation in the upper limb of 10
patients. The average time from injury to excision was
3 h 10 min (range 1 h 46 min to 4 h 40 min); at a 3
month follow-up, nine out of 10 patients showed no
evidence of necrosis (Telisselis et al., 2010). Another
retrospective case series analysed the clinical course
of 40 patients with doxorubicin extravasation. The
cohort underwent a two stage treatment protocol with
debridement initially (ranging from 24hrs to 2 months
following injury) and delayed closure with a variety of
different skin grafting/flap techniques. The authors
advocated early surgical debridement of these injuries
since the complications and morbidity secondary to
extravasation was considerable in the delayed treat-
ment part of the cohort. Complications in the study
included sepsis, nerve compression, joint stiffness,
weakness as well as sympathetic dystrophy syn-
dromes (Linder et al., 1983). In another clinical study,
14 patients with extravasation from a variety of agents
were evaluated in terms of function and cosmesis for
an average of 8.4 (range 1–24) months. In the first
cohort of patients initially managed conservatively,
four out of five needed surgical intervention for skin
necrosis and had poor functional and cosmetic out-
comes. The second cohort (nine patients) was treated
with surgical debridement within 72 h if erythema,
severe pain, and blistering persisted despite local first
aid. Five patients underwent debridement with delayed
primary wound closure; only one had a poor outcome
(Loth and Eversmann, 1991).
Liposuction
Under local or general anaesthesia, a small incision is
made alongside the area of extravasation. A blunt-
ended liposuction cannula with side holes is employed
to aspirate the extravasated material and fat within
subcutaneous channels as in conventional liposuc-
tion. In the original description of this technique, lipo-
suction was used either as an isolated modality or in
combination with the flush out technique (Gault, 1993).
The latter strategy proved effective in a series of 11
patients with hyperosmolar contrast medium injuries;
no cases of necrosis were reported in patients treated
within 2h of injury (Vandeweyer et al., 2000)
Decision-making for the acute
management of extravasation injuries
Given the vast array of agents capable of causing
extravasation injuries and the poor evidence base for
management, we recommend that clinicians consider
the following principles to decide on an interventional
versus conservative management strategy.
a) Non-agent–specific parameters (volume of extrav-
asant). If a significant volume of agent has extrav-
asated and results in significant pain, compression
of neuromuscular structures, loss of skin circula-
tion and/or development of compartment syn-
drome, emergency intervention is warranted.
Treatment modalities include fasciotomies, exci-
sion of the affected tissue, and removal of the
offending volume of extravasant either via the
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816 The Journal of Hand Surgery (Eur) 39(8)
‘squeeze’ method (Tsai et al., 2007) or liposuction
(Benson et al., 1996; Memolo et al., 1993; Pond
et al., 1992; Young, 1994).
b) Agent-specific parameters (chemical ‘viru-
lence’). If the extravasation injury threatens tissues
by virtue of the chemical properties of the agent
(vesicant, osmolar, pH, or vasoconstrictive), then the
majority of the extravasant should be removed or
neutralized. In the case of mechlorethamine and
anthracycline injuries, antidotes should be consid-
ered if available, namely sodium thiosulfate and
dexrazoxane, respectively (Dorr et al., 1988, Hasinoff,
2008; Kane et al., 2008; Mouridsen et al., 2007). For
other vesicant chemotherapeutic drugs, hyaluroni-
dase infiltration is effective (Bertelli et al., 1994;
Dorr et al., 1996; Heckler 1989; Laurie et al., 1984)
and therefore recommended as first-line treatment
when no antidote is available. Although there are no
studies proving an additional benefit of flush out as
an adjunct to hyaluronidase injection, there are no
reports of additional morbidity of this procedure,
hence its joint adoption is recommended. Other
modalities that can be considered include excision of
the affected tissue or liposuction (Gault, 1993; Telis-
selis et al., 2010).
c) Necrosis interval of each individual presenta-
tion. Consideration of the time elapsed between the
injury and clinical assessment is vital because most
interventions need to be performed within the ‘necro-
sis interval’. Cases presenting past this timescale can
be managed conservatively in the absence of clear
indications for surgery. Secondary surgery to debride
and close/cover wounds may be necessary.
d) Patient-related issues. Patients’ preferences or
comorbidities may preclude surgery or the need for
ongoing/adjuvant treatment (e.g chemotherapy) may
impose early intervention.
e) Facilities/expertise available in the particular health-
care environment. Given the wide range of treatment
modalities available for extravasation management, it
is important that early specialist referral is sought,
especially in cases involving vesicant agents. The
management plan needs to be tailored not only based
on agent, timing, and patient-related factors, but on
the resources and expertise available in the corre-
sponding healthcare setting.
A suggested algorithm for approaching the man-
agement of extravasation injuries is shown in Figure 5.
Immediate generic steps (igure3)
High volume extravasation
•‘Squeeze’ method
•Liposuction
•Excision
•Fasciotomies
Extravasation injury
Low volume extravasation
No tissue necrosis present;
antidote available
•Sodium thiosulfate
(mechlorethamine extravasations)
•Dexrazoxane
(anthracycline extravasations) Conservativemanagement
(dressings and regular clinical review)
Injury within the necrosis interval
Tissue necrosis present or likely
•Hyaluronidase injection and
saline lushout
•Liposuction
•Excision
Injury outside the necrosis interval
HealingNeed for deinitive surgical
debridement/wound cover
Tissue necrosis unlikely
Figure 5. Suggested algorithm for approaching the management options for extravasation injuries.
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Goutos et al. 817
Conclusion
Extravasation injuries are common emergencies in
clinical practice. Their management represents a
challenge due to the vast array of agents involved and
lack of evidence in the literature on the most appro-
priate therapeutic strategy. We advocate that clini-
cians consider key factors related to the patient,
agent, healthcare facilities available, as well as the
necrosis interval for each case of extravasation.
Timely and successful treatment of extravasations
can prevent devastating complications arising as a
result of these injuries.
Conflict of interests
None declared.
Funding
This research received no specific grant from any funding
agency in the public, commercial, or not-for-profit
sectors.
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