Extravasation of Adriamycin and other vasosclerotics (Proceedings)

When treating oncology patients, technicians realize more stress and job pressure with dealing with chemotherapy drugs that are vasosclerotics such as Adriamycin™ (doxorubricin). What is a vasosclerotic drug? How harmful are they when extravasated? What can be done to prevent problems? What can be done to soothe the situation once a spill is identified?

Vasosclerotic drugs create a variable degree of localized tissue injury around the vein resulting from a perivascular leak or spill. Doxorubricin (Adriamycin®) is the most potent vasosclerotic chemotherapy that this author is aware of. This agent belongs to the aminoglycoside family and is commonly used in veterinary oncology to treat a variety of malignancies including lymphoma and adenocarcinomas and soft tissue sarcomas.

Tissue injury can be extensive if the extravasation goes undetected and untreated. Even small amounts of adriamycin can create severe, irreversible indolent tissue damage. Actinomycin D is also a severe vasosclerotic. Vincristine, vinblastine and mechlorethamine (Mustargen®) are moderate vasosclerotics. Cis-platin, mitoxantrone, dacarbazine (DTIC), 5-fluorouracil, mithramycin, etoposide, streptozotocin and bleomycin are considered mild vesicants.

When dealing with chemotherapy agents is important to clearly identify drugs according to their "vasosclerotic" potential. This author uses chemotherapy treatment forms that have a vasosclerotic warning box that is circled or checked by the doctor as he/she writes the order. This safety precaution alerts the nursing staff that localized tissue injury will result if there is a spill.

The nursing staff will notice most perivascular leaks right away. A "bleb" or swelling appears immediately adjacent to the venipuncture site. Some oncology patients experience immediate discomfort. They squirm or cry or struggle. If the patient is sedated during the procedure, the nursing staff should have direct supervision during the infusion of the vasosclerotic.

It is important that the nursing staff feels free and obligated to point out loud and clear to the attending doctor when a leak is suspected. If the patient is sent home with an undetected extravasation, the client may notice a problem within hours or within 10 days following chemotherapy. The pet starts licking the venipuncture site. The client calls the hospital with the complaint that the pet has pain, swelling, inflammation, desquamation and/or limping.

Insist on Sedation When Needed for all Vasosclerotics

For their own safety, all cancer patients that resist restraint, during the administration of any caustic chemotherapy agent, require sedation. As a matter of policy, sedation must be recommended for patient safety to avoid struggling and accidental extravasation. There should be no exceptions when dealing with adriamycin. Take the time to educate the pet's family by saying something like this, "Without sedation, your pet may pull away or struggle during the chemotherapy administration. This could cause some of the drug to spill outside of the vein. The drug may cause severe tissue damage that may ultimately require amputation." The attending staff must be vigilant in deciding which patients need sedation and which do not. The sedation procedure will incur more expense but it is for the patient's own good. If your attending doctor is not in agreement with your recommendation for sedation and your gut feeling about a pet's cooperation, you must speak up and plead for the pet's safety.

When using adriamycin, avoid acepromazine and phenothiazines and drugs that cause arrhythmias or vasodilatation. This author's R.V.T. staff prefers to use the low dose combination of domitor-butorphanol-atropine (low dose DBA). It is given IV, and reversed with Antesedan™. We find this combination ideal for most otherwise healthy cancer patients. Many veterinarians prefer to use Domitor™ strictly on the recommended intramuscular (IM) dose. Telazol® is preferred by some clinicians for immobilization of healthy fractious dogs.

Animals with heart disease, advanced age, renal failure, hepatic compromise or wasting are at a somewhat higher risk of adverse events while under sedation. An option that some attending doctors prefer to use is a combination of fentanyl (a short acting opioid) and midazolam (a short acting benzodiazepine) IV. This combination avoids bradycardia which is commonly found with domitor. A combination of butorphanol and diazepam IM or IV is another good option for elderly pets that is safe and generally effective. Some attending doctors feel that the best method is to use a mask, or closed-chamber sedation/anesthesia, with inhalation anesthesia (sevoflurane/isoflurane). This method is often preferred for geriatric feline cancer patients. The objective is to immobilize the patient for safety, during administration of caustic vasosclerotic chemotherapy drugs.

