Beruflich Dokumente
Kultur Dokumente
Review article
JHS(E)
The Journal of Hand Surgery
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
Introduction
Extravasation can be defined as the accidental infiltra- infiltrate (Coleman et al., 1983; Heckler, 1989; Shenaq
tion of a medicinal product from a displaced intravas- et al., 1996).
cular cannula into the perivascular/subcutaneous It is important to differentiate extravasation from
tissues (Jones and Coe, 2004). The degree of tissue simple tissue reactions, which can present in a simi-
damage depends on the volume, toxicity of the agent, lar manner. These include flare reactions due to his-
site of the cannula, and patient factors (Kumar et al., tamine release, skin discoloration due to coloured
2001). The overwhelming majority of injuries relate to infusions, and vessel spasm or phlebitis due to the
peripheral intravenous catheters in the arm or hand, rapid injection of cold drugs. Lack of swelling around
but they can also occur in association with central the infusion site suggests tissue reaction as opposed
venous catheters. Extravasation rates of 0.01% to to extravasation. Early treatment of extravasation
6.5% have been reported in patients receiving chemo- injuries may prevent or minimize the development of
therapy, while rates up to 11% have been quoted in complications.
children receiving intravenous fluids (Schulmeister, We performed a PubMed search in the English and
2007; Sistrom et al., 1991). Clinical features of extrava- German literature using the keywords ‘extravasation’
sation include pain, oedema, and erythema around the and ‘treatment’ for the period between January 1965 to
infusion site. Blistering, pain, and induration (persist- the present time, and our strategy was approved by a
ing more than 24 h) signify a severe extravasation professional librarian. We identified 260 papers, the
injury and potential for ulceration (Heckler, 1989; abstracts of each were hand searched with the whole
TVCN, 2006). The swelling and erythema may subside paper being retrieved when the abstracts were
within 24 hours, but ulceration has a highly variable insufficient. Papers identified and selected had their
timescale and may only appear weeks later (Heckler,
1989). Figures 1 and 2 depict common appearances of Department of Plastic and Reconstructive Surgery, John Radcliffe
extravasation within 48 h of injury. Histologically, fea- Hospital, Headington, Oxford, UK
tures of extravasation comprise primary vasodilation
Corresponding author:
and sludging of red blood cells as early as 2 to 4 h post Ioannis Goutos, Department of Plastic and Reconstructive
injury, followed by vascular endothelial degenerative Surgery, West Wing, John Radcliffe Hospital, Headley Way,
changes over the next 24 to 48 h. Later, necrotic Headington, Oxford, OX3 9DU, UK.
lesions appear with a marked lack of an inflammatory Email: ioannisgoutos@hotmail.com
Risk factors
There are multiple risk factors for developing an
extravasation injury:
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).
inflammation and skin shedding, but are less likely to been recorded in the literature (Laufman et al., 2007;
cause subcutaneous tissue damage. Irritants cause Madhavan and Northfelt, 1995).
pain and inflammation at the administration site and
along the vein, but rarely result in necrosis. b) Extremes of pH. Agents with pH values outside
Inflammatory agents produce a mild-to-moderate 5.5–8.5 are particularly harmful to tissues
inflammatory reaction. Neutral or inert agents cause (National Extravasation Information Centre,
no inflammation or damage. 2005; Rao et al., 1988). Table 2 contains a list of
Table 1 lists agents involved in extravasation inju- agents commonly involved in extravasations
ries and their cytotoxic threat to tissues (TVCN, 2006). and their pH (BasePortal, 2012).
Chemotherapeutic vesicants are further classified c) Osmolality. Substances with osmolality different
into DNA binding and non-DNA binding. DNA binding from serum (281–289 mOsmol/L) may cause
drugs set-up a continuous cycle of tissue damage by significant tissue damage by cell implosion
cellular DNA–medication complexes, which are taken (hypertonic solutions) or cell explosion (hypo-
up by adjacent healthy cells via endocytosis propagat- tonic solutions). In clinical practice, injuries
ing tissue damage. Non-DNA−binding agents are from hyperosmolar agents are more common
metabolized and neutralized more easily in the tis- with some agents involved including (National
sues and result in less extensive injuries (Cox, 1984; Extravasation Information Centre, 2005):
Ener et al., 2004; Luedke et al., 1979). Special refer-
ence should be made to liposomal anthracycline 1). Glucose solutions (10% or greater).
