Extravasations of Vesicant / Non- Vesicant Drugs and Evidence - Based Management

Abstract

The intravenous applications that have been used widely can lead to some complications such as extravasation, ecchymosis, hematoma and phlebitis. The extravasation is one of these complications. Extravasation leads to some undesirable happenings such as prolonged times of hospitalization of the patients, unnecessary diagnostic procedures and even unnecessary treatments, stress effects on the relatives of patients, extra workload for health staffand the economic loss as well as to threatening the lives of patients.It is important for the health professionals, who are responsible for managing of intravenous applications, to know the drugs that cause tissue injury and take the necessary measures to prevent extravasation. Therefore, this article defines the pathogenesis of extravasation, types, symptoms, and evidence-based management. [PUBLICATION ABSTRACT]

Headnote

Abstract

The intravenous applications that have been used widely can lead to some complications such as extravasation, ecchymosis, hematoma and phlebitis. The extravasation is one of these complications. Extravasation leads to some undesirable happenings such as prolonged times of hospitalization of the patients, unnecessary diagnostic procedures and even unnecessary treatments, stress effects on the relatives of patients, extra workload for health staffand the economic loss as well as to threatening the lives of patients.It is important for the health professionals, who are responsible for managing of intravenous applications, to know the drugs that cause tissue injury and take the necessary measures to prevent extravasation. Therefore, this article defines the pathogenesis of extravasation, types, symptoms, and evidence-based management.

Keywords: Vesicant/non-vesicant drugs, Extravasation, Evidence-Based Management

Introduction

Intra-venous (IV) initiatives is one of the most common practices in hospitals (Hadaway, 2007). It is reported that in the US, 20 millions of almost 40 millions of hospitalized patients each year have received intravenous treatment (Jones, Coe, 2004). In general, any study has not been noticed yet to represent Turkey in this field. However according to a multicenter study of intensive care units in Turkey, it was observed that while the rate of catheter utilization was being noticed at 61% in the units (as per data of 2002-2005) in Turkey, this rate varied between 49-56 % in the US hospitals (as per data of NNIS -National Nasocomial Infection Surveillance- 1992-2004) thus it was determined that our country had a very high utilization rate (Aygün et al. 2004; Yarbro, Wujcik,, Gobel, 2011).

Intra-venous initiatives that are widely used can lead to some complications such as extravasation, ecchymosis, hematoma, and phlebitis (Uzun, 1991; Sauerland, Engelking, Wickham, Corbi, 2006; Yarbro, Wujcik, Gobel, 2010). Extravasation as one of these complications can be described as an inflammation as a result of when intravenous fluid or drug undergoes perivascular or subcutan tissue even tissue damage that can lead to ulceration and necrosis, loss of function in extremity or even amputation in extremity that can go up to contain all the layers of skin and subcutaneous tissue (Leslie, Ambler, 1995). Extravasation induces prolonged duration of the patient's hospital stay, unnecessary diagnostic procedures and treatment, stress in the life of the patients' relatives, extra work load on the health personnel and economic loss accordingly (Karadag, 1999; Sauerland, Engelking, Wickham, Corbi, 2006).

It is difficult to determine the incidence of extravasation since insufficient documentation in this matter. However, depending on some studies carried out, it is reported that vesicant chemotherapy extravasation is observed in children by 11% and in adults by 22%. (Ener,2004; Özbas, 2007; Hadaway, 2007; Yarbro, Wujcik,, Gobel, 2011). Vesicant chemotherapy extravasation is exposed in peripheral IV infusions by 0.1-6% and in port infusion by 0,3 - 4.7%. In addition, negative results caused by extravasation can be prevented. So it is important for the health professionals who are responsible for managing of IV applications to know the drugs that can cause tissue and be capable to early diagnose of extravasation and take the measures accordingly. Therefore, this article defines the pathogenesis of extravasation, types, symptoms and management (Sauerland, Engelking, Wickham, Corbi, 2006).

