Extravasation of antineoplastic agents in an Oncological Center

Introduction/Objective: This retrospective cross-sectional cohort study analyzed the extravasation index of antineoplastic therapy agents, demographic and clinical data. Methods: Seventy-six patients were evaluated in the period between 2017-2019. The project was approved by the Research Ethics Committee of a Brazilian Foundation. Results: In 72 months, 105,890 applications were administered, of which the incidence rate of extravasation of antineoplastic agents was 0.071%. Patients (N=311) selected for this study had a mean age of 55.42 years and a median age of 57. The most frequent diagnoses were breast cancer (11.66%), ovarian cancer (10%), colon cancer (8.33), rectal cancer (8.33) and uterine cancer (8.33%). The main variables that presented a significant impact with p <0.05 were ECOG Scale of Performance Status, ethnicity, age (risk ratio of 3% plus for each year of life), cancer staging, lymphadenectomy, use of venous catheter, forearm puncture, use of alkylating and alkaloids agents in peripheral venous access, and patients with tumor located in the pelvis using alkylating agents. Conclusion: The findings reinforce the need for further studies, since it was not possible to compare results with some variables that demonstrated a significant increase in the risk for the event.


Introduction
With the evolution of intravenous therapy, catheters became essential instruments in the treatment of cancer. The use of these devices minimized several adverse effects related to the administration of chemotherapy and supportive therapies.
With this, different types of catheters are available and the choice between them is determined by several factors, such as characteristics of the prescribed chemotherapy protocol, duration of treatment, integrity of the venous network and patient preferences. Thus, nurses play an important role indicating the most appropriate device to patients in the prevention and management of complications (Custódio et al., 2019).
There are some complications with regards to intravenous infusion therapies, with infiltration and extravasation being the most common. Both complications involve inadvertent leakage of a solution into the surrounding tissue. This may be nonirritating when the agent rarely produces acute reactions or destroys tissue or irritating if the agent induces pain at the site of application or along the vein, with or without inflammatory reaction, usually without persistent tissue damage. Extravasation results in local reactions ranging from local irritation to severe tissue necrosis of the skin, surrounding vasculature, and supporting structures. These complications can also mean delays in cancer treatment, which can reduce efficacy and may require additional cycles (NHS England, 2019).
Some patients with cancer may be at increased risk for extravasation due to: 1) multiple cannulations for chemotherapy veins, which lead to vessel hardness or sclerosis; 2) lymphedemas due to previous treatment such as mastectomy; 3) patients with long-term side effects of treatment such as peripheral neuropathy; 4) injury caused by previous site extravasation; 5) multiple punctures; 6) obstructed vena cava; 7) unconscious patients; 8) confused patients, or patients with communication problems who may be unable to report pain or discomfort around the device site or decreased sensation; 9) patients suffering from comorbidities that may lead to a decrease in sensation or poor circulation of concomitant medications such as: analgesics, anticoagulants, antifibrinolytics, vasodilators, hormone therapy, steroids, diuretics, antihistamines, or intravenous antibiotics that may, depending on the drug increase blood flow, predispose patients to bleeding, suppress the inflammatory response, reduce pain sensation and others (NHS England, 2019).
It is the responsibility of nurses to analyze and monitor risk factors and intervene when neccesary, providing educational actions for the best physical and global adjustment of patients, as well as ensuring efficiency, safety, and responsible administration of these drugs. In addition to knowing the possible complications in chemotherapy treatment, nurses must have knowledge about prompt intervention in the event of extravasation. Therefore, it is essential that the institution reinforce the means that encourage the constant training, practice and guidance of these professionals, especially in relation to the management of chemotherapy treatment complications (NHS England, 2019).
The aim of this study was to analyze the extravasation index of antineoplastic agents in the period between 2017 -2019 and the potential risks of extravasation, with the results evidenced in the literature.

Methodology
This is a retrospective, cross-sectional, descriptive study with a quantitative approach. According to PEREIRA et. al 2018, this type of study enables the generation of important data to better understand the phenomenon chosen for study. The work was carried out in an outpatient chemotherapy clinic affiliated with a reference oncology center in São Paulo, Brazil.
Data collection was performed through the institution's electronic medical records system, based on notifications of events made in the Institutional Standards Portal (SE Suite 2.0 system and DocNix system). Patients who underwent treatment with antineoplastic agents during the current study period were included. Factors such as race, age, protocol used, type of medication, socioeconomic data, level of education, presence of companion during medication infusion, and death resulting from the disease after the event were also considered.
Patients who underwent some type of infiltration of a drug other than antineoplastic agents or with incomplete data that prevented the patient's identification were excluded.
For data collection we created a database in Redcap, administered by the International Research Center of the institution where the project took place. The database consists of a spreadsheet aimed at optimizing time for information search and reduction of typos. We extracted data through the MV 2000 (used in the institution until 2018) and Tasy data systems.
For each occurrence recorded in the period, we used the number of the General Hospital Registry (RGH) to search the data, and then fed the database.