preparations, which are considered irritants due to 2). Sodium bicarbonate preparations (above 1.8%).
their long half-life and ‘tissue protective’ encapsula- 3). Potassium/sodium chloride, calcium gluconate,
tion. Extravasation with liposomal encapsulated magnesium sulphate, mannitol infusions.
anthracyclines can be treated in a less aggressive 4). Total parenteral nutrition preparations (with
manner because no extensive tissue necrosis has yet osmolalities averaging 650 mOsm/L).
5). Ionic, high osmolality radiological contrast media.
Table 2. Indicative list of agents commonly involved in extravasation injuries (in alphabetical order) and their corresponding
pH values (BasePortal, 2012).
Ketamine 3.5–5.5
Prevention
Complete extravasation documentation and ill out a clinical incident
form as per trust guidelines
Staff should be trained in the insertion of cannulae,
and regional/national guidelines must be followed
for preparing, administering, and monitoring inject- Figure 3. Immediate generic steps in the management of
able medicines. Patients at increased risk of extrava- extravasation injuries.
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, helped draw the following conclusions: early excision
antecubital fossa/other periarticular areas, and the in chemotherapy extravasation is a valid option for
lower limb should be avoided. Multiple punctures in management; steroid injection is ineffective in pre-
a vein, especially moving more distally along the venting ulcer formation in adriamycin injuries, and
same vein, risks extravasation. When a number of prompt subcutaneous injection of hyaluronidase is
drugs are to be injected, vesicants should be admin- key in reducing necrosis caused by common extrava-
istered first and the patency of the cannula checked sation agents: calcium chloride, hyperalimentation
regularly. Drug infusions should be monitored by solution, adriamycin, and paclitaxel.
trained staff, and if infusion pumps are used, alarms
should be incorporated to monitor increased intralu-
A) Conservative management
minal pressure. New devices for the detection of
accidental infiltration into perivascular tissues such This is the first and often only step needed for extrava-
as the extravasation detection accessory (EDA) show sation injury management and it includes: (Kumar
a high sensitivity and specificity in detecting clini- et al., 2009; Langstein et al., 2002; Larson, 1982;
cally relevant extravasation (more than 10 ml) Pitkänen et al., 1983; Shenaq et al., 1996):
(Birnbaum et al., 1999).
a) Pain relief.
b) Application of ice: Commonly 15 min sessions
Immediate generic steps following four times daily for 3 days to decrease the spread
extravasation of drugs into adjacent tissues (via vasoconstric-
If extravasation is suspected, prompt action is needed, tion), slow down the cellular metabolic rate, and
as shown in Figure 3 (Schulmeister, 2000; 2009; 2011; deactivate the extravasated agent.
Loth and Eversmann, 1991). c) Dressings with serial assessment in the outpa-
tient clinic.
Definitive management options The rationale for conservative treatment is that only
There are a variety of strategies for treating extrava- 11–21% of extravasation injuries require surgery (Loth
sation injuries described in the literature based solely and Eversmann, 1991). A conservative approach can
on experience. The controlled animal experiments most importantly prevent inaccurate and insufficient
identified in the literature search (Coleman et al., tissue excision given the slow evolution of clinical signs
1983; Dorr et al., 1996; Laurie et al., 1984; Loth, 1986) in many injuries (Kumar et al., 2001). Corticosteroid
preparations (topical creams and subcutaneous injec- 2008). Its effectiveness has been confirmed in two
tions) feature in some protocols for chemotherapy clinical trials. It must be administered intravenously
extravasations (Tsavaris et al., 1990), but their use is not within 6 hours of the injury in an area away from the
supported either by controlled clinical studies or by extravasation with the following regimen: 1000 mg/
existing histological evidence (lack of florid inflamma- m2 on day 1 and 2, and 500 mg/m2 on day 3. The maxi-
tion in tissues affected by extravasation) (Coleman mum daily dose is 2000 mg. This is reduced by 50% in
et al., 1983; Heckler, 1989; Shenaq, 1996). patients with creatinine clearance <40ml/min (Kane
In radiological contrast media extravasations, the et al., 2008; Mouridsen et al., 2007).
