Extravasation management

The purpose of this information is to provide guidance to health professionals in the management of antineoplastic extravasation. Only health care professionals who have attained competency as per institutional guidelines should perform the included procedures. This document should be used in conjunction with expert clinical judgement and with individual institutional guidelines or policies.

Evidence in the area of antineoplastic extravasation management is extremely limited. Recommendations regarding the treatment of antineoplastic extravasation are based on animal models, case reports and a limited number of small uncontrolled studies, and are often conflicting.^r eviQ has reviewed all the available literature and attempted to provide some guidance in this area.

Definitions

Extravasation	The unintentional instillation or leakage of a drug or substance out of a blood vessel into surrounding tissue.
Non-irritant (neutrals)	Drugs that do not cause local irritation when extravasated.
Irritant	Any drug or substance that causes stinging, aching, tightness, and phlebitis but without necrosis when extravasated.
Irritant with vesicant properties	These drugs or agents are difficult to classify as either a vesicant or irritant. They are capable of causing tissue damage and ulceration. The potential for tissue damage and ulceration, is proportional to the amount and concentration of the drug extravasated into the tissue.r Drugs that are classified as irritants with vesicant properties include docetaxel, liposomal doxorubicin, melphalan, mitozantrone, oxaliplatin, paclitaxel and nab-paclitaxel.
Vesicant	Any drug or substance that is capable of causing tissue destruction when extravasated. They are sub classified – DNA binding vesicants and DNA non-binding vesicants – according to the mechanism by which they cause cell damage.r Extravasation of a vesicant is a medical emergency; early detection and prompt appropriate action is required to prevent necrosis and functional loss of the tissue or limb involved. DNA binding vesicant drugs such as amsacrine, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin: have a direct affect on the cell in healthy tissue when they are extravasated cause progressive tissue destruction as they bind to cellular DNA and recycle locally may cause skin blistering, ulcer formation and necrosis. Tissue destruction may extend into underlying tendons, ligaments, nerves, and bone which may require excision and skin grafting. DNA non-binding vesicant drugs such as vincristine, vinblastine, vindesine, vinorelbine, vinflunine: have an indirect rather than a direct affect on the cell in healthy tissue when they are extravasated are metabolised in the tissue and are more easily neutralised than DNA binding agents the type of injury that results is similar to a burn, is mildly to moderately painful and can result in ulceration normal tissue healing occurs within 3 to 5 weeks. Cisplatin at concentrations > 0.5 mg/mL is considered a vesicant, while for concentrations less than this it is considered an irritant.rr

Anthracycline extravasation

Day 1 - Extravasation is red and painful	Day 4 - Redness and swelling worsens	Day 8 - Blistering develops
Day 10 - Blistering continues and peeling begins to occur	Day 12 - The patient's arm is indurated and tissue necrosis is apparent	Image post surgical debridement

Images copyright 2006 TopoTarget USA, Inc. Used with permission

Risk factors

Risk factors for extravasation may be patient-related or medication/infusion related.^r

Patient related risk factors:

• small and/or fragile veins (e.g. elderly and children)
• hard and/or sclerosed veins
• limited vein availability
• obesity in which peripheral access is difficult
• patient movement
• predisposition to bleeding, increased vascular permeability or coagulation abnormalities
• diseases with impaired or altered circulation (e.g. lymphoedema, advanced diabetes, Raynaud syndrome, superior vena cava syndrome)
• impaired communication (e.g. non-English speaking patients, patients with communication difficulties, sedation, young children).

Medication/infusion related risk factors:

• vesicant potential of drug
• concentration of drug
• volume of drug administered
• high flow pressure (e.g. infusion pump)
• long infusion period
• untrained or inexperienced staff in vascular access and the management of antineoplastic drugs
• multiple attempts at cannulation
• unfavourable cannulation site
• choice of equipment (e.g. cannula choice, size, steel “butterfly” needle)
• inadequate dressing or poor fixation of central venous access device (CVAD) or intravenous cannula (IVC)
• deeply implanted port, leading to wrong placement of needle or dislodgement of needle
• backflow secondary to fibrin sheath or thrombosis in CVAD
• CVAD damage, breakage or separation
• displacement or migration of CVAD catheter from the vein.