Communicating with Distraught Clients

The nursing staff and an inexperienced attending doctor may not fully comprehend the consequences of an adriamycin spill. This is understandable because the ramifications are hard to imagine unless you have actually seen a case. It is important not to understate the problem to the client. It is probably best to describe the worst-case scenario to clients from the start. The client must be carefully counseled that the site will most likely be very painful, swell, slough and get worse with time. Educate the client that the tissue damage happens, despite the best wound management and nursing care.

Insurance companies are teaching and encouraging physicians to apologize and empathize with their human patients whenever complications are encountered. They report fewer complaints and less bitterness when the doctor has offered an apology for the patient's aggravation and discomfort with complications. So it is definitely essential to show your concern and empathy for the patient and the client and apologize for the accident and address every one of your client's concerns.

In this author's experience, most veterinary facilities offer to bear the burden of cost for supportive care when dealing with extravasations. If the client signs an informed consent form for chemotherapy administration and complications, your clinic may make arrangements to share the cost of care with the client in some agreeable way. The informed consent form may specifically outline the risk of extravasation and potential costs to the client.

To explain the gravity of an adriamycin spill to a client, the attending technician or the attending doctor may say something like this, "Unfortunately, there was an accident while administering chemotherapy today. Some of the drug leaked outside of the vein. This is called 'extravasation' or a 'spill.' This problem can happen with any IV injection. Unfortunately we encounter more tissue injury and post treatment problems when we use certain chemotherapy drugs that are by nature, vasosclerotics. Although this drug is very good at killing cancer cells, when it is in direct contact with tissue it behaves like an acid. Adriamycin is one the most caustic chemotherapy drugs and it may continue to destroy tissue relentlessly, despite our very best efforts. If tissue damage is extensive, we may need to perform debridement surgery and regrettably, we might have to resort to an amputation to stop the pain."

A full explanation of the consequences of extravasation will help your clients understand why it is imperative to sedate all nervous and fractious cancer patients receiving caustic chemotherapy drugs, especially adriamycin.

Extravasation Slough

Vincristine type sloughs are evident within the first 1 to 7 days. The damaged tissue gets irritated for several days followed by necrotic crusting at the site. The spill area actually feels like stiff leather. When the dead tissue sloughs off, it may reveal an ulcer. This eventually heals over a 6-week period.

Adriamycin type extravasation sites may not look threatening at first. After the first 3 to 10 days or well into the second week things might appear hopeful. Undetected adriamycin sloughs usually become clinically obvious after 7 to 10 days. The extravasation sight appears swollen and inflamed for another 1 to 3 weeks. Unfortunately, with significant adriamycin spills, the sloughing area enlarges and worsens over the next 2-3 months. The tissue necrosis may spread deeper and expose muscle, tendons and bone. The eschar (a slough produced by a thermal burn or corrosive agent or gangrene) enlarges and deepens and may develop difficult to treat secondary infections.

Nursing care may seem futile and it is very frustrating for the pet owner to rationalize about what has happened to their beloved pet. The wound must be treated diligently every day. The attending doctor must provide adequate preemptive pain control to keep the patient as comfortable as possible. Surgical debridement may be needed to remove necrotic tissue from the site. Wound care management and products that draw out toxins may be of some help. Decision making regarding amputation of a cancer patient's leg is difficult. The risk benefit ratio and prognosis for the overall survival of the cancer patient must be taken into consideration. Always comfort the client and let them know that you share in their grief and that no one wanted this accident to happen.

Preventing Extravasations

The discomfort and cost described above should motivate your entire professional staff to prevent extravasations. The chemotherapy room should be quiet and free of distractions. The nurses and their assistants should be focused and should not be given cross-orders or be pressured to hurry through the procedure. There must be a clean stick into the vein when placing the catheter. Keep constant visual and hands-on monitoring of the injection site from start to finish. Ensure that the catheter or butterfly needle is still in the vein during the entire administration of every drop of the drug.

