FAILURE TO PROPERLY TREAT EXTRAVASATION OF DOXORUBICIN (Adriamycin)
By: Anthony H. Gair;
New York medical malpractice attorney elaborates on the extravasation of intravenously administered chemotherapeutic agents into the subcutaneous tissue of cancer patients undergoing chemotherapy is a known risk of treatment. The potential gravity of injury caused by extravasation is dependent upon the type of drug which extravasates. The most destructive extravasation injuries are those caused by anti-tumor drugs which bind to deoxyribonucleic acid (DNA), such as Doxorubicin, (Adriamycin) which has been a primary part of chemotherapeutic regimes since the late 1960’s. Extravasation of chemotherapeutic agents which bind to nucleic acids can lead to a prolonged course of injury. The most clinical experience has been derived from the extravasation of Doxorubicin. Rudolph, R, Larson, D. Etiology and Treatment of Chemotherapeutic Agent Extravasation Injuries: A Review. J. Clin. Oncol, 1987; 5:1116-1126. Doxorubicin causes severe progressive tissue necrosis that may involve muscles and tendons. Since no specific antidote has been developed, the recommended treatment of Doxorubicin extravasation is early excission of all infiltrated tissue. Dahlstrom, KK, Chenoufi, HL, Daujard, S. Fluorescene microscopic demonstration and demarcation of Doxorubicin extravasation. Experimental and Clinical studies. Cancer, 1990 Apr. 15; 65(8): 1722-1726.
It has been postulated that infiltration of Hyaluronidase, which may serve to dilute the extravasated Doxorubicin, will decrease the amount of ulceration caused by the extravasation. Disa JJ, Chang RR, Mucci JJ, Goldberg N.H., Prevention of Adriamycin-induced full-thickness skin loss using hyaluronidase infiltration. Plast. Reconstr. Surg. 1998 Feb., 101(2):370-374. In this regard the injection of saline solution at the site of extravasation of a vesicant (blistering) chemo-therapeutic agent in order to reduce the concentration of the extravasated drug has been reported to have been effective. Scuderini, Onesti MG, Anti-tumor agents: Extravasation, Management and Surgical Treatment. Am. Plast. Surg. 1994 Jan; 32(1):39-44. However, other authors have emphatically stated not to inject saline, sodium bicarbonate or hyaluronidase into the extravasation area as to do so may increase the diffusion of the extravasated agent into surrounding tissue. Hankin FM, Louis DS, Extravasation of Chemotherapeutic Agents. Am. Fam. Phys. 1985 March; 31(3)147-150.
For some time the injection of steroids into the subcutaneous tissue at the site of Doxorubicin extravasation was recommended on the theory that steroids would reduce inflammation. However, it has been demonstrated that inflammatory cells are uncommon in tissue damaged by Doxorubicin extravasation. Rudolph R, Stein RS, Patillo R: Skin Ulcers Due to Adriamycin. Cancer 38:1087-1094, 1976; Larson DL: What is the appropriate treatment of tissue extravasation by anti-tumor agents? Plast Reconstr Surg 75:397-405, 1985. In 1996 the package insert for Adriamycin was changed. Prior thereto, the injection of steroids was recommended in the event of extravasation. In 1996 it was stated that the benefit of local administration of drugs has not been clearly established. Close observation and plastic surgery consultation were recommended. The immediate treatment of DNA-binding chemotherapy extravasation should include elevation of the effected extremity and intermittent cold. There does not seem to be any agent that, injected locally, can alter the final result from extravasation of any binding chemotherapeutic agent. Persistent swelling, erythema and pain are indications for surgical consultation, even if ulceration is not yet apparent. Such consultation is mandatory when blistering and ulceration are first seen. Rudolph and Larson, supra. Snyderman RK, Krasna MJ, Adriamycin extravasation injuries. Plast Reconstr Surg 1986 Apr; 77(4):683-684.