Pathogenesis of Extravasation

Extravasation occurs as a result of vesicant, nonvesicant and irritant drugs leaked out of blood vessels (Table 1,2). The reason and mechanism of damage that have been formed due to vesicant, non-vesicant and irritant drugs is not fully understood. The severity of tissue damage concerns the drug linking on DNA (Leslie,Ambler, 1995; Schulmeister, Camp-Sorrel, 2000; Sauerland, Engelking, Wickham, Corbi, 2006; Schulmeister, 2007; Yarbro, Wujcik, Gobel, 2010). Antineoplastic agents have direct toxic effect on the cell. As an example; depending on a leading theory, it is widely accepted that the drug spreads the toxic agent to the surrounding healthy cells by means of necrotic cells during a period lasting up to weeks even months in doxorubicin extravasation (Schulmeister, 2007; Yarbro, Wujcik,, Gobel, 2011).The reasons of tissue damage that may occur depending on vesicant, non-vesicant and irritant drugs extravasation are given as follows;

Agents bound to DNA

Anthracyclines (Doxorubicin, Dounurobicin, Ðdarubicin and Mitoxantron), antitumor antibiotics (Mitomycin) and some alkalizing agents (Mechlorathamine and platinum analogs) are bound to nucleic acid in DNA thus lead to the formation of toxic topoisomeraz II and break out the fibers in DNA (Yarbro, Wujcik, Gobel, 2010). The resulting free radicals make complex cellular structure by inhibiting RNA and protein synthesis then cause the formation of apoptosis. For example; free radicals forming in doxorubicin extravasation create serious damage to small blood vessels by breaking the structure of damaged cell, cell membranes and vascular structure therefore those free radicals cause inflammation of the cells and the formation of necrosis in tissue thus lead to cell apoptosis (Sauerland, Engelking, Wickham, Corbi, 2006; Schulmeister, 2007).

Antineoplastic Agents unbound to DNA

Agents that are not bound to DNA cause less tissue damage compared to the agents bound to DNA. The drug group including vinca alkaloids containing microtubule toxins (Vincristin, vinblastin, and vinorelbin), microtubule inhibitors and taxans (paclitaxel, docataxel) improves the stability of microtubules. Intracellular microtubule toxins and topoisomerase inhibitors prevent mitotic cell division so inhibit the connection with DNA thus lead to cell apoptosis. Topoisomerase enzyme inhibitors (Etaposid, irrinotecan, topotecan) make DNA spirals initiative easier so primarily restructure DNA again then divide the cell. At the end, by preventing DNA copying and replication, it leads to cell death (Steele, 2001; Schulmeister, 2007).

Non-antineoplastic vesicant agents

Extravasation formed due to non-antineoplastic agents can lead to the results i.e. Tissue necrosis, debridement flap or skin graftreconstruction depending on the dugs' vesicant features. Hyper osmotic solutions lead to compartment syndrome due to vesicant features, concentrated electrolyte solutions lead to prolongation of muscle depolarization and finally ischemia, intracellular agents affecting pH (sodium bicarbonate) or various agents causing ischemia by forming severe vasoconstriction lead to the formation of necrosis in extravasated tissue(Schulmeister, 2007; Yarbro, Wujcik, Gobel, 2010).

Drugs w and w/o vesicant potential are given in the following Table 1 and 2; (Polovich, White, Kelleher, 2005; Schulmeister, 2007).

