INTRODUCTION — Extravasation refers to the escape of a drug into the extravascular space, either by leakage from a vessel or by direct infiltration. Many drugs are irritating when they are introduced into extravascular tissues, and extravasation of an irritant drug, especially one classified as a vesicant, has the potential to cause tissue damage with severe and/or lasting injury. Although the most well-known vesicants are cytotoxic chemotherapy drugs (table 1), many other non-antineoplastic drugs also have the potential for local toxicity if extravasation occurs (table 2).
The incidence, risk factors, clinical presentation, prevention, and management of extravasation injury from vesicants or irritants are reviewed here, with a focus on chemotherapy extravasation injury.
Venous irritation (chemical phlebitis) that occurs with drug administration into a vein that remains intact (eg, vinorelbine and epirubicin), and other cutaneous complications of chemotherapy are discussed elsewhere. (See "Catheter-related upper extremity venous thrombosis in adults", section on 'Phlebitis' and "Cutaneous adverse effects of conventional chemotherapy agents".)
INCIDENCE AND RISK FACTORS — Extravasation injury from vesicant/irritant drugs is best described with antineoplastic agents (table 1), but a number of other non-antineoplastic drugs can cause extravasation injury (table 2) [1-7]. It is important to note that even some nontoxic compounds can do harm if they are injected intra-arterially or extravasate into a muscle compartment, increasing the risk for acute compartment syndrome. (See "Pathophysiology, classification, and causes of acute extremity compartment syndrome" and "Acute compartment syndrome of the extremities".)
In addition to the specific drug itself, the properties of the drug solution may also contribute to the potential for injury. Infusates with pH values that are very low (<5.5) or very high (>8.5) pH are particularly harmful to tissues [8]. Similarly, infusion of hypo- or hyperosmolar agents (<281 or >289 mOsmol/L) can lead to significant tissue damage [8]. In clinical practice, injuries from hyperosmolar agents are more common. Such agents should be administered through a central venous access device (CVAD) rather than a peripheral venous access device. (See "Central venous access: Device and site selection in adults", section on 'Factors influencing catheter selection'.)
Vesicants versus irritants — Based on the severity of local toxicity if extravasated, cytotoxic chemotherapy drugs have been historically classified as vesicants or irritants [2,8,9]:
●Irritants – Irritants cause inflammation (warmth, erythema, tenderness) at the administration site and along the vein, but they rarely result in direct toxicity to the tissue (ie, necrosis) [10]. Some irritants can cause tissue necrosis if large volumes of concentrated solutions have extravasated. Drugs classified as irritants may be administered through a CVAD or peripheral venous access device. However, if the risk for injury is substantial in the setting of an extravasation, a CVAD is preferred.
●Vesicants – Extravasation of a vesicant drug has the potential to cause tissue necrosis (blistering, sloughing of tissue, and varying degrees of deep tissue damage) with a more severe and/or lasting injury than is typically seen with irritants because they are inherently toxic [10]. Chemotherapeutic vesicants are subclassified as non-DNA binding and DNA binding. Non-DNA-binding agents are metabolized and neutralized in the tissues, whereas DNA-binding drugs (eg, anthracyclines such as doxorubicin) set up a continuous cycle of tissue damage that is mediated by medication cellular DNA, resulting in more extensive injuries [8]. Anthracyclines are among the most important cytotoxic chemotherapy agents that cause extravasation injury because of their widespread use in various chemotherapy regimens and their tendency to produce severe tissue necrosis. Because of the risk for serious injury if extravasation occurs, any vesicant drug, particularly if it is administered as an infusion rather than a bolus, should preferably be administered via a CVAD rather than a peripheral venous access device [2,11]. (See "Central venous access: Device and site selection in adults", section on 'Factors influencing catheter selection'.)
For some cytotoxic chemotherapy agents, the distinction between vesicant and irritant chemotherapy drugs is not absolute. As examples:
●There are reports of severe tissue injury from extravasation of oxaliplatin [12,13], although another series of 11 patients showed no tissue destruction [14].
●Most injection site reactions following extravasation of paclitaxel consist of redness, tenderness, and swelling, but there are case reports that document necrosis and skin exfoliation [15-18]. However, only rarely are long-term sequelae reported, such as ulceration requiring surgical intervention [19]. In a compilation of 35 reported cases of paclitaxel extravasation, only three developed ulceration, two requiring skin closure [15]. Although most references classify paclitaxel as an irritant drug, the Oncology Nursing Society (ONS) and Multinational Association of Supportive Care in Cancer (MASCC) classify it as a vesicant [20,21].
●Mitoxantrone, usually classified as an irritant, has been reported to cause skin necrosis requiring surgical debridement and skin grafting [22].
●Ado-trastuzumab emtansine, an antibody-drug conjugate that consists of the anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab conjugated to emtansine, a highly cytotoxic antimicrotubule agent, has been classified as an irritant; however, a single case report of skin necrosis following subcutaneous extravasation has been reported [23].
