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

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^rrrr

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

Patient related risk factors:

• small and/or fragile veins (e.g. elderly and children)
• hard and/or sclerosed veins
• limited vein availability (due to lymph node dissection, lymphoedema)
• obesity in which peripheral access is difficult
• patient movement
• predisposition to bleeding, increased vascular permeability or coagulation abnormalities
• altering sensory perception that may impair patient’s ability to detect sensory changes at the site of administration
• diseases with impaired or altered circulation (e.g. advanced diabetes, Raynaud syndrome, superior vena cava syndrome)
• impaired communication (e.g. non-English speaking patients, patients with communication difficulties, sedation, young children)
• disseminated skin disease (e.g. eczema, or psoriasis).

Medication/infusion related risk factors:

Drug related risk factors:

• vesicant potential of drug
• multiple vesicants within a treatment protocol 
• concentration of drug
• volume of drug administered
• chemical properties of drug (e.g. pH or osmolarity).

Device and access related risk factors:

• high flow pressure (e.g. infusion pump)
• long infusion period
• repeated use of the same vein for vesicant administration
• 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.

Clinician related risk factors:

• untrained or inexperienced staff in vascular access and the management of antineoplastic drugs
• interruption or distractions during drug administration.

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.

Linogram/ 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

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

Prevention^rrrrr

The most effective approach to extravasation injury is prevention. It is important that a multidisciplinary approach is taken to mitigate risks of extravasation. The risk of extravasation can be reduced by taking the following preventative measures:

Patient education

• identify high risk patients
• ensure there are no barriers to effective communication for the purpose of assuring immobility and compliance during IVC insertion, and cooperation during drug infusion
• 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.

Clinician training

• do not inject against resistance
• 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
• ensure knowledge and access to current literature in extravasation management and international guidelines.

Appropriate vascular access

• 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
• infusion sites should be selected in the following order of preference: forearm (basilica, cephalic, and median antebrachial), dorsum of hand, wrist, antecubital fossae
• avoid sites with sclerosis, thrombosis, scar formation or previously irradiated areas
• if venous access via an IVC proves difficult, or inadequate, consider a CVAD.

Safety procedures

• 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
• 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
• flush with 10 to 20 mL of sodium chloride 0.9% or other compatible fluid between different drug infusions, checking for signs of extravasation.

Device selection

• do not use winged steel infusion devices for cannulation (“butterfly” needles), flexible cannulas should be used
• use the smallest adequate and appropriate size cannula in the largest available vein
• ensure the CVAD or IVC is stabilised and secure with a transparent dressing to allow the site to be visualised
• 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.

Vesicant administration

• administer vesicants via a newly inserted IVC
• 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, 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, recommend checking for blood return every 5-10 minutes).

Treatment ^rrrr

In the event of a mixed drug extravasation it is recommended to act in accordance with the drug that has the most harmful properties. Early initiation of treatment is important to minimise damage and prevent additional drug from being injected into the area.

It is recommended that an extravasation kit containing instructions, materials and antidotes, is kept in each patient care area where chemotherapy is administered. 

In the event of an extravasation, regardless of the nature of the drug, the initial steps are as follows:

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.
• ELEVATE the limb if it provides comfort to a patient
• 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.
• AVOID applying direct pressure to the extravasation site. 

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:^rrrrrr

• is used in the management of amsacrine, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin extravasation
• the exact mechanism underlying the benefits of DMSO is uncertain. However it is thought to have multiple actions: accelerating the systemic distribution of the extravasated drug through its vasodilating and anti-inflammatory effects, as well as free radical scavenging properties. 
• 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
• DO NOT use with liposomal doxorubicin as application may cause release of active drug from the liposomes
• DO NOT apply DMSO 99% solution to wet skin as a chemical burn can result
• 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:^rrrr

• is the recommended antidote for the extravasation of vinblastine, vincristine, vindesine, vinorelbine, vinflunine
• 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.

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

Dexrazoxane:^rrrrr

• 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
• is a cytotoxic drug, concomitant administration may cause additive cytotoxicity
• superiority of dexrazoxane over DMSO 99% solution has not been established
• 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
• 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), cap doses at BSA of 2 m². Administered as an intravenous infusion over 1 to 2 hours. Administer into a large vein of an extremity or area other than the one affected by the extravasation
• a 50% dose reduction should be considered for patients with renal impairment (CrCl < 40 mmol/min)
• refer to institutional guidelines for obtaining and administration procedures
• may cause additive myelosuppression effects with concomitant administration, patients should therefore be closely monitored.