The following case involved a patient being treated for Non-Hodgkins Lymphoma with, among other chemotherapeutic agents, Doxorubicin. During his second round of chemotherapy, the treating oncologist administered 60mg of Doxorubicin by I.V. push via a free flowing intravenous line. The infusion site was the right upper anterior arm just above the elbow. Fifteen minutes following the infusion the “chemo line” was noted to be red and swollen. Ninety minutes later, pursuant to order of the oncologist, Hydrocortisone, 100mgs was instilled subcutaneously. Hydrocortisone ointment was also topically applied. Two days thereafter, swelling and redness of the right arm was noted to be increased. The patient complained of increased swelling and redness in the right arm. The oncologist ordered topical application of Hydrocortisone cream four times a day. The patient was discharged from the hospital five days post extravasation with the right arm still swollen and hard, to be followed on an out-patient basis by his oncologist. The patient was, 3 ½ weeks later, noted to have a still swollen right arm with a necrotic area. Two weeks thereafter, he was admitted to the hospital with a fever of 103E, a swollen and erythematous right arm with a large necrotic area with dry eschars. The patient thereafter required numerous surgical debridements of the right arm as well as a fasciotomy, repair of a pseudoaneurism of the brachial artery and extensive skin grafting. The patient was left with significant atrophy of the right arm, a 90E extension contracture at the right elbow and significant restriction of motion of the wrist, hand and fingers.
The plaintiff alleged that the oncologist failed to recognize the significance of the extravasation injury, failed to understand how to treat it, failed to seek proper consultation and failed to understand the pathology of the extravasation injury. It was alleged that, given the signs and symptoms documented in the hospital record, a consult with a surgeon experienced in treating extravasation injuries was mandated and would have avoided the extensive and permanent injuries suffered by the patient.
The following is excerpted from the deposition of the oncologist:
Q. You have had training, have you, in the administration of chemotherapeutic agents such as doxorubicin?
Q. Adriamycin is doxorubicin; correct?
Q. Doxorubicin is a chemo-therapeutic agent which binds to nucleic acid, correct?
Q. Binds to DNA, true?
Q. In fact, that’s the mechanism by which it fights cancer cells, true?
Q. What is the significance of the fact that doxorubicin binds to nucleic acid with regard to the progression of injury which may be caused by extravasation of doxorubicin into subcutaneous tissue?
A. It makes the damage irreversible.
Q. During the patient’s admission to the hospital did he suffer an extravasation of intravenously administered chemotherapeutic agents?
A. The answer is yes.
Q. Doctor, by extravasation we mean the escape of intravenous fluids into subcutaneous tissues, correct?
Q. Do you recall what you did then?
A. I went straight back to the patient to see what happened.
Q. What did you observe or what did you find out?
A. I noticed that there was redness in the upper arm, a streak, along the long vein.
Q. Do you recall what you did next?
A. I took insulin syringes and first I aspirated around. Then I injected decadron a corticosteroid.
Q. Why did you do that?
A. To minimize the inflammatory process.
Q. Why did you want to do that?
A. This is a chemical irritant and to reduce the impact, the inflammatory impact.
Q. What is a chemical irritant?
Q. Adriamycin is not an irritant, it is a vesicant, isn’t it?
A. It’s a vesicant.
Q. A vesicant agent by definition is a blistering agent; is that right?
Q. Doctor, I believe you stated that you administered the steroids to combat the inflammation, if you will; is that right?
A. To limit.
Q. Would you agree that severe local tissue necrosis may occur following doxorubicin extravasation?
Q. Would you agree that the necrosis is progressive following extravasation?
Q. And would you agree that the extravasation of a DNA binding vesicant agent leads to a more prolonged course of injury than a non-binding agent?
Q. That’s because the pathogenesis of injury with a DNA binding agent is that, in this case, when the agent extravasates, it starts being up taken by healthy cells?
