Extravasation is a therapeutic emergency that does not support improvisation and it is paramount to be aware of the described treatments and principles for prevention and management
Irene Kriegel MD
Benoit Botrel MD
Institut Curie, Paris, France
Extravasation is the accidental release of a drug outside the vein (more rarely an artery) into the surrounding tissues. The drugs are classified according to their potential to cause local damage and whether they are non-irritants (do not cause inflammation or damage), irritants (do not give rise to necrosis) or vesicants (can cause irritation, vascular ulceration, and necrosis). The higher the volumes and concentrations, the more serious the consequences of extravasation, hence the differences that exist between certain existing classifications.1,2 Specifications for risk agents are:
- A highly acidic pH or very alkaline low pH (amiodarone, omeprazole, propranolol, vancomycin, acyclovir)
- An osmolarity greater than that of plasma (glucose and 20% NaCl, 10% KCl, parenteral nutrition, certain contrast agents)
- Type of excipient (alcohol)
- Ability to trigger vascular vasoconstriction (adrenaline, noradrenaline, dopamine, dobutamine).
- Vesicant cytotoxics are classified into two groups:
- Ability to bind to DNA, leading to a vicious cycle of tissue damage: anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin), amsacrine, chlormethine, dactinomycin, mitomycin C, mitoxantrone
- Not bound to DNA: vinca alkaloids (vincristine, vinblastine, vinorelbine and vindesine,) trabectedin.
Docetaxel, paclitaxel and platinum salts are considered as vesicant or irritant according to classifications and concentrations used.
Incidence and risk factors
In the absence of centralised registers of events, incidence data are poor and literature is mostly made up of clinical cases. The incidence varies from 0.01% to 6% in the literature.3,4 This is a rare complication that is underdiagnosed and undertreated.5 A retrospective monocentric study showed that, due to staff training, the incidence of this complication was reduced by a factor of ten (0.1% to 0.001% in 15 years).5
The main risk factors in the margins are now well known (small calibre veins and weakened sclerosed veins, obese patients, diabetic vascular disease with peripheral lymphoedema, coagulation disorders, peripheral sensory deficit or communication disorders, prolonged drip). In all cases where one chooses peripheral access, one must choose a straight vein on the forearm, avoiding the back of the hand, the elbow and the nearby joints. Putting a drip on a hemiplegic arm or after an axillary dissection should be avoided. Do not use steel needles.6
Central venous devices (central venous catheters, implantable venous catheters and peripherally inserted central catheters) are increasingly used. They are highly recommended when long duration vesicant drug infusions are used (more than 12h). The use of central lines has reduced the risk of extravasation but the risk remains and extravasation may be more difficult to diagnose and the consequences are more serious.
The causes of extravasation of central venous lines are: catheter malposition – especially in the pleura (Figure 1), malposition or secondary displacement of the Huber needle (Figure 2), perforation of the superior vena cava, a sleeve of fibrin, a costoclavicular clamp or the rupture of the catheter. Extravasation then occurs in the mediastinum, the pleural space or in the pre-thoracic or neck subcutaneous tissues. Prevention relies on the correct implementation of a Huber needle with a height adapted to the patient’s body size and depth of the box, its correct fixation to avoid secondary movements, the obsessive verification of the indicators of proper operation of the catheter (presence of blood reflux, good infusion rate), and thorough rinsing between each product use and before removal of the needle.
It is essential to monitor the product flow in the periphery and in central lines and to use a bandage to visualise the puncture site, and also to inform and educate the patient.
The main early clinical signs are erythaema, pain (which can be missed in obese patients), induration and oedema – all associated with a lack of blood reflux, decreased flow or increased resistance during administration. A positive diagnosis may require a chest X-ray or a CT scan (Figure 1). A differential diagnosis (chemical thrombosis and phlebitis) can be done via Doppler. Clinical signs may not appear until after a few days, especially with anthracyclines. Ulceration and necrosis may then increase over several months, which can lead to sequelae or necessitate mutilating surgery. It is important to consider that the extent of the lesions is related to the type of drug used, the drug concentration, the location of extravasation and the length of time the drug was in contact with the tissues.
Management of extravasation
Immediate general measures
- Stop the infusion immediately
- Note the time
- Mark the area with an indelible pen and take a picture
- Assess the volume and concentration of the extravasated solution
- Notify the physician
- Leave the Huber needle and syringe in place to facilitate removal of the maximum amount of vesicant product
- Inform the patient and let him/her fast; manage the pain
- Begin specific measures.
- Hot–cold: heat packs are recommended for vinca alkaloids and all non-cytostatic products, except for parenteral nutrition, acyclovir and vancomycin and the application of cold for the anthracyclines, provided the application is stopped 15 minutes before an injection of dexrazoxane (Savene®), parenteral nutrition, vancomycin and acyclovir. Applications should be carried out for 15–30 minutes four times a day.
- Specific antidotes:
– Subcutaneous injections of corticosteroids are not recommended
– 99% DMSO: non-consensual use of three-to-four drops per 10cm of skin surface three-to-four-times a day for 7–14 days, for extravasation of anthracyclines of mitomycin C and platinum.
