INTRODUCTION — Drugs can be harmful when directly exposed to tissues, especially those classified as vesicants, which have the potential to cause severe tissue damage with lasting injury. "Extravasation" refers to the escape of a vesicant drug into the extravascular space; leakage of a nonvesicant drug is referred to as "infiltration" [1,2]. The drug can enter the extravascular space by leaking from the point where the catheter enters the vessel, from a point where a catheter has punctured through a vein, by causing direct damage to the vein, or from central venous access device malfunction. Although the most well-known vesicants are cytotoxic chemotherapy (antineoplastic) drugs (table 1), many other noncytotoxic drugs also have the potential for local toxicity (table 2).
The clinical features and management of extravasation injury are reviewed. Venous irritation without leakage (phlebitis), and other cutaneous complications of infusion therapy 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
Incidence — The true incidence of extravasation injury is largely unknown because there are no central reporting mechanisms, with many incidents going unreported [3-5]. The estimated prevalence of chemotherapy extravasation through a peripheral intravenous line is 0.1 to 6 percent, and from 0.3 to 4.7 percent when administered through a central venous access device (CVAD) [6]. For noncytotoxic medications, the incidence also varies [3,7-10]. One review estimated that extravasation of noncytotoxic medications occurred in <1 to 6 percent of adults [8].
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 [11]. However, this series only included patients referred to plastic surgery not all extravasations, and as such, this rate underestimates the true incidence of chemotherapy extravasation injury.
Infusion of cytotoxic antineoplastic agents is frequently done through a CVAD to minimize venous injury and the consequences of peripheral extravasation. Although the risk of extravasation through a CVAD is lower compared with extravasation at peripheral sites, it is not zero [5,12-15]. Extravasation in this setting might be due to injection technique (eg, access needle misplaced) or device failure (eg, disconnected catheter) [12].
●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) [13].
●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) [5].
●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 [14].
Risk factors
Peripheral access sites — Risk factors for extravasation injury from a peripheral vein include the following [16-20]:
●Small and/or fragile veins.
●Age-related or medical comorbidities that alter the integrity of the skin and subcutaneous tissue or impair tissue perfusion (eg, peripheral artery disease, diabetes).
●Current infection.
●Increased body mass index >30, which may increase the difficulty of establishing intravenous access or contribute to dislodgment of a catheter.
●Difficult venous access or limited vein ability due to prior venous access, prior chemotherapy, or other irritating drugs (eg, potassium chloride).
●Patient movement, particularly if the intravenous catheter is placed near a joint (eg, antecubital fossa, hand/wrist, foot/ankle).
●Cognitive or neurologic deficits (eg, peripheral neuropathy), or other conditions that impair a patient's ability to sense or react to pain at the site of drug administration. These can increase the risk of extravasation, even in the setting of continuous supervision.
●Prolonged infusion duration (>24 hours).
●Bolus infusion (eg, power injectors for radiocontrast media).
●Use of winged steel infusion devices (ie, "butterfly needles").
Central access sites — Risk factors for extravasation from a central venous access site include the following [14,18,20-23]:
●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.
●Venous stenosis or thrombosis located more central than the catheter tip.
Prevention — The best approach to extravasation injury is prevention [22]. Guidelines for preventing extravasation are available from the Infusion Nurses Society [18], Oncology Nursing Society (ONS), and the European Oncology Nursing Society (EONS) [21,24].
●Peripheral intravenous devices – Appropriate peripheral venous site selection (large vein away from areas of sclerosis or scar) and proper device placement and securement can minimize the risk of extravasation injury. (See "Peripheral venous access in adults", section on 'Site selection' and "Routine care and maintenance of intravenous devices", section on 'Dressing and securement'.)
Vesicant agents should not be infused through veins in the antecubital fossa, wrist, or dorsum of the hand because extravasation in these regions can cause serious long-term morbidity. For irritants, we try to avoid these sites as well, if possible. The butterfly needle or plastic cannula should be secured to the skin with tape and a transparent dressing used to cover the skin entry site to allow for direct observation of the site. Just prior to starting a drug infusion, the patency of the intravenous line should be demonstrated (eg, flush with 5 to 10 mL of isotonic saline or a 5 percent dextrose solution) and good blood return verified.
