The document discusses the issue of extravasation, which is the unintentional leakage of chemotherapy drugs from intravenous sites into surrounding tissues, potentially leading to significant damage. It outlines the incidence rates, risk factors, classifications of drugs based on their effects on tissue, and the signs and symptoms indicative of extravasation. The document further details diagnostic approaches, treatment options, and specific antidotes for managing such events, highlighting substances like dimethyl sulfoxide, dexrazoxane, and others.

1. EXTRAVASATION
Presented By
Afreen Nasir
Kaustav Ghosh
PharmD Interns

2. Introduction
• Intravenous infusion is the principal modality of administration of anti-cancer drugs and it is associated with
adverse effects which occur at site of injection.
• Extravasation: It is the non intentional leakage of injected drug into the perivascular or subcutaneous space
that can result in significant tissue damage OR.
• It refers to the inadvertent infiltration of chemotherapeutic drugs in the tissues surrounding the IV site.

3. Incidence
• In adults it is reported to be between 0.1% and 6%.
• This incidence has been noted to be as high as 11% in children and 22% in adults.
• Some data suggest that the incidence is decreasing probably due to improvements in the infusion procedure,
early recognition of the drug leakage, and training in management techniques.

4. Risk factors

5. Classification of IV administered drugs
Class Damage caused Examples
Neutrals Neither cause inflammation nor damage. Asparaginase, bevacizumab, bleomycin,
bortezomib, cetuximab, cyclophosphamide,
cytarabine, eribulin, fludarabine, gemcitabine,
ifosfamide, melphalan, rituximab, trastuzumab.
Inflammitants Mild-moderate inflammation, painless skin
erythema, elevation (flare reaction) at the
extravasation site.
Bortezomib, 5-fluorouracil, methotrexate,
raltitrexed.
Irritants Inflammation, pain or irritation at the extravasation
site, without any blister formation.
Bendamustine, bleomycin, carboplatin,
dexrasoxane, etoposide, teniposide, topotecan.
Exfoliants Inflammation, peeling off of skin without causing
underlying tissue death, superficial tissue injury,
blisters, desquamation.
Aclacinomycin, Cisplatin, Docetaxel, Liposomal
Doxorubicin, Mitoxantrone, Oxaliplatin,
Paclitaxel.
Vesicants Tissue necrosis or formation of blisters when
accidentally infused into tissue surrounding a vein.
Actinomycin D, Dactinomycin, Daunorubicin,
Doxorubicin, Epirubicin, Idarubicin, Mitomycin
C, Vinblastine, Vindesine, Vincristine,
Vinorelbine.

6. Classification of vesicants & irritants

7. Pathophysiology of tissue damage
• The extent of tissue damage depends on the chemotherapeutic agent’s binding capacity to DNA.
• DNA-binding antineoplastics cause tissue damage by propagating lethal DNA crosslinking or strand breaks
caused by free radicals, which lead to cell apoptosis.
• Non–DNA-binding antineoplastics interfere with mitosis, they are cleared more easily from extravasation
sites and cause less tissue damage than DNA–binding-agents.

8. Signs & Symptoms
• Swelling, redness, burning sensation, stinging.
• Resistance during drug administration, a slow or sluggish infusion, and lack or loss of blood return from the
IV cannula, implanted port, other central venous access device may be indicators that a vesicant
extravasation is occurring.
• The discoloration and skin in durations may progress further with the developments of blisters or necrosis
and possibly ulceration and deep tissue injury.
• It may take several days for the full extent of the epithelial damage to be realized.

9. In the case of peripheral IV catheter In the case of central venous catheter
• No initial symptoms of extravasation.
• Redness, pruritus, edema around the injection site.
• Fluid injection rate slows down or stops.
• Blood backflow does not work well or there is
leakage of medication around the needle.
• A complaint of discomfort or pain, occasional
expression of searing pain or numbness.
• Initial physical symptoms usually appear
immediately but also might appear several days or
weeks later.
• Often causes stinging pain.
• Edema around the port insertion or in the chest.
• Medication leakage around the catheter insertion.
• Redness in the chest, collarbone, or neck where a
central venous catheter is inserted.
• No blood backflow.
• Symptoms may appear early or late.
Diagnosis

11. DIFFERENTIAL DIAGNOSIS
• A differential diagnosis assessment should be carried out if an extravasation is suspected.
• Some chemotherapy drugs, even if correctly administered, can cause a local reaction which resembles an extravasation.
• This should not be confused with a true extravasation.
• Signs and symptoms of local nonextravasation reactions include erythema around the cannula site, along the accessed
vein (‘flare’), urticaria, local itching.
• Chemical phlebitis: vein inflammation, followed by a thrombosis or sclerosis of the veins, may cause a burning sensation at
the cannula site and cramping along the vein proximal to the cannula site.

