Extravasation is the inadvertent escape, or leakage of cytotoxic drug into the extravascular space during infusion.
Terminology
- Irritants: short-term injury, does not lead to tissue necrosis. Local inflammatory reaction (tenderness, burning, erythema). Blood return remains intact. Causative agents: bendamustine, carboplatin, dexrazoxane, etoposide
- Irritants can display vesicant-like properties with increasing extravasation volume.
- Vesicants: Severe local or extensive tissue necrosis; erythema, blistering; may involve joints/tendons. Symptoms can be delayed 6-12 hours, can initially have only pruritic without pain. Blood return is absent. Damage depends on the drug, volume extravasated, solution conc, site of infiltration, drug exposure length, and measures taken to treat once infiltration occurs.
- DNA-binding: Bind to nucleic acids (prompt/continuous cell death). Injuries become larger, deeper, more painful. Causative agents: anthracyclines (dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, mitomycin; worst), mechlorethamine.
- Non-DNA binding: indirect effect on cells, metabolized more easily. Injury is localized, mild-moderately painful, improves over time. Causative agents: plant alkaloids (amsacrine, docetaxel, paclitaxel, trabectedin, vinblastine, vincristine, vindesine, vinorelbine).
- Exfoliants (may have low vesicant potential): cause inflammation and shedding (peeling off) of skin without causing underlying tissue death; may cause superficial tissue injury, blisters and desquamation. Causative agents include cisplatin, docetaxel, liposomal doxorubicin, mitoxantrone, oxaliplatin, paclitaxel
- Inflammations: cause mild to moderate inflammation, painless skin erythema and elevation (flare reaction) at the extravasation site. Causative agents include fluorouracil, methotrexate
- Neutrals: drugs that neither cause inflammation nor damage upon extravasation. Causative agents include monoclonal antibodies, cyclophosphamide, cytarabine, eribulin, gemcitabine, Ifosfamide
Prevention
- Central Catheters have decreased incidence, but extravasation can still occur.
- Patient education to report any symptoms (pain, burning, erythema, edema, swelling, tingling, itching) as they are the first to feel it.
- Careful administration, monitor IV site frequently with check of blood return.
- IV Site Selection: Distant from hand, foot dorsum, joint space (forearm > hand dorsum > wrist > antecubital fossa). Avoid chemo administration distal to recent venipuncture (higher extravasation risk).
- Technique: Consider hot compress for vein dilation. Bolus doses over 5-10 minutes through free-flowing line, vinca alkaloids in a minibag (may help with avoiding intrathecal administration). Flush line between bolus injections and at end of administration.
General Management Protocol (no universal or evidence-based data due to rarity and ethical concerns)
- Extravasation Kit should always be available
- Stop infusion immediately, keep needle (venous access device) in place
- Elevate affected limb decreasing capillary hydrostatic pressure more reabsorption of extravasated agent
- Aspirate agent via IV cannula with sterile syringe. Do not flush the line
- Remove catheter/needle
- Hot/cold compress for 15-20min x3-4/d x2-3d
- Cold (for DNA binding [anthracyclines]): cause vasoconstriction, “localize and neutralize” drug (reduce pain, local inflammation)
- Do not use cold for vincas- may cause further tissue damage
- Warm (for non-DNA binding [vincas, ?taxanes]): causes vasodilation, “disperse and dilute” drug (more absorption)
- Cold (for DNA binding [anthracyclines]): cause vasoconstriction, “localize and neutralize” drug (reduce pain, local inflammation)
- Antidote if available through different IV site, and mark the infected area and photograph it
- Pain relief, monitor area closely (24h, then at wk1, then wk2, then PRN for redness, swelling, pain, ulceration, necrosis)
- Consult plastic surgery (soft-tissue reconstruction), supportive care services
- Early surgery to minimize injury (f/b skin graft) has reduced later injury extent; however, residual damage may still be evident.
- Document incident in chart with photo.
- Patient/Caregiver Instructions: Monitor area, avoid touching, wear loose clothing, protect from sunlight, gently move/exercise area, no unprescribed topical treatments, raise injured area for comfort
The antidotes used depends on the causative agents: Dexrazoxane, Hyaluronidase, Dimethyl sulfoxide (DMSO), Sodium thiosulfate.
Dexrazoxane IV (Totect) x3d for anthracyclines (FDA-approved)
- Mechanism: chelated with iron, preventing anthracycline–iron complex formation reduces free radical–mediated tissue necrosis.
- Dosing: 1000 mg/m² (max 2g) IV within 6h and on D2 500 mg/m² (max 1g) on D3. Renal dosing (decrease by 50% if CrCl <40 mL/min). Administer ASAP (~6h) using different venous access point, remove cold packs 15 mins before/during dexrazoxane
- Efficacy: Prevented surgery for necrosis in 98.2%, continued their chemo on scheduled in 71%
Hyaluronidase SC (adjuvant) for vinca alkaloids, etoposide, taxanes
- Mechanism: enzyme degrading hyaluronic acid in tissues, accelerate local connective tissue breakdown, promote drug dispersion/absorption.
- Dosing: Dilute 150units with 1mL 0.9% NS; inject 1mL into cannula for each 1mL of estimated infiltrated drug (max 6mL total) or 5 separate 0.2mL injections into infiltration site (via 24-gauge or smaller needle). Change needle with each injection.