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 [19]. Patients should also be instructed to notify a clinician immediately if they experience any pain, leaking, or other changes in sensation at the infusion site.
●Central venous devices – Using a central venous catheter for infusion of vesicant drugs provides reliable venous access, high flow rates, and rapid drug dilution. However, extravasation can occur [25]. As with peripheral venous access devices, appropriate site selection and proper device placement and securement can minimize the risk of extravasation injury. (See "Central venous access: Device and site selection in adults" and "Routine care and maintenance of intravenous devices", section on 'Dressing and securement'.)
Following CVAD placement, the position of the catheter should be confirmed prior to drug administration. In addition, if there are any complaints of pain at the port/catheter site, reports of chest pain or dyspnea (even without soft tissue swelling), or inability to draw blood or flush the catheter, the position of the catheter should be assessed prior to continuing with the infusion. (See 'Risk factors' above and "Central venous access in adults: General principles", section on 'Confirming catheter tip position'.)
MECHANISMS OF INJURY — Extravasation injury can be due to the direct effects of a drug (eg, cytotoxicity that prevents cell replication or growth), or to other pharmacologic or physiochemical properties of the drug (table 2). Many other infusions may have irritant properties that can also cause tissue injury.
Extravasation injury is best described for cytotoxic (antineoplastic) agents [18,22,24], but a number of noncytotoxic drugs (eg, vasopressors, radiographic contrast agents) have been documented to cause tissue necrosis and thereby act as vesicants [7,16,26-31].
Cytotoxicity — Cytotoxicity refers to the direct effect of a drug. Based on the severity of local toxicity, cytotoxic chemotherapy drugs have been historically classified as vesicants or irritants [6,18,24,32,33]. However, there is no universally accepted scoring system for classifying a medication as an irritant or vesicant.
●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). 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. Some irritants can cause tissue necrosis if large volumes of concentrated solutions have extravasated.
●Vesicants – Extravasation of a vesicant drug has the potential to cause tissue necrosis (blistering, sloughing of tissue, and varying degrees of deep tissue damage), resulting in a more severe and/or lasting injury than is typically seen with irritants because they are inherently toxic.
In addition to a designation as an irritant or vesicant (table 1), 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 cellular DNA, resulting in more extensive injuries [33].
Anthracyclines are among the most important cytotoxic 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 [18,24]. (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 is not absolute. As examples:
●There are reports of severe tissue injury from extravasation of oxaliplatin [34,35], although another series of 11 patients showed no tissue destruction [36].
●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 [37-40]. However, only rarely are long-term sequelae reported, such as ulceration requiring surgical intervention [41]. In a compilation of 35 reported cases of paclitaxel extravasation, only three developed ulceration, two requiring skin closure [37]. 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 [42].
●Mitoxantrone, usually classified as an irritant, has been reported to cause skin necrosis requiring surgical debridement and skin grafting [43].
●Ado-trastuzumab emtansine, an antibody-drug conjugate that consists of the antihuman epidermal growth factor receptor 2 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 [44].
●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) [45]. 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.
Other drug properties — In addition to the cytotoxic effects of a specific drug , the properties of the drug solution (ie, osmolarity, pH), drug concentration, presence of diluents, and volume of escaping drug also contribute to the potential for injury (table 2). Infusates with pH values that are very low (<5.5 pH) or very high (>8.5 pH) are particularly harmful to tissues [8,33]. Similarly, infusion of hypo- or hyperosmolar agents (<281 or >289 mOsmol/L, respectively) can lead to significant tissue damage [33]. In clinical practice, injuries from hyperosmolar agents are more common (eg, hyperosmolar radiographic contrast, some parenteral nutrition solutions). Such agents should be administered through a CVAD rather than peripherally. (See "Central venous access: Device and site selection in adults", section on 'Factors influencing catheter selection'.)
Other mechanisms may also be responsible for extravasation injury. The presence of drug diluents used in the formulation of some medications (eg, benzyl alcohol, polyethylene glycol, propylene glycol) may also contribute. As an example, propylene glycol used as a solvent in some parenteral medications (eg, lorazepam, diazepam, phenobarbital, phenytoin, digoxin) may contribute to tissue injury by inducing inflammation or changes in physical properties.
