Necrosis Caused by Intra-arterial Injection of Promethazine: Case Report

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By Andrew Lee Foret
Andrew P. Bozeman
Waldo E. Floyd


Updated: Mon, 06 May 2013 01:49:32 EST

Promethazine injections have led to necrosis and gangrene of the distal upper extremity when inadvertently injected into an artery. There have been few case reports of this alarming complication in the literature. We report on 2 cases of intra-arterial promethazine injection that led to amputation. (J Hand Surg 2009;34A:919–923. Copyright © 2009 by the American Society for Surgery of the Hand. All rights reserved.)


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.<br>
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.<br>
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
<strong>CASE REPORTS</strong><br>
Case 1<br>
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.<br>
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.<br>
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.<br>
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<br>
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.<br>
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.<br>
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.<br>
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.
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<br>
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<br>
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.<br>
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<br>
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.<br>
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<br>
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
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
1. Hager DL, Wilson JN. Gangrene of the hand following intra-arterial
injection. Arch Surg 1967;94:86–89.<br>
2. Webb GA, Lampert N. Accidental arterial injections. Am J Obstet
Gynecol 1968;101:365–371.<br>
3. Cohen SM. Accidental intra-arterial injection of drugs. Lancet 1948;
4. DeAngelis CD, Fontanarosa PB. Prescription drugs, products liability,
and preemption of tort litigation. JAMA 2008;300:1939 –1941.<br>
5. Glantz LH, Annas GJ. The FDA, preemption, and the Supreme
Court. N Engl J Med 2008;358:1883–1885.<br>
6. Curfman GD, Morrissey S, Drazen JM. Why doctors should worry
about preemption. N Engl J Med 2008;359:1–3.<br>
7. Sen S, Chini EN, Brown MJ. Complications after unintentional
intra-arterial injection of drugs: risks, outcomes, and management
strategies. Mayo Clin Proc 2005;80:783–795.<br>
8. Paparella S. The dangers of intravenous promethazine administration.
J Emerg Nurs 2007;33:53–56.<br>
9. Mostafavi H, Samimi M. Accidental intra-arterial injection of
promethazine HCl during general anesthesia: report of a case. Anesthesiology
1971;35:645– 646.<br>
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.<br>
11. Phenergan (promethazine HCI) injection package insert. Available
pharmaceuticals/downloads/phenergan.pdf. Accessed October 30, 2008.<br>
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.<br>
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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