In children, the frequency of GI bleed with

Ibuprofen and Chronic Pyloric

ibuprofen, 17 in 100,000, is similar to that
Stricture
(2)
for acetaminophen . Although the gastric
Ibuprofen and acetaminophen are the most mucosa is most often affected, the intestinal
widely used over-the-counter (OTC) pain mucosa may also be injured (35).
relievers and antipyretics in the United
States. Ibuprofen 2-(isobutylphenyl) Despite the increased use of NSAIDs in

propionic acid has been available without a adults and children, current reports describe

prescription for those older than 12 years of adverse events with high-dose short-term

age since 1984. Prescription for pediatric- use, or with chronic exposure, primarily in

strength liquid ibuprofen in children older adults. Reports of single exposures causing

than 6 months of age was approved by the adverse events are few and represent the

Food and Drug Administration in 1989, and sequelae of massive 1-time ingestions (6).

OTC administration for children older than 2

We report a previously healthy 2-year-old
years of age since 1995. Its OTC use is now
male who developed chronic gastric outlet
recommended by the American Academy of
obstruction and pyloric stricture after a
Pediatrics for children as young as 6 months
single ingestion of liquid ibuprofen at a dose
of age.
not thought to cause adverse events.

Chronic use of nonsteroidal anti-

CASE REPORT
inflammaory drugs (NSAIDs) and aspirin
increases the risk for gastrointestinal (GI) Initial Presentation
toxicity. The majority of peptic ulcers result
A 2-year-old previously healthy white male
from Helicobacter pylori infection and/or
was discovered by parents at home with a
chronic NSAID use. An estimated 3% to
nearly empty bottle of liquid ibuprofen that
4.5% of adults taking regular NSAIDs for
had been approximately 30% to 50% full
arthritis develop significant GI
minutes before. The Rocky Mountain Poison
complications, with endoscopy revealing
(1) Control hotline advised his mother that no
ulcers in 15% to 30%. A single dose of
intervention was necessary because the dose
aspirin may cause subepithelial hemorrhage,
was unlikely to be toxic. For the remainder
and a 1-week course of aspirin or NSAIDs is
of the day, he behaved normally, with
associated with ulcers in 8% of adults (1).
normal oral intake, no abdominal pain, was normal. An upper gastrointestinal (UGI)
vomiting, or diarrhea. series at an outside hospital showed pyloric
channel stricturing. He was transferred to
The day following ingestion, 2 episodes of
our hospital.
coffee ground emesis and 2 episodes of
hematochezia were noted, but resolved On arrival, he was in no apparent distress.
within hours. At this time, the patient was Weight was 10.5 kg, 0.6% weight-for-age,
behaving normally and tolerating solids and and decreased from his prior weight of 12
liquids, so medical care was not sought. kg, 18% weight-for-age. The abdomen was
noted to be soft, nondistended, nontender,
One week after ingestion, the patient's entire
with no organomegaly or peritoneal signs.
family developed nausea, emesis, diarrhea,
Tests for fecal occult blood were negative.
and mild fever for several days, thought to
An abdominal radiograph showed a
be an acute gastroenteritis. Although the
distended stomach containing residual
family recovered within several days, the
barium from the UGI the previous day. An
patient continued to have nonbloody,
esophagogastroscopy revealed stomach wall
nonbilious emesis 3 to 5 times per day, with
edema, pyloric thickening, erythema, and
decreased oral intake, tolerating only small
stiffness with inability to advance the
sips of clear liquids. The patient was brought
Olympus GIF 160 (8.6 mm diameter)
to his primary care physician approximately
endoscope into the duodenum. Biopsies of
2 weeks following initial ingestion for
the gastric mucosa were normal. A
concern of emesis and feeding intolerance.
computed tomography scan with intravenous
The physician identified a 0.5-kg weight
(IV) contrast revealed nonspecific
loss, but otherwise found him appearing
thickening of the posterior gastric wall and
well and not dehydrated. He was started on
pyloric region without lymphadenopathy,
lansoprazole 7.5 mg daily, which was
and normal duodenum and small bowel (Fig.
increased to 15 mg 3 days before his
1). Because of continued intolerance of oral
hospital admission.
intake, treatment included IV fluid
resuscitation, parenteral nutrition, acid
The emesis and feeding intolerance
suppression, and oral sucralfate. The patient
persisted, and 1 day before hospital
was discharged to his home after 8 days to
admission, a comprehensive metabolic panel
continue parenteral nutrition while tolerating At 6, 9, 17, and 24 months postingestion,
only sips of clear liquids. endoscopies showed persistence of the
pyloric narrowing, the noncompliant antral
Course
opening increased minimally in size, and

One week after discharge and approximately inability to advance the 5.9-mm diameter