12. Treatment
Steps to be
taken in case
of peripheral
line
extravasation.

13. *No recommended antidote. †Recommended antidote: dexrazoxane or dimethyl sulfoxide (DMSO). ‡Recommended
antidote: DMSO. §Recommended antidote: hyaluronidase.

14. • Continuous monitoring every 5 to 10 min.
• “Extravasation Kits”:
- Cannulas, gauze pads, adhesive bandage, gloves, disinfection swabs
- Hyaluronidase 1500 IU(1 ampoule)
- Hydrocortisone 1% cream – labelled with direction for use
- Sterile water for injection
- Dimethyl sulphoxide (DMSO) 99% solution 1 x 10 ml bottle with applicator (swabsticks)
- 25 G needles, 10- cc syringe,1-mL syringe
- Hot pack & Cold pack
- Saline solution (1 ampule);
- Cytotoxic drug extravasation documentation form
- Patient information leaflet

18. • Mitomycin extravasation with DMSO 99% given twice daily for 14 days. The result was a complete reversal of erythema
and mild skin ulceration.DMSO was also found to be effective in delayed extravasation treatment.

19. DIMETHYL SULFOXIDE (DMSO)
• Properties: Vasodilatatory, analgesic, anti-inflammatory.
• Topical application.
• Use: Anthracyclines extravasation.
• Inhibit free radical formation: It is a potent free radical-scavenger that rapidly penetrates tissues when applied topically.
It is hypothesized that the local damage induced by chemotherapeutic agents may be caused by hydroxyl radical formation.
• If DMSO 99% is not readily available, DMSO 50%, can be used until DMSO 99% is obtained.
• Apply topically to the skin twice the size of infiltration with a cotton swab and allow it to dry (do not cover), repeating
every 6-8 h for 7-14 days.
• Side effects: itching, erythema, mild burning, a characteristic breath odor.
PROSPECTIVE STUDIES
• When applied every 6 hours for 14 days was found to be
effective in avoiding the morbidity of debridement and skin
grafting after doxorubicin, daunorubicin extravasation.
• If applied topically every 8 hours for 7 days it is also safe
and effective.

20. DEXRAZOXANE
• Class: Ethylene diamine tetra acetic acid (EDTA) derivative, topoisomerase inhibitor II catalytic inhibitor.
• Brand: Totech, Zinecard
• Property: Cardioprotective
• Use: Anthracyclines (Daunorubicin, Doxorubicin) induced cardiotoxicity & extravasation.
• MOA: It has a dual mechanism of action:
- it acts as an iron chelator, preventing formation of iron-anthracycline complexes & iron-mediated hydroxyl radicals
that cause oxidative damage;
- it stabilizes topoisomerase II & makes it inaccessible to anthracycline chemotherapy. It blocks the enzyme so that it is
no longer affected by anthracycline and prevents damage to the healthy cells in tissue.
• Dosage form: Powder for inj. 250, 500 mg, pyrogen-free lyophilized powder in a single dose vial for reconstitution.
- Each carton contains one 50 mL Type I glass vial. Each vial contains dexrazoxane hydrochloride equivalent to 500
mg dexrazoxane (free base).
• Route: IV infusion
• Dilution: Mixed & diluted with 50 mL of 0.167 M sodium lactate injection solution before use.
- The admixture contains dexrazoxane (10 mg/mL) and the following excipients: hydrochloric acid, sodium lactate, water
for injection, sodium hydroxide, lactic acid.
- The admixture should be further diluted in 0.9 % NaCl prior to administration to patients.
- The solution is slightly yellow.