Corticosteroids^rrr

• 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.
• 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.

Cold and warm compresses

Cold compresses^rr

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 (vinblastine, vincristine, vindesine​, 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.

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^r

Topical application of warm compresses is recommended for use in vinca alkaloid (vinblastine, vincristine, vindesine​, 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.

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 patient's skin)
• apply every 6 hours for 48 hours
• refer to your local institutional guidelines on using warm packs.

Limb mobilisation^r

• 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.

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^r

• 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.
• It is important to note that early vesicant extravasation signs or symptoms can be subtle, and not always evident until several days or weeks later. Regular patient review is recommended. 
• Patients should be informed about the follow-up policy before leaving the treatment area.
• Take photographs at follow up appointments.
• Community nurse or GP referral may be required for follow up care.

Link to the Assessment tool

Patient education should be a multidisciplinary approach. Clinicians involved hold responsibilities for informing patients about potential administration issues, in order to mitigate the risk of extravasation. 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
  • avoid occlusive dressing over the 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 increase in pain or any skin changes (such as change in colour, temperature or breakdown)
• 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.

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Bibliography

Polovich, M.; White, J. & Kelleher, L. (eds) 2005. "Chemotherapy and Biotherapy Guideline". 2nd Ed. Oncology Nursing Society. Pittsburgh.

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Reeves, D. 2007. "Management of anthracycline extravasation injuries." Ann.Pharmacother. 41(7):1238-1242.

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OBJECTIVE: To review the evidence for the management of anthracycline extravasation and determine the optimal treatment of such injuries. DATA SOURCES: A search of MEDLINE (1966-February 2007) and International Pharmaceutical Abstracts (1970-February 2007) was performed using the search terms anthracyclines and extravasation. DATA SYNTHESIS: Extravasation of anthracyclines can have devastating effects. After infiltration of these drugs into the interstitial tissue, damage may range from mild erythema and pain to severe tissue necrosis. Many agents have been studied in the management of these injuries; however, few have demonstrated efficacy and treatment remains controversial. Nonpharmacologic modalities shown to limit extravasation injuries include local tissue cooling and elevation of the affected area. Corticosteroids, sodium bicarbonate, hyaluronidase, hyperbaric oxygen, heparin fractions, alpha-tocopherol, N-acetylcysteine, and granulocyte macrophage-colony stimulating factor have all either been shown to be ineffective or have limited data supporting their use. Topical dimethyl sulfoxide (DMSO) has been shown in prospective studies to limit the course of extravasation injuries. Dexrazoxane has been shown in animal models and case reports to be useful in the management of anthracycline extravasation. Two recent prospective clinical trials examining intravenous dexrazoxane 1000 mg/m2 within 6 hours of extravasation, 1000 mg/m2 24 hours after extravasation, and 500 mg/m2 48 hours after extravasation injuries add to the data supporting the use of this agent in such injuries. Of the 54 patients enrolled, surgery-requiring necrosis was avoided in 98.2%. CONCLUSIONS: The optimal treatment of anthracycline extravasation includes local tissue cooling, elevation of the afflicted extremity, dexrazoxane administration, and possibly topical DMSO. Many other drugs have been investigated; however, due to a lack of data, they cannot be recommended for the management of anthracycline extravasation.

Valencak, J., M. Troch and M. Raderer. 2007. "Cutaneous recall phenomenon at the site of previous doxorubicin extravasation after second-line chemotherapy." J Natl.Cancer Inst. 99(2):177-178.

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Schulmeister, L. 2005. "Article on mitoxantrone-induced extravasation raised useful questions." Oncol Nurs.Forum. 32(4): 719-720.

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Luke, E. 2005. "Mitoxantrone-induced extravasation." Oncol Nurs.Forum. 32(1):27-29.

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Levin, M., D. Caravone and C. Geiser. 1996. "Mitoxantrone extravasation and tissue necrosis." Am J Health Syst.Pharm. 53(10):1192, 1194.

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Bertelli, G., D. Dini, G. B. Forno, et al. 1994. "Hyaluronidase as an antidote to extravasation of Vinca alkaloids: clinical results." J Cancer Res.Clin Oncol. 120(8):505-506.

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Skin necrosis is a recognized potential consequence of an inadvertent extravasation of Vinca alkaloids in the surrounding tissues during i.v. administration. Experimental studies suggest that hyaluronidase, an enzyme that degrades hyaluronic acid and improves the absorption of locally injected drugs, can reduce the risk of progressing to skin necrosis. On this basis, we used this enzyme as a local treatment after extravasations of Vinca alkaloids in seven patients. No patient suffered from subsequent skin necrosis. To the best of our knowledge, this is the first clinical report confirming the positive findings of experimental studies on the effectiveness of this antidote.

