Download Massive ibuprofen overdose requiring extracorporeal

Massive ibuprofen overdose requiring extracorporeal membrane
oxygenation for cardiovascular support
Kira E. Marciniak, MD; Ildiko H. Thomas, MD; Thomas V. Brogan, MD; Joan S. Roberts, MD;
Angela Czaja, MD; Suzan S. Mazor, MD
Objective: Ibuprofen is rarely associated with severe toxicity.
We report a massive ibuprofen overdose that resulted in refractory hypotension requiring extracorporeal membrane oxygenation
(ECMO) for cardiovascular support.
Design: Individual case report.
Setting: Pediatric intensive care unit of a tertiary care hospital.
Patient: A 14-yr-old male presented with apnea and cardiovascular collapse after a nonaccidental ingestion of approximately 50 g of ibuprofen. His laboratory evaluation demonstrated
an anion gap metabolic acidosis and elevated lactate levels.
Interventions: The patient required pressor support with norepinephrine, phenylephrine, and vasopressin infusions. Due to
refractory hypotension, he was placed on ECMO. His serum ibuprofen level at an estimated 5–10 hrs postingestion was 776
␮g/mL (therapeutic 20 –30 ␮g/mL). Urine toxicological screen for
drugs of abuse, serum acetaminophen, salicylate, and carboxy-
I
buprofen became the first overthe-counter nonsteroidal antiinflammatory drug in 1984 and
continues to account for the majority of nonsteroidal anti-inflammatory
drug overdoses in the United States. Patients with ibuprofen overdose are typically asymptomatic or have mild gastrointestinal upset or central nervous
system toxicity (1). However, more serious toxicities including coma, seizures,
apnea, hypotension, bradycardia, metabolic acidosis, renal and hepatic dysfunction, and death have been described (1,
2). We report a case of an adolescent boy
who developed severe toxicity resulting in
cardiovascular collapse requiring extra-
From the University of Washington School of Medicine (KEM, IHT), Division of Critical Care Medicine,
Department of Pediatrics (TVB, JSR, AC), and Division
of Emergency Medicine, Department of Pediatrics
(SSM), Seattle, WA.
No institutional or departmental funds were used
for this report.
The authors have not disclosed any potential conflicts of interest.
Copyright © 2007 by the Society of Critical Care
Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
180
hemoglobin levels showed that these levels were not elevated.
The patient developed high-output renal failure, pulmonary hemorrhage, and gastric bleeding, all of which resolved by hospital
day 3.
Measurements and Main Results: ECMO was discontinued on
hospital day 4, inotropic support was discontinued, and the patient was extubated on hospital day 5. He was transferred to an
inpatient psychiatric unit on hospital day 9 with no identifiable
medical sequelae.
Conclusions: Although ibuprofen overdose typically has few
consequences, severe hypotension, renal failure, and gastrointestinal bleeding can occur. We report the first known case of
successful ECMO therapy for ibuprofen overdose. (Pediatr Crit
Care Med 2007; 8:180 –182)
KEY WORDS: ibuprofen toxicity; metabolic acidosis; lactic acidosis; extracorporeal membrane oxygenation; hypotension; pediatric
corporeal membrane oxygenation (ECMO)
with excellent outcome. This report received exemption status from our hospital’s institutional review board.
CASE REPORT
A 14-yr-old, 75-kg boy was found in his
bedroom unresponsive approximately 5.5 hrs
after he was last seen. At his side was an empty
500-tablet (200-mg) bottle of ibuprofen. A
note pleading for help was nearby. The patient
had a history of a first episode of superficial
cutting 2 wks previously and a self-reported
history of depression but was otherwise
healthy with no past hospitalizations or surgeries. He was taking no medications and had
no history of substance abuse. Other medications available in the home included citalopram, escitalopram, and lorazepam. On arrival
of a medic unit, the patient had a heart rate of
98 but no palpable pulses, respiration of 26,
and vomitus on his face. He was unresponsive
with no gag response; Pediatric Glasgow Coma
Scale score was 3. His trachea was intubated
for airway protection; he received a 1-L fluid
bolus en route to a community hospital.
Approximately 1.5 hrs after discovery, at
the community hospital, the patient was hypotensive (64/30 mm Hg) in sinus tachycardia
with normal oxygenation. He had no signs of
trauma. His pupils were reactive, but he exhibited no spontaneous movements. Blood
pressure did not respond to 45 mL/kg normal
saline bolus and 4 mg of naloxone. Sequential
use of vasopressors (norepinephrine to 1.7 ␮g/
kg/min, phenylephrine to 1.6 ␮g/kg/min, and
vasopressin to 10 mU/kg/hr) resulted in no
improvement in the blood pressure. Similarly,
glucagon produced no change in blood pressure. Before transfer, an arterial blood gas
revealed a mixed respiratory and metabolic
acidosis (Table 1). Comprehensive urine toxicologies and blood cultures were obtained.