●Enfortumab vedotin, a nectin-4-directed antibody and microtubule inhibitor drug conjugate that is approved for advanced refractory urothelial cancer, has been associated with skin and soft tissue reactions secondary to extravasation (1.3 percent of 310 treated patients) [24]. Some of the extravasation reactions were associated with secondary cellulitis, bullae, or exfoliation. However, whether this drug causes deep tissue damage is uncertain.
In such cases, the extent of tissue injury may be a function of the amount of drug extravasated.
Incidence — The true incidence of chemotherapy vesicant extravasation is unclear because there is no central reporting mechanism. Similarly, with overall poor reporting, the incidence of extravasation of nonneoplastic vesicant medications is largely unknown [1,25].
With an increasing awareness of the risks of extravasation, the frequency of chemotherapy-related extravasation appears to have fallen. Data from MD Anderson Cancer Center indicate that the rate of serious extravasation injury (as determined by referral patterns to a plastic surgery clinic) declined from 0.1 to 0.01 percent over a 15-year period, based on individual doses of chemotherapy administered [26]. However, this series only included patients who were referred to plastic surgery, rather than all extravasations, whereas the denominator included all individual doses of chemotherapy delivered over the six-year study period. As such, this rate probably underestimates the true incidence of chemotherapy extravasation injury. Furthermore, this rate may not reflect the actual rate in other clinical settings. In an older review, infiltration and extravasation injuries to the soft tissue were noted to be more common, occurring in up to 6 percent of patients [27].
Infusional administration of vesicant antineoplastic agents is frequently done through a CVAD to minimize the likelihood of venous injury and the consequences of any subcutaneous extravasation. Although the risk of chemotherapy extravasation through a CVAD is small, it is not zero. Extravasation in this setting may be due to injection technique or device failure:
●In a single-center report of 376 patients receiving high-dose chemotherapy and peripheral blood stem cell transplantation through a totally implanted port device over a five-year period, there was one case of extravasation (0.26 percent) [28].
●Another series noted three extravasations in 225 CVADs (various tunneled catheters, implanted ports) implanted in 217 patients over an 11-year period (1.3 percent) [29].
●A third report noted 15 cases of drug extravasation among 815 consecutive cancer patients (1.8 percent) who received chemotherapy with a totally implanted port over a one-year period, not all of whom were receiving vesicants [30].
Risk factors — As noted above, every patient who receives a vesicant is at risk for extravasation. (See 'Vesicants versus irritants' above.)
Risk factors for extravasation from a CVAD include the following [31-33]:
●Difficulty encountered during insertion of the device, such as probing or inability to advance the guidewire or catheter. With improper technique, catheters can also become inadvertently damaged, before or during insertion, or malpositioned.
●Catheter migration from the vein into the tissue.
●Long dwell time (six months or longer); soft catheter materials are prone to weakening and "pinch off" syndrome, which occurs when the catheter is compressed between the clavicle and the first or second rib.
●The presence of a fibrin sheath or thrombus at the catheter tip, which may cause vesicant chemotherapy to backtrack along the catheter and leak from the vein at the access site.
●A deeply implanted port device increases the risk that the length of an access needle will not be sufficiently long to be correctly positioned into the port septum, or that patient movement will cause "rocking" of the needle within the port septum.
Other risk factors for extravasation from a peripheral vein include the following [32,34,35]:
●Small and/or fragile veins, or limited vein availability. (See 'Prevention' below.)
●Obesity, which may increase the difficulty of establishing intravenous access or contribute to dislodgment of a catheter.
●Sclerosed veins due to multiple prior chemotherapy courses or numerous venipunctures.
●Patient movement, particularly if the intravenous catheter is placed near a joint.
●Cognitive or neurologic deficits that impair a patient's ability to sense or react to pain at the site of chemotherapy administration can increase the risk of extravasation, even in the setting of continuous supervision.
●Prolonged infusion duration.
●Bolus infusion (eg, power injectors for radiocontrast media).
●Use of winged steel infusion devices ("butterfly needles").
MANIFESTATIONS — Early symptoms and signs of extravasation injury are often subtle. They usually appear immediately after the extravasation but can be delayed for days to weeks [36]. Initially, there is local burning or tingling at the infusion site, mild erythema, pruritus, and swelling. Within two to three days, increased erythema, pain, brawny discoloration, induration, dry desquamation, and/or blistering may appear [37]. With a small volume of extravasation, symptoms may disappear over several weeks. With more extensive infiltrations, necrosis, eschar formation, and ulceration with raised, red, painful edges and a yellow necrotic base may develop over several weeks. The severity of an extravasation injury can be divided into five grades, as outlined in the table (table 3).
●An extravasated irritant drug causes a local inflammatory reaction, with aching, burning, tightness, pain, and phlebitis at the needle insertion site or along the vein. Clinical signs include warmth, erythema, and tenderness in the extravasated area, without tissue sloughing or necrosis. Symptoms are usually of short duration with no long-lasting sequelae.