Barutca, S., G. Kadikoylu, Z. Bolaman, et al. 2002. "Extravasation of paclitaxel into breast tissue from central catheter port." Support Care Cancer. 10(7):563-565.

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A 53-year-old woman with advanced-stage ovarian cancer experienced extravasation of paclitaxel into the breast tissue as a result of inappropriate needle insertion and/or dislodgement; it came from a central catheter port (CCP) that was found to be intact under radiological examination with contrast material. The breast became tender and oedematous with erythema, and local warming was observed within a few hours. The patient improved in the next few days during nonsteroidal anti-inflammatory medication and close observation, and the breast healed with thickened and darkened skin and central scarring in the 6th month of follow-up. To the best of our knowledge, extravasation into breast tissue is rare in the literature. Extravasation of vesicant drugs from CCP can cause tissue necrosis; it is therefore essential that ports be carefully assessed and used by experienced staff to lessen the likelihood of such an unpleasant complication.

Mateu, J., M. Alzamora, M. Franco, et al. 1994. "Ifosfamide extravasation." Ann.Pharmacother. 28(11):1243-1244.

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OBJECTIVE: To report a case in which a local reaction is attributed to an ifosfamide extravasation. Previously, extravasated ifosfamide has been considered a nonirritant. CASE SUMMARY: A 54-year-old woman with a non-Hodgkin's lymphoma in stage IV B developed a local reaction in her right arm after an ifosfamide extravasation. No pressure was prescribed, no bandaging was applied on the affected area, and the limb was elevated to the heart level. In addition, chondroitinsulfatase 150 turbidity-reducing units was administered subcutaneously around the area. This procedure was repeated 12 hours later, resulting in a satisfactory decrease in the inflammatory signs and pain. DISCUSSION: The local reaction in the patient's arm cannot be attributed to the hypertonicity of the infusing solution or to the vehicle of the infusate. The antidote used was chondroitinsulfatase, an enzyme similar to hyaluronidase. It enhances the systemic uptake of the drug from the tissue. CONCLUSIONS: Extravasated ifosfamide is a potential irritant. General measures applied after its extravasation can be potentiated strongly by local subcutaneous administration of chondroitinsulfatase or hyaluronidase, repeated if necessary.

Kennedy, J. G., J. P. Donahue, B. Hoang, et al. 2003. "Vesicant characteristics of oxaliplatin following antecubital extravasation." Clin Oncol (R.Coll.Radiol.). 15(5):237-239.

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Oxaliplatin is a novel class of platinum chermotherapeutic agent used in refractory adenocarcinoma. It has previously been regarded as a non-vesicant, and as such was considered safe to administer through peripheral veins. This report documents severe muscle and subcutaneous reaction with a single dose of oxaliplatin at the site of extravasation in a patient aged 58 years. Conventional therapeutic modalities were employed to reduce the effect of the soft tissue infiltrate. Despite that, significant muscle necrosis and fibrosis occurred. Surgery was deferred secondary to patient choice, and eventual extensive physical therapy restored function to the elbow joint. This case shows that oxaliplatin may not be an appropriate cytotoxic agent to be administered through a peripheral line and consideration must be made for central access when this drug is used. In addition, when extravasation does occur, the current report indicates that non-surgical management can be successful.

Bertelli, G., M. A. Cafferata, A. Ardizzoni, et al. 1997. "Skin ulceration potential of paclitaxel in a mouse skin model in vivo." Cancer. 79(11):2266-2269.

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de Lemos, M. L. and S. Walisser. 2005. "Management of extravasation of oxaliplatin." J Oncol Pharm.Pract. 11(4):159-162.

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Oxaliplatin extravasation has been associated with local pain and inflammation which may be severe and lead to complications including necrosis. Recent case reports suggest that oxaliplatin may be better classified as an irritant when extravasated. The optimal management of oxaliplatin extravasation however remains uncertain. Cold compress may cause local vasoconstriction and reduce cellular injury. However, it may potentially precipitate or worsen peripheral neuropathy. Warm compress may increase drug removal by local vasodilation and avoid peripheral neuropathy. However, it may potentially increase cellular uptake and hence injury. Further research into this area is needed.

Baur, M., H. R. Kienzer, T. Rath, et al. 2000. "Extravasation of Oxaliplatin (Eloxatin(R)) - Clinical Course." Onkologie. 23(5):468-471..