For some agents, the mechanism of injury is unclear. As an example, esmolol has been associated with thrombophlebitis, necrosis, and blistering but how extravasation injury occurs is unknown.
Mechanical effects — In addition to the chemical and other drug properties, tissue injury can also be caused by the mechanical effects of the fluid escaping from vasculature [8]. The necessary volume to result in an adverse mechanical effect depends on the potential space available and the structure surrounding the vein.
CLINICAL FEATURES
Symptoms and signs — 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 [2,7,18,24,46]. 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 (picture 1), and/or blistering may appear [47]. With a small volume of extravasation, symptoms may disappear over several weeks. With larger volumes, necrosis, eschar formation, and ulceration with raised, red, painful edges and a yellow necrotic base may develop over a few days to several weeks. The National Cancer Institute Common Terminology Criteria for Adverse Events has provided a clinical classification of extravasation injury (table 3).
●Escape of an 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 area, without tissue sloughing or necrosis. Symptoms are usually of short duration with no long-lasting sequelae provided the volume is limited.
●Escape of a vesicant can produce local tissue necrosis both within and outside the venous system [33]. 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 [46].
●When a drug escapes from a central venous access device (CVAD), the 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 to the same drug administered at a remote intravenous site. This phenomenon has been reported with paclitaxel [48-50], docetaxel [51,52], doxorubicin [53,54], and epirubicin [55].
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 CVAD, the infusion should be stopped, and a chest radiograph should be obtained to evaluate the position of the tip of the catheter and to verify the integrity of the components. (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 'Catheter management' below.)
The extent of CVAD extravasation can be initially evaluated with cross-sectional imaging, typically with a CT scan of the neck/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 other causes of catheter malfunction.
All patients with suspected mediastinal extravasation from a CVAD should undergo an initial CT scan of the chest; follow-up imaging can be performed with standard chest radiographs.
TREATMENT OVERVIEW — In general, the goals of treatment of suspected extravasation injury are to prevent local as well as any systemic effects of extravasated agent. Initial measures focus on limiting the amount of the agent within the tissues, thereby reducing the mechanical effects but also the amount of the agent that can be absorbed systemically. Application of cold or heat and selective use of antidotes aims to minimize tissue loss.
An overview of our recommended approach to the management of cytotoxic extravasations (including the use of specific antidotes), which follows the general guidelines of the Oncology Nursing Society (ONS) and European Oncology Nursing Society (EONS) [24], is summarized in the table (table 4). Similarly, an approach to the management of extravasation of noncytotoxic agents, which is based upon collective reviews, is summarized in the table (table 2) [7,8,18,56]. Specific treatment for selected agents is discussed below. (See 'Local treatment of selected extravasations' below.)
Initial measures — When extravasation of an irritant or vesicant drug is suspected (peripheral or central venous access), the following initial management is recommended [8,18,24]:
●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, which may help reduce edema and pain [57].
●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 'Selective use of antidotes' below.)
●If an antidote will not be injected into the extravasation site, the peripheral catheter/needle can be removed after attempting 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, provided there is no evidence of mediastinitis or empyema [15,58-60]. 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 likely protect against damage from extravasation [15]. Conservative management that includes antibiotics, analgesics, and pleural drainage (ie, thoracostomy tube) is typically sufficient. Antipyretics should be considered since fever is reported in 80 percent of chest extravasation cases [15]. If imaging demonstrates significant fluid collection, drainage or more extensive procedures may rarely be necessary [58,59]. (See 'Imaging' above and 'Mediastinal extravasation' below.)
Application of cold or heat — Whether cold or heat is appropriate depends on the nature of the extravasated drug (cytotoxic (table 4), noncytotoxic (table 2)) and mechanism of injury.
●Cold compresses reduce pain and inflammation, and vasoconstriction localizes the vesicant potentially facilitating administration of an antidote [61-63].
●Application of warmth causes vasodilation and may facilitate dispersion and absorption. Warmth is often used in conjunction with hyaluronidase to facilitate its mechanism of action.
