Problem: Promethazine (PHENERGAN) injection is a commonly used product that possesses antihistamine, sedative, anti-motion sickness, and antiemetic effects. The drug is also a known vesicant which is highly caustic to the intima of blood vessels and surrounding tissue. Formulated with phenol, promethazine has a pH between 4 and 5.5. Although deep intramuscular injection into a large muscle is the preferred par-enteral route of administration, product labeling states that the drug may be given by slow IV push, which is how it is typically given in most hospitals. However, due to the frequency of severe, tragic, local injuries after infiltration or inadvertent intra-arterial injection, ISMP recommends that the FDA reexamine the product labeling and consider eliminating the IV route of administration.
Severe tissue damage can occur regardless of the route of parenteral administration, although intravenous and inadvertent intra-arterial or subcutaneous administration results in more significant complications, including: burning, erythema, pain, swelling, severe spasm of vessels, thrombophlebitis, venous thrombosis, phlebitis, nerve damage, paralysis, abscess, tissue necrosis, and gangrene. Sometimes surgical intervention has been required, including fasciotomy, skin graft, and even amputation.
The true extent of this problem may be unknown. However, scores of reports submitted to ISMP, USP, and the Pennsylvania Patient Safety Reporting System; articles in professional literature; news of lawsuits in the media; and communications on various Internet listservs and message boards (ISMP, National Patient Safety Foundation, allnurses.com, and others) suggest that patient harm may be occurring more frequently than recognized. A few examples follow.
In 2005, a 19-year-old woman went to the emergency department with flu-like symptoms and received the branded drug Phenergan IV (Friederich S. Malpractice allegations spotlight anti-nausea medication. The Daily World, Aberdeen, WA; December 7, 2005. Accessed at: www.thedailyworld.com/articles/2005/12/07/local_news/02news.txt). During the injection, she yelled out in pain and was tempted to pull out her IV line. After the injection, she told the nurse that her arm was still in significant pain and that she felt “something was wrong.” The nurse reassured the patient and left the room. The patient’s arm and fingers became purple and blotchy. The patient remained in the hospital for 30 days, during which she watched her previously healthy fingers turn black and shrivel (see photo in the PDF version of the newsletter). Her thumb, index finger, and top of her middle finger had to be amputated.
In 2005, a patient received 12.5 mg of promethazine IV into an IV site in the hand. During the injection, the patient complained of extreme burning, but the nurse continued administering the medication. The patient developed an area of necrosis on his hand, eventually requiring skin grafting and physical rehabilitation.
In 2005, a physician intern posted the following request on the ISMP message board: “I am hoping by posting this message I might get some immediate feedback…I am currently doing a rheumatology consult and saw a patient who presented with a history of an intra-arterial injection of Phenergan at another hospital, likely causing her extreme pain throughout the arm and gangrenous first two digits, which will most likely be amputated. I am hoping anyone who reads this with experience handling this problem or knows of a possible reversal please contact me ASAP. From what I have been able to gather, there is no current published treatment protocol. The patient will likely have her two fingers amputated soon, and in my opinion, could require more and suffer from lifelong chronic pain. This is a relatively young individual which makes everything more tragic.”
In 2004, a professional guitar player was awarded $2.4 million for her past and future medical expenses and $5 million for her pain and suffering after she endured two amputation surgeries following accidental arterial administration of the branded drug Phenergan (Patrick J. Marshfield woman wins 7.4 million jury award after she loses arm. The Barre Montpelier Times Argus; Barre, VT; March 19, 2004). Suffering from a migraine, the woman had gone to the emergency department, where she received the Phenergan, intended for IV administration. She developed circulatory problems and then progressive gangrene which led to amputation of her arm in stages.