Symptoms and signs

Assess IVC or CVAD site throughout administration of chemotherapy. Extravasation should be suspected if the following occurs:^r

• patient complains of burning, stinging, pain or discomfort
• patient complains of thoracic pain
• evidence of swelling, oedema, erythema, leakage at the site
• absence of free flow of infusion
• change in infusion flow i.e. slow or sluggish
• loss of blood return or change in blood flow
• increase in resistance when administering IV bolus drugs.

Late symptoms of an extravasation injury include inflammation, induration and/or blistering.

Investigations

In the event of an extravasation or infiltration injury, important assessment parameters include:

• drug extravasated, dose, volume
• position and size of injury
• amount and type of exudate
• presence of swelling, oedema
• extent and spread of erythema
• pain.

Assessment should be ongoing to allow for the early detection and management of skin changes such as ulceration and necrosis.^r

Link to Assessment tool

Issues specific to CVAD extravasation

In the event of a suspected extravasation from a CVAD, imaging techniques such as X-ray, CT or MRI may be performed. There is limited evidence regarding the benefit of specific imaging techniques in confirming an extravasation.

Lineogram/ portogram may be performed to ensure that there is no fracture in the catheter of the CVAD. For implanted venous ports, ensure confirmation that the non-coring needle is in the correct position prior to performing a linogram/ portogram.

The above imaging techniques should be performed at the advice of the medical officer or radiologist.

Grading

Grade	Infusion site extravasation
1	Painless oedema
2	Erythema with associated symptoms (e.g. oedema, pain, induration, phlebitis)
3	Ulceration or necrosis: severe tissue damage; operative intervention indicated
4	Life-threatening consequences; urgent intervention indicated
5	Death

Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, November 27, 2017

Prevention

The risk of extravasation can be reduced by taking the following preventative measures:^rr

• administration and management of antineoplastic drugs by trained and accredited health professionals
• insertion, access and management of CVADs and IVCs by trained and accredited health professionals
• identify high risk patients
• educate patients and carers to monitor and immediately report symptoms such as pain, burning, stinging, swelling, or erythema during and after administration of cytotoxic drugs
• administer vesicants via a newly inserted IVC
• identify most appropriate site for IVC insertion
  • large veins in the forearm are recommended for insertion of an IVC
  • avoid insertion of an IVC over joints, the inner wrist, lower extremities, antecubital fossa or where lymphoedema is present
  • avoid multiple punctures
  • do not insert an IVC distal to a previous venepuncture site
• if venous access via an IVC proves difficult consider a CVAD
• do not use winged steel infusion devices for cannulation (“butterfly” needles)
• ensure the CVAD or IVC is stabilised and secure with a transparent dressing to allow the site to be visualised
• when accessing and before drug administration, ensure patency of the CVAD or IVC by checking
  • for blood return
  • no resistance is felt when flushing with 0.9 % sodium chloride or other compatible fluid
  • intravenous infusion flows freely
• do not inject against resistance
• if unable to confirm patency of CVAD, do not proceed without a full review of the CVAD and radiologic confirmation of patency
• if unable to confirm patency of IVC, insert a new IVC
• monitor the patient and CVAD or IVC site regularly for the appearance of symptoms such as swelling, pain, erythema or a change in the infusion rate
• for administration of vesicant drugs
  • administer vesicant drugs before other antineoplastic drugs (unless recommended otherwise by protocol)
  • if there is more than one vesicant drug, administer DNA binding drugs followed by non DNA binding drugs e.g. anthracyclines followed by vinca alkaloids
  • do not use infusion pumps to administer vesicants (unless recommended otherwise by protocol or institutional guidelines). For paediatric patients refer to local institutional guidelines when using infusion pumps to administer vesicant drugs
  • for bolus injections, administer concurrently with a fast running infusion of 0.9% sodium chloride or other compatible fluid
  • for bolus injections, patency and blood return should be checked regularly as per local institutional guidelines (e.g. ONS,^r recommend checking for blood return every 2-5 mL of administration)
  • for infusions (mini bag), patency and blood return should be checked regularly as per local institutional guidelines (e.g. ONS,^r recommend checking for blood return every 5-10 minutes).

Treatment

In the event of a mixed drug extravasation it is recommended to act in accordance with the drug that has the most harmful properties.

