Extravasaciones de quimioterápicos y su manejo.

 

Definición.

 

La extravasación es un proceso por el cual un líquido o droga, accidentalmente se sale fuera de su vía de administración e invade los tejidos circundantes. En los tratamientos del cáncer se refiere a infiltración inadvertida de quimioterapia en los tejidos subcutáneso o subdérmicos tras una administración intravenosa o intraarterial. (Guias ESMO 2012)

 

Las drogas extravasadas se clasifican en función de su daño en "vesicantes", "irritantes" y no vesicantes. Algunas drogas vesicantes también se clasificanen en las que se unen al ADN y las que no se unen al ADN. Otros autores las clasifican en vescantes, exfoliantes, irritantes, inflamatorias y neutrales. 

 

Incidencia

Data on the incidence of either extravasation or infiltration are scant due to the absence of a centralized register of chemotherapy extravasation events. Incidence rates vary greatly. Estimates between 0.01% and 7% are noted invarious publications [2–7]. Some data suggest that the incidence is decreasing probably due to improvements in the infusion procedure, early recognition of drug leakage and training in management techniques. A single-institution retrospective study confirmed that the overall incidence was 10 times less frequent in 2002 than 15 years earlier (0.01% versus 0.1%; P = 0.001) [8]. Data regarding extravasation from central venous access devices (CVAD) are limited.

Risk factors for extravasation

Adequate identification of the potential factors for extravasation is important to minimize the risk in some patients. In case of an increased risk of extravasation, preventive measures should be encouraged or in some cases,insertion of a CVAD should be considered. These factors can be classified under patient-associated and procedure-related risk factors [4, 7, 9].

Prevention

Most extravasations can be prevented with the systematic implementation of careful, standardized, evidence-based administration techniques.

In order to minimize the risk of extravasation, the staff involved in the infusion and management of cytotoxic drugs must be trained to implement several preventive protocols [4, 7, 9].

Should an extravasation occur, it is important to remember that the degree of damage is dependent on the type of drug, the drug concentration, the localization of the extravasation and the length of time a drug develops its potential for damage.

Diagnosis

Patients must be informed to report any changes in sensation, signs or symptoms during the i.v. administration of any chemotherapy drug and to alert the healthcare professional to early signs of extravasation. Particular information must be given when a vesicant drug is administered.

Extravasation must be suspected if any of the specific signs or symptoms are present. Initially, among the most common symptoms are feelings of tingling, burning, discomfort/pain or swelling, and redness at the injection site. Later symptoms may include blistering, necrosis and ulceration.

Signs that frequently raise suspicion of an eventual extravasation are the absence of blood return, resistance on the plunger of the syringe during delivery of a bolus drug, or an interruption to the free flow of an infusion.

If an extravasation is suspected, the cannula should never be removed immediately and general and specific measures should be started.

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 and along the accessed vein (‘flare’), urticaria and local itching. Drugs that may cause these reactions are shown in Table 4.

Another potential differential diagnosis is chemical phlebitis. This vein inflammation, frequently 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. This chemical phlebitis can be caused by several drugs (see Table 4).

Management of extravasations

No randomized trials on the treatment of extravasation have been carried out until now for ethical reasons as well as certain difficulties in including an adequate number of patients in such a trial. However, many extravasations may cause very little damage if left untreated and only a comparative study with a control group receiving the standard local care would allow clinicians to clearly define the efficacy of an antidote.

Many of the reported management policies for extravasations are based on non-biopsy confirmed data and in many cases, simultaneous treatment with antibiotics was initiated. It should be also considered that many of the recommendations date back to a drug’s original registration, which can be several decades ago when requirements for approval were less strict.

General measures

Regardless of the chemotherapy drug, early initiation of treatment is considered mandatory. In this context, patient education is crucial for a prompt identification of the extravasation.The initiation of general unspecific measures as soon as an extravasation is diagnosed is highly recommended[10] (See Figure 1) [V, A]. For that purpose, it is highly recommended that every department that administers chemotherapy has trained persons who know what to do in case of extravasation. An extravasation kit containinginstructions, materials and medication to handle any incidence should be always available. An early multidisciplinary evaluation by nurses, medical oncologists and surgeons is recommended.