Risk Factors Affecting the Formation of Extravasation

The potential for tissue damage is affected by the factors such as the drug concentration, high vesicant potential of drug and the unfiltered amount, tissue exposure and extravasated zone, repeated use of drugs having the vesicant characteristic (Luke, 2005; Schulmeister, 2007; Yarbro, Wujcik, Gobel, 2010). For example; excess quantity extravasation management of an agent bond to DNA in high dose is rather difficult. In addition, nerves, blood vessels, antecubital region that is rich in terms of tendons and the chest wall in patients exposed to port application and the thoracic structures are the parts under risk. The risk factors affecting the formation of extravasation or making this formation easier are given as follows;

In terms of patient: In newborns, children, adults, seniors (patients with fragile veins), those who are less sensitive to pain, the patients exposed to repeated times of catheter and those with problem in vascular thrombosis of the veins, those having difficulty in communication (those with hearing problems etc), unconscious, sedated or confused patients, Patients treated with an infusion in mastectomy side or in the field of lymph edema, patients who experience intense anxiety or fear, patients who are unable to lodge complaints from the point of view of cultural aspects (Polovich, White, Kelleher, 2005; Schulmeister, 2007).

In terms of history of disease: Cancer patients, people with diabetes, cardiovascular patients. (Polovich, White, Kelleher, 2005; Schulmeister, 2007).

Issues related to Peripheral IV Catheter: thickness of the IV catheter tip, IV catheter length ,IV access area ( antecubital fossa, on hand, on foot, wrist.), Using the butterfly infusion set. (Polovich, White, Kelleher, 2005; Schulmeister, 2007).

Issues related to Central venous catheters: Placement of catheter in the region instable to motion, bending or dislocation of the catheter, injection needle on the port not fully accessed or have never accessed, excessive back pressure around the needle, washing done with injector with small needle, fibrin deposition or thrombosis at the catheter (Polovich, White, Kelleher, 2005; Schulmeister, 2007; Yarbro, Wujcik,, Gobel, 2011).

Clinical issues: Intensive work conditions, knowledge lack of staff, inexperienced staff, and insufficient information on the drug management (Polovich, White, Kelleher, 2005; Schulmeister, 2007).

Types of Extravasation

National Extravasation Information Service (NEIS) examined the types of extravasation by separating into three types (Jones, Coe, 2004).

Pre-extravasation syndrome: It leads to flexibility and local hyper-sensibility in various degrees.

Type I: stiffness and swelling that around buller and infusion area;

Type II: softtissue damage at infusion area;

Extravasation is examined in 4 types according to the process of change created by the drug in tissue (Schulmeister, 2007);

a. When it is formed with vesicant agents, blistering of the skin and tissue damage, the formation of pain and tissue necrosis can develop.

b. When it is formed in terms of exfoliate flaking off, the inflammation occurs. Tissue death is less common.

c. In the case of irritant formation, inflammation, a sense of tension, pain, swelling, bruising in the zone and rarely damage in tissues

d. In case of inflammation, pain and redness occur in the area.

Symptom and Results in Extravasation

The symptoms of extravasation can occur during or after infusion in two-three days. The widespread stiffness, pain, and burning, stinging, tissue damage occur at extravasation area. All symptoms of cellular injury such as inflammation and pain felt by touch occur 3-5 days after extravasation (Clifton, 2006; Hamilton, 2006; Yarbro, Wujcik,, Gobel, 2011). In case of the results e.g. resistance that occurs in applying the IV drug, bleeding from cannula, slower infusion, swelling at the point of cannula, burning and pain around the cannula burns are the findings reminding the extravasation. (Fig1). In addition, the volume of the fluid unfiltered in the subcutaneous tissue, exposure to extravasated fluid for a long time, osmolarity and PH value of the liquid etc can result in the formation of scar. As a result of extravasation of isotonic liquids such as dextrose 5%, the bullous and necrosis can occur (Jones, Coe, 2004; Clifton, 2006). Additionally, there is always risk to develop compartment syndrome in various extravasations. Developed compartment syndrome can affect the local circulation and cellular function in tissue. In the area of extravasation, irreversible ulceration and necrosis can occur (Clifton, 2006).