21. • Administration:
• The individual dosage is based on calculation of the Body Surface Area (BSA) up to a maximum dose of 2000 mg (each on
Day 1 and 2) and 1000 mg (Day 3), corresponding to a BSA of 2 m².
• Stability: The infusion bag should be used immediately after preparation. The product is stable for 4 hours from the time of preparation when
stored below 25ºC (77ºF).
- Unused solution should be discarded.
Doxorubicin-induced cardiomyopathy Extravasation
• Do not administer IV push.
• Infuse final diluted solution IV over
15 minutes before administering the
doxorubicin.
• Administer doxorubicin within 30
minutes after the completion of
dexrazoxane infusion
• Remove cooling procedures (eg, ice packs) if used, from extravasation area at
least 15 minutes before administration in order to allow sufficient blood flow to
the area of extravasation.
• Initiate 1st infusion as soon as possible & within the 1st 6 hours after
extravasation.
• Infuse final diluted solution IV over 1-2 hr once daily for 3 consecutive days, at
room temperature and normal light conditions in a large caliber vein in an
extremity/area other than the one affected by the extravasation.
• Start Day 2 and Day 3 treatment at the same hour (+/- 3 hr) as on the 1st day.
• Regularly examine for extravasation after treatment and until resolution.
• Not effective against the effects of vesicants other than anthracyclines

22. • Dose Modifications:
• Pharmacokinetic:
- Peak plasma: 36.5 µg/mL
- Half-Life: 2-2.5 hr
- Protein Bound: No
- Vd: 22.4 L/m²
- Renal Clearance: 3.35 L/hr/m2
- Excretion: Urine (42%)
- Dialyzable: Yes
• Side effects: Myelosuppression: leukopenia, neutropenia, thrombocytopenia.
Renal impairment Hepatic impairment
• Mild (CrCl ≥40 mL/min): No dosage adjustment.
• Moderate-severe (CrCl <40 mL/min): Reduce dose by 50%
(dexrazoxane to doxorubicin ratio reduced to 5:1;such as
dexrazoxane 250 mg/m2 to doxorubicin 50 mg/m2).
• Extravasation: Not recommended.
• Cardiomyopathy: Reduce dosage proportionately
(maintaining the 10:1 ratio) in patients with hepatic
impairment, since a doxorubicin dose reduction is
recommended in the presence of hyperbilirubinemia.

23. GRANULOCYTE-MACROPHAGE COLONY STIMULATING FACTOR (GM-CSF)
• Classes: Hematopoietic Growth Factors
• Drug: Sargramostim (gmcsf, Leukin, EMGRAST-M)
• Indication: wound healing & skin ulceration due tocyclophosphamide, Doxorubicin, 5-Fluorouracil induced extravasation.
• MOA:
- It is a hematopoetic growth factor that stimulates proliferation of neutrophils, monocytes and eosinophils, augments cell
killing activity and phagocytosis, and the in-situ immobilization of neutrophils.
- It has been shown to act as a neutrophil migration inhibition factor, to rapidly induce surface expression of MOl antigen (cell
surface adhesion protein - CD11b) and to increase leukocyte adhesion molecule 1 (LAM-1) affinity on granulocytes which
may enhance neutrophil aggregation and their endothelial binding.
- It induce local ervthema at the site of injection which may be due to local margination of neutrophils and tissue infiltration
with monocytes and subsequent stimulation of other cytokines such as TNF, IL-1 and Interferon which may participate in the
healing process

24. HYPERBARIC OXYGEN (HBO) THERAPY
• Indication: Doxorubicin, Calcium chloride extravasation (skin lesion)
• MOA:
- O2 is essential to the healing process. The energy required for cell proliferation comes from aerobic sources, and in presence of O2
new collagen cross-linking, the hydroxylation of proline and lysine takes place.
- The formation of granulation tissue is optimized in a well-oxygenated environment. HBO enhance several of the interlocking
mechanisms that contribute to healing insuch lesions.
- Increased O2 availability may stimulate temporarily the more energy efficient Kreb's cvcle metabolic pathway in the regenerating
tissue, enabling more energetic fibroblasts to migrate farther from their proximal capillary sources and out into the more hypoxic
areas of the wound.
- Hyperoxygenation can also increase collagen production, enabling these rapidly migrating fibroblasts to laydown larger, stronger
beds of collagen for the advancing capillary beds, leading to increased granulation tissue formation and enhanced overall healing.
- HBO increase re-epithelialization in guinea pigs. Many clinical series have shown that HBO improved healing in problem wounds
refractory to standard therapy.
- It reduced cell damage by reversing regional tissue hypoxemia from edema, wound healing enhancement by neovascularization,
fibroblast proliferation, and enhanced polymorphonuclear cell function. These benefits may reduce the significant morbidity seen
with routine care of the extravasated ulcer.