●Extravasation of vesicants can produce local tissue necrosis both within and outside the venous system [8]. This may result in full-thickness loss of the skin and, if severe, underlying structures. Vesicant-induced ulcerations lack granulation tissue and have little epithelial ingrowth. Although very small ulcers typically heal gradually, larger lesions tend to persist, gradually expanding over time. If left untreated, underlying tendons, nerves, and vessels may be destroyed, potentially leading to nerve compression syndromes, permanent joint stiffness, contractures, and neurologic dysfunction [36].
●When extravasation occurs from a central venous access device, the extravasated solution may accumulate in the subcutaneous tissues near the catheter exit site, leading predominantly to pain in the neck, anterior chest, or groin. However, the extravasated solution can also accumulate in the mediastinum or pleural space.
There have been reports of an extravasation recall phenomenon, where previous sites of extravasation of a vesicant drug become inflamed upon re-exposure of the patient to the same drug administered at a remote intravenous site. This phenomenon has been reported with paclitaxel [38-40], docetaxel [41,42], doxorubicin [43,44], and epirubicin [45].
IMAGING — Peripheral extravasation injuries are best assessed and followed with clinical examination. In select cases, imaging (eg, ultrasound) can help quantify the volume and determine the peripheral margins of the extravasation.
For patients with suspected extravasation from a central venous access device, a chest radiograph should be obtained to evaluate the positioning of the catheter/port and the location of the catheter tip once the infusion is stopped. (See 'Initial measures' below.)
If plain radiography is suspicious for extravascular catheter migration, a computed tomography (CT) scan should be obtained. Apparent extravascular catheter tip migration requires immediate attention. (See 'Surgical referral' below and 'Central venous catheter malfunction' below.)
The extent of extravasation can be initially evaluated with cross-sectional imaging, typically with a CT scan of the chest (internal jugular, subclavian venous access) or abdomen/pelvis (femoral venous access). An alternative is ultrasound, which also assesses the underlying vein (eg, extrinsic compression causing deep vein thrombosis). During the follow-up period, B-mode ultrasound can be used to follow for resolution of the fluid collection or development of complications (eg, subcutaneous abscess).
If the catheter tip is properly positioned and there are no large fluid collections, fluoroscopy with administration of dilute intravenous contrast can help to localize any malfunction in the catheter. (See 'Surgical management' below.)
All patients with suspected mediastinal extravasation should undergo an initial CT scan of the chest; follow-up imaging can be performed with standard chest radiographs.
SURGICAL REFERRAL — Although conservative management resolves many extravasation injuries without the need for surgical intervention, appropriate referral (eg, general surgery, thoracic surgery, vascular surgery, plastic surgery) is important for facilitating planning, particularly under the following circumstances [2] (see 'General care' below and 'Surgical management' below):
●Significant subcutaneous extravasation with a collection-exerting mass effect (skin ischemia, venous compression)
●Extravasation into the chest (eg, pleural cavity, mediastinum)
●Central venous catheter malfunction (disconnect, migration, perforation)
The European Oncology Nursing Society (EONS) guidelines recommend urgent surgical consultation for possible incision and surgical drainage of accumulated subcutaneous fluid collections.
GENERAL CARE — General care of suspected extravasation is discussed in the following sections. An overview of our recommended approach to the management of chemotherapy extravasations (including the use of specific antidotes), which follows the general guidelines of the Oncology Nursing Society (ONS) and European Oncology Nursing Society (EONS), is summarized in the table (table 4) and discussed in further detail below. (See 'Specific antidotes' below.)
Initial measures — When extravasation of an irritant or vesicant drug is suspected (peripheral or central venous access), the following initial management is recommended [2,20,46,47]:
●Stop the infusion immediately. Do not flush the line, and avoid applying pressure to the extravasated site.
●For peripheral sites (peripheral cannula, midline) and peripherally inserted central catheters, elevate the affected extremity.
●Do not remove the catheter/needle immediately. Instead, it should be left in place to attempt to aspirate fluid from the extravasated area and to facilitate the administration of an antidote to the local area, if appropriate. Whether aspiration is effective with a central venous access catheter is uncertain, but this can be tried. (See 'Specific antidotes' below.)
●If an antidote will not be injected into the extravasation site, the peripheral catheter/needle can be removed after attempted aspiration of the subcutaneous tissues. The handling of central venous access devices (CVADs) is discussed below. (See 'Local tissue injury' below.)
For extravasations into the chest, initial conservative management is reasonable, including antimicrobial therapy, pain control, and supplemental oxygen, provided there is no evidence of suppurative mediastinitis or empyema [48,49]. Antipyretics should be considered since fever is reported in 80 percent of chest extravasation cases [48]. If imaging demonstrates significant fluid collection, drainage may be needed. (See 'Imaging' above and 'Mediastinal extravasation' below.)
Application of cold or heat — Topical application of ice or cold packs is recommended for extravasation of most vesicant or irritant drugs, with the exception of the vinca alkaloids (vincristine, vinblastine, vinorelbine) and epipodophyllotoxins such as etoposide.
Intermittent cooling is thought to cause vasoconstriction, thereby diminishing the spread of the drug and the extent of the local injury [50]. Cold compresses also reduce local inflammation and pain. Efficacy of cold application was suggested in a series of 175 patients with extravasation of a variety of chemotherapeutic agents, in which close to 90 percent of those treated with ice alone (15 minutes four times daily for three days) required no further therapy [51].
