The Journal of Emergency Medicine, Vol. 26, No. 3, pp. 305⫺307, 2004
Copyright © 2004 Elsevier Inc.
Printed in the USA. All rights reserved
0736-4679/04 $–see front matter

doi:10.1016/j.jemermed.2003.09.009

Selected Topics:
Toxicology

CEREBRAL INFARCTS IN A PEDIATRIC PATIENT SECONDARY TO
PHENYLPROPANOLAMINE, A RECALLED MEDICATION
Nicole M. DeIorio, MD
Department of Emergency Medicine, Oregon Health and Science University, Portland, Oregon
Reprint Address: Nicole M. DeIorio, MD, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Mail code CDWEM, Portland, OR 97201

e Abstract—Phenylpropanolamine (PPA) recently has
been publicly implicated as a cause of stroke and other
neurologic events. In November of 2000, the Food and Drug
Administration (FDA) requested a voluntary recall of the
product from all manufacturers. However, medications
containing PPA still can be found in many homes of those
unaware of the voluntary recall. We present a case of stroke
after PPA ingestion that occurred 4 months after the recall
in an 8-year-old boy on chronic peritoneal dialysis. The
patient developed occipital infarcts and was found to have
extremely elevated levels of PPA in his blood and dialysis
fluid. Though the voluntary recall was in effect, the family
already had a bottle of the medication at home. Physicians
must be aware that the public is still ingesting the drug and
remain rigorous in including its toxicity in the differential
diagnosis of acute neurologic events. © 2004 Elsevier Inc.

ingredient in over 100 over-the-counter formulations as
cold medications and diet aids (2,3). Prompted by the
results of the Yale study, Phenylpropanolamine & Risk
of Hemorrhagic Stroke: Final Report of the Hemorrhagic Stroke Project, which linked the drug with hemorrhagic stroke, the FDA issued a request that drug
manufacturers voluntarily remove PPA from their medications (4). However, despite the FDA issuing a Public
Health Advisory, the public may remain unaware of
these events. As a result, PPA still exists on the medicine
shelves of consumers.
CASE REPORT
An 8-year-old boy on chronic peritoneal dialysis secondary to renal agenesis developed upper respiratory tract
infection symptoms with a cough and fevers as high as
38.4°C. At home, he was treated with approximately 3
days of acetaminophen, ibuprofen, and an unknown
amount of over-the-counter cold remedy containing
phenylpropanolamine. The father stated that he was administering the medications according to the packaging
directions, but could not be more specific regarding the
amount of PPA-containing product the child had received. Other chronic medications were ranitidine, paroxetine, calcium, epoetin alfa, and growth hormone. He
did have a history of mild hypertension, for which he was
on no medication; he had no past medical history of

e Keywords—phenylpropanolamine; cerebral infarction;
cerebrovascular accident; pediatrics; overdose

INTRODUCTION
Phenylpropanolamine (PPA) has been suspected to be
the cause of various adverse neurologic effects since at
least the 1960s (1). Case reports have noted associations
of PPA use with headache, seizure, intracranial hemorrhage, hypertensive encephalopathy, and cerebral vasculitis (2).
Until as recently as November of 2000, PPA was an

Selected Topics: Toxicology is coordinated by Kenneth Kulig, MD, of Denver, Colorado

RECEIVED: 28 October 2002; FINAL SUBMISSION RECEIVED: 27 August 2003;
ACCEPTED: 16 September 2003
305

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N. M. DeIorio

Figure 1. Bilateral parieto-occipital infarcts secondary to PPA-induced vasculitis.

seizures. Other past medical history included a failed
cadaveric renal transplant, recurrent peritonitis, and anemia of chronic disease. On the 3 days preceding the
admission, his father had noted the patient’s blood pressure to be elevated in the 140 –150/100 mm Hg range,
when it was usually about 120 mm Hg systolic. This was
treated as it routinely was, by manipulating the peritoneal
dialysis fluid. The patient presented to the Emergency
Department (ED) the next day when he developed a
diffusely severe headache, one episode of vomiting, and
blurry vision.
Physical examination on admission revealed an uncomfortable-appearing patient holding the front of his
head. He seemed sleepy and slightly confused. The blood
pressure was 154/90 mm Hg and pulse was 64 beats/min.
He was afebrile. The neurological examination showed
that he was disoriented to location. He had no light
perception bilaterally, but the other cranial nerves were
normal. The fundi could not be visualized. Motor and
sensory components of the examination were normal, but
because the patient was blind, cerebellar testing was
difficult to assess.
After the administration of intravenous antibiotics,
computed tomography (CT) scan of the head without
contrast was performed, demonstrating bilateral watershed infarcts in the parieto-occipital areas with edema,
though without mass effect (Figure 1). An MRI/MRA
confirmed the presence of a focal vasculitis.