Piperacillin-tazobactam was administered.
During transport, an increase in the vasopressin infusion transiently improved the patient’s blood pressure, but bigeminy ensued.
Vasopressin was decreased to 5 mU/kg/hr. On
arrival at our institution, he remained hypotensive with poor perfusion, nonreactive pupils, and no other neurologic activity. Toxicological studies revealed an ibuprofen level of
776 ␮g/mL (therapeutic 20 –30 ␮g/mL). His
echocardiogram showed good biventricular
function. Epinephrine (0.2 ␮g/kg/min) and
stress-dose hydrocortisone were then added
to norepinephrine and vasopressin infusions, without improvement in his blood
pressure. His metabolic acidosis persisted,
Pediatr Crit Care Med 2007 Vol. 8, No. 2
Table 1. Laboratory values and vasopressor dose at indicated time after patient initially discovered
Value
1.5 Hrs
4.5 Hrs
6.5 Hrs
8.5 Hrs
12 Hrs
16 Hrs
26 Hrs
45 Hrs
93 Hrs
Arterial pH
PCO2, torr
PO2, torr
Base excess, mEq/L
Sodium, mEq/L
Bicarbonate, mEq/L
Creatinine kinase (CK), IU/L
CK-MB, IU/L
Lactic acid, mmol/L
Ibuprofen level, ␮g/mL
Vasopressin drip, mU/kg/hr
Epinephrine drip, ␮g/kg/hr
Norepinephrine drip, ␮g/kg/hr
7.19
57
310
⫺8
139
19
7.13
43
175
⫺15
147
13
7.09
44
124
⫺17
150
7.16
42
143
⫺15
156
7.13
30
106
⫺19
152
7.47
54
105
⫹15
152
7007
7.48
39
132
⫹6
153
31
5126
7.42
41
99
⫹2
158
32
1358
15.5
4803
677
13.7
7.15
55
107
⫺15
153
19
8668
3.6
47
⬍8
40
0.1
0.2
40
0.2
0.2
Off
0.25
Off
60
10
776
20
0.2
0.1
8770
13.1
13.8
1.7
40
0.2
0.2
40
0.2
0.25
Off
0.1
0.25
CK, creatine kinase; MB, muscle and brain isoenzymes.
Extra corporeal membrane oxygenation was started at 7 hrs after discovery.
and he was treated with a total of 8 mEq/kg
sodium bicarbonate over the next 12 hrs. He
had elevated liver enzymes, renal function
studies, and cardiac enzymes, which peaked
at 24 hrs postadmission. Despite the high
levels of vasopressors the patient remained
severely hypotensive, and at 7 hrs after discovery he was placed on venoarterial ECMO
with a Stockert SIII (Cobe Cardiovascular,
Arvada, CO) using a Medtronic I-4500 lung
(Medtronic, Minneapolis, MN), with cannulation of his right common carotid artery
and internal jugular vein. He was placed on
flows of 3.5 L/min (47 mL/kg/min) with immediate improvement in his blood pressure.
Vasopressin, norepinephrine, and epinephrine
were weaned during the 4 days he was on
ECMO (Table 1).
On the day of admission, the patient developed high output renal failure, with 29 L of
isothenuric urine (urine Na⫹ of 139 mEq/L)
during the first 16 hrs of admission, despite
concurrent vasopressin infusion. His urine
output declined during the second day and
normalized on day 3. He also suffered mild
pulmonary hemorrhage and severe gastrointestinal bleeding, with nasogastric tube output
of 3750 mL of frank blood in the first 48 hrs on
ECMO. He was treated with transfusion of 10
units of packed red blood cells, 10 units of
fresh frozen plasma, and 14 units of platelets
over the first 48 hrs on ECMO, and his proton
pump inhibitor dose was increased. Heparin
infusion was adjusted to maintain goal activated clotting time between 180 and 200 secs
during ongoing gastrointestinal hemorrhage.
When hemorrhage resolved, the activated
clotting time was maintained at 200 –220 secs.
On hospital day 3, the patient awoke and followed commands. He was weaned from ECMO
on day 4. His norepinephrine was weaned
shortly after decannulation, and he was
weaned from mechanical ventilation the following day. Following ECMO decannulation,
his clinical neurologic exam was normal. He
Pediatr Crit Care Med 2007 Vol. 8, No. 2
was discharged to the floor on hospital day 6
and to the inpatient psychiatric unit on hospital day 9.