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BACKGROUND: Up to now the cytostatic oxaliplatin was classified as nonvesicant. This is the first report on tissue necrosis induced by oxaliplatin extravasation in literature. A clinical course following oxaliplatin extravasation is reported. CASE REPORT: A 52-year-old white female with adenocarcinoma of the colon and hepatic and pulmonary metastases received palliative chemotherapy consisting of oxaliplatin, leucovorin, and 5-fluorouracil. By mistake oxaliplatin infusion extravasated subcutaneously in the left forearm; consequently, a painless red swelling occurred without any sign of further damage of the tissue. The infusion cannula was removed and oxaliplatin was infused into the right median cubital vein at the elbow. Again oxaliplatin extravasated subcutaneously. A severe painful necrotic reaction of the underlying flexor muscles of the right elbow developed, disabling the patient for 2 months, showing red-brown painful swelling, sclerosis of the skin, induration, fixation, and immobilization of the right elbow. Nonsteroidal analgesics and antibiotics were given, and lymphatic drainage and physiotherapy performed as generally accepted polypragmatic unspecific therapeutic procedure. After 2 months, the patient was able to bow and extend the right elbow except for an extension deficit of 20 degrees, pro- and supination became possible again, pain had completely resolved and strength recovered without limitation. Sclerosis of the skin and stiffness of the underlying tissue were slowly subsiding. CONCLUSION: Oxaliplatin can induce severe necrosis of underlying muscles by extravasation and therefore must be considered as a vesicant. Therefore oxaliplatin should be applied via a central venous access. Copyright 2000 S. Karger GmbH, Freiburg

Berghammer, P., R. Pohnl, M. Baur, et al. 2001. "Docetaxel extravasation." Support Care Cancer. 9(2):131-134.

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We report on an accidental extravasation of docetaxel given intravenously as chemotherapy in a cancer patient. The extravasate was immediately diluted subcutaneously with saline, in addition to which hypothermia (ice-packs) was implemented and topical dimethylsulfoxide (DMSO) was applied three times every 45 min. Corticosteroids and diclofenac were also administered. Dermatitis developed immediately but had disappeared within 24 h. Notably, dermatopathological changes were absent on days 2-4, minimal on day 5, and increased thereafter. Dermatitis developed as a late symptom, resulting in brown discoloration and skin hyperplasia. No plastic surgical intervention was necessary. We propose that isotonic saline, topical DMSO and local hypothermia may have restricted the inflammation and tissue necrosis induced by the extravasation of docetaxel. Repetitive topical application of DMSO beyond the day of extravasation had no additional benefit

Bairey, O., J. Bishara, B. Stahl, et al. 1997. "Severe tissue necrosis after cisplatin extravasation at low concentration: possible "immediate recall phenomenon"." J Natl.Cancer Inst. 89(16):1233-1234.

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Raley, J., J. P. Geisler, T. E. Buekers, et al. 2000. "Docetaxel extravasation causing significant delayed tissue injury." Gynecol.Oncol. 78(2):259-260.

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PURPOSE: Docetaxel is a relatively new taxane that has not been associated with significant tissue injury after extravasation. We present a case of a patient who had grade 4 tissue toxicity after extravasation of docetaxel infused through a peripheral intravenous site. CASE REPORT: A 71-year-old female was being treated for recurrent ovarian cancer with docetaxel and carboplatin. Shortly after the docetaxel infusion began, she experienced docetaxel extravasation into the dorsum of her left hand. The infusion was halted, and then the administration was continued in a peripheral intravenous site in the other upper extremity. Erythema was noted by the patient on the dorsum of her left hand 6 days after infiltration. The following day, the patient noted severe pain, decreased function, and blistering along with increased erythema. The patient presented to the gynecology oncology clinic 11 days after the extravasation injury occurred. Conservative management was undertaken, and over the next 4 weeks the patient had resolution of the skin changes and full return of function. CONCLUSION: Docetaxel can cause significant delayed tissue injury if extravasation occurs.

El Saghir, N. S. and Z. K. Otrock. 2004. "Docetaxel extravasation into the normal breast during breast cancer treatment." Anticancer Drugs. 15(4):401-404.