When used, dry cold or warm compresses should be applied to the affected area for 20 minutes once every four to six hours for one to two days after removal of the needle or catheter. If compresses provide comfort and symptomatic relief, the frequency can be increased (eg, up to 20 minutes per hour).
Cytotoxic drugs — Topical application of cold is recommended for extravasation of most cytotoxic vesicant or irritant drugs, except for the vinca alkaloids (vincristine, vinblastine, vinorelbine), epipodophyllotoxins such as etoposide, and possibly taxanes. The 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 cold alone (15 minutes four times daily for three days) required no further therapy [64].
For extravasation of vinca alkaloids or epipodophyllotoxins, application of cold is contraindicated, as cold worsens the skin ulceration caused by these drugs, at least in animal models [61,65]. Cold opposes the action of hyaluronidase and is contraindicated in this setting. 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 [65].
For taxanes, the choice between cold or heat is less clear. Early guidelines suggested application of cold [37], 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 [24]. Aside from extravasation recall phenomena, the long-term effects of paclitaxel extravasation are minimal and usually entail mild fibrosis around the extravasation site. However, 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 [24,66].
Noncytotoxic drugs — For noncytotoxic agents, suggestions for application of cold or heat vary depending on the mechanism of potential injury and the use of antidotes [7-9]. (See 'Selective use of antidotes' below.)
●Acidic – For most acidic extravasations, cold compresses are appropriate with the exception of vancomycin, for which the selection of cold or warm depends upon whether hyaluronidase is administered (table 2).
●Alkaline – For most alkaline extravasations, cold compresses are appropriate with the exception of phenytoin, for which the selection of cold or warm depend upon whether hyaluronidase is administered (table 2).
●Hyperosmotic – For most hyperosmotic extravasations, warm compresses are used if hyaluronidase is administered, and cold compresses can be used if an antidote is not administered (table 2).
●Vasopressor – For most vasopressor extravasation causing vasoconstriction, warm compresses are used, often in combination with vasodilator therapy (table 2).
Selective use of antidotes — Antidotes include dexrazoxane (anthracyclines), sodium thiosulfate (alkylating agents), hyaluronidase (vinca alkaloids, taxanes), dimethyl sulfoxide (DMSO) anthracyclines for cytotoxic extravasation and vasodilators and hyaluronidase for noncytotoxic agents. For some drugs (eg, trabectedin [67]), there are no specific published antidotes [68]. (See 'Cytotoxic agents' below and 'Noncytotoxic agents' below.)
●Peripheral intravenous device extravasation – Following extravasation from peripheral venous devices, specific antidotes have been suggested to prevent necrosis and ulceration, although none of these has been validated in randomized clinical trials (table 4 and table 2).
●Central venous device extravasation – For extravasation of cytotoxic agents from a CVAD, intravenous dexrazoxane is more established as an antidote for anthracycline extravasation. However, the utility of other local antidotes (hyaluronidase, sodium thiosulfate) is unclear, and their use is not recommended in guidelines from the EONS [24].
Dexrazoxane — Dexrazoxane is believed to chelate intracellular iron, block iron-assisted oxidative radical production, and inhibit the topoisomerase II beta isoenzyme, which has been implicated in anthracycline cardiotoxicity (See 'Anthracyclines' below and "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity".)
Sodium thiosulfate — Sodium thiosulfate creates an alkaline-rich site to which alkylating agents bind instead of to the tissue [69]. Local injection of sodium thiosulfate is used for cisplatin extravasations as well as large volume injections or concentrated dacarbazine (table 4) [70,71]. (See 'Alkylating agents' below.)
Sodium thiosulfate infusion may also be beneficial for severe forms of cutaneous calcinosis related to calcium chloride extravasation (table 2) [72]. (See 'Hyperosmotic, acidic, or alkaline agents' below.)
Hyaluronidase — The proteolytic enzyme hyaluronidase promotes the diffusion of subcutaneously injected solutions by hydrolyzing hyaluronic acid, one of the chief ingredients of connective tissue stroma. It is postulated that this creates a wider surface for dilution and aspiration of the drug [73,74]. Warmth is often used in conjunction with hyaluronidase to facilitate its mechanism of action. (See 'Application of cold or heat' above.)