3 weeks after ingestion, he had regained his endoscope into the duodenum despite

previous weight (12.4 kg) and was tolerating repeated attempts at dilation with TTS

liquids. By 7 to 8 weeks postingestion, he balloons. Dilations were attempted using 6-,

began to tolerate increasing amounts of 7-, and 8-F TTS dilators over a guidewire.

liquids and soft solids, except for corn or At 24 months, with the 10-mm size dilator, a

popcorn, which caused vomiting. The tiny waist was noted. After each of these

parenteral nutrition was discontinued. He attempts at dilation, the patient would have

continued to have 1 to 2 episodes of emesis up to 5 to 7 days of vomiting and

daily, but maintained his weight. dehydration refractory to antiemetics and

steroids, during which he would keep down
At 11 weeks postingestion, the frequency of only small amounts of liquids. These
emesis decreased to twice weekly with episodes were managed with intravenous
continued weight gain tracking along his fluids.
previous growth curve.
He continues with normal growth and
At 5 months postingestion, because of tolerates solids except for corn/popcorn. His
continued low level vomiting and concern most recent UGI, 24 months after initial
for a circumferential ulcer, a repeat ingestion, revealed significant gastric
endoscopy was performed, revealing a antral/pyloric spasm and thickening
pinpoint, stiff, noncompliant antral opening requiring multiple gastric contractions to
through which neither the Olympus XP160 empty into the duodenum. Thickening
(5.9 mm diameter) nor the Olympus GIF appears more prominent than on the
160 endoscope (8.6 mm diameter) would previous examination.
pass even after pyloric dilation for 1 minute
with a through-the scope (TTS) 9-mm
balloon.
DISCUSSION The most popular of the NSAIDs, ibuprofen
is a relatively water-insoluble compound
On the basis of the lack of previous
with a pKa of 4.43. Ibuprofen is well
significant medical history, the estimated
absorbed from the gut, with peak levels
ingestion of 600 to 1200 mg or 57 to 114
within 1 hour after ingestion and a plasma
mg/kg of ibuprofen in this patient led to
half-life of approximately 2 hours. It is
chronic pyloric channel injury. Endoscopy
transported largely protein bound in plasma
and computed tomography scan would
and rapidly metabolized and excreted in the
suggest that this patient has developed
urine. It is well known in adults to have a
fibrotic changes of the pylorus leading to
significant GI adverse effect profile, with
stricturing. The patient was not taking any
upper GI ulcers, gross bleeding, or
other medications concurrently, nor did he
perforation in 1% of patients treated for 3 to
have any known risk factors for increased
6 months and 2% to 4% of patients treated
GI toxicity. His family history is significant (7)
for 1 year . Risk factors for GI adverse
for maternal grandmother with celiac and
effects include smoking, corticosteroids,
autoimmune thyroid disease and father with
alcohol, advanced age, and poor overall
factor V Leiden. Because the reported level (8,9)
health . The most frequently reported
of ibuprofen ingestion has not previously
acute overdose symptoms include abdominal
been associated with adverse outcomes, this
pain, nausea, vomiting, lethargy, and
case raises several important questions: (7)
drowsiness . Metabolic acidosis, apnea,
coma, and acute renal failure are rare
1. What is the mechanism of the initial
adverse effects in young children.
insult? Why did this patient experience such
a severe outcome from a historically
Despite its known adverse effect profile,
harmless overdose?
ibuprofen is considered relatively safe
compared with other NSAIDs. In a meta-
2. How did this lead to the chronic pyloric
analysis of 3 retrospective case-control
stricture?
studies in England, Scotland, and Sweden,
3. Is the mechanism of injury and repair ibuprofen showed the lowest odds ratio (1.7)
different for single doses than for repeated for upper GI bleeding compared with
doses? diclofenac (4.9), indomethacin (6.0),
naproxen (9.1), piroxicam (13.1), and mg/kg were to induce emesis and observe,
(10)
ketoprofen (34.9) . Ibuprofen doses less and 200 to 400 mg/kg were to induce
than 1200 mg daily were not associated with emesis, give activated charcoal, and seek
(11,12)
increase risk for GI bleed (odds ratio 1.1) medical care . On the basis of a limited
There were significant dose-response number of prior cases, risk for serious
relations and risk was highest in all groups adverse events increases significantly with
during the first week of use. However, this doses of 200 to 400 mg/kg. Current
study included only adults, with mean ages recommendations from the Rocky Mountain
between 58 and 74 years (10). Poison Control Center (which directly
reflect the position of the American
Reports of acute ibuprofen toxicity are
Association of Poison Control Centers) are
relatively rare. Of 61 cases reported to the
observation at home for ingestions of <200
Rocky Mountain Poison Control Center
mg/kg. For ingestions >200 mg/kg, medical
from 1985 to 1986, 5 of 39 children reported
care should be sought, with possible
(11,12)
adverse events . Isolated GI symptoms
charcoal administration and renal function
of cramping, nausea, and emesis were
testing. Induction of emesis is not
reported in 3 patients with moderately high
recommended for any ingestion currently.
doses. The doses ingested were higher than
that of our patient, ranging between 104 and In a thorough review of the current medical
131 mg/kg. Two massive ingestions of 708 literature, we have identified only 2 other
mg/kg and 666 mg/kg yielded central pediatric cases of chronic sequelae
nervous system symptoms of decreased secondary to high-dose ibuprofen ingestion.
level of consciousness and apnea as well as A duodenal perforation was reported in a 17-
GI symptoms. No permanent damage or year-old girl who ingested a large dose (14
deaths were reported (12). g) of ibuprofen at one time (6). Similar to our
patient, a nonobstructive pyloric deformity
On the basis of the relatively low numbers
was still present after almost 2 years. A
of acute overdose or serious outcomes,
pyloric stricture, similar to our patient, was
recommendations for ibuprofen overdosing
reported after 1 month of high-dose
have changed in the past 20 years. Original
ibuprofen (1000 mg twice daily) in a 12-
recommendations for ingestion of <100 (13)
year-old white girl with cystic fibrosis .
mg/kg were observation only, 100 to 200
Unlike our patient, balloon dilation the higher pH environment and trapped
successfully opened the pyloric channel. intracellularly. When this process involves
supratherapeutic doses, they can become
Several possible mechanisms for ibuprofen
directly toxic to cells (9,17).
toxicity have been postulated. The
interruption of the formation of In several experiments with rat models using
cyclooxygenase (COX)-1 (constitutive) by indomethacin, high doses induced
NSAIDs may reduce the protective uncoupling of oxidative phosphorylation and
mechanisms of the gut (9). Nonsteroidal anti- mitochondrial damage in rat enterocytes in
inflammaory drugs are known to decrease vivo as well as in rat intestinal villus cells in
the mucus and bicarbonate formation in the vitro. There was also evidence of
gastric/duodenal mucosa, as well as reduce uncoupling in rat liver mitochondria in vitro
mucosal blood flow. Intestinal mucosal by indomethacin, aminosalicylic acid,
blood flow is reduced within 7 days of naproxyn, and piroxicam (18). This appears to
(14)
NSAID administration . In addition, there be a topical rather than systemic effect
is an increase in neutrophil adherence to because of localized topical effects in the
mucosa that may induce free radical gut mucosa before these drugs become
formation as well as reduce mucosal blood bound to albumin in the bloodstream. There
flow (15). However, other studies suggest that was no evidence of uncoupling in rat
gut damage by NSAIDs is independent of enterocytes when indomethicin was given
level of COX inhibition (16). parenterally (17).

