In the spring 2000, Diana Levine went to a clinic near her home in Vermont for symptoms of a migraine headache. She had been there many times before for the same problem, and, as in the past, she was treated with Demerol for pain and promethazine (Phenergan) for nausea.
But this time something went catastrophically wrong. It was decided to administer the promethazine not as a deep intramuscular injection or as an intravenous drip — the safer methods — but by rapid intravenous push. According to testimony in the malpractice suit that followed, the amount of promethazine given by IV push was twice the recommended dose, and was administered much faster than the suggested maximum rate of 25 mg/min.
Despite Ms. Levine's complaints of immediate severe burning pain at the injection site and along her arm, the physician's assistant who was administering the drug did not stop the injection as recommended by the manufacturer. In fact, severe pain during injection is a strong indication that the promethazine is being accidentally injected into an artery, or has extravasated. Over the next days and weeks, Ms. Levine's hand and lower arm began to darken, and then developed frank gangrene. Eventually, the 52-year-old musician had her right arm amputated below the elbow.
Promethazine is a versatile drug, with several different effects. It's an antihistamine, a sedative, and an effective anti-emetic. While it has been used extensively with only occasional significant problems, many clinicians do not realize that it is in fact a highly caustic preparation with a pH of 4–5.5. It also contains phenol. When injected rapidly, especially if introduced inadvertently into an artery or if it extravasates, it can trigger these events in sequence: burning and pain, erythema and swelling, arterial spasm, thrombosis, phlebitis, necrosis, and gangrene. The chance of this catastrophic cascade occurring can be reduced if a few simple principles governing the administration of promethazine are followed. (See table.)
This story has now taken on significant legal importance. Ms. Davis received a financial settlement from the clinic, the supervising doctor, and the physician's assistant who actually gave the drug, but she went on to sue Wyeth, the manufacturer of Phenergan, in Vermont State Court. Her attorney argued that the package insert did not warn strongly enough against administering promethazine via IV push. Although the insert was vetted and approved by the U.S. Food and Drug Administration, he claimed that merely adhering to the FDA-sanctioned language was not sufficient, and that the State of Vermont had the power to demand a more stringent warning. A jury agreed, ordering Wyeth to pay Ms. Levine $6 million. The Vermont Supreme court upheld the verdict.
Wyeth appealed to the U.S. Supreme Court. The key issue of Wyeth v. Levine focuses on the doctrine of conflict pre-emption, which derives from the Supremacy Clause of the U.S. Constitution. This holds that if a state law and a separate federal law have irreconcilable conflicts, the federal law will “pre-empt” the state law and prevail. Arguing before the nine justices of the Supreme Court, Seth Waxman, the counsel for Wyeth, insisted that by following federal FDA standards established for labeling Phenergan, the company was protected from challenge by the state or its courts.
Mr. Waxman: Repeatedly over the years, the FDA approved Phenergan injection as safe and effective under all the conditions and methods of use described in the labeling, including what is referred to as “IV push” injection. Yet a state jury, evaluating the same risk that the FDA had considered, determined that the precise labeling that FDA had required Wyeth to use in fact rendered Phenergan “unreasonably dangerous.”
Justice Ginsburg: But that doesn't answer the question. The risk of gangrene and amputation is there. No matter what benefit there was, how could the benefit outweigh that substantial risk?
Mr. Waxman: Justice Ginsburg, this is labeling that is directed at medical professionals. It is labeling that is directed at physicians who have to be able to determine what method of administration to use.
Chief Justice Roberts: When [the FDA] determines that it's safe to use [Phenergan] under those circumstances that necessarily includes a consideration of the risk.
Mr. Frederick: Mr. Chief Justice, here there was no way the FDA could have made this determination because the risks of IV push are so catastrophic compared to the benefit which the testimony at trial showed….
Justice Scalia: Well, you're just contradicting the label. The fact is they could not have approved that label unless they made that determination. Now, if you're telling me the FDA acted … irresponsibly, then sue the FDA.
The entire oral argument can be found at www.supremecourtus.gov. A decision is expected in June.
Safe Administration of Promethazine
▪ Consider alternate drugs such as ondansetron for nausea.
▪ Use large patent veins, not hand or wrist veins.
▪ Note that promethazine discolors arterial blood on contact, and aspiration of dark blood does not rule out intra-arterial needle placement.
▪ Do not administer promethazine in a concentration greater than 25 mg/mL.
▪ Consider diluting 25 mg/ml promethazine with 10-20 ml of normal saline.
▪ Give initial dose slowly, at a rate no faster than 25 mg/min.
▪ Stop infusion immediately if the patient reports pain or burning at the IV site.
Source: J Emerg Nurs 2007;33(1):53.