Some oncologists propose the use of an indwelling catheter and dilution of the adriamycin into a small bag of saline. This is infused over a 30 to 45 minute period. This technique may yield the largest extravasations. Other oncologists prefer to run the adriamycin IV through a well-placed indwelling catheter simultaneously with rapidly flowing saline over a period of 15 to 20 minutes. Many oncologists (me included) and oncology nurses feel most comfortable with direct, close supervision of every drop of adriamycin given via small gauge butterfly catheters (no larger than 23 gauge).

The total calculated dose of adriamycin is diluted in a 12 cc syringe with sterile saline to 10 ml for the average cat. We dilute the dose for dogs to approximately 1 ml/lb with sterile saline or sterile water, for injection using a 35 ml syringe for small dogs and a 60 ml syringe for large dogs. The carefully placed butterfly catheter is flushed with saline. The diluted adriamycin is administered while frequently pulling the syringe back just enough to see that blood is aspirated into the tubing. This verifies that the catheter remains well positioned and not up against the wall of the vein. We administer adriamycin to cats over a slow bolus over 5 to 7 minutes and to dogs at a slow, steady infusion rate over 15 to 20 minutes. Our chemotherapy technicians feel that hands on, direct visual supervision during the administration is best. Using diluted solutions of drug is also helpful. Selecting for well-behaved patients and sedation of fractious patients also helps to avoid problems.

An excellent suggestion to prevent extravasation appeared in the "Tech Talk" section of the Veterinary Cancer Society Newsletter, Vol. 28-1, Spring, 2004 by Jenny Rose, CVT. Rose recommends using a small gauge butterfly catheter with 12 inch tubing. She attaches a 3-way stopcock to the catheter and places a 12 ml luer-lock syringe with 0.9% saline solution for flushing at one port and the chemotherapy drug at the other port. Flushing before and after drug administration is easily performed without switching from one syringe to another. The chemotherapy nurse monitors flow by continuous aspiration of small amounts of blood to verify placement of the catheter in the vein during the entire administration of the drug.

Treatment for Extravasations

All references instruct the attending staff to act immediately if a spill is detected. The authors recommend not removing the catheter, but rather keeping it in place to clean it before withdrawing. Use a syringe to remove as much drug as possible from the catheter, tubing and tissue. Removal of 5 to 6 ml of blood in a cat and 10 ml in a dog should be adequate. Insert a 27-gauge needle into the spill bleb and aspirate as much of the drug as possible to minimize the amount of drug at the site. Some references say to administer the "appropriate antidote" or flush saline through the catheter to dilute residual drug.

Ice packs or cold compresses are recommended for adriamycin, actinomycin-D and mechlorethamine spills for 6 to 10 hours. All references agree that warm compresses should be placed on vincristine/vinblastine and etoposide spills for the first 3 to 4 hours. These procedures are recommended to minimize the vesicant drug's toxicity. The objective for warm compresses is to disperse the drug into the circulatory system. The opposite effect is desired with cold compresses. The rationale is that cold packs are intended to reduce circulation and to localize adriamycin spills to reduce toxicity.

It is disheartening to read the literature. Most experts agree that nothing, including the list of recommended "antidotes" such as dexrazoxane (Zinecard®), DHM3, steroids, and hydrophilic wound dressings actually offset the devastating tissue damage from undetected anthracycline (adriamycin family) extravasations. Using Zinecard or DHM3 injected into the area within 3 hours of the accident is helpful. Some oncologists use IV Zinecard at 10 times the adriamycin dose within 3 hours and at 24 and 48 hours after a spill. (Vail 2006) It is used to offset cardio toxicity in people and costs approximately $250-350 for the 250mg and 500mg vials respectively.