Specific measures (antidotes)

Various suggestions have been published with possible topical or injected pharmacologic methods for certain vesicant chemotherapy drugs. One should be aware that many are considered ineffective or further damage the extravasated area.

It should be noted that many of these substances are not available or at best have limited access for use in many European countries [5, 7, 11].

Local injection or topical corticosteroids

A single-arm clinical study in 53 patients with extravasations due to different drugs (21 with old lesions and 32 with recent extravasations) showed that multiple subcutaneous injections of hydrocortisone followed with topical betamethasone prevented tissue necrosis or sloughing necessitating surgicaltreatment. In fact, none of the patients was submitted to surgical debridement and all lesions were resolved. Healing time depended on the extent of extravasation and the type of drug [12]. However, in a retrospective series of 175 cases of extravasation, up to 46% patients receiving intralesioncorticoids needed surgical debridement versus only 13% of those without corticoids, suggesting a deleterious effect of these agents [5, 11]. In this context, subcutaneous corticoids are not recommended [V, C].

Sodium thiosulfate

Mechloretamine is a DNA-binding vesicant that produces severe and prolonged skin ulceration after extravasation. In several animal experiments, sodium thiosulfate was not able to prevent mechloretamine skin toxicity when given i.v. immediately before or after extravasation. However, when givenimmediately after extravasation by intradermal injection, it had a protective effect [13]. Therefore, in humans the recommendation in case of mechloretamine extravasation is an immediate subcutaneous administration of 2 ml of 1/6 molar solution of sodium thiosulfate which can be obtained bymixing 4 ml of 10% sodium thiosulfate and 6 ml of sterile water for injection; 2 ml of the solution is injected for each milligram of mechlorethamine suspected to have extravasated [V, C].

DMSO

Dimethyl sulfoxide (DMSO) is a common solvent that penetrates tissue when applied topically. This compound has free-radical scavenging properties and has the capacity to speed up the removal of extravasated drugs from tissues.

Despite the initial discouraging results of DMSO in animal models [14], in the 1980s, a prospective pilot trial in 20 patients showed clinical benefit in the management of anthracycline extravasation [15]. Topical DMSO was appliedimmediately after extravasation covering twice the area affected. This treatment was repeated twice daily for 14 days. No ulceration developed and no surgical intervention was necessary.

In 1995, a series of 144 patients [3] treated with DMSO after inadvertent extravasation secondary to several chemotherapy drugs including doxorubicin (n = 11), epirubicin (n = 46), mytomicin (n = 5), mitoxantrone (n = 13), cisplatin (n = 44), carboplatin (n = 6), ifosfamide (n = 14) and fluouracil (n = 5) was reported. In these patients, DMSO 99% was topically applied at four drops per 10 cm2 of skin surface twice over an area that was affected and left to air dry without dressing. The application was repeated every 8 h for 1 week. Administration of DMSO was performed in the first 10 min after extravasationin 84% of the patients. Only 1 patient presented ulceration after epirubicin extravasation. Topical DMSO is a treatment option in extravasations occurred during anthracyclines, mitomycin C or platin salts infusion [III, B]. It should benoted that DMSO 99% can cause local erythema which could affect the correct evaluation of the tissue damage. Some countries have only DMSO at a concentration of 50% available.

Dexrazoxane

Dexrazoxane has been used successfully to reduce cardiac toxicity in patients receiving anthracycline-based chemotherapy for cancer (predominantly women with advanced breast cancer) [16]. The drug is thought to reduce the cardiotoxic effects of anthracyclines by binding to free and bound iron, thereby reducing the formation of anthracycline-iron complexes and thesubsequent generation of reactive oxygen species which are toxic to surrounding cardiac tissue [17].

Langer et al. [18] demonstrated that systemic dexrazoxane prevented anthracycline wound formation when administered 3 h after extravasation in a mouse model.

One single systemic dose of dexrazoxane immediately after s.c. administration of doxorubicin, daunorubicin, or idarubicin reduced the tissue lesions (expressed as area under the curve of wound size times duration) by 96%, 70%, and 87%, respectively. The protective effect of dexrazoxane was dose-dependent and it could be administered until 3 h later without loss of protection.