DISCUSSION
In contrast to our patient, the majority of patients with acute ibuprofen overdose remain asymptomatic or develop
only mild symptoms. Two case series examined the incidence and relative severity of symptoms after ibuprofen ingestion. Hall et al. (3) found that six (7%) of
88 pediatric patients became symptomatic following an overdose of ibuprofen,
one with mild central nervous system depression, four with gastrointestinal upset,
two with seizures, and one each with apnea, hypotension, and death. In contrast,
18 (47%) of the 38 adult patients in their
series became symptomatic, 16 with mild
symptoms of gastrointestinal upset, mild
central nervous system depression, or
headache, one with hypotension, and two
with elevated renal function (3). Similarly, McElwee et al. (2) reported that
49.8% of 329 patients were asymptomatic, 34% had minor symptoms (nausea,
abdominal pain, drowsiness, dizziness),
1.8% developed stupor or coma without
altered vital signs, and 1% died. Of note,
24% of patients in their series reported
ingesting at least one drug other than
ibuprofen. Symptoms typically occurred
within 4 hrs of ingestion, although reports exist of symptomatic adults with
renal failure who had onset of their symptoms up to 48 hrs after ingestion (3–5).
Overall, the medical literature contains
few reports of severe symptoms following
isolated ibuprofen ingestion; only 23 reports of coma and six reports of death
currently exist.
Although significant symptoms are
rare, several authors have examined
whether larger ingestions or higher serum ibuprofen levels can predict symptom severity. Hall et al. (3, 5) reported a
statistically significant association between ingestion of ⬎440 mg/kg and
symptom development in pediatric patients. Based on adult and pediatric ibuprofen levels after ingestions, the authors
constructed and later revised an ibuprofen nomogram designed to predict toxicity. However, they acknowledged limited
clinical application. Subsequently, McElwee et al. (2) found no correlation between serum ibuprofen levels and symptoms and reported that the nomogram by
Hall was not predictive of toxicity in their
cohort. In a study of 44 patients, Jenkinson and colleagues (4) proposed another
model of toxicity based on log ibuprofen
concentrations but found that it lacked
sensitivity and specificity. Our patient’s
case illustrates the limited utility of these
nomograms. His ibuprofen level of 776
␮g/mL was among the highest reported
in the literature; four higher levels up to
1034 ␮g/mL have been reported with
subsequent survival (2, 4, 6). However,
despite an ibuprofen concentration high
in the “probable toxicity” range on the
nomogram by Hall et al., the nomogram alone could not predict his clinical
course.
The severe symptoms encountered in
large ibuprofen ingestions stem from ibuprofen’s competitive inhibition of the cyclooxygenase-1 and cyclooxygenase-2 enzymes that catalyze the initial step of
prostaglandin synthesis. Cyclooxygenase
enzymes are found in the stomach, kidney, and blood vessels. The adverse gas181
trointestinal effect may result from decreased production of the protective
prostaglandins I2 and E2 following ibuprofen ingestion. Inhibition of prostaglandin synthesis is hypothesized to contribute to hypotension and altered mental
status in overdose, although the role of
prostaglandins in blood vessels and the
central nervous system remains unclear.
Similarly, acute renal failure is caused by
inhibition of prostaglandin synthesis at
the afferent arteriole, which decreases
glomerular capillary perfusion pressure
and glomerular filtration. Anion gap metabolic acidosis is thought to occur because of the resultant changes in electrolyte and fluid balance, accumulation of
the acidic metabolites of ibuprofen, and
hypoperfusion leading to lactic acidosis
(1, 4). Although ibuprofen overdose is
generally not listed in the “MUDPILES”
differential diagnosis of anion gap metabolic acidosis, a massive ibuprofen overdose is a well-described cause. Anion gap
metabolic acidosis occurs with other substances as well, and the possibility of a
co-ingestion should also be considered.
The pharmacokinetics of ibuprofen
help to explain its effects. The gastrointestinal tract rapidly absorbs ibuprofen,
whereas its elimination half-life is approximately 2 hrs. Ibuprofen binds avidly
to plasma proteins (99%) with no data to
support delayed absorption or prolonged
half-life in overdose (7). The short elimination half-life of ibuprofen is important
therapeutically because its effects persist
only as long as the drug remains in the
circulation. In addition, significant protein binding minimizes the benefit of
elimination-enhancing therapies such as
multiple-dose activated charcoal or hemodialysis. Renal insufficiency prolongs
the elimination half-life and can increase
toxicity; however, hemodialysis may be
beneficial in such circumstances. Ibuprofen is oxidized to two inactive acidic metabolites that are excreted in the urine,
with minimal enterohepatic recirculation
(3, 7). Due to this rapid excretion, supportive care is the mainstay of ibuprofen
overdose. Of note, Stipetic et al. (8) also
182
reported the successful use of flumazenil
in a case of ibuprofen overdose, although
this has not been widely studied. When
patients with significant ibuprofen ingestions have appropriate management of
their respiratory depression, cardiovascular compromise, metabolic acidosis, and
renal failure, their outcomes are generally excellent.
