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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. 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