In the event of an extravasation, the initial steps are as follows:^r

STOP the injection or intravenous infusion immediately.
LEAVE the venous access device (VAD) in place.
ASPIRATE any residual drug from the VAD using a sterile syringe.
PLAN

• CALL for assistance - notify medical officer, pharmacist and/or a senior nurse.
• COLLECT the extravasation kit.
• ASSESS the affected area for the presence of symptoms e.g. erythema, swelling, burning, pain and TRACE the affected area with a marker pen.
• PHOTOGRAPH the area.
• REMOVE the IV device or port needle. Do not apply pressure. If a central line is in situ this should remain in position - refer to a medical officer for further instructions.
• INITIATE appropriate drug specific management measures as per protocol.
• ADMINISTER pain relief if indicated.
• REFER to a plastic surgeon or other specialist surgeon (according to individual case and site of extravasation) if clinically indicated.

Antidotes

The use of antidotes in the management of extravasation is controversial and is based on limited evidence from animal studies and small case reports.

Dimethyl sulfoxide (DMSO) 99% solution:

• is used in the management of amsacrine, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin extravasation^r
• has multiple actions - it accelerates the systemic distribution of the extravasated drug through its vasodilating and anti-inflammatory effects^r
• should be applied as soon as possible after extravasation has occurred (ideally within 10 – 25 minutes)
• should be available in an extravasation kit (glass bottle)
• should not be used concurrently with IV dexrazoxane as has been reported to decrease the efficacy of dexrazoxane^r
• DO NOT use with liposomal doxorubicin as application may cause release of active drug from the liposomes^r
• DO NOT apply DMSO 99% solution to wet skin as a chemical burn can result^r
• side effects of DMSO 99% solution include itching, erythema, mild burning and a characteristic 'garlic' breath odour.

For further information regarding safety issues with DMSO 99% solution see the  Material Safety Data Sheet

Link to the Clinical procedure - extravasation management of vesicants using dimethyl sulfoxide solution (DMSO)

Hyaluronidase:

• is the recommended antidote for the extravasation of vinblastine, vincristine, vindesine, vinorelbine, vinflunine^rr
• acts by promoting the dispersion of extravasated drug
• has been reported to produce positive outcomes for paclitaxel extravasation; if used for a paclitaxel extravasation, no compress is recommended.^rr

Link to the Clinical procedure - extravasation management of vesicants using hyaluronidase

Dexrazoxane (Savene®):

• must be administered within 6 hours of an extravasation
• is not registered for use in Australia, but is available via Special Access Scheme (SAS)
• has shown efficacy in preventing anthracycline wound formation
• superiority of dexrazoxane over DMSO 99% solution has not been established^r
• should not be used in children
• should not be used concurrently with DMSO 99% solution as DMSO has been reported to decrease the efficacy of dexrazoxane^r
• consider use with large volume anthracycline extravasations
• cooling compress should be removed 15 minutes prior to the administration of dexrazoxane
• dose is 1,000 mg/m² IV within 6 hours of extravasation followed by 1,000 mg/m² IV on Day 2 (24 hours +/- 3 hours after Day 1) and 500 mg/m² on Day 3 (48 hours +/- 3 hours after Day 1). Administered as an intravenous infusion over 1 to 2 hours, maximum single dose should not exceed 2,000 mg. Administer into a large vein of an extremity or area other than the one affected by the extravasation
• refer to institutional guidelines for obtaining and administration procedures.

Corticosteroids

• There is little evidence to support the use of corticosteroids in the management of extravasation and recommendations from the Oncology Nursing Society (ONS) and the American Society of Health-System Pharmacists (ASHP) do not advocate their use.^rr
• Corticosteroids are usually given to treat inflammation, however it has not been shown that tissue damage from vesicant extravasation is the result of an inflammatory process.
• Corticosteroids may worsen the skin damage from etoposide and vinca alkaloids, and they are specifically contraindicated in these situations.
• If corticosteroids are to be administered, it is important to note that their use is exclusively for symptomatic relief only. In the literature corticosteroids have been administered topically or given locally by subcutaneous injection or intravenously, at a site distant from the injury.
• One circumstance where oral corticosteroids may be of benefit is in patients who have extravasated large amounts of oxaliplatin. In one series of five such patients, the early administration of high dose dexamethasone appeared to have a beneficial effect on the severity and clinical course of the inflammatory reaction.^r

Cold and warm compresses

Cold compresses

The topical application of cold compresses is recommended for the management of extravasation of drugs classed as vesicants, or irritants with vesicant properties, with the exception of the vinca alkaloids (vincristine, vinblastine, vinorelbine, vinflunine) and oxaliplatin. In the case of an oxaliplatin extravasation, the use of a cold compress may exacerbate sensory neuropathy. The use of cold compresses for irritant extravasation is recommended in this document for comfort measures only.^rr

Intermittent cooling is thought to:

• cause vasoconstriction, localising the extravasation
• reduce local inflammation and pain
• decrease cellular uptake of drug.