For extravasations of vinca alkaloids or epipodophyllotoxins, application of ice is contraindicated, as cold worsens the skin ulceration caused by these drugs, at least in animal models [50,52]. Heat is generally recommended for these agents, although most of the available data are derived from animal studies rather than clinical reports. Local heating is thought to result in localized vasodilation and increased blood flow, thereby enhancing the early, distributive phase of drug removal [52].
For taxanes, the choice between heat and cold is less clear:
●For paclitaxel extravasations, some guidelines suggest the application of ice [15,20], although EONS/European Society for Medical Oncology (ESMO) guidelines suggest application of heat in this setting because the taxanes, similar to the vinca alkaloids, are non-DNA-binding agents and the general strategy for these types of extravasations is to dilute and diffuse [2]. Aside from extravasation recall phenomena, the long-term effects of paclitaxel extravasation are minimal and usually entail mild fibrosis around the extravasation site.
●Skin toxicity, including desquamation following accidental extravasation, is more frequent with docetaxel than paclitaxel, although serious long-term sequelae have not been described. The relative benefit of topical cooling for docetaxel extravasations is less clear than for paclitaxel; some (including the EONS) suggest that heat rather than cold be applied in such cases [2,53].
Specific antidotes — There are no randomized trials that have established the role of specific interventions in the management of chemotherapy extravasation [54,55]. Information regarding treatment for chemotherapy extravasation is largely based on animal models, anecdotal case reports, and a limited number of small uncontrolled studies [55]. Furthermore, evaluation of the published data on treatment of extravasation injury in humans is difficult owing to the variability in methods and treatment endpoints, and the confounding influence of nonpharmacologic therapy (ie, the application of cold or heat).
Guidelines for management of chemotherapy extravasation are available from the ONS and EONS [2,20]. The ONS standards were initially developed in 2009 [56] and were reiterated in 2011 and 2013 with little, if any, change [57,58]. The use of a standardized protocol will allow most extravasations to be managed conservatively, thereby minimizing the need for surgical intervention [59].
Following peripheral extravasation of certain drugs, specific antidotes have been recommended to prevent necrosis and ulceration, although none of these has been validated in randomized clinical trials (table 4). These include the following:
●Systemic administration of dexrazoxane following anthracycline extravasation. (See 'Dexrazoxane' below.)
●Local injection of sodium thiosulfate for extravasations of mechlorethamine, dacarbazine, and cisplatin. (See 'Sodium thiosulfate' below.)
●Local injection of hyaluronidase for extravasations of vinca alkaloids, paclitaxel, epipodophyllotoxins, and ifosfamide. (See 'Hyaluronidase' below.)
●Topical application of dimethyl sulfoxide (DMSO) for anthracycline extravasation when dexrazoxane is not immediately available. A single, subcutaneous, local injection of DMSO for mitomycin extravasation, followed by topical application [34]. (See 'Dimethyl sulfoxide' below.)
●For other drugs (eg, trabectedin [60]), there are no specific published antidotes [61].
For extravasation of chemotherapy agents from CVADs, intravenous dexrazoxane can be considered as an antidote if the extravasated agent is an anthracycline. However, the utility of other local antidotes (hyaluronidase, sodium thiosulfate) is unclear, and their use is not recommended in guidelines from the EONS [2,20].
Dexrazoxane — Dexrazoxane has been approved by both the European Agency for the Evaluation of Medicinal Products (EMEA) and the US Food and Drug Administration (FDA) for the treatment of anthracycline extravasation injury. Treatment should be started as soon as possible and within the first six hours after extravasation.
A benefit for dexrazoxane after anthracycline extravasation was initially suggested in animal studies and isolated case reports [62-65]. Dexrazoxane was subsequently evaluated in a review that included two multicenter studies involving patients with presumed anthracycline extravasations [66]. Dexrazoxane was administered intravenously as three one- to two-hour infusions through a different venous access location, with the first dose given within six hours of the actual extravasation, and subsequent doses administered 24 and 48 hours after extravasation. The first and second doses were 1000 mg/m2, and the third dose was 500 mg/m2, up to maximum total doses of 2000, 2000, and 1000 mg, respectively. Extravasation was confirmed by fluorescence microscopy of a biopsy specimen in 54 cases. Only one patient (2 percent) who received therapy within six hours after the event required surgical debridement. The most frequent sequelae of the extravasations were mild pain and sensory disturbances (19 and 17 percent, respectively). Chemotherapy was able to be continued without interruption in 71 percent of cases.
Extravasation of liposomal anthracycline preparations (daunorubicin or doxorubicin) is generally not associated with necrotic injury [67,68]. Application of ice alone to reduce local inflammation (and avoidance of DMSO) is recommended (table 4). However, for the rare patient who develops symptomatic extravasation of pegylated liposomal doxorubicin, dexrazoxane may be beneficial [69,70].