Hyaluronidase may be useful for extravasation of cytotoxic (table 4) or noncytotoxic (table 2) agents. Local injection of hyaluronidase for extravasations of vinca alkaloids, paclitaxel, epipodophyllotoxins, ifosfamide, sodium bicarbonate, sodium chloride, calcium solutions, dextrose, and mannitol. (See 'Vinca alkaloids and taxanes' below.)
Dimethyl sulfoxide — 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 [75,76]. Topical application of DMSO can be used for anthracycline extravasation when dexrazoxane is not immediately available. A single, subcutaneous, local injection of DMSO is used for mitomycin extravasation, followed by topical application. The mechanism underlying a potential benefit from DMSO is uncertain. (See 'Anthracyclines' below.)
Vasodilators — For vasoactive drugs, phentolamine (eg, for dobutamine extravasation), or nitroglycerin (eg, for dopamine, epinephrine, methylene blue, phenylephrine extravasation) can be administered. (See 'Vasoactive drugs' below.)
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, except for large-volume extravasations of oxaliplatin (see 'Alkylating agents' below). This position is consistent with recommendations from the ONS and EONS for most cytotoxic drug extravasations [24]. Glucocorticoids may worsen the skin damage from etoposide or vinca alkaloids, and they are specifically contraindicated in these situations.
LOCAL TREATMENT OF SELECTED EXTRAVASATIONS — Information regarding treatment for extravasation is largely based on animal models, anecdotal case reports, and a limited number of small uncontrolled studies [8,77]. No clinical trials have been performed to establish the role of specific interventions in the management of extravasation injury [77,78]. Furthermore, evaluation of the available 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).
For extravasation from cytotoxic agents, guidelines for management are available from the Oncology Nursing Society (ONS) and European Oncology Nursing Society (EONS) [24]. The ONS standards were initially developed in 2009 [79], and were reiterated in 2011 and 2013 with little, if any, change [80,81]. With the use of standardized protocols, most extravasations are able to be managed conservatively with a reduced need for surgical intervention [82].
Our recommendations are based on case descriptions, experience at some leading centers, or extrapolated according to mechanism of injury (table 4 and table 2). Consult local protocols if available. Antidotes are used as potential adjuncts to initial care of extravasation injury. (See 'Initial measures' above.)
Cytotoxic agents
Anthracyclines — For extravasations of nonliposomal anthracyclines (daunorubicin, doxorubicin, epirubicin, idarubicin), which have a high likelihood of producing tissue ulceration, in addition to cold therapy, we administer dexrazoxane as the initial treatment (table 4). Treatment should be started as soon as possible, ideally within the first six hours after extravasation. Dimethyl sulfoxide (DMSO) (where available) represents an acceptable alternative to dexrazoxane if dexrazoxane is unavailable or cannot be started within six hours of the actual extravasation event. Studies of dexrazoxane demonstrate a slightly better efficacy compared with DMSO for anthracycline extravasations [83]. There is no evidence that combined use of dexrazoxane and topical DMSO provides any additional benefit. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity".)
Liposomal anthracycline formulations are generally not associated with necrotic injury, and treatment with dexrazoxane is generally not indicated; application of cold alone to reduce local inflammation (and avoidance of DMSO) is usually sufficient [84-86]. However, for the rare patient who develops symptomatic extravasation of pegylated liposomal doxorubicin, dexrazoxane may be useful [87,88].
A benefit for dexrazoxane after anthracycline extravasation was initially suggested in animal studies and isolated case reports [89-92]. Dexrazoxane was subsequently evaluated in a review that included two multicenter studies involving patients with presumed anthracycline extravasations [93]. 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.
The evidence supporting the use of DMSO comes from two observational studies in patients with chemotherapy extravasations, both of which used topical administration [94,95]. However, these studies 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.
●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) [94]. 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 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 [95].
Dexrazoxane has been approved by both the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) for the treatment of anthracycline extravasation injury (table 4). Guidelines from the ONS do not include DMSO, and even the manufacturer's package labeling information fails to recommend its use for anthracycline extravasations. DMSO was also not included in the recommended treatments for extravasation in 2012 guidelines from European Society for Medical Oncology (ESMO) and EONS [24].