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We report a new case of central line extravasation of docetaxel into the normal breast of a patient with metastatic left breast cancer. During the infusion of docetaxel, the patient complained of mild discomfort at the site of a subclavian Port-a-Cath, followed by redness, warmth and itchiness of the entire skin of the right breast beneath the port of entry, and it involved the entire right breast by the next day. Over the following few days, she developed blistering, desquamation and oozing of serous fluid through skin fissures. Anti-histamines and hydrocortisonebased ointment induced partial relief of symptoms. Warm soaks induced skin relief. Reaction resolved over few weeks leaving a brownish pigmentation of the skin of the breast, with clearly demarcated lines, as the only sequlae.

Stanford, B. L. and F. Hardwicke. 2003. "A review of clinical experience with paclitaxel extravasations." Support Care Cancer. 11(5):270-277.

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Paclitaxel is a novel anti-neoplastic with a wide spectrum of activity in various malignant tumors. Extravasation of chemotherapy drugs is a widely feared adverse event in oncology patients. A Medline search between 1966 and October 2002 was conducted to identify case reports related to paclitaxel extravasation, as well as a bibliography screening of identified papers. The goal of this work is to summarize the available reports of paclitaxel extravasation and assess its vesicant potential. Additionally, management strategies for extravasation events due to paclitaxel are assessed.

Schulmeister, L. and D. Camp-Sorrell (2000). "Chemotherapy extravasation from implanted ports." Oncol Nurs.Forum. 27(3): 531-538.

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PURPOSE/OBJECTIVES: To describe the four primary causes of extravasation from implanted ports. DATA SOURCES: Journal articles, textbooks, medical records, depositions, serial photographs, and the authors' personal experiences. DATA SYNTHESIS: Extravasation from ports can occur by four major mechanisms: incomplete needle placement and needle dislodgment, thrombus or fibrin sheath formation, perforation of the superior vena cava, and catheter fracture. The degree of tissue injury can vary but may be severe enough to require that a simple mastectomy be performed to manage chest wall necrosis. CONCLUSIONS: Extravasation is a known risk of chemotherapy administration via implanted ports. Vesicants should be administered only after a blood return has been obtained and the needle inserted into the port septum has been adequately secured. IMPLICATIONS FOR NURSING PRACTICE: Extravasation of vesicant drugs from ports can cause tissue necrosis and may prompt litigation. Risk-management strategies include careful assessment and use of ports, comprehensive patient teaching about the risk of extravasation and measures to decrease the likelihood of needle dislodgment, and development of extravasation-management policies that address port extravasations.

Froiland, K. (2007). "Extravasation injuries: implications for WOC nursing." J Wound.Ostomy.Continence.Nurs. 34(3): 299-302.

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Viale, P. H. 2003. "Complications associated with implantable vascular access devices in the patient with cancer." J Infus.Nurs. 26(2):97-102.

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Implantable vascular access devices (IVADs), or implantable ports, have been used for patients with cancer for more than 20 years. Although these devices have greatly improved infusion access for this population of patients, complications may still occur. Nurses working with oncology patients who have IVADs must be aware of possible problems for these patients, as well as the importance of early assessment and intervention. The diagnosis of cancer and potential treatments for this disease may make these patients at higher risk for complications associated with the use of IVADS.

Nesti, S. P. and R. Kovac. 2000. "5-fluorouracil extravasation following port failure." J Intraven.Nurs. 23(3):176-180.

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A case is presented of cytotoxic extravasation as a result of an implantable venous port being perforated by a standard Huber needle. A patient receiving 5-fluorouracil via a dual reservoir port, implanted within the left chest wall, presented with hemoserous discharge from the right needle entry site. The left chest wall was warm to touch, erythematous, and swollen. Subcutaneous infiltration was suspected, and the infusion was ceased. A venogram was performed demonstrating significant extravasation around the left reservoir only. On port removal, inspection showed the Huber needle had penetrated the base plate on the left side. It is recommended that this complication be added as a possible sequelae of central venous port use.

Common Terminology Criteria for Adverse Events Version 4.03, DCTD, NCI, NIH, DHHS June 14,2010

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Dorr, R. T. 1990. "Antidotes to vesicant chemotherapy extravasations." Blood Rev. 4(1):41-60.