Sodium thiosulfate — Local injection of a freshly prepared 4 (1/6 Molar) or 2 percent solution of sodium thiosulfate (2 mL for each mg thought to be extravasated) is recommended for the treatment of mechlorethamine (nitrogen mustard) extravasations, as well as for large-volume extravasation of concentrated dacarbazine or cisplatin (table 4) [20,47,71]. The solution is injected subcutaneously into the extravasated site using a separate 25 gauge or smaller needle.
To make a 4 percent solution:
●If using 10 percent sodium thiosulfate, mix 4 mL with 6 mL of sterile water for injection.
●If using 25 percent sodium thiosulfate, mix 1.6 mL with 8.4 mL of sterile water for injection.
The recommendation for use of thiosulfate is based largely on in vitro data demonstrating an interaction of thiosulfate with both cisplatin and mechlorethamine, and in vivo animal data demonstrating the ability of thiosulfate to inactivate mechlorethamine [72-76].
The clinical benefit of thiosulfate in patients with mechlorethamine extravasation is poorly documented, with one report demonstrating protection from ulceration in a single patient who received an inadvertent intramuscular injection [77]. Nevertheless, both the ONS and EONS recommend the use of sodium thiosulfate for mechlorethamine extravasation despite the lack of conclusive evidence of benefit [2,20].
In addition, sodium thiosulfate has also been suggested for extravasations of bendamustine (a mechlorethamine derivative that usually acts as an irritant but can cause local tissue injury if extravasated) [32]. However, neither the ONS nor EONS has addressed the issue of sodium thiosulfate with this drug [2,20].
Clinical efficacy of sodium thiosulfate in patients with extravasation of other agents was suggested in a series of 63 patients who had received doxorubicin, epirubicin, vinblastine, or mitomycin C [71]. One-half were treated with hydrocortisone and dexamethasone alone, whereas the remainder also received sodium thiosulfate (2 percent solution injected subcutaneously). No patient in either group developed skin ulceration or required surgery. The mean healing time for the group receiving thiosulfate was one-half that of the other group, although the lack of randomization in treatment assignment rendered this result inconclusive.
Hyaluronidase — For extravasations of vinca alkaloids, paclitaxel, and docetaxel, we suggest local injection of hyaluronidase. While the EONS suggests the use of hyaluronidase for extravasations of taxanes and vinca alkaloids [2], guidelines for treatment of extravasation from the ONS recommend hyaluronidase only for extravasations of vinca alkaloids, not other agents [20].
The proteolytic enzyme hyaluronidase promotes the diffusion of subcutaneously injected solutions by hydrolyzing hyaluronic acid, one of the chief ingredients of the connective tissue stroma. It is postulated that this creates a wider surface for dilution and aspiration of the drug.
The evidence supporting the use of local infiltration with hyaluronidase for extravasations of these chemotherapy agents is based on small series and case reports [2,15,78]. In one published study of six patients with extravasation of a vinca alkaloid (vinorelbine, vinblastine, or vincristine), pain resolved within several days of the extravasation in all six without the application of cold compresses [78]. A review of reports of treatment of paclitaxel extravasation found inconsistent results with hyaluronidase [15]. In a series of four cases (two managed with cold compresses with hyaluronidase injections around the extravasated area, and two treated with cold compresses alone), the use of hyaluronidase was associated with delayed healing. In contrast, in another small series, there was a complete disappearance of local symptoms (pain, erythema, swelling) with the use of hyaluronidase for a paclitaxel extravasation in five patients.
Single case reports also support potential benefit with extravasations of phenytoin [79], nafcillin [80], and other compounds, such as mannitol and high concentrations of dextrose [78,81-84].
Preparations of hyaluronidase are commercially available, but they have not been approved for this indication (ie, off-label use). The recommended dose is 1 mL (150 units) infiltrated subcutaneously, as five separate injections of 0.2 mL each, into the extravasated site along the leading edge of the erythema using a separate 25 gauge or smaller needle.
Dimethyl sulfoxide — Guidelines for extravasation management from the ONS do not include DMSO [20], and even the manufacturers' package labeling information fails to recommend its use for anthracycline or mitomycin extravasations. DMSO was also not included in the recommended treatments for extravasation in 2012 guidelines from ESMO/EONS [2]. However, a subsequent letter to the editor by the author of these guidelines seemed to reverse this position, stating that although the studies with dexrazoxane reflected a slightly superior level of evidence than those with DMSO, both treatments could be considered for the treatment of an anthracycline extravasation through a peripheral line [85].
In our view, DMSO (where available) represents an acceptable treatment for mitomycin extravasation, and an alternative to dexrazoxane for peripheral anthracycline extravasations if dexrazoxane is unavailable or cannot be started within six hours of the actual extravasation event (table 4). There is no evidence that combined use of dexrazoxane and topical DMSO is of any benefit in patients with anthracycline extravasations. (See 'Dexrazoxane' above.)