Alkylating agents — For large volume extravasation or concentrated dacarbazine, cisplatin or carboplatin, or bendamustine, in addition to cold therapy, we inject sodium thiosulfate directly into the extravasation site (table 4) [70,71].
The recommendation for thiosulfate for the treatment of extravasation of alkylating agents is based largely on in vitro data demonstrating an interaction of thiosulfate and cisplatin [96-100]. 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) [20]. However, neither the ONS nor EONS has addressed the issue of sodium thiosulfate with this drug [24].
The 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 [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.
In addition, 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 [36].
For dacarbazine, cisplatin, or carboplatin, 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 [70,71]. 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.
Vinca alkaloids and taxanes — For extravasation of the vinca alkaloids (vinblastine, vincristine, vinorelbine) or taxanes (paclitaxel, docetaxel), in addition to heat, we inject hyaluronidase directly into the extravasation site. While the EONS suggests the use of hyaluronidase for extravasations these agents [24], guidelines from the ONS recommend hyaluronidase only for extravasations of vinca alkaloids, not other agents.
The evidence supporting the use of local infiltration with hyaluronidase is based on small series and case reports [24,37,101]. 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 [101]. A review of reports of treatment of paclitaxel extravasation found inconsistent results with hyaluronidase [37]. 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.
Hyaluronidase is administered as multiple subcutaneous injections around the affected area. Hyaluronidase should be administered within one hour of extravasation; some benefit may be derived if hyaluronidase is used within 12 hours. When hyaluronidase is used (all indications), avoid cold compresses as they oppose its action; warm compresses may be used.
Commercial preparations of hyaluronidase are available, but these 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 erythema using a separate 25 gauge or smaller needles.
Noncytotoxic agents — The optimal approach to local therapy for extravasation of noncytotoxic vesicants is unclear, and there are no guidelines. The information provided in the table (table 2), which is based on case descriptions, experience at some leading centers, or extrapolated according to mechanism of injury, can help guide management.
Vasoactive drugs — Vasodilators may be helpful for counteracting the vasoconstrictive effects of some noncytotoxic vasoconstrictive agents by helping to limit local ischemia that can lead to tissue necrosis (table 2).
●Phentolamine – Phentolamine is the preferred agent for most extravasations of vasopressor agents. Phentolamine antagonizes alpha-adrenergic receptors that are stimulated by catecholamine extravasation [56,102-104]. Phentolamine is administered as multiple subcutaneous injections around the affected area. It should be administered as soon as possible; greater benefit may be derived if it is used within 12 hours.
●Nitroglycerin/terbutaline – For dobutamine extravasation, topical nitroglycerin ointment and/or terbutaline administered subcutaneously may be considered. These agents are an alternative for vasopressor extravasation if phentolamine is not available [105]. Topical nitroglycerin 2% is applied as a 1-inch (2.5 cm) strip over affected area. It should be applied within one hour of extravasation. Avoid warm compresses when topical nitroglycerin is used.
Hyperosmotic, acidic, or alkaline agents — Hyaluronidase may be useful for treating predominantly hyperosmolar noncytotoxic extravasations, but also some acidic (eg, vancomycin) or alkaline (eg, phenytoin) extravasations (table 2).
Case reports also support potential benefit of hyaluronidase with extravasations of phenytoin [106], nafcillin [107], and other compounds, such as mannitol, high concentrations of dextrose [101,108-111], and extravasation of radiocontrast media [112-114].
For severe calcinosis, a thiosulfate infusion is administered once weekly for three weeks [72]. Intravenous sodium thiosulfate administration can be associated with anion gap acidosis more typically associated with patients who have chronic kidney disease [115]. (See "Calcinosis cutis: Management", section on 'Topical or intralesional sodium thiosulfate'.)
CATHETER MANAGEMENT — The management of the catheter largely depends on the device location, severity of extravasation, and for central venous access devices (CVADs), the cause. All patient factors, the events leading up to the extravasation, and the ongoing need for peripheral or central venous access should be assessed. When ongoing venous access is required, replacement should be well away from the site of extravasation. Alternative venous sites can be chosen using ultrasound guidance.