recent switch to low osmolality, non-ionic contrast A number of early experimental animal studies have
media has resulted in a marked reduction in soft- shown encouraging results with topical antidotes in
tissue complications (Sbitany et al., 2010; Schaverien cytotoxic extravasations including n-acetylcysteine,
et al., 2008). Magnetic resonance agents are less vitamin C, basic fibroblast growth factor, and granulo-
likely to produce significant extravasation injuries, cyte macrophage colony stimulating factor (Hajarizadeh
given the markedly lower osmotic loads and admin- et al., 1994; Shamseddine et al., 1998; Vasilev et al.,
istered volumes compared with X-ray and computed 1992). These agents have not undergone evaluation in
tomography contrast agents (Bellin et al., 2002). The human studies, so cannot be recommended for inclu-
majority of extravasations involve small volumes sion in therapeutic protocols at present.
and symptoms tend to resolve without treatment
within 24 h (Cohan et al., 1996; 1997; Federle et al.,
C) Bedside intervention/ Surgical
1998; Jacobs et al., 1998; Sistrom et al., 1991). In a
management
large 6-year retrospective study of 40 000 CT scans,
102 extravasation injuries were treated successfully Bedside/surgical intervention can be categorized
with conservative therapy (Sbitany et al., 2010). according to the timescale following injury into:
Based on data analysis, the authors proposed an
extravasation volume of 150 ml as a cut-off to define a) Emergency: Compromise to the neurovascular
a high volume injury. A number of other studies have status of the limb or suspected compartment
agreed that extravasation of up to 150 ml of contrast syndrome.
can be treated conservatively (Cohan et al., 1990; b) Acute: Signs of imminent tissue necrosis, blister-
1997; Sistrom et al., 1991). However, the critical vol- ing, induration, and intractable pain.
ume of extravasant should be correlated to the posi- c) Time-independent intervention including sepsis,
tion of the affected site with sites below the elbow, established ulceration, patient’s desire not to
evidence of skin or neural compromise, large vol- undergo dressings or delayed secondary healing,
umes and possible compartment syndrome qualify- and interference with planned adjuvant therapy
ing for a plastic/hand surgery consultation (Sbitany (Fallscheer et al., 2007; Heckler, 1989; Larson,
et al., 2010). 1982; Loth, 1986; Pitkänen et al., 1983; Rudolph
and Larson, 1985; 1987; Shenaq et al., 1996).
B) Antidote administration
Subcutaneous hyaluronidase injection
Sodium thiosulfate is the first-line agent for the treat-
ment of extravasations with mechlorethamine, a Hyaluronidase breaks down hyaluronic acid, a normal
nitrogen mustard DNA binding vesicant. Its mecha- component of the interstitial fluid barrier and its use
nism of action is thought to rely on reduced produc- aims to aid agent dispersion into the surrounding tis-
tion of reactive alkylating species and hydroxyl sues. (Laurie et al., 1984). Current recommendations
radicals (Dorr et al., 1988). It is administered as a 1/6 suggest subcutaneous injection of 1 ml of hyaluroni-
molar solution (4 ml of 10% agent diluted with 6 ml dase (150 U/ml solution) per ml of extravasated agent
sterile water) injected into the injured area in 2 ml ali- in a clockwise manner to the affected area
quots for each ml of agent extravasated (Schulmeister, (Schulmeister, 2009). The effectiveness of hyaluroni-
2011). Mouse skin toxicity experiments have con- dase in reducing necrosis caused by calcium chloride,
firmed the need for urgent administration of the agent hyperalimentation solution, and adriamycin was inves-
with delays of more than 4 hours resulting in loss of tigated in a rabbit experiment. Immediate subcutane-
antidotal action (Dorr et al., 1988). ous injection with hyaluronidase produced a statistically
Dexrazoxane is an antidote used in anthracycline significant reduction in the area of necrosis (p = 0.01),
extravasations and it prevents the formation of free but only when used in the first hour from injury (p =
radicals by binding DNA topoisomerase II (Hasinoff, 0.01) (Laurie, 1984). In a similar mouse model
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.