The evidence supporting the use of DMSO comes from two observational studies in patients with chemotherapy extravasations, both of which used topical administration:
●In the largest series, 144 patients with chemotherapy extravasation of a variety of drugs received topical DMSO (application of a 99 percent solution every eight hours for seven days) plus local cooling therapy (60 minutes every eight hours for three days) [86]. The authors reported complete recovery within one week in 103 patients (71 percent), whereas 22 others recovered with more prolonged DMSO therapy (total success rate 87 percent). Ulceration developed in a sole patient with epirubicin extravasation. Interpretation of these results is difficult because of the combined use of both DMSO and topical cooling. Furthermore, only 62 extravasations were due to known vesicants (doxorubicin, mitomycin, epirubicin), while the remainder involved irritant rather than vesicant drugs (cisplatin, ifosfamide, mitoxantrone).
●Benefit for DMSO independent of cold application in patients with anthracycline extravasation was also suggested in a prospective series in which 0 of 20 patients who received topical DMSO (99 percent solution every six hours for 14 days) developed ulceration or required surgical management [87].
The mechanism underlying benefit from DMSO is uncertain. DMSO has activity as a free radical scavenger, and at least some data support the view that tissue damage from vesicants (particularly anthracyclines) is caused by the formation of hydroxyl free radicals [88,89]. The two studies cited above both used a DMSO concentration of >90 percent, which is not available in the United States. The only available preparation is a 50 percent solution, which is marketed for intravesical use.
Role of glucocorticoids — Glucocorticoids are presumed to reduce local inflammation, but it has never been shown that tissue damage from vesicant extravasation is the result of an inflammatory process. In general, glucocorticoids are not indicated in the management of vesicant extravasations, with the possible exception of large-volume extravasations of oxaliplatin. This position is consistent with recommendations from the ONS and EONS [2,20]. Glucocorticoids may worsen the skin damage from etoposide or vinca alkaloids, and they are specifically contraindicated in these situations.
Oral glucocorticoids may be of benefit in patients who have extravasated large amounts of oxaliplatin. In one series of five patients, the early administration of high-dose oral dexamethasone (8 mg twice daily for up to 14 days) appeared to have a beneficial effect on the severity and clinical course of the inflammatory reaction [14].
For patients with anthracycline extravasation, systemic, subcutaneous, and intradermal administration of glucocorticoids at the extravasation site has been advocated in the past, although whether there is benefit for this approach is unclear. Interpretation of the published literature is confounded by variability in the dose and duration of therapy, route of administration, and outcome measures [36].
The lack of consensus on the benefit of glucocorticoids for anthracycline extravasation is illustrated by the product labeling information from two of the three suppliers of doxorubicin, daunorubicin, and idarubicin, which does not recommend glucocorticoids as a component of extravasation management.
Catheter retention versus removal — Following the administration of any antidotes or saline irrigation, peripheral intravenous catheters are removed. Significant injuries may require surgical management. New intravenous access will need to be established at a site away from the injury. (See 'Local tissue injury' below and 'Establishing new venous access' below.)
Whether to remove a CVAD depends on the extent of extravasation and the severity of symptoms:
●If symptoms related to extravasation are minimal, alternative access sites are limited, and a catheter malfunction was identified, the catheter/port may be amenable to repair or replacement at the same site. Once the symptoms are resolved, use of the catheter/port can be resumed.
●However, if symptoms or signs are more serious (eg, severe or persistent pain, exposure of the catheter or port device) or significant fluid accumulation causing blistering or tissue ischemia has occurred, removal of the CVAD is not likely to be avoided. If the extravasation is detected early, the CVAD should be removed during intraoperative subcutaneous washout to help minimize ongoing exposure of the tissues to the extravasated agent and to reduce the risk of tissue necrosis. For more severe cases, surgical management includes debridement of all necrotic material and wound irrigation and may require skin or soft tissue coverage [90]. (See 'Local tissue injury' below and 'Establishing new venous access' below.)
SURGICAL MANAGEMENT — Surgical intervention is required to manage tissue necrosis and provide skin/soft tissue coverage in the event of loss, as well as to manage issues related to central venous catheter malfunction. The available data regarding surgical intervention for extravasation from a central venous access device are sparse and come from case reports [17,90-92].
Local tissue injury — Indications for surgical exploration include development of infection (cellulitis, abscess, bacteremia/sepsis), progression of the radiographic abnormalities concurrent with clinical deterioration, or clinical deterioration (tissue necrosis) even if radiographic imaging appears to be improved. Surgical debridement is also recommended for failure of response to general care measures with unresolved local tissue injury (ischemia, necrosis) or pain lasting more than 10 days [2]. Whether local surgical intervention is necessary in a patient complaining of persistent pain in the presence of normal-looking skin is unclear. (See 'General care' above.)
Full-thickness tissue necrosis and nonhealing skin ulcers resulting from an extravasation injury require debridement and skin closure, which may require skin grafting or flap coverage. However, the optimal timing of surgical intervention is controversial. Although some clinicians suggest early surgical intervention to prevent ulceration [37,93], a conservative approach is more often recommended [27,46,94-97], particularly because fewer than one-third of vesicant extravasations ultimately result in ulceration. Failure of initial conservative management with continued erythema, swelling and pain, or the presence of large areas of tissue necrosis or skin ulceration is an indication for surgery [94,98].
