By Alice Villalobos, DVM

Adriamycin and vincristine, the most commonly used chemotherapy drugs in the battle against cancer in pets, are caustic vasosclerotics. If Adriamycin is extravasated into the perivascular tissues, the results may turn into one of your worst nightmares.

We use the term “vasosclerotic” on our chemotherapy treatment forms to warn our staff that localized tissue injury will result if there is a spill. Most perivascular leaks are noticed right away as a “bleb” or swelling immediately adjacent to the venipuncture site.

Occasionally a few spills go home undetected and untreated only to be noticed anywhere from one to10 days later. The pet owner calls into the office with complaints that the pet has pain, or is limping or has swelling or desquamation or is licking the venipuncture site.

The most notorious vasoclerotic is Adriamycin and its anthracyline relatives, doxorubicin, daunorubicin, epirubicin and idaruricin. Vincristine, vinblastine, cis-platin, mitoxantrone, mechlorethamine (Mustargen), mithramycin and etoposide are also vesicant, but they pale in their toxicity when compared to the irreversible indolent tissue damage inflicted by the Adriamycin group.

In my opinion, there is no equal to the tissue necrosis that even small amounts of Adriamycin can cause to a limb. The nickname given long ago to Adriamycin is “Red Death.” I tell clients, “It means death to the tumor cells, but if we get any of it out of the vein, we are in trouble.”

The important point here is that the attending nurse and clinician must act immediately and vigorously to literally and totally remove every drop of the spilled adriamycin from the tissues.

Unfortunately, there is not much written on how to effectively do that. Most textbooks say that whatever is done probably won’t make a real difference. So there is a sense of doom when Adriamycin is extravasated. That was unacceptable for me.

The extravasation may cause overt immediate discomfort. Some patients will cry out or struggle with the person who is restraining them for the injection. If a cancer patient fights restraint, it is best to recommend sedation to safely administer of any caustic chemotherapy agent especially, Adriamycin. We insist on sedation to protect the pet from the nightmare of extravasation.

I educate pet owners that, “If we do not use sedation, the patient’s leg could literally fall off.” We rely on the attending staff to be vigilant in deciding who needs sedation and in pointing out loud and clear when even small, suspected extravasations occur.

At first, the sight may not look dramatic even after the first few days and one might feel optimistic well into the second week. Vincristine sloughs show up within the first seven days. The damaged tissue forms crusts, causing the injured skin to look like leather. When the dead tissue falls off, it may leave a deeper ulcer that will heal.

Adriamycin sloughs may begin to show only after seven to10 days. Then, it looks inflamed for another one to three weeks, then slowly worsens as the weeks and months wear on.

The ulceration and tissue necrosis from adriamycin will infiltrate and spread deeper and deeper, exposing muscle, tendons and bone.

The area of eshar (a slough produced by a thermal burn or corrosive agent or gangrene) enlarges and deepens, forming necrotic sequestration of tissue that may get infected and the case turns into the worst nightmare that one can imagine.
Why the tissue damage spreads is poorly understood but the eshar from an Adriamycin spill continues to fungate for more than three to four weeks, according to most textbooks.

In actual fact, the effects of an Adriamycin extravasation will persist for months. Over 3 months in my experience and will involve much more area than the initial spill touched. The tissue damage seems to worsen over these months.

The injured tissues do not heal or regenerate. There is severe pain, swelling and corruption of the tissues of the entire limb. In most cases, amputation is the only option because of the extensive and irreversible indolent nature of the tissue necrosis. The real nightmare is deciding whether to amputate the leg of a cancer patient who may die from its cancer in the near future.

Do we continue the futile nursing care, despite the pain, because the pet has a primary problem with its cancer? There is no easy way out of this situation.
Inexperienced clinicians and nursing staff may not understand the full impact of an Adriamycin spill and may initially understate the ramifications to the pet owner. Adriamycin spills can be described to clients in this way: “This accident is like an acid burn that will continue to eat the tissue relentlessly with no response to even the best of treatment and, regrettably, may require amputation.”

If there is a spill, even the most optimistic client needs to be carefully counseled and warned that the wound will most likely only get worse with time despite the best bandage changing and nursing care.

Rather than healing and shrinking with time, the wound enlarges and penetrates into deeper tissues, macerating muscle and ligaments.

The damage, swelling and pain are truly unrelenting. This article may serve as an informative client handout in the event of a spill.
 
How to avoid disaster
Precaution against extravasation of any chemotherapy drug is the best control. There must be a clean stick into the vein when placing the catheter and there must be constant monitoring of the injection site to make sure that one is still in the vein during the entire administration of the drug.

Some oncologists propose the use of an indwelling catheter and dilution of the Adriamycin into a small bag of saline that is infused over a 30 to 45 minute period. (This technique may yield the largest extravasations). Others prefer to run the adriamycin into an IV line and indwelling catheter over a period of 15 to 20 minutes simultaneously while fluids are flowing into the vein.

The majority of oncologists and oncology nurses seem to feel most comfortable with direct, close supervision of each drop of Adriamycin. They our service included use very small-gauge butterfly catheters, no larger than 23 gauge. The total dose is diluted to 10 ml for a cat and approximately 1 ml per pound for dogs with sterile saline or water for injection.