Dimethyl Sulfoxide (DMSO) topical (organosulfur solvent)
- Mechanism: increases skin permeability (more absorption), free radical scavenger
- Dosing: 99% DMSO applied topically (15mL q6h x14d, or q8h x7d with cold packs 1h TID). Optimal dose/schedule unknown, but literature review recommends q6h x7d. >50% DMSO is not available for human use in US for this indication
- Efficacy: effective (98-100% prevention of ulceration vs cold packs alone).
- Toxicities (mild, reversible): burning and blistering itch, erythema, superficial scaling. DO NOT use concomitantly with dexrazoxane (reduced dexrazoxane activity).
Sodium thiosulfate SQ for alkylating agents (Bendamustine, cisplatin, mechlorethamine [controversial])
- Efficacy: improve lesion healed in 5d (vs 21d with steroids)
- Administration: Injected directly into extravasation site. For mechlorethamine, 2 mL of solution for each mg extravasated.
Recommended Extravasation Antidotes
- Anthracyclines (doxo/daunorubicin): Dexrazoxane (preferred) + cold compress (x1h 15-20min x3-4/d x2-3d) OR DMSO 50-99% topical
- Vinca alkaloids (vinblastine, vincristine, vinorelbine): Hyaluronidase + NS + warm compress (15-20 mins x3-4/d x2d)
- Taxanes (docetaxel, paclitaxel): Hyaluronidase (mouse study) + cold compress (conflicting data).
- Etoposide, teniposide, oxaliplatin: Warm compress (cold may worsen oxaliplatin neuropathy).
- Cisplatin: 1/6 or 1/3 molar sodium thiosulfate.
- Bendamustine, mechlorethamine, mitomycin: DMSO 50-99% topical OR 1/6 molar sodium thiosulfate (for bendamustine, mitomycin only).
Anticancer Agents That Are Irritant And/Or Vesicants
| Drug | Irritant | Vesicant | Other informations |
|---|---|---|---|
| Ado-trastuzumab | Yes | ? | Case reports of skin necrosis after extravasation |
| Arsenic trioxide | ? | No | Conflicting data on being an irritant |
| Bendamustine | Yes | No | Co-administration of D5W decreases infusion pain |
| Bevacizumab | Yes | ? | |
| Bleomycin | ? | No | Conflicting data on being an irritant |
| Brentuximab vedotin | ? | Yes | Conflicting data on being an irritant |
| Busulfan | ? | No | Conflicting data on being an irritant |
| Cabazitaxel | Yes | No | |
| Carboplatin | Yes | No | ≥10mg/mL |
| Carfilzomib | Yes | No | Venous irritation rare |
| Carmustine | Yes | Yes | |
| Cisplatin | Yes | Yes/No | Vesicant if >20 mL of a 0.5 mg/mL solution infiltrates |
| Cladribine | Yes | No | |
| Cyclophosphamide | ? | No | Conflicting data on being an irritant |
| Cytarabine | Yes | No | |
| Cytarabine-daunorubicin, liposomal (CPX-351) | Yes | ? | Conflicting data on being a vesicant |
| Dacarbazine | Yes | No | |
| Dactinomycin | No | Yes | |
| Daunorubicin | No | Yes | |
| Daunorubicin, liposomal | ? | No | Conflicting data on being an irritant |
| Dexrazoxane | Yes | No | |
| Docetaxel | ? | ? | Conflicting data on being an irritant Has been reported as a vesicant |
| Doxorubicin | Yes | Yes | |
| Doxorubicin, liposomal | ? | No | Conflicting data on being an irritant |
| Enfortumab vedotin | Yes | No | |
| Epirubicin | No | Yes | |
| Etoposide | Yes | No | Vesicant treatment required if a large volume infiltrate |
| Etoposide phosphate | Yes | No | |
| Floxuridine | ? | No | Conflicting data on being an irritant |
| Fluorouracil | ? | No | Conflicting data on being an irritant |
| Gemcitabine | Yes | No | Co-administration of D5W decreases infusion pain |
| Idarubicin | No | Yes | |
| Ifosfamide | ? | No | Conflicting data on being an irritant |
| Ipilimumab | No | No | |
| Irinotecan | ? | No | Conflicting data on being an irritant |
| Ixabepilone | Yes | No | |
| Lurbinectedin | ? | Yes | |
| Mechlorethamine | No | Yes | |
| Melphalan | Yes | No | |
| Mitomycin | No | Yes | |
| Mitoxantrone | Yes | Yes | Higher concentrations can cause ulcerations |
| Nelarabine | Yes | No | |
| Oxaliplatin | Yes | ? | Has been reported as a vesicant |
| Paclitaxel, conventional | No | Yes | Weak vesicant |
| Paclitaxel, albumin-bound | Yes | No | |
| Streptozocin | Yes | Yes | |
| Temsirolimus | No | No | |
| Teniposide | Yes | Yes | Vesicant treatment required if a large volume infiltrates |
| Thiotepa | ? | No | Conflicting data on being an irritant |
| Topotecan | ? | No | Conflicting data on being an irritant |
| Trabectedin | ? | Yes | |
| Trastuzumab emtansine | Yes | No | |
| Triptorelin | Yes | No | |
| Vinblastine | No | Yes | |
| Vincristine | No | Yes | |
| Vincristine, liposomal | ? | Yes | |
| Vindesine | No | Yes | |
| Vinorelbine | Yes | Yes | Flush line with > 75 to 124 mL of IV fluid437 |