Deep partial-thickness (wounds extending through the epidermis and into the deep dermis) or full-thickness (wounds extending through the entire dermis) skin defects can be closed with split- or full-thickness skin grafts, depending on the area of the body that is involved and the defect size. Larger defects typically require split-thickness skin grafts (most commonly harvested from the anterior thigh), given the paucity of full-thickness skin graft donor sites (most commonly harvested from the inguinal crease or lower abdomen). Full-thickness grafts are preferred for highly important functional and aesthetic areas of the body, such as the hands and face, respectively. Graft take may be poor in areas of extravasation if debridement is incomplete and a healthy, vascularized wound base is not present. (See "Skin autografting".)
Deeper injuries that have exposed the underlying tendons or bones require closure with a well-vascularized tissue flap, as a skin graft will not take on these poorly vascularized tissues. Local, regional, or distant free flaps can be used. Local options may be limited due to tissue damage from the extravasation, which can compromise the local blood supply and cause fibrosis of the surrounding tissue. Flaps bring their own blood to the area of reconstruction and can improve the vascularity of the damaged area. Prior to performing a free flap, an arteriogram is recommended to ensure that the recipient blood vessels near the site of the extravasation are patent and available for use. (See "Overview of flaps for soft tissue reconstruction".)
Central venous catheter malfunction — Central venous catheter malfunction can occur under a number of circumstances, some of which can result in extravasation injury. In addition to managing the local effects of the extravasated fluid, the catheter itself needs to be addressed.
Catheter malfunction can result from a catheter that is disrupted (torn, disconnected [eg, port separated from catheter]), that has become malpositioned such that one of the infusion holes is no longer intravascular, or that has perforated the vessel such that the tip of the catheter no longer resides in a vessel. (See "Routine care and maintenance of intravenous devices".)
For central venous catheters that have migrated out of the vessel, the catheter should be removed under controlled circumstances, and the site should be evaluated for bleeding. Endovascular or open surgical management may be needed depending on the location of the vascular injury. (See "Vascular complications of central venous access and their management in adults".)
Mediastinal extravasation — Conservative management of chest extravasations is usually sufficient, but drainage or more extensive procedures may rarely be necessary. Removal or retention of the catheter depends on the extent of extravasation and the severity of symptoms.
While extravasation injuries can cause severe tissue damage and necrosis of the skin and subcutaneous tissue, the extent of damage to mediastinal or pulmonary structures tends to be more limited. The serous layers of the mediastinum are likely protective against damage from extravasation [48]. Antibiotics, analgesics, and pleural drainage (ie, thoracostomy tube) are typically sufficient.
Depending on the area of involvement and the agent, mediastinoscopy or thoracoscopy can be used to assess the severity of the extravasation and the potential need for surgical debridement (eg, video-assisted thoracoscopic surgery [VATS], open thoracotomy if VATS is not possible), but this is uncommonly needed [48]. (See "Overview of minimally invasive thoracic surgery".)
Outcomes following thoracic extravasation are overall very good; complications and long-term thoracic sequelae are rare.
ESTABLISHING NEW VENOUS ACCESS — For patients in whom the access catheter required removal, replacement should be well away from the site of extravasation. All patient factors, the events leading up to the extravasation, and the ongoing need for the intravenous agent should be assessed.
When full-thickness tissue necrosis is present and requires reconstruction with a skin graft or soft tissue flap, it is almost certain that the subcutaneous veins in the area have been severely damaged. In most cases, there will not be any remaining superficial veins present at the site of the skin graft or flap to permit future intravenous line placement. Alternative sites can be chosen using ultrasound guidance. Central venous access may be preferred for the new access following a peripheral extravasation. (See "Principles of ultrasound-guided venous access" and "Peripheral venous access in adults" and "Central venous access: Device and site selection in adults".)
PREVENTION — The best approach to extravasation injury is prevention [31]. Guidelines for preventing chemotherapy extravasation are available from the Oncology Nursing Society (ONS) and the European Oncology Nursing Society (EONS) [2,20]. Several simple precautions can minimize the risk of extravasation:
●For peripheral infusions of chemotherapy, the vein selected should be large and intact, with good blood return established prior to starting the infusion.
●The patency of the intravenous line should be verified just prior to drug infusion by flushing with 5 to 10 mL of isotonic saline or a 5 percent dextrose solution.
●Peripheral infusion sites should be selected in the following order of preference: forearm (basilic, cephalic, and median antebrachial), dorsum of hand, wrist, and antecubital fossa. Vesicants should not be infused through veins in the antecubital fossa or dorsum of the hand. With irritants, try to avoid the antecubital fossa, wrist, and dorsum of the hand, if at all possible, because extravasation in these regions can cause serious long-term morbidity.
●Sites with sclerosis, thrombosis, or scar formation should be avoided, as should limbs with impaired circulation. Previously irradiated areas should be avoided whenever possible.
●The butterfly needle or plastic cannula should be secured to the skin with tape. Taping of the entry site itself should be avoided so that the area can be examined. Instead, once the hub of the cannula or butterfly needle is secured to the skin with tape, a clear dressing, such as Tegaderm, should be applied to cover the skin entry site.