Then the butterfly catheter is flushed with saline and then the Adriamycin solution is administered while frequently pulling the syringe back just enough to see blood in the hub of the syringe. This helps verify that the catheter is still well positioned in the vein and not up against the vein wall. This type of intense, direct supervision during the administering diluted solutions of Adriamycin seems to be what works best in our experience to avoid extravasation.

An excellent suggestion to avoid extravasation was in the “Tech Talk” section of the latest on line issue of the Veterinary Cancer Society Newsletter. Jenny Rose, CVT, recommended using a small gauge butterfly catheter with 12 inch tubing and attaching a three-way stopcock affixed with a 12 ml luer-lock syringe of 0.9 percent saline solution at one port and the chemotherapeutic drug at the other port.

Flushing before and after drug administration is easily performed without switching from one syringe to another. This also allows the continuous aspirating to see if one is still in the vein during the entire administration of the drug.

Treat the Site
All references say to act immediately and do not remove the catheter when extravasation occurs. Use a syringe to remove as much drug as possible from the catheter, tubing and tissue. Removing 5 to 6 ml of blood in a cat and 10 ml in a dog is adequate.

Then insert a 27-gauge needle into the bleb and aspirate as much of the drug as possible. This is intended to minimize the amount of drug at the site.

Some references then say to administer the “appropriate antidote” or flush saline through the catheter to dilute residual drug. Then use ice cold packs or cold compresses for 6 to10 hours on the Adriamycin, actinomycin-D or mechlorethamine spills. Place warm compresses on the vinca alkaloid and etoposide spills for 3-4 hours.

These procedures should minimize the vesicant’s toxicity. The idea is to spread the vinca alkaloid with the warm compresses to help disperse the drug into the circulatory system. The opposite idea is to use cold compresses to localize Adriamycin spills to reduce its toxicity. Confused? The most disheartening thing is to read the literature that says nothing, including the list of recommended “antidotes,” seems to work.
 
Recommended “Antidotes” for Extravasations
Adriamycin spills, a compound called DHM3 or the timely use of
dexrazoxane (Zinecard) injected directly into the tissue area of the spill within three hours of the accident may offset the damage.

I could not find anyone who has used these agents for extravasation in dogs or cats. The price of Zinecard is $250 and $350 for the 250 mg and 500 mg vial respectively.

Zinecard is used in humans to reduce the cardiotoxic effects of anthracycline drugs. The use of 1 ml of 1/6 molar isotonic sodium thiosulfate for each ml of extravasated cisplatin can inactivate it. This antidote is recommended only if a large amount of cisplatin is extravasated.

Hyaluronidase at 150 units/ml is recommended at 1 ml for every ml of extravasated vinca alkaloid or etoposide. This is purported to enhance absorption and disperse the spilled drug.

Topical DMSO or infiltration of the area with 1 mg/kg of hydrocortisone or using intralesional dexamethazone is considered controversial and probably a waste of time
 
An Aggressive Technique
There is only fleeting mention in the literature about flushing with saline with the caution that this procedure may, indeed, spread the drug to a deeper or wider area.

In my experience, there is only one way that I can sleep at night if adriamycin is extravasated: We treat every Adriamycin spill like the worst snakebite on earth and we treat it immediately.

First of all, there is no blame or anxiety placed on the technician who observes and or reports the spill. Rather, there is encouragement and gratitude. We want to know if there is an extravasation because the patient’s well-being is our most important priority.

After the aspirations from the catheter and the bleb are completed, we infiltrate saline into the site as described above. Then we prep the leg for surgical incisions. Then I take charge. Using the bevel of a sterile 18-gauge needle, I make 10 to 30 vertical, deep skin incisions (slits) that extend into the perivascular SQ tissues in a lettuce-bag pattern.

The slits extend beyond the entire extravasation site and 360 degrees around the limb. Then we run copious amounts of saline or isolyte solution through the entire site and around the limb with the philosophy of flush, flush and flush, and then flush some more.

We gently squeeze or “milk” the tissue. I may poke the 18-gauge needle into the deeper parts of the limb into the muscle and fat to allow the solution to bathe those tissues and ooze out. Hopefully every drop of the offending vesicant will percolate out through the skin slits in a diluted fashion.

On one occasion, we were pleased to see the distinctive red color of the adriamycin as it exited the tissue. In a typical 60-pound dog, we may flush one to two liters through the extravasation site over a 30 to 45 minute period, depending on what drug was spilled.

We recommend using nothing short of this extreme measure to get every drop of drug out of the spill area, especially if it involves Adriamycin.

We send the pet home with a light wrap and instructions for cold compresses for the next 24 hours. We recheck the patient weekly for the next 3 weeks to monitor for tissue damage and healing of the skin slits.

We completely avoid the nightmares that are so predictable with extravasations by using this “Modified Villalobos Snake Bite Slit Technique” because it works.
We hope that by contributing our successful experience to the profession that the potential for suffering of patient, pet owner and practitioner can be minimized.

Dr. Villalobos owns Animal Oncology Consultation Service in Woodland Hills. She received the 1999 Bustad Companion Animal Award and is associated with VCA Clarmar and Coast Animal Hospitals in Torrance and Hermosa Beach, Calif. Her e-mail is dralicev@aol.com.

This article appeared in Veterinary Practice News, August 2004