– hyaluronidase at a dose of 1–6ml of 150U/ml could be effective in the extravasation of vinca alkaloids
– Savene® (dexrazoxane) (or Totect® in the US) is currently the only proven and licenced antidote in Europe for the treatment of anthracycline extravasation in adults. Savene® was granted orphan medicinal product status by the European Commission in 2001 and received marketing authorisation in 2006, renewed in July 2011. Authorisation was based on two multicentre prospective studies in patients with anthracycline extravasation that was confirmed by the fluorescence microscopy of skin biopsy.7 Its mechanism of action is the inhibition of DNA topoisomerase 2 and iron chelation, which prevents the formation of free radicals and the vicious circle of skin lesions. A recent study in Belgium confirmed the efficiency and the safety profile of Savene® when used routinely: the use of surgery was necessary in only two out of 28 cases of extravasation of implantable catheters and in no cases of peripheral extravasation (13 patients).
The chemotherapy plan was maintained for 73% (30/41) of patients.8 The administration of Savene should begin within the first six hours at a dose of 1000mg/m2 IV over two hours in a vein located at a distance from the extravasation and should be repeated at the same time on D2 (1000mg/m2) and D3 (500mg/m2). Using Savene counter-indicates immediate recourse to surgery. The cost of Savene, although high, must be weighed against the cost of surgery and efforts sharing the product must be made, if possible, between neighbouring hospitals to reduce the cost.
Savene® eliminated the need for surgical intervention in 98% of patients.7
Lavage and drainage
Examples of surgical lavage and drainage and lipoaspiration9,10 are shown in Figures 3 and 4:
- These surgical techniques should be introduced in the first six hours. They can be implemented by any surgeon, including non-plastic surgeons, trained in these techniques. They require, as a rule, general anaesthesia in the operating room. These techniques may require the loss of the implantable chamber
- Pleural or mediastinal extravasations may require chest tube drainage, thoracoscopy or thoracotomy.11 The major cardiac toxicity of anthracyclines intrapleural calls for the primary and systematic use of Savene®.
Late surgical treatment, at necrotic stage, is a failure of early diagnosis or of initial treatment.
It is essential to develop, within a multi-professional group, procedures for installation, use and maintenance of venous devices.
It is essential to develop, within a multi-professional group, early extravasation procedures to ensure the practical organisation of surgical and pharmacological treatment.
It is essential to regularly check the dissemination of these recommendations and provide information to patients.
It is essential, in case of accidents, to document and analyse the issue, taking into account the psychological impact on the treatment team.
- The extravasation of vesicant agents is a therapeutic emergency that must be recognised promptly so that treatment can be initiated within the first six hours of the accident, to avoid the risk of severe tissue necrosis and major late sequelae (chronic pain, dystrophy, loss of function, aesthetic sequelae).
- Prevention of this kind of accident is crucial, as is an informed patient, trained staff and an institutional policy that can anticipate risks and be able to react.
- This incident has an almost inevitable forensic impact, not to mention the risk of loss of opportunity due to a delay in the expected treatment. There is no room for improvisation and traceability of documents and information must be rigorous.
- Carers have a key role in prevention as well as the immediate action to be taken.
- Allwood M et al. The Cytotoxics Handbook, 4th edn 2002. UK: Radcliffe Medical Press Inc.
- Pérez Fidalgo JA et al. ESMO Guidelines Working Group. Management of chemotherapy extravasation: ESMO-EONS Clinical Practice Guidelines. Ann Oncol 2012;23(Suppl 7):vii167–73.
- Kassner E. Evaluation and treatment of chemotherapy extravasation injuries. J Pediatr Oncol Nurs 2000;17(3):135–48.
- Schulmeister L. Extravasation management: clinical update. Semin Oncol Nurs 2011;27(1):82–90.
- Langstein HN et al. Retrospective study of the management of chemotherapeutic extravasation injury. Ann Plast Surg 2002;49(4):369–74.
- European Oncology Nursing Society (EONS). Extravasation Guidelines. Eur J Oncol 2008;12:357–61.
- Mouridsen HT et al. Treatment of anthracyclines extravasation with Savene (dexrazoxane): results from two prospective clinical multicentre studies. Ann Oncol 2007;18(3):546–50.
- Fontaine C et al. Savene® (dexrazoxane) use in clinical practice. Support Care Cancer 2012;20(5):1109–12.
- Lambert F et al. Iatrogenic extravasations of cytotoxic or hyperosmolar aqueous solutions. Value of surgical emergency by aspiration and lavage. Ann Chir Plast Esthet 1997;42(4):305–13.
- Steiert A et al. Subcutaneous wash-out procedure (SWOP) for the treatment of chemotherapeutic extravasations. J Plast Reconstr Aesthet Surg 2011;64(2):240–7.
- Uges JW et al. Intrapleural extravasation of epirubicin, 5-fluouracil, and cyclophosphamide, treated with dexrazoxane. Int JClin Oncol 2006;11(6):467–70.