Necroses that can occur extend to fascia, tendon, and periostiuma. The necrosis that cannot be noticed at early stage can lead to significant organ insufficiency even to extremity amputation (Yesilbalkan, 2005; Keskin, 2006). An urgent treatment has to be planned and the measures have to be taken (Wickham, Engelking, Sauerland, Corbi, 2006).

The extravasation process of Doxorubicin that leads to tissue damage by bounding to DNA takes part by days as follows; (Fig 1).

In scope of intravenous attempts of vesicant or non-vesicant drugs, the reactions such as fever reaction at vascular structure against the drug, vascular irritation, phlebitis development on the vessel wall and development of venous shock etc can occur. The fever reaction has shown itself by itching along the vessel; in case the vessel patency is taken under control, bleeding starts (Hamilton, 2006; Yarbro, Wujcik,, Gobel, 2011). IV Ondansetron is a common symptom in scope of Epirubicin and Doxurobicin application. In case of vascular irritation, pain and stiffness occur throughout the vascular. It is a common symptom during the application of Vinorelbin and Dacarbazin. When the PH value of drugs leads to irritation at vascular wall, phlebitis develops on vascular wall. It is a common reaction in scope of the applications of 5-FU, Doxorubicin, Epirubicin and Etoposide. Additionally, in case the drug is given cold or too fast, spasm develops at venous muscular wall thus vascular venous shock occurs. It is necessary to distinguish the extravasation formation from such reactions then the necessary attempts should be started. (Hamilton, 2006).

Evidence - Based Management Extravasation Management

The patients particularly newborns have to be taken under treatment urgently when extravasation develops in IV zone. Extravasation that is one of avoidable complications of intravenous applications can be reduced significantly in case it is determined within the first 24 hour and the treatment is applied accordingly (Yesilbalkan, 2005; Wickham, Engelkin, Sauerland, Corbi, 2006).The nurses have great responsibility for ensuring the benefits of the fluid applications to the patient, the effective maintenance of the application and preventing the onset of complications. The nurse should observe IV attempt zone in terms of damage, pain and sensitivity. Particularly, upper part of the hand and intravenous zone taking part in antecubital area should be monitored in terms of nerves, tendons, blood vessels. The chest wall or thoracic structures should permanently tracked in terms of significant signs of damage, pain and signs of organ failure that can cause a variety of surgical interventions (MacCara,1983; Wickham, Engelkin, Sauerland, Corbi, 2006; Yarbro, Wujcik,, Gobel, 2011).

The nurses should keep the records of the pextravsation subjects including the patient's identification information and the details of the process such as the location of extravasated zone, diagnoses of the zone, time, the drugs and the order of administration, the estimated amount of extravasated drug, photo of the lesion, if possible, venous intervention site, number of catheter and the date of application, patient complaints, extravasation treatment plan and treatment outcomes (MacCara, 1983;Karadag, 1999; Schulmeister, Camp-Sorrel,2000;Ener,2004; Hayden, Goodman, 2005). In case extravasation is detected as developed within 24 hour in the patient, the following steps have to be taken respectively (Table 3).

In Table 4, the steps taken and appropriate antidotes that have been used are explained in details with the purpose to extravasation of irritant and vesicant antineoplastic agents (Wickham, Engelkin, Sauerland, Corbi, 2006; Yarbro, Wujcik,, Gobel, 2011).