A complete blood count was normal. A basic metabolic panel showed a sodium of 138 mEq/L, potassium
of 2.9 mEq/L, chloride of 91 mEq/L, CO2 of 32 mEq/L,
BUN of 37 mg/dL, creatinine of 8.2 mg/dL, glucose of
99 mg/L, and a calcium of 8.7 mEq/L; with the exception
of the potassium, these values were similar to the patient’s baseline levels. An initial phenylpropanolamine
level obtained from the serum was 300 ng/ml. Reference
values for our laboratory report the “normal range” for
PPA to be 90 ng/ml after a 50-mg dose (suggested adult
dose). Therapeutic blood concentrations are believed to
range from 30 to 200 ng/mL (5). Serial levels were found
to be 190 ng/mL on hospital day (HD) 2, 140 ng/mL on
HD 3, 110 ng/mL on HD 4, 89 ng/mL on HD 5, 62
ng/mL on HD 6, and 53 ng/mL on HD 7. Dialysate levels
of PPA peaked at 120 ng/mL on HD 2 . Lumbar puncture
was performed, which showed an opening pressure of
40. All viral and bacterial serologic exams were negative. Two grand mal seizures and further episodes of
hypertension complicated the patient’s hospital course.
Fosphenytoin was begun but discontinued before discharge. The patient’s hypertension did resolve without
treatment. The blindness began to resolve spontaneously,
and at follow-up 7 weeks later his vision was completely
normal.
The discharge diagnosis was “cortical infarct, thought
to be secondary to phenylpropanolamine-induced vasculitis.”

Cerebral Infarcts Secondary to PPA

DISCUSSION
Phenylpropanolamine is a catecholamine, which, though
less potent than amphetamines, still causes many similar
effects such as hypertension and vasoconstriction. It is
also a direct alpha-1 agonist and indirect alpha and beta
agonist. Its first use occurred early in the 20th century,
when it was administered as a parenteral vasopressor
agent. Over-the-counter use began in the 1930s as a
decongestant, and in the 1940s drug manufacturers began
exploiting its anorexia-causing properties by marketing it
as a diet aid.
Though PPA is known to be excreted 80 –90% unchanged in the urine within 48 h, little is published about
its effects in patients with renal failure (5). Citations of
problems with the drug began in the 1960s (1). Case
reports through the 1990s note an apparent association
with PPA and hemorrhagic strokes, cerebral hypertension, seizures, cerebral infarcts, and cerebral vasculitis
(2,5). Renal problems such as acute interstitial nephritis,
acute tubular necrosis, and acute renal failure have been
reported as well (5). In 1982, the FDA banned products
that contained PPA, ephedrine, and caffeine in combination. However, the FDA still regarded PPA used without
those other medications to be safe.
Until recently, few studies adequately and effectively
addressed the safety of PPA. Previous references are
limited to case reports, small trials, or supratherapeutic
dosing regimens. However, in 2000 the FDA received
the results of a Yale study that looked at the odds ratios
(OR) for the associations of cerebral hemorrhage and use
of PPA (4). Analysis showed that an increased OR did
exist, with the highest subgroup analysis showing an OR
of 16.58 for the association of stroke and PPA-containing
appetite suppressants in the previous 72 h. However, the
study does not address the association of PPA with
cerebral infarctions as occurred in our patient, and this
issue remains poorly investigated in the literature.
Though the etiology of our patient’s hypertension and
ultimate stroke may have been multi-factorial, epogen
and paroxetine also have been associated with hypertension. The temporal association of elevated PPA levels
and acute cerebral vasculitis in this patient cannot be
denied. Eighty to ninety percent of the drug is normally

307

excreted unchanged through the kidneys (5). Thus, a
patient with renal failure such as this one would be at a
much higher risk for potential toxicity from prolonged
exposure in the bloodstream.
As a result of the Yale Hemorrhagic Stroke Project
and other literature review, the FDA concluded that there
is an association between PPA and hemorrhagic stroke.
In November 2000, the FDA formally recommended that
PPA not be considered safe for over-the-counter use and
asked drug manufacturers to voluntarily discontinue
marketing any products containing PPA (6,7). All manufacturers have complied.
The FDA also issued a public health advisory warning
consumers and health care providers of the risk of PPA.
However, as our case illustrates, penetration of this information into households is less than 100%. Though
many physicians realize that the drug has been voluntarily taken off the market, they may not be aware that the
drug still exists in the medicine cabinets of many consumers. When CNS catastrophe occurs in the absence of
other risk factors, PPA toxicity must be on the differential diagnosis. Patients should be warned to avoid expired
or recalled medications.

REFERENCES
1. Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine
and the risk of hemorrhagic stroke. N Engl J Med 2000;343:1826 –
32.
2. Lake CR, Gallant S, Masson E, Miller P. Adverse drug effects
attributed to phenylpropanolamine: a review of 142 case reports.
Am J Med 1990;89:195–208.
3. Mersfelder T. Phenylpropanolamine and stroke: the study, the FDA
ruling, the implications. Cleve Clin J Med 2001;68:208 –23.
4. Horwitz RI, Brass LM, Kernan WN, et al , preparers. Phenylpropanolamine and risk of hemorrhagic stroke. Final report of The
Hemorrhagic Stroke Project; 2000 May 10. Available at: www.
fda.gov/ohrms/dockets/ac/00/backgrd/3647b1&umbar;tab19/doc.
Accessed November 10, 2001.
5. Poisindex [computer program]. Micromedex Healthcare Series. Accessed August 31, 2001.
6. FDA letter to manufacturers of drug products containing phenylpropanolamine (PPA) dated 11/03/2000. Available at: www.
fda.gov/cder/drug/infopage/ppa/ppaltr.htm. Accessed August 14,
2003.
7. Phenylpropanolamine (PPA) Information Page. Available at:
www.fda.gov/cder/drug/infopage/ppa/default.htm. Accessed August 14, 2003.