The "Modified Villalobos Snake Bite Slit Technique"

Early in my career, this author and our staff oncology technicians had the feeling of dread and helplessness with adriamycin extravasations. It was hard for me to accept that we should live this amount of hopelessness looming in our daily oncology service. It seemed that if our technicians were going to work every day with caustic chemotherapy drugs, we needed a more aggressive procedure to stop the severe sloughing problems and eliminate the threat to our patients. A sense of doom forced this author to come up with a contingency plan. Either we had to alter the drug or better yet, remove every drop of drug from the perivascular spill site. Unfortunately, there is not much written about this approach. Most textbooks say that whatever is done probably won't impact the outcome. Experience with our new technique says otherwise. The literature makes only fleeting mention about flushing extravasation sites with saline. It also mentions caution with this procedure, as it may spread the drug to a deeper or wider area. It seemed reasonable to develop a better technique for flushing. We started treating every caustic drug spill as an emergency and the worst snakebite on earth.

Most importantly, there is no blame or anxiety placed on the technician/nurse who observes and or reports the spill. Rather than putting tension in the air, we offer encouragement and gratitude for reporting a spill. Accidents happen and pride and feelings are hurt. Those personal issues need to be set aside to treat the patient and avoid the problems described above.

We aspirate any residual drug from the catheter and the bleb. Then we infiltrate saline into the site as described above. The team preps the leg for surgical incision. Using the bevel of a sterile 18-gauge needle, this author makes 10 to 30 interrupted parallel, deep skin incisions (slits) avoiding the vein. We make the slits to extend into the perivascular SQ tissues in a "lettuce bag" pattern or staggered parallel incisions. The slits should extend beyond the entire extravasation site and 360 degrees around the entire limb if necessary. With the same technique that is used to give SQ fluids, run saline or isolyte solution through the entire site and around the limb for 20-45 minutes.

Flush, Flush and Flush and then Flush more while gently squeezing or "milking" out the fluids. This action helps exit the fluid and offending drug out through the skin slits. For larger spills, insert the 18-gauge needle into deeper parts of the limb, into muscle and fat, to let the fluids infiltrate and flush deeper tissues. This allows the vesicant drug to ooze out with the fluids. Hopefully, every drop of the offending vesicant will percolate out through the skin slits in a diluted fashion. On one occasion we saw the distinctive red color of adriamycin as it exited the tissue. Run one or two liters through the extravasation site over a 20 to 45 minute period, depending on which drug was spilled and the patient's size. Be sure that all staff involved wears protective eye shields, gowns and chemotherapy gloves.

In is this author's opinion this technique actively removes the threatening vesicant drug out of the spill site. The patient may go home with a light wrap and instructions for the family to apply cold compresses over the next 24 hours. The patient is rechecked weekly for 3 weeks to monitor for tissue damage, infection and healing of the skin incisions.

This technique has worked well for the technicians in our practice. We have completely avoided the problems associated with known extravasations of any type. Using the "Modified Villalobos Snake Bite Slit Technique" in your practice should yield similar success. Hopefully this technique will increase staff confidence and minimize complications for your patients, their families and your practice.

References

Kisseberth, W.C., MacEwen, E.G., Complications of Cancer and Its Treatment, Chapter14, Small Animal Clinical Oncology, 3rd Ed., S.J. Withrow & E.G. MacEwen, Eds., W.B. Saunders Co., 2001, p 198-219.

Morrison, W.B., Principles of Treating Chemotherapy

Complications, Chapter 25, Cancer in Dogs and Cats, 2nd Ed., W.B. Morrison, Ed., Teton New Media, 2002, p 365-374.

Vail, D.M., et al., Consensus Document: Veterinary Co-operative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE) Following Chemotherapy or Biological Antineoplastic Therapy in Dogs and Cats, Veterinary and Comparative Oncology, Vol. 2, No. 4, 2004, p194-213.

Vail, D.M., New supportive therapies for cancer patients. 24th Annual ACVIM Forum Proceedings, 2006.

Villalobos, A.E. (personal experience 1975-present)

Villalobos, A.E., Adverse Effects of Cancer Therapy in Geriatric Pets, Chapter 6D, Canine and Feline Geriatric Oncology Honoring the Human-Animal Bond, Blackwell Publishing, to be released in 2006.