According to the package insert, “Proper IV administration of this product is well tolerated, but use of this route is not without some hazards.” To reduce the risk of these hazards, manufacturer labeling recommends to: give the drug in concentrations no greater than 25 mg/mL; administer the drug at a rate no greater than 25 mg/minute; inject the drug through the tubing of an infusion set that is running and known to be functioning satisfactorily; and to stop the injection immediately if the patient reports burning to evaluate possible arterial placement or perivascular extravasation. Nonetheless, ISMP believes these long-standing hazards require further action on the part of healthcare providers, FDA, and promethazine manufacturers. In the 1970s, after numerous reports of infiltration and inadvertent intra-arterial injection of hydroxyzine, FDA asked the manufacturer to revise the label and remove IV as an approved route. Today the drug is only indicated for IM or oral administration. Similarly, FDA should carefully investigate adverse events with this drug to determine if labeling changes are warranted, including removal of approval for IV administration.
Safe Practice Recommendations: Along with the manufacturer recommendations, the following strategies should be considered to prevent or minimize tissue damage when giving IV promethazine.
Limit concentration. Since 25 mg/mL is the highest concentration of promethazine that can be given IV, stock only this concentration (not the 50 mg/mL concentration).
Limit the dose. Consider 6.25 to 12.5 mg of promethazine as the starting IV dose, especially for elderly patients. Hospitals have reported that these smaller doses have proven quite effective.
Dilute the drug. Require further dilution of the 25 mg/mL strength to reduce vesicant effects and enable slow administration. For example, dilute the drug in 10 to 20 mL of normal saline if it will be administered via a running IV, or prepare the medication in minibags containing normal saline if there is time for pharmacy to dispense them as needed for individual patients. (Trissel confirms that promethazine is physically compatible when diluted in normal saline, with little or no drug loss in 24 hours at 21 degrees C in the dark, when prepared in glass, PVC, and polyethylene-lined laminated containers [Handbook on Injectable Drugs, 13th edition. ASHP, Bethesda, MD; 2005:1266].) Extravasation can also be recognized more quickly when promethazine is diluted than if the drug is given in a smaller volume.
Use large patent veins. Give the medication only through a large-bore vein (preferably via a central venous access site, but absolutely no hand or wrist veins). Check patency of the access site before administration. Note: according to the package insert, aspiration of dark blood does not preclude intra-arterial placement of the needle because blood can become discolored upon contact with promethazine. Use of syringes with rigid plungers or small bore needles might obscure typical arterial backflow if this is relied upon alone.
Inject into the furthest port. Administer IV promethazine through a running IV line at the port furthest from the patient’s vein.
Administer slowly. Consider administering IV promethazine over 10-15 minutes.
Revise orders. Revise preprinted order forms to ensure orders for promethazine reflect the safety measures listed above.
Educate patients. Before administration of the drug, tell patients to let you know immediately if burning or pain occurs during or after the injection.
Create alerts. Build an alert to appear on computer-generated medication administration records (MARs), electronic MARs, and on automated dispensing cabinet screens for nurses to view each time they access and administer a dose of promethazine, reminding them that the drug is a vesicant and should be diluted and administered slowly through a running IV.
Treat. The manufacturer notes there is no proven successful management of unintentional intra-arterial injection or perivascular extravasation. However, sympathetic block and heparinization have been employed during acute management of promethazine extravasations.
Use alternatives. Consider safer alternatives that can be used for the various conditions treated with IV promethazine. For example, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists may be used for both prophylaxis and as a rescue antiemetic. The package insert for ZOFRAN (ondansetron), for instance, states: “For patients who do not receive prophylactic Zofran injection and experience nausea and/or vomiting postoperatively, Zofran injection may be given to prevent further episodes. (Zofran goes off patent in late 2006, so generic alternatives should be available by 2007.) Also ensure that appropriate surgical patients are receiving a 5-HT3 for prophylaxis and are well hydrated to reduce the risk of post-operative nausea and vomiting and, thus, the need for a rescue antiemetic.
Remove from formulary. Some hospitals that have continued to experience adverse outcomes despite safety measures have removed promethazine from their formulary or banned its IV use.