26. HYALURONIDASE
• Brand: Amphadase, Hynidase, Omnidase, Facidase
• Class: Extravasation Antidotes
• Indication: Vinka alkaloid, Paclitaxel, Etoposide extravasation.
• Dosage Forms & Strengths: injectable solution- 150unit/mL, 200unit/mL
• Skin Test: 0.02 mL (3 units) of 150 units/mL solution intradermally; a wheal with pseudopods appearing within 5 min and
persisting for 20-30 min with itching will indicate positive hypersensitivity reaction.
• MOA: It is dispersion agent (enzyme) which modifies permeability of tissue through hydrolysis of hyaluronic acid at the
glucosaminidic bond between C1 of glucosamine and C4 of glucuronic acid, breaks down subcutaneous tissue bonds
promoting drug diffusion through the interstitial space and enhances the absorption of injected substances.
• Doses: Ranging from 150- 1,500 units diluted in 1 mL of normal saline subcutaneously or intradermally within 1 hour of
extravasation.

27. • Route: It is injected locally subcutaneously into the extravasation area.
- Administer 1 mL of the hyaluronidase solution in five 0.2 mL injections into the extravasation site using a 25 gauge or
smaller needle, changing the needle for each injection.
• Pharmacokinetics:
- Onset of action: Immediate (SC)
- Duration: 24-48 hr
- Metabolism: Protein drugs are expected to be degraded by proteases and other catalytic enzymes to smaller peptides and
amino acids.
- Elimination: After nonspecific proteolysis, the amino acids from protein drugs are reused for protein synthesis or further
broken down and eliminated by the kidneys.
- t1/2: 2 min
• Adverse effects: Angioedema, urticaria, allergic reactions (<0.1%).

28. SODIUM THIOSULFATE
• Brand name: Pedmark
• Class: Inorganic sodium salt
• Dosage forms & Strengths: injection solution 250mg/mL (25%)
• Indications: Cyanide Antidotes, Mechlorethamine (nitrogen mustard), oxaliplatin, cisplatin extravasation.
• Dose: immediate subcutaneous administration of 2 ml of 1/6 molar solution of sodium ; 2 ml of the solution is injected for
each mg of mechlorethamine or every 100 mg cisplatin; remove needle, then inject 0.1 mL injections clockwise around
extravasation area up to 1 mL; repeat several times within the 3-4 hr of extravasation incident.
- Preparation of 1/6 Molar solution: 1.6 mL of 25% solution + 8.4 mL sterile water for injection or mix 4 mL of 10% sodium
thiosulfate + 6 mL of sterile water for injection.
- Inject the solution into the extravasation site using a 25 gauge or smaller needle, changing the needle for each injection.
- When given immediately after extravasation by intradermal injection, it had a protective effect.
• MOA: It neutralizes the vesicant by creating an alkaline-rich site, to which alkylating agents have an affinity. The vesicant
binds to the sodium thiosulfate instead of the tissue and the by-product is excreted in the urine.

29. • Pharmacokinetics:
- Peak plasma concentration: 13 mM
- Vd: 0.23 L/kg
- Metabolism: Thiosulfate is an endogenous intermediate product of sulfur-containing amino acid metabolism. Metabolized
through thiosulfate sulfur transferase and thiosulfate reductase to sulfite, which is oxidized to sulfate.
- Total clearance: 2.2 mL/min/kg for fully developed renal function
- Half life: Thiosulfate- 3 hr
- Excretion: Urine unchanged
• Storage:
- Unopened vials: Store at 20-25ºC (68-77ºF); excursions are permitted to 15-30ºC (59-86ºF).
- Withdraw drug from vials: Use immediately. If not used immediately, may store in an infusion bag for ≤18 hours at 20-22ºC
(68- 72ºF); discard unused portion.
• Side effects: Vomiting (85%), Nausea (40%), ↓ hemoglobin (34%), Hypokalemia (15-27%),Hypernatremia (26%),
Hypophosphatemia (15-20%)