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The foregoing sections have reviewed the experimental studies and clinical anecdotes describing potential pharmacologic antidotes to extravasations of vesicant anticancer agents. Numerous prior reviews have also suggested specific antidotes or very conservative, non-pharmacologic approaches. Many antidotal approaches to extravasation have not been experimentally validated and thus, few 'antidotes' share a rationale which is founded on positive experimental and clinical studies. However, using this criteria, a few active antidotes can be distilled from the literature. These are outlined in Table 6. These antidotes include isotonic (1/6 M) sodium thiosulfate for mechlorethamine (and optionally for cisplatin), hyaluronidase for the vinca alkaloids (and optionally for epipodophyllotoxins such as etoposide), and cooling with very topical DMSO and low dose hydrocortisone for the anthracyclines. For the alkylating agent mitomycin C, topical DMSO has been effective experimentally but has not yet received clinical validation, at least in published studies. Nonetheless, the severity of mitomycin C ulcerations and the documented safety of topical DMSO in the small series of doxorubicin extravasation patients argues for its use when mitomycin extravasates in the clinic. Furthermore, except for DMSO, all of these extravasation antidotes are listed in the official FDA-approved package inserts for each vesicant agent. Thus, the inserts for vincristine and vinblastine specify hyaluronidase, for doxorubicin, glucocorticosteroids, and for mechlorethamine, sodium thiosulfate. New studies are clearly needed to clarify the role of topical DMSO with anthracyclines and mitomycin C. In addition, efforts should be made to begin clinical development of radical dimers such as DHM3 which can directly inactivate quinone-containing vesicants like doxorubicin and mitomycin C. Although the incidence of chemotherapy extravasation may be lessened with vascular access devices, it nonetheless, continues to comprise a serious and highly litigious area of oncology practice. This commands continued extravasation intervention studies and diligent prevention when ever possible.

Olver, I. N. and M. A. Schwarz. 1983. "Use of dimethyl sulfoxide in limiting tissue damage caused by extravasation of doxorubicin." Cancer Treat Rep 67(4):407-408.

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Olver, I. N., J. Aisner, A. Hament, et al. 1988. "A prospective study of topical dimethyl sulfoxide for treating anthracycline extravasation." J Clin Oncol 6(11):1732-1735.

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Twenty patients with extravasation of anthracyclines were treated on a single-arm pilot study with topical 99% dimethyl sulfoxide (DMSO) and observed for 3 months with regular examinations and photographs. DMSO was applied to approximately twice the area affected by the extravasation and allowed to air dry. This was repeated every six hours for 14 days. The initial signs of extravasation included swelling in 17 patients, erythema in 15, and pain in 12. The median area of damage was 8.25 cm2 and a median of 25 minutes elapsed between extravasation and application of DMSO with one patient not treated until seven days postextravasation. Sixteen patients were observed for 3 months, two died of disease earlier after receiving 2 weeks of DMSO and three days of DMSO, respectively, and two were lost to follow-up having received one day and five days of DMSO. In no patient did extravasation progress to ulceration or require surgical intervention, suggesting with 95% confidence a true ulceration rate of between 1% and 17%. At 3 months there was no sign of residual damage in six patients, while a pigmented indurated area remained in ten. Two patients had a recall reaction with increased pain at the extravasation site when further intravenous (IV) doxorubicin was administered. The only toxicities of DMSO included a burning feeling on application subsequently associated with itch, erythema, and mild scaling. Blisters occurred in four patients. Six patients reported a characteristic breath odor associated with DMSO. Topical DMSO appears to be a safe and effective treatment for anthracycline extravasation.

Ludwig, C. U., H. R. Stoll, R. Obrist, et al. 1987. "Prevention of cytotoxic drug induced skin ulcers with dimethyl sulfoxide (DMSO) and alpha-tocopherole." Eur J Cancer Clin Oncol 23(3):327-329.

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Accidental subcutaneous extravasation of several antineoplastic agents may provoke skin ulcerations for which there has been no simple and effective treatment. Since January 1983 we have treated all patients in our institution sustaining extravasation by a cytotoxic drug with a combination of DMSO and alpha-Tocopherole. During the first 48 hr after extravasation a mixture of 10% alpha-Tocopherole acetate and 90% DMSO was topically applied. The bandage was changed every 12 hr. So far eight patients with extravasation of an anthracycline or Mitomycin were treated on this protocol. No skin ulceration, functional or neurovascular impairment occurred in any of these patients. The only toxic effect observed by this treatment was a minor skin irritation. The combination of DMSO and alpha-Tocopherole seems to prevent skin ulceration induced by anthracyclines and Mitomycin.

Maslovsky, I. 2007. "Extravasation injury as a result of VAD chemotherapy." J Wound.Ostomy.Continence.Nurs. 34(3):297-298.

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Comas, D. and J. Mateu. 1996. "Treatment of extravasation of both doxorubicin and vincristine administration in a Y-site infusion." Ann.Pharmacother. 30(3):244-246.