employing paclitaxel, hyaluronidase reduced ulcer size within 24 h of injury healed with no soft tissue loss; 15
by 50% (p <0.05) (Dorr et al., 1996). In a cohort of 148 out of 52 patients presenting more than 24 h post-
patients with antineoplastic extravasations, hyaluroni- extravasation required extensive reconstruction (6
dase prevented ulceration in all cases (Heckler, 1989). 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
Saline flush out than 20 min after injury, 17 patients recovered sponta-
This method relies on dispersion of the noxious agent neously (Khan, 2002). This treatment was also suc-
via flushing saline into the extravasation area and the cessful in infants who had extravasation of parenteral
egress of irrigation fluid out through stab wounds in nutrition (Davies et al., 1994). A variation of saline
the surrounding skin. It is often used in conjunction washout was described in a case series using a single
with hyaluronidase and is ideally performed within 1–2 stab incision outside the affected area, infiltration of
hours of the injury. This technique was used by Gault in saline to produce swelling and induration beyond the
37 patients with subcutaneous infiltration of 1500 IU of extravasation area, and fluid aspiration using a 2 mm
hyaluronidase after local anaesthetic infiltration with cannula. No evidence of skin necrosis was noted in 13
1% lidocaine. Four stab incisions were then made patients undergoing this treatment at an average 345
around the periphery of the extravasation and a blunt- (range 140–795) min post-chemotherapy extravasation
tipped catheter or needle was used via one of the inci- (Steiert et al., 2011). D’Andrea et al. (2004) successfully
sions to flush 500 ml of saline through the subcutaneous used repeated saline infiltration into the extravasation
tissue and out via the other three incisions (Gault, area (without flushing or aspirating) to dilute chemo-
1993). Eighty-six percent of patients receiving treatment therapeutic agents with only three out of 229 patients
developing ulceration. Late washout may be effective, different skin grafting/flap techniques. The authors
so could still be considered even after days have passed advocated early surgical debridement of these injuries
after the injury (Dionyssiou et al., 2011). Figure 4a-e since the complications and morbidity secondary to
shows the steps employed for hyaluronidase infiltra- extravasation was considerable in the delayed treat-
tion and saline flushout in our institution. ment part of the cohort. Complications in the study
included sepsis, nerve compression, joint stiffness,
weakness as well as sympathetic dystrophy syn-
Squeeze technique dromes (Linder et al., 1983). In another clinical study,
In a series of eight patients with digital vascular com- 14 patients with extravasation from a variety of agents
promise due to extravasation of a high-volume (>50 were evaluated in terms of function and cosmesis for
ml) radiological contrast, the intravenous catheter an average of 8.4 (range 1–24) months. In the first
was removed and an 18 gauge needle used to create cohort of patients initially managed conservatively,
five to eight openings near the catheter insertion site. four out of five needed surgical intervention for skin
The extremity was then squeezed in a distal-to-proxi- necrosis and had poor functional and cosmetic out-
mal direction. Treatment was successful with imme- comes. The second cohort (nine patients) was treated
diate resolution of the vascular compromise in all with surgical debridement within 72 h if erythema,
cases (Tsai et al., 2007). This technique was modified severe pain, and blistering persisted despite local first
using a combination of liposuction, subcutaneous aid. Five patients underwent debridement with delayed
irrigation, and compression with a Rhys–Davies primary wound closure; only one had a poor outcome
exsanguinator to successfully treat a 100 ml contrast (Loth and Eversmann, 1991).
medium injury causing median nerve compromise
(Schaverien et al, 2008).