30. SURGICAL MANAGEMENT OF SEVERE TISSUE DAMAGE
• Indications: full-thickness skin necrosis, chronic ulcer, persistent pain, severe extravasations or to patients in whom
conservative therapy has not been appropriately initiated.
• The treatment of unresolved tissue necrosis or pain lasting more than 10 days is surgical debridement.
• It is crucial that all necrotic tissue be removed until bleeding occurs and only healthy tissue left for wound coverage.
• To ensure complete excision, some surgeons use intraoperative fluorescent dye injection to detect the doxorubicin HCl
in the tissue to ensure complete excision.
• Such procedure consist of wide, three-dimensional excision of all involved tissue, temporary coverage with a biologic
dressing, simultaneous harvesting, storage of a split-thickness skin graft.
• Once the wound is clean, delayed or immediate application of the graft or surgical reconstruction is performed (usually at
2–3 days).
• Subcutaneous wash-out procedure is a surgical technique that has been tested in patients not treated with antidotes or
topical treatment as unique immediate therapy to extravasation. Due to scarce experience, this technique cannot be
recommended as routine management in a nonexperienced surgical unit.

31. CENTRAL VENOUS ACCESS DEVICE (CVAD) EXTRAVASATION
• Extravasation of chemotherapy agents administered through a CVAD is a rare complication.
• In this situation, the solution may accumulate in the mediastinum, pleura or in a subcutaneous area of the chest or neck.
• The most frequent symptom of central line extravasation is acute thoracic pain.
• Diagnosis must be based on clinical presentation and confirmed with imaging techniques, usually a thoracic CT scan [V, A].
• Data about management and evolution are based on case reports.
• The management of this infrequent extravasation should include stopping of the infusion and aspiration through the
central venous catheter of as much amount of the solution as possible.
• If the extravasated agent is an anthracycline, dexrazoxane might be considered as an antidote [V, C].
• Conservative therapy (surgical procedures with the objective of draining the remaining solution might be considered) [V, C].
• Antibiotics, i.v. corticoids, analgesia and other treatments leading to the control of the symptoms derived from the
mediastinitis or pleuritis secondary to extravasation can be considered [V, B]

32. Steps to be taken
in case of central
venous access
device
extravasation.

33. PREVENTION
• Most extravasations can be prevented with the systematic
implementation of careful, standardized, evidence-based
administration techniques.
• The staff involved in the infusion, management of cytotoxic drugs
must be trained to implement several preventive protocols for the
minimization of the risk of extravasation.
• It is important to remember that the degree of damage is
dependent on the type of the drug, drug concentration,
localization of the extravasation, length of time for which the drug
develops its potential for damage.
• Be familiar with the extravasation management standard
guidelines & prepare the extravasation kit.
• Regularly check the extravasation kit refill any used medications.
• Assess patient’s sensory changes, tingling or burning, always pay
attention to the words of patients.

35. DOCUMENTATION
• Each incident of extravasation must be correctly documented and reported.
• Documentation procedure may differ between treatment centers; however, certain items are mandatory for patient safety and
for legal purposes:
- Patient name and number
- Date and time of extravasation
- Name of drug extravasated as well as diluent used (if applicable)
- Signs and symptoms (also reported by patient)
- Description of the i.v. access
- Extravasation area (also the approximate amount of drug)
- Management steps with time and date
• Photographic documentation can be helpful for the follow- up procedures and decision-making.
• The patient must be informed about the scope of the problem. If a vesicant drug has extravasated, information about the time
involved in the resolution, as well as legal implications must be addressed.

36. FOLLOW UP
• The patient should be regularly reviewed daily or every 2 days for follow-up during the first week and then weekly until
complete resolution of symptoms.
• Sign symptoms: In the following days, initial inflammation increases with more redness, edema and pain.
• Depending on the vesicant drug, after several days or weeks blisters may appear and inflammation evolve to a necrosis.
• If required, referral to a (plastic) surgeon is recommendable.
• Patients must be informed about the follow-up policy before leaving the treatment area.

37. Extra details