More recently, direct mucosal toxicity In conclusion, we report a chronic pyloric

independent of COX-1 has been proposed. stricture in a previously healthy 2-year-old
The role of ion trapping of substances with a boy after a single ingestion of a dose of
lower pKa in the mucosa of the stomach or liquid ibuprofen that was not thought to be
pylorus has been suggested. Most NSAIDs, sufficient to cause adverse events. The
including ibuprofen, are weak acids that are chronic course seen after a moderate dose
nonionized in the acidic environment of the ingestion has not previously been reported.
stomach. However, when these weak acids It is unlikely that he had some previously
diffuse readily into the gastric or proximal undiagnosed pathology that was uncovered
duodenal mucosa, they become ionized in by this ingestion. The mechanism of injury
is still unknown, but could include any or all intestine. Curr Opin Gastroenterol 2005;
or the proposed pathways of COX 21:169175.
inhibition, drug trapping, reduced blood
flow/ischemia, or direct injury via 4. Fortun PJ, Hawkey CJ. Nonsteroidal
mitochondrial damage. This leads us to antiinflammatory drugs and the small
wonder whether he and perhaps other intestine. Curr Opin Gastroenterol 2007;
children have some unknown physiological 23:134141.
predisposition toward mucosal injury from
NSAIDs. Clinicians should be aware of the 5. Adebayo D, Bjarnason I. Is non-steroidal
possibility of ibuprofen toxicity and chronic anti-inflammaory drug (NSAID)
sequelae even with lower doses and single enteropathy clinically more important than
exposures. The optimal management of NSAID gastropathy? Postgrad Med J 2006;
these cases remains to be determined. It 82:186191.
seems reasonable to begin acid suppression .
and possibly sucralfate early and monitor for
sequelae. 6. Clarke SF, Arepalli N, Armstrong C, et al.
Duodenal perforation after ibuprofen
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