Liposuction
Under local or general anaesthesia, a small incision is
Surgical excision of the extravasation made alongside the area of extravasation. A blunt-
area and direct closure ended liposuction cannula with side holes is employed
A controlled animal experiment with adriamycin to aspirate the extravasated material and fat within
extravasation in rats compared the effect of the fol- subcutaneous channels as in conventional liposuc-
lowing three interventions: immediate excision and tion. In the original description of this technique, lipo-
closure, delayed (48hrs) excision and closure and suction was used either as an isolated modality or in
treatment with hydrocortisone injection. The results combination with the flush out technique (Gault, 1993).
revealed that all five rats treated with immediate exci- The latter strategy proved effective in a series of 11
sion and 4 out of 5 treated with delayed excision and patients with hyperosmolar contrast medium injuries;
closure healed with no necrosis at 7 days. The rats no cases of necrosis were reported in patients treated
treated with steroid injection developed ulcers, which within 2h of injury (Vandeweyer et al., 2000)
remained static at 16 days post extravasation (Coleman
et al., 1983). Another rat experiment examined early
minimal debridement in doxorubicin-induced skin Decision-making for the acute
ulcers. The debrided sites developed significantly management of extravasation injuries
smaller ulcers than those in the control animals. Given the vast array of agents capable of causing
Re-debridement of necrotic skin 1 week after the ini- extravasation injuries and the poor evidence base for
tial minimal debridement procedure produced a fur- management, we recommend that clinicians consider
ther significant decrease in ulcer size (Loth, 1986). the following principles to decide on an interventional
A clinical series examined direct excision of vesicant versus conservative management strategy.
chemotherapy extravasation in the upper limb of 10
patients. The average time from injury to excision was a) Non-agent–specific parameters (volume of extrav-
3 h 10 min (range 1 h 46 min to 4 h 40 min); at a 3 asant). If a significant volume of agent has extrav-
month follow-up, nine out of 10 patients showed no asated and results in significant pain, compression
evidence of necrosis (Telisselis et al., 2010). Another of neuromuscular structures, loss of skin circula-
retrospective case series analysed the clinical course tion and/or development of compartment syn-
of 40 patients with doxorubicin extravasation. The drome, emergency intervention is warranted.
cohort underwent a two stage treatment protocol with Treatment modalities include fasciotomies, exci-
debridement initially (ranging from 24hrs to 2 months sion of the affected tissue, and removal of the
following injury) and delayed closure with a variety of offending volume of extravasant either via the
Extravasation injury
Figure 5. Suggested algorithm for approaching the management options for extravasation injuries.
‘squeeze’ method (Tsai et al., 2007) or liposuction c) Necrosis interval of each individual presenta-
(Benson et al., 1996; Memolo et al., 1993; Pond tion. Consideration of the time elapsed between the
et al., 1992; Young, 1994). injury and clinical assessment is vital because most
interventions need to be performed within the ‘necro-
b) Agent-specific parameters (chemical ‘viru- sis interval’. Cases presenting past this timescale can
lence’). If the extravasation injury threatens tissues be managed conservatively in the absence of clear
by virtue of the chemical properties of the agent indications for surgery. Secondary surgery to debride
(vesicant, osmolar, pH, or vasoconstrictive), then the and close/cover wounds may be necessary.
majority of the extravasant should be removed or
neutralized. In the case of mechlorethamine and d) Patient-related issues. Patients’ preferences or
anthracycline injuries, antidotes should be consid- comorbidities may preclude surgery or the need for
ered if available, namely sodium thiosulfate and ongoing/adjuvant treatment (e.g chemotherapy) may
dexrazoxane, respectively (Dorr et al., 1988, Hasinoff, impose early intervention.
2008; Kane et al., 2008; Mouridsen et al., 2007). For
other vesicant chemotherapeutic drugs, hyaluroni- e) Facilities/expertise available in the particular health-
dase infiltration is effective (Bertelli et al., 1994; care environment. Given the wide range of treatment
Dorr et al., 1996; Heckler 1989; Laurie et al., 1984) modalities available for extravasation management, it
and therefore recommended as first-line treatment is important that early specialist referral is sought,
when no antidote is available. Although there are no especially in cases involving vesicant agents. The
studies proving an additional benefit of flush out as management plan needs to be tailored not only based
an adjunct to hyaluronidase injection, there are no on agent, timing, and patient-related factors, but on
reports of additional morbidity of this procedure, the resources and expertise available in the corre-
hence its joint adoption is recommended. Other sponding healthcare setting.
modalities that can be considered include excision of
the affected tissue or liposuction (Gault, 1993; Telis- A suggested algorithm for approaching the man-
selis et al., 2010). agement of extravasation injuries is shown in Figure 5.
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