●Instruct the patient to notify a clinician immediately if he or she experiences any pain, leaking, or other changes in sensation at the infusion site. For patients with central venous catheters, this may include chest pain or dyspnea from pleural effusion if the tip should penetrate the superior vena cava. Ensure that barriers to effective communication are minimized.
●The chemotherapeutic agent, appropriately diluted, should be infused through the side arm of the freely flowing intravenous line with isotonic saline or 5 percent dextrose. During the infusion, patients should be closely monitored for pain (often described as mild to severe burning radiating along the vein), and the site should be inspected for erythema or swelling [34].
●Use of a central venous catheter for infusion of vesicant drugs provides reliable venous access, high flow rates, and rapid drug dilution. However, extravasation can occur [91]. Following placement, the position of the catheter should be confirmed prior to drug administration. In addition, if there are any complaints of pain, even without soft tissue swelling or lack of ability to draw blood or infuse a flush solution, the position of the catheter should be assessed prior to continuing with the chemotherapy infusion. (See 'Risk factors' above and "Central venous access: General principles", section on 'Confirming catheter tip position'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of symptoms and toxicities of anticancer therapy".)
SUMMARY AND RECOMMENDATIONS
●Proper infusion technique is the most important component of preventing extravasation injury from chemotherapy and other nonneoplastic vesicants. (See 'Prevention' above.)
●If extravasation of a vesicant agent is suspected, initial management should focus on minimizing the extent of drug extravasation (see 'General care' above):
•Stop the infusion immediately. Do not flush the line, and avoid applying pressure to the extravasated site.
•Elevate the affected extremity.
•Do not remove the catheter/needle immediately. Instead, it should be left in place to attempt to aspirate fluid from the extravasated area and to facilitate the administration of an antidote to the local area, if appropriate. (See 'Specific antidotes' above.)
•If an antidote will not be injected into the extravasation site, the catheter/needle can be removed after attempted aspiration of the subcutaneous tissues.
•Once the wound has been irrigated and/or an antidote has been administered, the peripheral intravenous catheter should be removed and replaced, as needed, at a site remote from the site of extravasation.
●Specific therapies include the following:
•For extravasations of vesicant agents other than the vinca alkaloids and etoposide, we suggest topical application of cold (table 4) (Grade 2C). For the vinca alkaloids and etoposide, we suggest application of heat rather than cold (Grade 2C). (See 'Application of cold or heat' above.)
•For extravasations of anthracyclines that have a high likelihood of producing tissue ulceration (ie, nonliposomal preparations), we recommend systemic administration of dexrazoxane (Grade 1B). Liposomal anthracyclines are generally not associated with necrotic injury, and treatment with dexrazoxane is generally not indicated in this situation. (See 'Dexrazoxane' above.)
•For extravasations of oxaliplatin, we suggest administration of high doses of oral glucocorticoids (dexamethasone 8 mg twice daily for up to 14 days) (Grade 2C). (See 'Role of glucocorticoids' above.)
•For extravasations of mechlorethamine, bendamustine, dacarbazine, or cisplatin, we suggest local injection of sodium thiosulfate (Grade 2C). (See 'Sodium thiosulfate' above.)
•For extravasations of the vinca alkaloids and taxanes (paclitaxel, docetaxel), we suggest local injection of hyaluronidase (Grade 2C). (See 'Hyaluronidase' above.)
•The optimal approach to local therapy for extravasation of nonneoplastic vesicants is unclear, and there are no guidelines. Although the available data are limited to case reports with a few drugs (ie, nafcillin, phenytoin, mannitol, high concentrations of dextrose), local injection of hyaluronidase represents a reasonable approach. (See 'Hyaluronidase' above.)
●There are no uniform guidelines for the surgical treatment of extravasation injuries. General care follows the basic principles of wound management. Indications for surgical exploration include development of infection (cellulitis, abscess, bacteremia/sepsis), progression of the radiographic abnormalities concurrent with clinical deterioration, or clinical deterioration (tissue necrosis) even if radiographic imaging appears to be improved. Surgical debridement is also recommended for failure of response to general care measures with unresolved local tissue injury (ischemia, necrosis) or pain lasting more than 10 days. (See 'Surgical referral' above and 'Surgical management' above.)
●For patients with suspected extravasation from a central venous access device, once the infusion is stopped, a chest radiograph should be obtained to evaluate the position of the catheter/port and the location of the catheter tip. The extent of extravasation can be evaluated with cross-sectional imaging, typically computed tomography (CT) of the chest (internal jugular, subclavian venous access) or abdomen/pelvis (femoral venous access). Conservative management of chest extravasations is usually sufficient, but drainage or more extensive procedures may rarely be necessary. Removal or retention of the catheter depends on the extent of extravasation and the severity of symptoms. (See 'Catheter retention versus removal' above and 'Mediastinal extravasation' above and 'Establishing new venous access' above.)
ACKNOWLEDGMENTS — The editorial staff at UpToDate would like to acknowledge Aimee S Payne, MD, PhD, and Charles E Butler, MD, FACS, who contributed to an earlier version of this topic review.
