THE FIRST REPORTED cases of intra-arterial promethazine (Phenergan; Baxter International, Deerfield IL) injection causing complications were in the late 1960s.1,2 On a broader scale, there have been literature reports of adverse outcomes after accidental intra-arterial injections of drugs since the 1940s.3 In our literature review, we found a total of 8 patients with reported cases of accidental intra-arterial promethazine injection. All 8 patients received injections in the hand or upper extremity.1,2,4 –10 We report on 2 additional cases of intra-arterial injection of promethazine that led to necrosis and arterial injury of the hand.
Promethazine is a commonly prescribed drug. It may be administered by oral, rectal, intramuscular, or intravenous routes. The common use of the medicine lends to a comfortable familiarity with its administration. The uncommon but devastating complications of the drug when administered intra-arterially are not well known in the medical community. Hand surgeons must be knowledgeable about this subject because they may be required to evaluate and manage these injuries.
We present 2 cases of intra-arterial promethazine injection that led to digital necrosis. Both cases eventually led to amputations. Our report is pertinent at this time because a case involving intra-arterial promethazine injection has recently been heard by the Supreme Court of the United States. That case involves a 62- year-old woman, and the incident led to the amputation of her right arm below the elbow.4–6 Promethazine hydrochloride is a phenothiazine derivative. It possesses antihistaminic, sedative, anti–motion sickness, antiemetic, and anticholinergic effects. Promethazine is buffered with acetic acid–sodium acetate and has a pH between 4.0 and 5.5. It has been suspected that the damage caused by inadvertent intra-arterial injection of promethazine may be related to its relative acidity. It is well known that promethazine injection, in any route, can cause severe chemical irritation and tissue damage. The package insert warning label states that extreme care should be exercised to avoid perivascular extravasation or unintentional intra-arterial injection.11 However, the literature suggests that nurses may be perfunctory with promethazine administration because of their familiarity with the drug.8

CASE REPORTS
Case 1
A 43-year-old woman was receiving treatment in an emergency department for dehydration resulting from an episode of viral gastroenteritis. The emergency room personnel experienced difficulty placing peripheral intravenous (IV) lines in the patient. After multiple attempts, an IV line was placed in the left antecubital fossa. The patient also reported nausea and was administered promethazine through a presumed left antecubital IV line. However, the promethazine was accidentally injected into the brachial artery of the left arm. Immediately after the injection, the patient experienced burning pain from the left antecubital fossa to the hand. The patient also experienced initial vasospasm of the left hand, as it was noted to be cooler than the other hand on examination, yet the patient’s radial pulse remained palpable. Subsequently, the patient’s left hand became erythematous. She was discharged home.
The patient returned to the same emergency department 5 days later, reporting pain and discoloration of the left index and ring fingers. The patient also stated she had noticed a purple discoloration of the thumb and little finger after the initial event that was not present at this examination. The patient’s radial pulse was noted to be intact. The patient was given a prescription for pain medicine and again discharged home.
Ten days after the initial event, the patient sought care at a different emergency department. The patient was seen by a vascular surgeon who noted that the thumb and digits of the left hand appeared cyanotic distal to the proximal segments. The radial pulse was palpable. The patient was taken to the catheterization laboratory with a diagnosis of left upper extremity ischemia caused by a chemical irritant vasospasm or an embolic event. An angiogram demonstrated an occluded ulnar artery from its origin. There was also occlusion of multiple distal digital arteries (Fig. 1). The patient was treated with intra-arterial injections of lidocaine, papaverine, and alteplase. The line was left in place overnight for continuous injection of papaverine. The following day, the patient returned to the catheterization lab, where a follow-up angiogram demonstrated a patent radial artery, an occluded ulnar artery with some collateral flow, a patent arch, and occlusion of the distal digital arteries to the thumb and fingers. The patient was discharged home after receiving oral aspirin, clopidogrel, and warfarin.
The patient developed necrosis of all 5 digits of the left hand (Fig. 2). She was ultimately referred to us, and amputations of all digits were carried out 6 weeks after the initial event. Histopathology showed coagulation necrosis.

Case 2
A 26-year-old woman received treatment in an emergency department for sickle cell crisis. She had required multiple hospitalizations for IV fluid hydration, blood transfusions, and analgesic administration. Frequent venopuncture had contributed to worsening phlebosclerosis with subsequent stenosis, thereby making venous access a challenging task. The patient had no history of digital ischemia.
After infiltration of a left external jugular IV line, the anatomic snuffbox of the left wrist was chosen as an alternate access site. Normal saline, as well as a single dose of 50 mg meperidine and 12.5 mg promethazine, was infused through the newly placed 24-gauge angiocatheter. The patient reported pain, swelling, and discoloration of her left hand, which prompted emergent hand surgical consultation. On physical examination, the hand was grossly edematous with second digit cyanosis distal to the proximal interphalangeal joint. A recent venipuncture site was present over the radial artery in the anatomical snuffbox. The patient received a stellate ganglion block in an effort to relieve vasospasm, and she was anticoagulated with heparin and later coumadin. The patient was then discharged home.
Two weeks later, there was demarcation of the terminal segment of the left index finger. The left thumb appeared to be involved concomitantly, with focal ischemia and cyanosis along the ventral aspect of the terminal pulp. In addition, there was cephalic vein thrombosis extending from the left mid-forearm to the level of the first carpometocarpal joint, which was intimately associated with a healing venipuncture site near the proximal aspect of the anatomical snuffbox. There was no overlying cellulitis or clinical evidence of infection associated with the thrombosed vein. A left upper extremity arteriogram demonstrated normal anatomic blood flow to the level of the left wrist; however, there was occlusion of the radial artery in the anatomic snuffbox (Fig. 3A) with segmental occlusion of multiple distal digital arteries (Fig. 3B). Three weeks after the initial injury, the left index finger had fully demarcated from the middle segment distally, necessitating amputation. However, there was no further progression of left thumb involvement.
Microscopy of the amputated index digit showed intimal hyperplasia with occlusion of the small vessel muscular arteries. Although the patient’s wound healed well postoperatively without complication, the patient complained of moderate cold intolerance in the left hand over the next year.