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OBJECTIVE: To describe a patient treated with vincristine, doxorubicin, and dexamethasone who experienced extravasation of both doxorubicin and vincristine during a Y-site infusion. CASE SUMMARY: A 74-year-old white woman was diagnosed with multiple myeloma IgA kappa in stage IIA. One year after a complete remission she relapsed. Her treatment included daily doxorubicin 16 mg in 500 mL of dextrose 5% and vincristine 0.4 mg in 500 mL of dextrose 5% administered in a Y-site continuous infusion into a peripheral vein of her left forearm. Extravasation occurred during administration of these drugs. Immediately, chondroitinsulfatase, a mucopolysaccharidase similar to hyaluronidase, was administered subcutaneously around the extravasation area and repeated 24 hours later. Furthermore, dimethyl sulfoxide 90% v/v was applied topically on the area four times daily for 2 weeks. All inflammatory signs resolved and no necrosis developed. DISCUSSION: Ths is the first report of an extravasation of two cytotoxic drugs. Doxorubicin and vincristine have different antidotes and opposite physical treatments for their extravasation. The antidotes dimethyl sulfoxide and chondroitinsulfatase have different mechanisms of action, but both cause uptake of the cytotoxic agent from the tissue and are likely to be administered together. No warming or cooling was performed. CONCLUSIONS: Topical dimethyl sulfoxide four times daily for 14 days plus subcutaneous chondroitinsulfatase in one or two applications effectively treated an extravasation of both doxorubicin and vincristine in our patient

Hadaway, L. C. 2004. "Preventing and managing peripheral extravasation." Nursing 34(5):66-67.

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Viale, P. H. 2006. "Chemotherapy and cutaneous toxicities: implications for oncology nurses." Semin.Oncol Nurs. 22(3):144-151.

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OBJECTIVE: To review common cutaneous effects and dermatologic or cutaneous toxicities related to the administration of chemotherapy. These range from mostly cosmetic, such as hyperpigmentation or alopecia, to dose-limiting toxicities such as palmar-plantar erythrodysesthesia or hand-foot syndrome. DATA SOURCES: Current research, published literature, and internet resources. CONCLUSION: Assessment and grading of associated toxicities of therapy is an integral part of caring for this patient population. Early intervention may reduce toxicities associated with therapies for this patient population IMPLICATIONS FOR NURSING PRACTICE: As more patients receive chemotherapy, dermatologic effects are becoming more common. Oncology nurses must be skilled in managing these side effects

NSW Health. 2005. Consent to Medical Treatment - Patient Information. PD2005_406. NSW Department of health.

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NSW Health. 2007. Infection Control Policy PD2007_36. NSW Department of Health 2007

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SafeWork NSW. 2017. Cytotoxic Drugs and Related Waste Risk Management Guide 2017. New South Wales Government

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Hadaway, L. C. 2004. "Preventing extravasation from a central line." Nursing 34(6): 22-3.

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Saini, A., A. Berruti, P. Sperone, et al. 2006. "Recall inflammatory skin reaction after use of pegylated liposomal doxorubicin in site of previous drug extravasation." Lancet Oncol. 7(2):186-187.

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Madhavan, S. and D. W. Northfelt. 1995. "Lack of vesicant injury following extravasation of liposomal doxorubicin." J Natl.Cancer Inst. 87(20):1556-1557.

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Loth, T. S. and W. W. Eversmann, Jr. 1986. "Treatment methods for extravasations of chemotherapeutic agents: a comparative study." J Hand Surg Am 11(3):388-396.

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A rat model was used to compare early surgical intervention with injectable and topical antidotes with regard to their effectiveness in preventing cutaneous ulcers that were caused by intradermal injections of vesicant chemotherapeutic agents. The (animals) rats received bilateral flank injections of doxorubicin, vincristine, actinomycin D, mitomycin C, or carmustine (BCNU) in concentrations that were comparable to concentrations used for human patients; after the injections they underwent debridement at various intervals or received immediate applications of selected antidotes. Many antidotes which were frequently used, were not effective in limiting the size of the ulcer and in producing rapid healing of ulcers that were caused by experimental vesicant extravasations. Early surgical debridement was the most effective method of decreasing vesicant ulcer size and facilitating rapid ulcer healing of all the interventions tested.

Jones, L. and P. Coe. 2004. "Extravasation." Eur J Oncol Nurs 8(4):355-358.

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Ener, R. A., S. B. Meglathery and M. Styler. 2004. "Extravasation of systemic hemato-oncological therapies." Ann Oncol 15(6):858-862.