Hot or cold application methods are determined according to cytotoxic agents as specified in table 4. The hot application disrupts DNA helix and increases the absorption and distribution of the drug y performing vasodilatation; thus reduces the density of local drug in tissue. The hot application is done for 4 times a day at 20 minutes sessions during 24-48 hour (Sauerland, Engelking, Wickham, Corbi, 2006). The local hot application is done after the extravasation of Vinca alkaloids that increase the formation of ulcers. The cold application limits the field of extravasation causing the vasoconstriction (Jones, Coe, 2004; Sauerland, Engelking, Wickham, Corbi, 2006; Yarbro, Wujcik,, Gobel, 2011). The local cold application is done to reduce swelling after ÐV extravasation and determine the limits of tissue damage reducing the metabolic needs of damaged tissue. The cold application particularly done in scope of doxorubicin extravasation forms vasoconstruction due to its cold effect thus reduces the effect of local spread of the drug, makes the drug intake slower by the cell and prevents peripheral damage. The cold application is done for 4 times a day at 20 minutes sessions during 24-48 hour (Wickham, Engelkin, Sauerland, Corbi, 2006; Sauerland, Engelking, Wickham, Corbi, 2006). In fact, local hot or cold application to be done after extravasation should be discussed in newborns and non- evidence-based researches. In fact, because of the structure of the epidermis the temperature of the zone should be controlled in scope of local hot and cold applications. In the literature there is no enough research that identifies the effect of hot and cold applications (Wickham, Engelkin, Sauerland, Corbi, 2006; Sauerland, Engelking, Wickham, Corbi, 2006).

Drugs Used in the Administration of Extravasation and Evidence-Based Applications

The mechanisms of action of antidotes used in the administration of extravasation and the information regarding to the evidence-based applications are given in Table 5 (Wickham, Engelkin, Sauerland, Corbi, 2006; Sauerland, Engelking, Wickham, Corbi, 2006).

Is it Possible to Avoid from Extravasation?

According to the definition in the literature, the protection from extravasation is identified as the limitation of tissue damage (Yarbro, Wujcik,, Gobel, 2011). It is possible to avoid from most of vesicant extravasation occurrences. It is very important for nurses who are managing all chemotherapy treatment or who take part continuously in intravenous chemotherapy treatment and responsible for the chemotherapy treatment to protect the patient from extravasation (Hadaway, 2007). The protection from extravasation should include simple and understandable chemotherapy education, patientcentered information related to the specific drugs, and critical appraisal skills. The nurses should keep on providing safe patient care, preventing the development of damage and providing continuity by using extravasation directive (Hayden, Goodman, 2005). It is necessary to distinguish the risk factors that may lead to the development of extravasation, use suitable venous catheters and control the risk factors permanently. In case of extravasation happening, the administration of occurrence and the measures to be taken to prevent the development should be properly managed (Hadaway, 2007; Yarbro, Wujcik,, Gobel, 2011).

To reduce the risk of progression in patients developed extravasation, the nurses and doctors should use implant systems reducing the vesicant damage or prefer using the central venous catheters complying with the use of vesicant drugs (Hadaway, 2007).Using appropriate venous access equipment will enable the vesicant and irritant drugs to be conveyed safely by keeping the peripheral access ready constantly thus it reduces the patient's anxiety related to frequently vein access (Hamilton, 2006; Hadaway, 2007).

In the patients with central venous catheter, before giving the vacant drug, it should be controlled whether the blood comes back; if not, the placement of central venous catheter should be controlled in accompany with fluoroscopy or x - ray. The nurses primarily have to check the septum in the patients with port then control whether the blood comes back or not by flushing (Keskin, 2006; Yarbro, Wujcik,, Gobel, 2011).