Q. And it progresses and progresses as a result of that?
Q. Doctor, the cause of injury as a result of doxorubicin extravasation is not an inflammatory process; is it?
A. Inflammation follows.
Q. See if you can answer this question: We are talking about an agent, a vesicant agent that binds to nucleic acid. The injury caused by the extravasation of such agent is not caused by an inflammatory process; is it?
A. The initial injury is not an inflammatory – inflammation follows.
Q. I would like an answer to this question: In the face of extravasation of a vesicant chemo-therapeutic agent such as doxorubicin, which is a nucleic acid binding agent, it binds to DNA, how would the injection of steroids prevent the process of injury?
A. As I said before, the secondary process – I cannot remove the Adriamycin which is already bound to the nucleic acid. But the secondary process is the inflammation and I can do everything to limit that.
Q. But the progress of the injury I think we agree, is caused by the doxorubicin being up taken by healthy cells?
Q. It progresses and progresses, correct?
Q. Would you agree that doxorubicin, when extravasated into subcutaneous tissue, produces a permanent loss of that tissue’s ability to heal itself?
A. I don’t think it’s permanent to heal itself. It is a lasting damage. But I don’t think it’s permanent to heal itself.
Q. You think eventually it could heal itself?
Q. Doctor, would you agree that there is no agent, that when injected locally, can alter the final result from extravasation of doxorubicin?
A. I believe so.
Q. You believe there is no agent or your believe there is an agent?
A. There is no agent that has been proven to reverse the damage produced by Adriamycin.
Q. Given the fact that you had no experience in treating a patient who had sustained an extravasation of doxorubicin, do you think it would have been a good idea for you to have talked to a physician who had experience in treating such patients; “yes” of “no”?
A. As I have stated before, I have discussed it with some colleagues and the conclusion was it’s not severe enough. Just monitor it carefully.
Q. Those are the people you don’t remember who they were, right?
Q. The ones you made no note of, correct?
Q. Would you agree that the only effective remedy for doxorubicin extravasation is the complete excision of the tissue containing the doxorubicin?
Q. Well, if that’s so, why didn’t you obtain a surgical consult?
A. I thought it was improving. The arm was improving.
Q. As far as this patient’s arm was concerned and the effect of the possibility of extravasated chemo-therapeutic agents, that was your responsibility, correct, that was your expertise as an oncologist; wasn’t it?
A. I believe we all were involved, had this responsibility.
Q. But you were the attending oncologist, true?
Q. That was in your particular area of expertise, correct?
Q. Certainly when you are an oncologist and you are using chemotherapeutic agents such as doxorubicin, you should be aware of the effects of extravasation of such a drug, correct?
Q. You should be aware of how to treat it, correct?
Q. That is within your responsibility as the oncologist administering those drugs, true?
Q. Is it the responsibility of the oncologist to determine when surgery should be performed in a given patient?
A. It is usually a team approach between the oncologist and vascular surgeon.
Q. Or a plastic reconstructive surgeon?
A. Plastic reconstructive surgeon.
Q. And a plastic reconstructive surgeon should be part of the team?
Q. Doctor, you never ordered a plastic surgical, vascular surgical or any type of surgical consult for the patient at any time during your treatment of this man, true or not true?
A. I have not ordered the initial consult.
The deposition of the treating oncologist demonstrated a complete failure to understand the significance of the extravasation. Further, it was apparent that the physician did not understand how to treat the extravasation injury either acutely or long term. The deposition left no doubt that the physician had no understanding regarding the pathology of an extravasation injury caused by doxorubicin, had no training in treating same and had no knowledge as to the indications for injecting steroids into an extravasation.
Based on the total lack of knowledge of this physician, undeniably confirmed by the deposition testimony, the case settled for a substantial sum prior to trial. Further, it demonstrates that the plaintiff’s attorney must, prior to the deposition of the defendant physician in a malpractice case, be fully versed in the area of medicine involved as would be the case at trial.