Instructions for use:

• cover a cold pack with a waterproof covering and place over the affected area
• leave for 15 to 20 minutes (no moisture should come in contact with the patients skin)
• apply every 6 hours for 48 hours.

Warm compresses

Topical application of warm compresses is recommended for use in vinca alkaloid (vinblastine, vincristine, vinorelbine, vinflunine) extravasations because:

• the application of warmth may decrease local drug concentration, increasing the blood flow which results in enhanced resolution of pain and reabsorption of local swelling
• the application of cold has been shown in animal models to increase the risk of tissue damage
• the application of warmth has been reported to be synergistic with hyaluronidase.

There is an absence of documented benefit for the application of local warmth in all other types of extravasations. Studies in the animal model indicate that warmth may increase cellular uptake of drug increasing the risk of cell damage.^r

Instructions for use:

• cover a warm pack with a waterproof covering and place over the affected area
• leave for 15 to 20 minutes (no moisture should come in contact with the patients skin)
• apply every 6 hours for 48 hours
• refer to your local institutional guidelines on using warm packs.

Limb mobilisation

• A study evaluating the efficacy of limb elevation post an infiltration injury found that a 10 cm elevation of the extremity made no difference in the rate of fluid reabsorption.
• Movement should be encouraged to prevent adhesion of damaged areas to underlying tissues.
• Elevate the limb if it provides comfort to a patient.^r

Surgical intervention

There are no uniform guidelines in the literature on the surgical management of extravasation injuries, nor on the optimal timeframe for referral to a plastic surgeon.

In most patients conservative management (including “watch and wait”, the use of pharmacological measures, and the application of topical heating or cooling) is sufficient; however in those where conservative measures fail or functional damage is suspected, surgical intervention may be required.

Clinical assessment of the individual case is paramount in determining if surgical review is necessary. Referral to a plastic surgeon or other specialist surgeon (according to individual case and site of extravasation) is recommended:

• for vesicant extravasations at discretion of medical officer
• for extravasations that involve a fractured or displaced CVAD
• in the event that the patient develops pain or the area is not healing
• for large volume extravasations (the volume which constitutes a large extravasation is undefined in the literature and clinical judgement must be used).

Follow up care

• Patient to monitor the affected area daily for any skin changes or breakdown, and to notify medical team immediately of any changes.
• Careful monitoring by a healthcare professional is recommended; the length of monitoring should be at the advice of the medical officer, and will depend on the cytotoxic drug extravasated and the clinical course of the injury. Consider daily or second daily review for the first week, and then weekly until complete resolution of symptoms.
• Obtain photographs at follow up appointments.
• Community nurse or GP referral may be required for follow up care.

Link to the Assessment tool

It is important to educate the patient and provide written information regarding:

• the potential complications associated with administering antineoplastic drugs and potential risks of an extravasation
• keeping the extremity still when receiving vesicant drugs or irritants with vesicant properties via an IVC
• immediately reporting any pain, swelling, redness, discomfort, burning or stinging.

In the event of an extravasation injury, educate and provide patient with written information on:

• what an extravasation is
• what treatment has already been given
• measures for general management and reducing further damage:
  • do not rub or scratch the area
  • do not wear tight clothing on area
  • protect the area from sunlight
  • raise the affected arm on a pillow if it provides comfort
  • move/exercise the affected arm gently
  • do not use creams or lotions on affected area without speaking with your doctor or nurse
• how to safely care for the injury and specific management required
• equipment required to care for the injury
• how to check the affected area daily and report any skin changes or increase in pain
• how to monitor temperature and seek urgent medical attention if temperature 38°C or higher
• contact numbers for during and after hours
• when to contact clinic or present to emergency
• dates and times of follow up appointments
• the importance of follow up.