Incidence of extravasation
In the period from 2017 to 2019, 105,890 antineoplastic agents were administered. Of these, 311 patients were selected for the study sample, 76 of whom suffered extravasations, with 16 cases (21%) that were not included here due to lack of registration, such as inclusion of the RGH in the notification, and thus they were excluded from the descriptive analysis, inclusion, and exclusion criteria. From this, 60 events were eligible for extraction of the data. The incidence rate of extravasation of antineoplastic therapy calculated in the period 2017 to 2019 was 0.071%.
The sample consisted of a small percentage difference between genders, however the majority were female, totalling 166 (53.37%), but those who presented the event were 28, corresponding to 46.6%. The total number of males was 145 (46.6%), with those who presented the event at 32 (53.3%). Breast and female reproductive system 110 20

Clinical Characteristics
Male reproductive system 11 02 Nervous system and skull 03 01 Lymphoma and myeloma 19 04 Other unknown location 08 02
The body surface area (CS) presented an average of 1.77913 and median of 1.76000. The body mass index (BMI) had a mean of 26.1294 and median 25.2691.
The most frequent diagnoses were breast cancer 94 (30%), followed by colon cancer 26 (8.3), rectal cancer 24 (7.7), larynx cancer, pharynx cancer, bronchi and lungs cancer 22 (7.0%) and hematopoietic and lymphatic system 19 (6.0%). Among the events, 52 presented mild damage and 8 presented moderate damage. Forty-three patients were treated with a cold compress and 11 used a warm compress. Of the topical solutions, 45 were treated with hydrocortisone acetate and 7 were treated with hyaluronidase. Three events required referral for outpatient follow-up; 3 for emergency department and 1 for plastic surgery.  (2019). Table 3 presents the relation of patients who underwent lymphadenectomy regardless of the site of leakage, considering the total sample and the cases that presented the event. From the data in the table it is possible to observe that there is a higher risk for those patients with cervical, pelvic, and abdominal lymphadenectomy. Analysis of extravasation events showed that carboplatin was present 13 (21.6%) times at the time of an occurrence, followed by taxol 11 (18.3%), fluorouracil 7 (11.6%), cisplatin 5 (8.3%) and oxaliplatin 5 (8.3%), as shown in Table 4.