Systemic treatment with dexrazoxane recently proved to be significantly protective in mice, against extravasation of other anthracyclines such as amrubicin, mitoxantrone and liposomal pegylated doxorubicin [19].

Two prospective single-arm clinical trials demonstrated that i.v. dexrazoxane prevented severe tissue damage following anthracycline extravasation. Among the 54 patients included in the trials only one (1.8%) finally needed surgical tissue debridement. Dexrazoxane was administered i.v. in a 3-dayschedule (1000, 1000 and 500 mg/m2) starting no later than 6 h after the extravasation event [20]. Dexrazoxane was well tolerated. Hematologic toxicity, hypertransaminasemia, nausea and local pain at the site of the dexrazoxane infusion were the most frequent toxic effects attributed to dexrazoxane [21]. It should be considered that in patients with creatinine clearance values <40 ml/min dexrazoxane should be reduced to 50%. DMSO should not be applied and topical cooling (i.e. ice packs) should be removed 15 min before and during the administration. Dexrazoxane as an i.v. administration in a large vein in an area away from the extravasation (i.e. the opposite arm) is recommended after anthracycline extravasation [III, B].

Hyaluronidase

Hyaluronidase is an enzyme that degradates hyaluronic acid, improving the absorption of extravasated drugs. One study [22] in animal models analyzed the impact on ulcer formation of local infiltration with sodium heparine, hyaluronidase or saline. Infiltration with hyaluronidase decreased the ulcer rateby 50–60% and decreased ulcer size by up to 50%.

In 1994 [23], a study on seven patients with accidental vinca alkaloids extravasation showed no skin necrosis after treatment with local hyaluronidase. These data suggested that hyaluronidase might be efficacious in preventing skin necrosis by extravasation due to vinca alkaloids [V, C] (see Table 4). A dose of 1–6 ml of 150 U/ml solution is injected through the existing i.v. line. The usual dose is 1 ml of hyaloronidase solution for 1 ml of extravasated drug.

Surgical management of severe tissue damage

The treatment of unresolved tissue necrosis or pain lasting more than 10 days is surgical debridement. It is considered that only one-third of extravasations progress to ulceration [24]. Thus, surgical procedures are relegated to those severe extravasations or to patients in whom conservative therapy has not been appropriately initiated. Such a procedure should consist of wide, three-dimensional excision of all involved tissue, temporary coverage with a biologic dressing, and simultaneous harvesting and storage of a split-thickness skin graft. Once the wound is clean, delayed application of the graftis performed (usually at 2–3 days) [5] [IV, B].

Subcutaneous wash-out procedure is a surgical technique that has been tested in 13 patients not treated with antidotes or topical treatment as unique immediate therapy to extravasation. The mean time interval to the subcutaneous wash-out was 345 min and none of the patients developed atissue breakdown during a 3-month follow-up period [25]. Nevertheless, due to scarce experience, this technique cannot be recommended as routine management in a nonexperienced surgical unit [V, C].

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:(i) Patient name and number(ii) Date and time of extravasation(iii) Name of drug extravasated as well as diluant used (if applicable)(iv) Signs and symptoms (also reported by patient)(v) Description of the i.v. access(vi) Extravasation area (also the approximate amount of drug)(vii) Management steps with time and datePhotographic documentation can be helpful for the followup 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.

Central venous access device extravasation

Extravasation of chemotherapy agents administered through a CVAD is a rare complication. In a recent series of 815 patients, this complication occurred in only 0.24% [26]. 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 infrequentextravasation 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].

Although in most reported cases conservative therapy was preferred, 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 orpleuritis secondary to extravasation can be considered [V, B] (see Figure 2).

Follow-up

Data about extravasation follow-up and management follow-up are scarce. In order to initiate the most appropriate follow-up, clinicians should be aware that early vesicant extravasation signs or symptoms can be subtle and not always evident. However, in the following days, initial inflammation increaseswith more redness, edema and pain. Finally, depending on the vesicant drug, after several days or weeks blisters may appear and inflammation evolve to a necrosis [27]. In this context, it is recommended that the patient should be regularly reviewed, possibly daily or every 2 days for follow-up during the firstweek and then weekly until complete resolution of symptoms. If required, referral to a ( plastic) surgeon is recommendable. Patients must be informed about the follow-up policy before leaving the treatment area [V, B].