Urgent message: Due to versatility, the urgent care clinician will find promethazine an appropriate choice in many situations. Awareness of potentially serious side effects maximizes the chance of good outcomes while minimizing risk.

Shailendra Saxena, MD, PhD, Naureen Rafiq, MD, Liji George, MD, Cara Olsen, PharmD, and Mikayla Spangler, PharmD

Introduction
Promethazine (Phenergan) is a drug commonly prescribed in emergency departments and urgent care clinics for treatment of a variety of conditions (Table 1). Because it possesses antihistamine, sedative, anti-motion sickness, and anti-emetic effects, it is often used for nausea and vomiting.

Physicians may not be fully aware that it is also toxic to the intima of blood vessels and surrounding connective tissue; this can result in severe tissue damage and necrosis.

Although this is not a common side effect of this medicine, the purpose of this article is to bring awareness to and familiarize urgent care physicians with serious complications which can happen with this commonly used medication.

Table 1. Common Uses of Promethazine

Allergic reactions

  • hay fever
  • urticaria
  • vasomotor rhinitis
  • skin allergies
  • poison ivy
  • insect bites

Relief of pruritus due to various dermatologic conditions
Nausea and vomiting of various etiologies

  • motion sickness
  • radiation sickness
  • surgery
  • anesthesia and gastroenteritis
  • centrally acting emetics
  • metabolic or endocrine disorders


Case Presentation
A 48-year-old African-American male presented to the emergency department with an abscess on the right lower abdominal wall and a four-day history of nausea.

The patient underwent incision and drainage (I&D) of the abscess and received 25 mg of promethazine by intramuscular route on the right gluteal area.

Immediately after, he reported a severe burning sensation going down his right thigh. It subsided after an hour, at which time he was discharged home to follow up with his primary care physician.

Two days later, the patient presented to his primary care clinic for the repacking of I&D. He complained that the pain at the injection site was worse – so much so that he was unable to walk.

On physical examination, he had:
temperature: 100.1° F
heart rate: 96 BPM
respiration: 4 RPM
blood pressure: 110/75 mmHg.
His right thigh was warm, tender, and swollen; erythema extended from the right hip down to the knee (Figure 1).
The patient was immediately admitted to the hospital and had a complete work-up for inpatient treatment of cellulitis. He had an elevated white cell count of 14,000, with no bands and a sodium level of 120 mEq.

CT scan of the right thigh demonstrated multiple congruent abscesses extending from the injection site on the right hip to the knee. The surgical team was consulted for possible fasciotomy of the right thigh.

Hospital Course

The patient was admitted for the treatment of cellulites and possible fasciotomy of the right thigh. He was started on intravenous fluids, the broad-spectrum antibiotic piperacillin-tazobactam (Zosyn), and the pain medication hydromorphone (Dilaudid). He had fasciotomy and wound vac placement. The culture grew methicillin-resistant staphylococcus aureus (MRSA), for which IV vancomycin was added in addition to piperacillin-tazobactam. Subsequently, the patient was taken to the operating room a few more times for wound vac changes. He remained in the hospital for one month and was later transferred to a rehabilitation facility.

Discussion
It is apparent in reviewing the literature that promethazine can cause potentially serious side effects, ranging from mild edema to soft tissue necrosis at the site of injection.

Administering promethazine by intravenous or intraarterial routes has been found to result in arterial spasm and, in turn, to impaired circulation and gangrene in specific cases.1 Extravasations of promethazine in the soft tissue are also believed to cause similar effects, as shown in our patient.

In 1999, Malesker, et al reported a similar experience with a 43-year-old woman who was admitted for a hysterectomy and received post-operative promethazine 25 mg every two hours by intravenous route for nausea and vomiting.2 She developed pain, swelling, and erythema at the site of injection in her right hand.
Patrick J. Marshfied in 2004 described the case of a professional guitar player who was awarded $7.4 million in a lawsuit for pain and suffering following complications associated with the intra-arterial injection of promethazine. The patient was simply treated for migraine headache, initially.3

More recently (2009), Grissinger described a case of a 19-year-old woman who received promethazine by intravenous route and developed pain and swelling at the site of injection in her right arm.4 Her arm and fingers became purple and blotchy; eventually, she underwent amputation of the thumb, index finger, and the top of her middle finger.4

Our case report clearly demonstrates the potential for serious complications associated with promethazine.
In this case, the patient was treated aggressively by the surgical team on board and had significant improvement. However, we believe that to date there have not been any scientific studies to summarize definitive treatment for the catastrophic consequences that may occur with promethazine and other drugs (e.g., phenytoin, thiopental, and propofol).5-7

Local anesthetic agents to promote vasodilatation, anticoagulation therapy, sympatholytic therapy (i.e., Stellate ganglion block), and limb elevation have all been described in case studies, with varying results.8-10 Nevertheless, it is important to point out that in case of inadvertent intra0arterial injection, the catheter should be left in place in order to administer emergency medications. The true extent of the problems associated with promethazine may not be known.

We, along with the manufacturer’s recommendations, suggest that the following strategies be considered to prevent or minimize tissue damage:

  • As 25 mg/ml is the highest strength of promethazine, try to use this concentration instead of 50 mg/ml.
  • The starting dose should be between 6.26 mg/ml and 12.5 mg/ml, especially in elderly patients.
  • Dilute 25 mg/ml of promethazine in 10 ml to 20 ml of normal saline (or prepare it in mini bags of normal saline).
  • Promethazine should be administered only via a large-bore vein, such as the central venous catheter or deep intramuscular.
  • IV promethazine should be administered over 10 to 15 minutes.
  • Before administration, advise patients to let the physician know immediately whether pain or burning occur during or after injection.

References

  1. Reents S, ed. Clinical Pharmacology. Vol 1.16 Tampa, FL: Gold Standard Multimedia: 1998.

Malesker MA, Malone PM, Cingle, et al. Extravasation of i.v. promethazine. Am J Health Syst Pharm. 1999; 56: 1742-1742.

  1. Marshfield PJ. Woman wins $7.4 million jury award after she loses arm. The Barre Monlpelier Times Argus, Barre, VT; March 19, 2004.
  2. Grissinger M. Preventing serious tissue injury with intravenous promethazine (Phenergan). Medication Errors. 34: 175-176. 2009.
  3. Twardowschy CA, Paola RL, Germiniani FMB, et al. Soft-tissue necrosis as a result of intravenous leakage of phenytoin. Neurology. 2009; 73: e94-e95.
  4. MacPherson RD, Rasiah RL, McLeod LJ. Intra-arterial thiopentone is directly toxic to vascular endothelium. Br J Anaesth. 1991; 67(5): 546-552.
  5. Chong M, Davis TP. Accidental intra-arterial injection of propofol. Anesthesia. 1987; 42(7): 781-782.
  6. Crawford CR, Terranova WA. The role of intra-arterial vasodilators in the treatment of inadvertent intra-arterial injection injuries. Ann Plast Surg. 1990; 25: 279-281.
  7. Zachary LS, Smith DJ, Heggers JP, et al. The role of thromboxane in experimental inadvertent intra-arterial drug injections. J Jand Surg. 1987; 12(2): 240-245.
  8. Keene JR, Buckley KM, Small S, et al. Accidental intra-arterial injection: A case report, new treatment modalities, and a review of the literature. K Oral Maxillofac Surg. 2006; 64(2): 965-968.

 

Promethazine-induced Tissue Necrosis: A Case Presentation

Shailendra K. Saxena, MD, PhD

Professor at Creighton University Medical School, Editorial Board Member at The Journal of Urgent Care Medicine
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