For our patient, mechanical ventilation, correction of metabolic acidosis,
and inotropic support did not alter his
hemodynamic perturbations. The application of ECMO for cardiovascular support is the first known report in ibuprofen overdose. Extracorporeal circulatory
support for acute intoxication has been
described for a number of different medications, including calcium channel
blockers, tricyclic antidepressants, antiarrhythmics, and polypharmacy overdose
that resulted in cardiovascular collapse
(9 –12). ECMO was used in these cases for
cardiovascular support until drug clearance allowed return of baseline cardiac
function, and all patients had full recoveries. Banner (13) acknowledged that
there is a sound pathophysiologic basis
for using ECMO in cases of poisoning
leading to cardiovascular collapse but
cautioned that experience was limited. In
our patient, ECMO allowed for drug
clearance, cardiovascular support, and
resolution of his high-output renal failure. This patient suffered pulmonary and
gastrointestinal hemorrhage, well-described complications of heparinization
used for ECMO therapy. These complications may have been exacerbated by ibuprofen inhibition of platelet activity. Our
patient’s case demonstrates that with appropriate support, ibuprofen overdose is
self-limited.
CONCLUSIONS
This case report presents the first use
of ECMO as supportive care for cardiovascular collapse due to massive ibuprofen
overdose. Our patient’s outcome was excellent, due to early anticipation and
early initiation of ECMO by a trained surgical and intensive care team. Thus
ECMO should remain on the list of possible supportive therapies for acute ibuprofen intoxication.
REFERENCES
1. Paloucek FP, Rynn KO: Nonsteroidal antiinflammatory drugs. In: Clinical Toxicology.
First Edition. Ford MD, Delaney KA, Ling LJ,
et al (Eds). Philadelphia, Saunders, 2001, pp
281–283
2. McElwee NE, Veltn JC, Bradford DC: A prospective, population-based study of acute
ibuprofen overdose: Complications are rare
and routine serum levels not warranted. Ann
Emerg Med 1990; 19:657– 662
3. Hall AH, Smolinske SC, Conrad FL, et al:
Ibuprofen overdose: 126 cases. Ann Emerg
Med 1986; 15:1308 –1313
4. Jenkinson ML, Fitzpatrick R, Streete PJ, et
al: The relationship between plasma ibuprofen concentrations and toxicity in acute ibuprofen overdose. Hum Toxicol 1988;
7:319 –324
5. Hall AH, Smolinske SC, Stover B, et al: Ibuprofen overdose in adults. Clin Toxicol 1992;
30:23–37
6. Chelluri L, Jastremski MS: Coma caused by
ibuprofen overdose. Crit Care Med 1986; 14:
1078 –1079
7. Linden CH, Townsend PL: Metabolic acidosis
after acute ibuprofen overdosage. J Pediatr
1987; 111:922–925
8. Stipetic ME, Blair HW, Borys DJ: Multiple
system involvement in an ibuprofen overdose. A case report. J Toxicol Clin Toxicol
1996; 34:564 –565
9. Durward A, Guerguerian AM, Lefebvre M:
Massive diltiazem overdose treated with extracorporeal membrane oxygenation. Pediatr
Crit Care Med 2003; 4:372–376
10. Auzinger GM, Scheinkestel CD: Successful
extracorporeal life support in a case of severe
flecainide ingestion. Crit Care Med 2001; 29:
887– 890
11. Tecklenburg FW, Thomas NJ, Webb SA: Pediatric ECMO for severe quinidine cardiotoxicity. Pediatr Emerg Care 1997; 13:111–113
12. Maclaren G, Butt W, Cameron P: Treatment
of polypharmacy overdose with multimodality extracorporeal life support. Anaesth Intensive Care 2005; 33:120 –123
13. Banner W: Risks of extracorporeal membrane oxygenation: Is there a role for use in
the management of the acutely poisoned patient? J Toxicol Clin Toxicol 1996; 34:
365–371
Pediatr Crit Care Med 2007 Vol. 8, No. 2