●Peripheral intravenous catheters – Following the administration of any antidotes or saline irrigation for the early treatment of extravasation, all peripheral intravenous catheters should be removed. New intravenous access will need to be established at a site away from the injury often in the contralateral extremity. Central venous access may be preferred for the new access following a peripheral extravasation.
●CVADs – In addition to managing the local effects of the extravasated fluid, the CVADs needs to be addressed. Central venous catheter malfunction may be the cause of the extravasation injury, which can be related to a catheter that has disconnected (eg, port separated from catheter), has become malpositioned such that one of the infusion holes is no longer intravascular, or has perforated the vessel such that the tip of the catheter no longer resides in a vessel. (See "Central venous catheters: Overview of complications and prevention in adults".)
For central venous catheters associated with vascular perforation, surgical consultation is appropriate. The catheter should be removed, and the site should be evaluated for bleeding. Endovascular or open surgical management may be required depending on the site of the vascular injury. (See "Vascular complications of central venous access and their management in adults".)
Whether to remove a CVAD depends on the extent of extravasation and the severity of symptoms:
•If a catheter malfunction was identified, symptoms related to extravasation are minimal, and alternative CVAD sites are limited, the CVAD can be evaluated for repair or replacement at the same site. Once the symptoms are resolved, use of the CVAD can be resumed.
•However, if symptoms or signs are more serious (eg, severe or persistent pain, exposure of the catheter or port device, blistering or tissue ischemia), the CVAD should be removed, usually during the initial washout or debridement procedure. If ongoing central venous access is needed, it should be placed away from the site of extravasation. Temporary central venous access will be needed until any catheter-related infection has resolved. (See 'Local tissue injury' below.)
SURGICAL MANAGEMENT — Surgical consultation and intervention may be necessary to help limit and manage tissue necrosis and provide coverage in the event of tissue loss. Data regarding surgical intervention for extravasation injury from central venous access devices (CVADs) are limited to case reports and case series [25,39,116-120]. In one review, 27 of 545 patients (5 percent) required escharectomy, skin graft, or flap (regional or free) reconstruction [120].
Surgical referral — Although conservative management resolves many extravasation injuries without the need for surgical intervention, early referral (eg, general surgery, thoracic surgery, vascular surgery, plastic surgery) is important for facilitating planning, particularly under the following circumstances (see 'Treatment overview' above and 'Surgical management' above) [24]:
●Significant subcutaneous extravasation leading to skin compromise (erythema, eschar) or with a collection exerting a mass effect (skin ischemia, vascular compression).
●Extravasation into the chest (eg, pleural cavity, mediastinum).
●Central venous catheter malfunction (disconnect, migration, perforation).
Local tissue injury — If tissue necrosis develops, the injury should be dressed with a nonadherent dressing (eg, petrolatum-based [Xeroform], semipermeable [Adaptic]) while the extent of tissue death demarcates [121]. The nonadherent dressing provides a moist, clean environment for healing and should be changed daily. Although wet-to-dry dressings can be considered to debride any open wounds, they are often painful for the patient and may induce bleeding with dressing changes. (See "Basic principles of wound management", section on 'Wound dressings'.)
Indications for surgical exploration include development of site infection or abscess, progression of the radiographic abnormalities concurrent with clinical deterioration, or clinical deterioration (tissue necrosis). Surgical debridement is also recommended for failure of response to general care measures with unresolved local tissue injury (ischemia, necrosis) [24]. Whether local surgical intervention is necessary in a patient complaining of persistent pain in the presence of normal-looking skin is unclear.
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 [47,122], a conservative approach is more often recommended [123-128], 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 [123,129]. Some agents (eg, doxorubicin, epirubicin) are autofluorescent, a characteristic can be used to define the extent of extravasation [130,131]. In one small study, with the removal of all fluorescing tissue, no subsequent tissue necrosis occurred [130].
Deep partial-thickness (wounds extending through the epidermis and into the deep dermis) or full-thickness (wounds extending through the entire dermis) skin defects that cannot be closed primarily can be managed 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 given the paucity of full-thickness skin graft donor sites. Full-thickness grafts, which have less contracture and greater thickness, may be preferred if they are available, for highly important functional and aesthetic areas of the body at sites. Graft take may be poor in areas of extravasation if debridement is incomplete and a healthy, vascularized wound base is not present. The principles of skin grafting are reviewed separately. (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".)