DISCUSSION We have found only 4 previous case reports of intraarterial promethazine injection in the literature.1,2,9,10 There have been other cases reported in the news, in editorials, and in review articles.4–8 From these reports, we found a total of 8 patients diagnosed with intraarterial promethazine injection. Two patients required forearm amputations.1,8 Three other patients required amputations or partial amputations of a finger or multiple digits.8–10 One patient required fasciotomies, multiple debridements, and 4 skin grafts.7 Another patient required solely skin grafting over a necrotic area.8 Only one patient did not develop necrosis. From that particular case report, it appears that only a partial injection was given, which may have saved the patient from further damage.2
Intra-arterial administration of promethazine is associated with tissue necrosis. Promethazine is most safely administered by enteral routes or intramuscular injection; intravascular injections should be avoided. Many patients for whom IV promethazine is prescribed, as in our 2 patients, are dehydrated as a result of gastrointestinal illnesses. The accompanying hypovolemic state may make veins more difficult to cannulate accurately. In these situations, venous access sites near arteries such as the radial artery at the wrist and the brachial artery in the antecubital fossa should be avoided.12
In these cases, aspiration of dark blood does not rule out an intra-arterial line. This is because blood becomes dark or discolored on contact with promethazine.11 Although a nurse is responsible for injection of the drug, ultimately it is the responsibility of the physician to understand its complications. Therefore, the ordering physician must carefully consider the route of administration of promethazine.
Some experiments have looked at the cause of necrosis after intra-arterial drug injection. Intra-arterial injection of pharmaceutical agents in a canine model consistently produced lower extremity necrosis after injection of the femoral artery with various medicines while occluding the proximal arterial circulation. The pharmaceutical agents were selected because of their known clinical history of producing necrosis. These agents included promazine hydrochloride, dextro amphetamine, and bromosulfalein. The study demonstrated a specific chain of events after intra-arterial injection. There were early inflammatory reactions followed by extravasation of blood, vessel wall necrosis, and ultimately intra-arterial thrombosis terminating in massive tissue necrosis. The pattern first affected the smaller vessels.13
There is no effective management for intra-arterial promethazine injection. Thrombolytics, anticoagulation, and sympathetic blockade may limit the zone of necrosis, but the efficacy of this management is speculative. This is underscored by the fact that there are no published treatment algorithms at this time. The damage caused by the injection may be irreversible; nevertheless, we recommend that a hand surgeon follow certain steps when evaluating these patients.
Once an intra-arterial injection injury has occurred, immediate recognition of the injury by the hand surgeon is imperative. If possible, the intra-arterial line should be left in place. This will allow diagnostic confirmation as well as immediate delivery of medications. If there are no contraindications, the next step should be anticoagulation. This should initially involve a heparin IV drip. Elevation of the extremity can also be helpful to alleviate edema. The next major step we recommend is stellate ganglion blockade. This serves several functions, including pain relief, decreasing vasospasm, and maintaining perfusion. One of our patients received intra-arterial local anesthetic and thrombolytics. Management of the arterial spasm should be attempted with one of a variety of methods, including calcium channel blockers, papaverine (antispasmodics), local anesthetic injections, and thromboxane inhibitors. If indicated, reestablishment of blood flow should be attempted with thrombolytics. These interventions should be considered on a case-by-case basis because these medications can have severe systemic complications. If available, hyperbaric oxygen therapy may also be considered as a noninvasive therapy. Time is required for the zone of necrosis to be defined before debridement. Because of small vessel involvement and progressive necrosis, subsequent debridement or a more proximal amputation may be required before wound closure or coverage. Finally, the patient should begin hand therapy and rehabilitation when appropriate.7
Both of our cases arose within 13 months from a single hand surgeon’s practice. This suggests that the injury may be underreported. However, we have no way of knowing the true incidence of this injury until it is more widely known and better understood. These 2 cases provide greater awareness to this unfortunate complication.
Inadvertent intra-arterial administration of this commonly prescribed antiemetic typically results in ischemia that ultimately leads to tissue necrosis. Hand surgeons must be aware of this complication and consider the diagnosis of intra-arterial promethazine administration when evaluating patients with digital and hand ischemia, who have recently had IV lines or IV injection of medications. Furthermore, all health care personnel must be familiar with the devastating complication associated with this commonly prescribed medication and exercise caution when ordering promethazine.

REFERENCES
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9. Mostafavi H, Samimi M. Accidental intra-arterial injection of promethazine HCl during general anesthesia: report of a case. Anesthesiology 1971;35:645– 646.
10. Keene JR, Buckley KM, Small S, Geldzahler G. Accidental intraarterial injection: a case report, new treatment modalities, and a review of the literature. J Oral Maxillofac Surg 2006;64:965–968.
11. Phenergan (promethazine HCI) injection package insert. Available from: http://www.baxter.com/products/anesthesia/anesthetic_ pharmaceuticals/downloads/phenergan.pdf. Accessed October 30, 2008.
12. Lirk P, Keller C, Colvin J, Colvin H, Rieder J, Maurer H, et al. Unintentional arterial puncture during cephalic vein cannulation: case report and anatomical study. Br J Anaesth 2004;92:740 –742.
13. Engler HS, Freeman RA, Kanavage CB, Ogden LL, Moretz WH. Production of gangrenous extremities by intra-arterial injections. Am Surg 1964;30:602– 607.

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