Intravenous catheters, central venous catheters and ports should be placed in the manner of easily visible and the applied serum sets should be fixed functionally and finally easy observation should be provided. Especially, the drugs having strong vesicant effects should be marked with dark stickers. The nurses should observe IV zone and surrounding during the vesicant infusions lasting more than 60 minutes. Before starting the vesicant treatment, the nurses should control whether the intravenous blood comes back again and if it is placed properly, intravenous treatment is commenced (Schulmeister, 2000; Hadaway, 2007). Particularly after the nurse had started the vesicant treatment, intravenous zone should be observed in terms of erythema, redness, swelling once 5-10 minutes. Any local pain and intravenous sensory change in the area should be carefully observed (Polovich, White, Kelleher 2005). When the extravasation develops, the nurse should observe the zone of IV catheter in terms of good current ( arterial, venous and lymphatic), sensory disability, loss of function and the necessity of surgical repair. It is possible that the loss of tissue and organ can develop in hand, wrist and antecubital areas following the extravasation process such parts of the body should not be used as much as possible (Hadaway,2004; Luke, 2005). For IV zone, muscular forearm can be chosen. Initially, the direct selection of the proximal veins is not suitable. One or more vein attempts in chosen zone IV increases the risk of extravasation. (Hadaway,2004; Luke, 2005). In addition, there are conflicting opinions about the sequence of vesicant drugs. According to one of these opinions, the vesicant drugs should be given before the non-irritant drugs. However any other opinion suggests the vesicant drugs can be given in the manner of "sandwich method" sequentially together with non-vesicant drugs. There is no sufficient proof for both views. The important point here is that the nurses should have information regarding to the vesicant drug administration very well (Sauerland, Engelking, Wickham, Corbi, 2006; Yarbro, Wujcik,, Gobel, 2011). The frequency of observation on the zone under chemotherapy treatment varies depending on the giving method of chemotherapeutic agent whether bolus or infusion. If the chemotherapeutic agent was given in manner of bolus or in case of extravasated position, 2-5 ml blood can be drawn back. In case of vesicant drugs given in continuous drops, the catheter position should always be observed and should a sensitivity is noticed in the zone IV, a saline solution of 5-10 ml is given and the zone will be observed accordingly. In addition, the nurse should carefully observe the patients who are chemotherapy treated with permanent central venous catheters in terms of intra-thoracic extravasation findings (fever not bringing down, plevratic pain, cough, swelling of the upper limbs or neck ...) (Sauerland, Engelking, Wickham, Corbi,2006; Bozkurt, Uzel, Akman et. al. 2003). IV pump alarms signaling that intravenous set is clogged should be taken into consideration by the nurses for early detection of extravasation. In such a case, the rate of infusion should be reduced and the infusion are has to be observed. (Sauerland, Engelking, Wickham, Corbi,2006).

The nurse should have the control on the pain that has developed in extravasated zone. If it is necessary, the nurse can use nonopids with the previous approval of the doctor. However it is required to observe the patient in terms of any possible adverse effects when nonopiodis are used in pain control (Yarbro, Wujcik, Gobel, 2010). The detailed chapters including the risk factors that may lead to extravasation should take part in concerning documentation about chemotherapy. These sections will provide the nurses with great benefits to determine the population of the patients under risk and keep strict tracking (Polovich, White, Kelleher, 2005; Clifton, 2006)

Education of Patient and Family

The education of the patients and caregivers especially for those who take vesicant drug treatment in the clinics and the outpatient emphasize a vital importance. Both patient and caregiver should be trained about potential harmful effects in scope of verbal training techniques and written educational materials. The nurse is responsible for arranging the training programs by evaluating the patient's language or communication barriers and anxiety so the nurse should keep the patient informed at some certain intervals (Yarbro, Wujcik, Gobel, 2011).

The patient's initial training should be given before the administration of drugs affecting the central nervous system and the patient has to be questioned at some certain intervals to determine if he/she understands the given trainings properly (Özbas, 2007; Yarbro, Wujcik, Gobel, 2010).

The patient and the caregiver should be kept informed about the importance to observe the effects at intravenous area in scope of local pain, swelling, temperature rise, changes in the skin during the intravenous process. It is also important to inform the patient about the measures to be taken e.g. elevation of the arm, hot or cold application type depending on the type of chemotherapeutic drug used, application time in case of extravasated fluid (Yarbro, Wujcik, Gobel, 2011).

Conclusion

Extravasation injuries are a potentially serious consequence of all intravenous therapy. The best "treatment" of extravasation is prevention. While there is no real treatment per se, there are some techniques that can be applied in case of extravasation, though their efficacy is modest. If there is tissue necrosis, surgical reconstruction may be helpful.

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