Discussion
Chemotherapy extravasation has an incidence that can range from 0.1 to 6% when administered by a peripheral venous access, and 0.26 to 4.7 when in central venous access. Factors related to the chemotherapy agent itself, such as vesicant agents, drug volume, concentration, infusion time, lack of professional training and material used for catheter fixation, may influence the occurrence of extravasation (Kreidieh et al., 2016).
The clinical and demographic characteristics of cancer patients who experienced extravasation of antineoplastic agents were heterogeneous, and cases were observed in different genders, ages, tumor sites, staging, and types of treatment, demonstrating that any patient may present this type of complication. It was not possible to identify the mean volume of antineoplastic agents due to the absence of data in the notification. Patients were classified according to the severity of the event as mild 52 (86.7%), moderate 8 (13.3%), and severe 0 (0.0%).
According to data collection, extravasation occurred more frequently in males than in females. As for age, the mean was 57, with the maximum of 88 and minimum of 16, exponential of 1.030 for the risk ratio, thus raising the risk for each year of life to 3%. The literature differs when it comes to age and occurrence of extravasation, however, advanced age is characterized as a risk factor associated with greater venous fragility (Sagica et al., 2017). Ferrari et al. (2016) presented data where female patients presented higher rates of extravasation compared with male patients (64% vs. 36%), and the mean age was 58 and 59, respectively. Other variables increased the risk for extravasation, such as: elderly patients; associated comorbidities (impaired circulation, vascular disease, diabetes, lymphedema, superior vena cava syndrome); coagulation abnormalities or increased vascular permeability; obesity; sensory deficit; communication difficulties (e.g., children); and prolonged infusion.
According to Schulmeister (2014) patient factors, such as advanced age and comorbidities such as diabetes are factors that increase extravasation. Contrary to a study conducted in a university hospital in Cairo by Abd El-Salaheena et al. (2018) and Sayied & Ahmed (2017) presented an expressively higher rate for female patients between ages 18 and 30 years, justified by the profile of the patient attended, being mostly women. In the age variable when it comes to the occurrence of the event, the statistical relevance was p=0.004, indicating that the risk to present the event increases according to the patient's increase in age.
Due to the deficiency in the data from the electronic medical records, it was not possible to measure the level of education of the selected patients. However, Abd El-Salaheena et al. (2018) reports that the low level of education may represent a higher risk for the event, particularly during cytotoxic administration. This data is congruent with other studies that demonstrate a higher risk in this population, as Sagica et al. (2017) that the origin and level of education are relevant variables from the statistical point of view with p value < 0.001.
Abd El-Salaheena et al. (2018) reports that the risk for the event is higher for patients whose BMI is below 18.5, however, the mean BMI in the present study was 25.2263, with its minimum and maximum of 16.97 and 42.16, with p=0.140, demonstrating that in this study, BMI was not a relevant factor that would increase risk of extravasation.
Regarding cancer diagnoses, breast cancer, colon cancer, and rectal cancer were the most prevalent, which Regarding the type of chemotherapy, this sample did not show a significant increase in risk, with p=0.283.
Carboplatin was present 13 times (21.6%) at the time of an occurrence, followed by taxol 11 (18.3%), fluorouracil 7 (11.6%), cisplatin 5 (8.3%) and oxaliplatin 5 (8.3%). This result was also obtained by Sagica et al. (2017) who reported that the type of chemotherapy was also not a significant risk factor p=0.209, but that taxol was 44% present in extravasation events, as well as Ferrari et al. (2016) where they presented 30 cases of taxol extravasation, 26 oxaliplatin and 16 of doxorubicin.
In the infused volume, we obtained a minimum of 4.69ml/hour, measured 290ml/hour and maximum 1,000ml/hour, with p= 0.062. Schulmeister (2014) reports that many cases of extravasation in peripheral venous access occur when large volumes and long-term chemotherapy are performed, such as etoposide (98% of peripheral events), taxanes (98% of peripheral events) and oxaliplatin (98% of peripheral events). complained of edema, 20% of erythema and 10% of pain, burning or discomfort at the site of application.
Forty-three patients were treated with a cold compress, 11 used a hot compress, 45 used hydrocortisone acetate concomitance and 7, hyaluronidase topically in the affected area. All patients were followed up with until the outcome of the case, and there were no cases of sequelae or loss of function as a result of the event. Ferrari et al. (2016) found in his study that antidotes were used in 65% of the cases, hyaluronidase in 46 of the cases, tissulfate in 16, Dimethyl sulfoxide (DMSO) in 12 and dexrazoxane in 1 doxorubicin extravasation. In about half of the cases, the administration of the antidote alone was sufficient to achieve complete recovery within 48 hours.
NHS England (2019) guides the use of hot compresses to promote vasodilation and thus stimulate blood flow in tissues, thus propagating the extravasated agent. Hyaluronidase can be used in order to promote the spread of the drug and increase the absorption of the drug. To locate and neutralize the agent, cold compresses are used to limit the spread of the outagent. It is proposed that the cellular absorption of the agent by tissues is reduced when cold compresses are used. Cold compresses can also reduce local discomfort. There are several antidotes available for certain cytotoxic agents and these are specific to the medicine and/or group, which should be considered to reduce the potential for serious tissue damage or injury.

Conclusion
The incident rate of extravasation of antineoplastic therapy calculated in the period from 2017 to 2019 was 0.071%, which is below the level expected in the literature.
Through this analysis, we could verify that ethnicity, age (risk ratio of 3% increased for each year of life), ECOG, staging, lymphadenectomy (mainly in cervical, abdominal and pelvic region), PVA, use of alkylating agents in VPA, location of the tumor related to ECOG (especially in tumors in the thoracic and pelvic region), and patients with tumors in the pelvic region using alkylating agents were the main aggravating factors that led to the extravasation of the drug.
All events were classified as mild to moderate damage, and for 3 of these cases, it was necessary to refer to the emergency department or plastic surgery, but all evolved without permanent damage.
The findings reinforce the need for further studies, since it was not possible to compare results with some variables that demonstrated a significant increase in risk for the event. Continuous education of the team is needed regarding the importance of the adequate registration of the notification document, so that this is not a factor that compromises data analysis and consequently negatively interferes in the processes of improvements in patient care.
It is recommended that studies be conducted that better track events, with proper recording in patient records, and that compare new variables to better understand some relationship between devices, type of antineoplastic agent used, and studies that test prevention and safety strategies in administering atineoplastics to patients.