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Systemic intravenous chemotherapeutic agents can cause multiple emergency situations including acute and chronic local and systemic reactions. Amongst them, drug extravasation is one of the most devastating complications, as many drugs can cause varying degrees of local tissue injury when extravasated. Although it is difficult to give an accurate measurement, the incidence of extravasation of systemic infusional chemotherapeutic agents has been reported to occur in 0.1-6.5% of cases. Since most extravasations can be prevented with the systematic implementation of careful administration techniques, guidelines have been published for the administration of vesicant drugs. The proper maintenance of intravenous lines, application of local cooling or warming for certain extravasations, and the use of antidotes to prevent the local toxic action of the extravasated drugs are the basis of medical management. The specific antidotes for certain chemotherapeutic agents are also discussed in this article.

Boyle, D. M. and C. Engelking. 1995 "Vesicant extravasation: myths and realities." Oncol Nurs Forum 22(1):57-67.

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PURPOSE/OBJECTIVES: To provide a comprehensive review of the literature pertinent to the phenomenon of antineoplastic vesicant extravasation within the framework of common misconceptions held by oncology nurses. DATA SOURCES: National guidelines, published articles in professional specialty journals and proceedings, and the authors' clinical experiences in the care of patients receiving vesicant agents. DATA SYNTHESIS: Antineoplastic vesicant extravasation can result in significant morbidity, severely limiting quality of life for patients with cancer. It also is a liability concern for oncology nurses. Many unanswered questions regarding extravasation exist because the phenomenon is difficult to study in humans and actual extravasation injuries are both sporadic and underreported. The incidence of extravasation from vascular access devices is unknown. Similarly, many recommended management strategies are empirically based. Misconceptions about the nature of extravasation injuries and the manner in which they should be managed contribute to poor patient outcomes and increased liability. CONCLUSIONS: The disproval of 10 myths regarding the nature and management of vesicant extravasation is an adjunctive step in the translation of existing national guidelines to workable institutional standards and appropriate professional practice. NURSING IMPLICATIONS: Oncology nurses are in a strategic position to observe the feasibility and efficacy of prevention and management guidelines established at national and local levels. Oncology nurses involved in the administration of antineoplastic vesicant agents are responsible for maintaining a current knowledge base about vesicants and for planning nursing care within the established standards of practice.

Rudolph, R. and D. L. Larson. 1987. "Etiology and treatment of chemotherapeutic agent extravasation injuries: a review." J Clin Oncol 5(7):1116-1126.

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While extravasation from intravenous (IV) lines is common and usually benign, leakage of certain drugs can cause severe skin ulceration. These ulcerogenic drugs can be conveniently divided into two categories, depending on whether they bind to DNA. Chemotherapeutic agents such as doxorubicin, which bind to DNA, are especially prone to cause severe extravasation skin ulcers. These ulcers are often chronic and progressive. Neither clinical nor experimental studies have shown an antidote to doxorubicin extravasation, which is best prevented by careful technique. If extravasation is suspected, the infusion should be immediately stopped. In the event of extravasation, elevation and ice are the currently recommended treatment. While small ulcerations may on occasion heal, large ulcerations require surgical excision for relief of pain and salvage of underlying tissues.

Wood, L. S. and S. M. Gullo. 1993. "IV vesicants: how to avoid extravasation." Am J Nurs 93(4):42-46.

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Schrijvers, D. L. 2003. "Extravasation: a dreaded complication of chemotherapy." Ann Oncol 14 Suppl 3:iii26-30.

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Davis, M. E., D. DeSantis and K. Klemm. 1995. "A flow sheet for follow-up after chemotherapy extravasation." Oncol Nurs Forum 22(6):979-983.

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PURPOSE/OBJECTIVES: To introduce and describe the development and implementation of a flow sheet used to document patient follow-up after chemotherapy extravasation. DATA SOURCES: Published articles, institutional standards of nursing practice, and the Oncology Nursing Society Cancer Chemotherapy Guidelines. DATA SYNTHESIS: Extravasation is a potentially serious and severe complication of vesicant chemotherapy administration. A tool was designed to streamline documentation of patient symptoms, nursing interventions, patient education, and follow-up care after a suspected or actual extravasation. CONCLUSIONS: The flow sheet improves nursing documentation after a suspected or actual vesicant chemotherapy extravasation and provides a consistent, concise method for monitoring extravasations over time. IMPLICATIONS FOR NURSING PRACTICE: The flow sheet standardizes nursing assessment, intervention, patient education, and follow-up care after a suspected or actual chemotherapy extravasation. Use of the flow sheet saves time and improves consistency of nursing documentation.

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