Mediastinal extravasation — 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 [15]. (See "Overview of minimally invasive thoracic surgery".)
Outcomes following thoracic extravasation are overall very good; complications and long-term thoracic sequelae are rare.
Compartment syndrome — While most extravasations occur superficial to the fascial compartments, compartment syndrome has been reported to occur (eg, mannitol, high-pressure injection) [132-134]. The patient should be monitored for this complication, particularly for extravasations that occur in the hand. When compartment syndrome is identified, fasciotomy is used to treat compartment syndrome. (See "Pathophysiology, classification, and causes of acute extremity compartment syndrome", section on 'Extravasation injury' and "Acute compartment syndrome of the extremities".)
SUMMARY AND RECOMMENDATIONS
●Risk for extravasation injury – The main risk factors for extravasation injury are improper catheter type or site selection for the type of pharmacologic agent/fluid being administered, and improper infusion technique. (See 'Incidence and risk factors' above.)
●Initial treatment – If extravasation of a vesicant agent is suspected, initial management should focus on minimizing the extent of drug extravasation (see 'Treatment overview' 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. Rather, it should be left in place to aspirate fluid from the extravasated area to the extent that is possible and to facilitate the administration of an antidote to the local area (table 4 and table 2), if appropriate. (See 'Selective use of 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.
-If appropriate and available, once 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.
•For most extravasations of vesicant agents other than the vinca alkaloids and etoposide, we use the thermal therapy listed in the tables (table 4 and table 2). (See 'Application of cold or heat' above.)
•Glucocorticoid therapy is generally not indicated in the management of vesicant extravasation for most patients
●Local treatment of specific extravasations – We use the following antidotes, when available, rather than no antidote to lessen the local tissue effects of the extravasation. (See 'Local treatment of selected extravasations' above.)
•Anthracyclines – For extravasation of nonliposomal anthracyclines, we suggest systemic administration of dexrazoxane (Grade 2C). Topical dimethyl sulfoxide (DMSO) is an alternative if dexrazoxane is unavailable or cannot be started within six hours of the actual extravasation event. Liposomal anthracyclines are generally not associated with necrotic injury, and treatment with dexrazoxane is generally not indicated. (See 'Anthracyclines' above.)
•Alkylating agents – For large volume extravasation or concentrated dacarbazine, cisplatin or carboplatin, or bendamustine, we suggest sodium thiosulfate injected directly into the extravasation site (Grade 2C).
For extravasation of oxaliplatin, we suggest administration of high doses of oral glucocorticoids (dexamethasone 8 mg twice daily for up to 14 days) (Grade 2C). (See 'Alkylating agents' above.)
•Vinca alkaloids and taxanes – For extravasation of the vinca alkaloids (vinblastine, vincristine, vinorelbine) and taxanes (paclitaxel, docetaxel), we suggest local injection of hyaluronidase (Grade 2C). (See 'Vinca alkaloids and taxanes' above.)
•Noncytotoxic vesicants – The optimal approach to local therapy for extravasation of noncytotoxic vesicants is unclear, and there are no guidelines. The information provided in the table (table 2), which is based on case descriptions, experience at some leading centers, or extrapolated according to mechanism of injury, can help guide management. (See 'Noncytotoxic agents' above.)
●Central venous access-related extravasation – For patients with suspected extravasation from a central venous access device (CVAD), once the infusion is stopped, a chest radiograph should be obtained to evaluate the position of the catheter tip and the integrity of the catheter and any connections between components (eg, port device). The extent of extravasation can be evaluated with cross-sectional imaging, typically CT of the chest (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 be necessary. Removal or retention of the CVAD depends upon the extent of extravasation and the severity of symptoms. (See 'Catheter management' above and 'Mediastinal extravasation' above.)
●Surgical management – 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, progression of the radiographic abnormalities concurrent with clinical deterioration, or clinical deterioration (tissue necrosis). Surgical debridement is also recommended for inadequate response to general care measures with unresolved local tissue injury (ischemia, necrosis). (See 'Surgical referral' above and 'Surgical management' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Aimee S Payne, MD, PhD, who contributed to an earlier version of this topic review.
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