Treatment of Ibuprofen Toxicosis in a Dog with IV Lipid Emulsion

Introduction

IV lipid emulsion (ILE) infusions have been used as a treatment of various intoxications, such as tricyclic antidepressants, Ca channel blockers, and β-blockers in both humans and animal models.^1–4 Recently, ILE was used to treat moxidectin toxicosis in a dog and lidocaine toxicity in a cat.^5,6 Rapid ILE infusion may be a therapeutic option for patients with toxicosis due to other lipid-soluble drugs, like ibuprofen. Ibuprofen is the most popular over-the-counter pain reliever in the United States, and the National Animal Poison Control Center has noted a corresponding increase in the number of calls related to canine exposures to ibuprofen.^7,8

Ibuprofen reversibly inhibits cyclo-oxygenase (COX) by competing with the substrate arachidonic acid for the active site of the enzyme. The majority of toxicoses involve the gastrointestinal (GI) tract, kidneys, hematopoietic system, and, in higher dosages, the central nervous system. Treatment of ibuprofen toxicosis has traditionally been limited to symptomatic care, including the use of prostaglandin analogs (e.g., misoprostol), IV fluids, antiemetics, and other gastric protectants.⁹

This report describes a case of a 3 yr old spayed female mixed-breed dog that was presented after ingesting 1,856 mg/kg (180 tablets) of ibuprofen^a, a human formulated nonsteroidal anti-inflammatory drug (NSAID). The dog developed severe neurologic signs, thrombocytopenia, anemia, and coagulopathy. ILE therapy was used to treat ibuprofen toxicosis in a dog.

Case Report

A 3 yr old spayed female mixed-breed dog weighing 19.4 kg was presented to the Veterinary Teaching Hospital, University of Illinois.for ingestion of 1,856 mg/kg of ibuprofen, a human formulated NSAID. According to the owner, the dog ate the contents of an entire bottle (180 tablets) of ibuprofen between 1 hr and 6 hr before presentation.

The owner had contacted the American Society for the Prevention of the Cruelty to Animals Animal Poison Control Center prior to presentation and was advised to administer 30 mL of hydrogen peroxide per os to induce emesis. The dog vomited three times, and the presence of scant pills in the emesis was noted, but the number of pills was unable to be quantitated.

At the time of presentation, the patient was bright, alert, responsive, and hypersalivating. Heart rate (HR, 102 beats/min), respiratory rate (RR, 24 breaths/min), and temperature (37.9°C) were within normal limits. The mucous membranes were pink and moist, with a capillary refill time of < 2 sec. Neither murmurs nor arrhythmias were present on cardiac auscultation. Femoral pulses were strong and synchronous, and normal bronchovesicular lung sounds were ausculted in all lung fields. Abdominal palpation was soft and nonpainful, and the remainder of the physical examination was unremarkable.

After the initial physical examination, an IV catheter^b was placed in the right cephalic vein. Maropitant^c (1 mg/kg) was subcutaneously administered for nausea and vomiting. Blood pressure was 90 mm Hg systolic using indirect Doppler measurement, electrocardiography revealed normal sinus rhythm, and O₂ saturation was 98%. A limited abdominal ultrasound screening was performed, and free abdominal fluid was not observed.

A point-of-care (POC) venous blood gas^d and electrolyte analysis was performed that revealed metabolic acidosis, hypokalemia, hyperglycemia, and hyperlactatemia. Packed cell volume (PCV) and total solids (TS) were both normal (Table 1). Blood was collected for a complete blood count (CBC) and serum biochemical profile (Table 2). The CBC revealed leukopenia with neutropenia, hemoconcentration, and adequate platelet count. The manual differential revealed rare polychromasia, poikilocytosis, and anisocytosis. Serum biochemical analysis revealed hypokalemia, hypoglobulinemia, and hypotriglyceridemia. The serum was immediately frozen at −28.8°C for further testing^e.

TABLE 1 Abnormal POC Blood Work at Presentation and During Treatment

*

Reference ranges and units are indicated in parentheses.

Glu, glucose; HCO₃, bicarbonate; K, potassium; lac, lactate; Mg, magnesium; pCO₂, partial pressure of CO₂; PCV, packed cell volume; POC, point-of care; TS, total solids.

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TABLE 2 Abnormal Blood Work Values at Presentation and During Treatment

*

Reference ranges and units are indicated in parentheses.

ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; BUN, blood urea nitrogen; Glob, globulin; HCT, hematocrit; Neut, neutrophils; Plt, platelets; PT, prothrombin time; Tri, triglycerides.

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Urinalysis (obtained by cystocentesis) revealed cloudy, yellow-orange urine with a specific gravity of 1.026, pH of 8, and 300/gL of protein. Urine cytology revealed moderate blood, few WBCs, red blood cells, epithelial cells, and no bacteria. Moderate granular casts and moderate amorphous crystals were present.

Within 30 min of presentation, the patient’s level of consciousness rapidly progressed to coma. The HR increased to 180 beats/min, the RR increased to 42 breaths/min, and the body temperature dropped to 35.5°C. Naloxone^f was given, at the suggestion of the American Society for the Prevention of Cruelty to Animals Poison Control Center at a dose of .01 mg/kg IV, and the dog became briefly aroused. The naloxone was repeated, but the dog rapidly progressed back to a comatose state. Naloxone administration may be beneficial in cases of ibuprofen intoxication and signs of central nervous system dysfunction as NSAIDs may share a common mechanism of action with opioids.¹⁰

The systolic blood pressure dropped to 60 mm Hg, and a bolus of 20 mL/kg of isotonic crystalloids^g was administered followed by a 5 mL/kg bolus of a synthetic colloid solution^h. Forced warm air was used to maintain normal body temperature, and an endotracheal tube was placed to protect the airway. Sedation was not needed. Ventilation and oxygenation were assessed by monitoring end-tidal CO₂ and O₂ saturation.

Due to the patient’s rapid deterioration, an IV lipid solutionⁱ was administered at 1.5 mL/kg over 15 min, followed by a constant rate infusion (CRI) at .5 mL/kg/min for 2 hr. Blood was collected 2 hr after completion of lipid infusion, and serum was frozen at −28.8°C for future analysis. Serum ibuprofen analysis detected a baseline (preILE) concentration of 190 μg/mL, and an undetectable postILE concentration. In humans, therapeutic concentrations of ibuprofen range from 10 μg/mL to 50 μg/mL.¹¹

The patient was admitted to the intensive care unit for continued monitoring and supportive care. A urinary catheter and a double-lumen jugular catheter were placed. A peripheral catheter was placed in the right dorsal pedal artery for direct blood pressure monitoring and arterial blood gas sampling. IV crystalloid fluids with 20 mEq/L potassium chloride was administered at a rate of 8 mL/kg/hr and colloids were administered at 1 mL/kg/hr. Systolic blood pressure remained low at 80 mm Hg despite crystalloid and colloid support, and a CRI of vasopressin^j was started at .07 μg/kg/hr.

Approximately 3 hr after completion of lipid infusion (i.e., 4 hr after presentation), the patient had a slight improvement in level of consciousness but remained dull. Positive palpebral and menace responses were noted.

Approximately 6 hr after presentation, the dog remained hypothermic (36.3°C) and became tachycardic (HR was 158 beats/min) and tachypneic (RR was 48 breaths/min). Systolic blood pressure was 110 mm Hg. A nasogastric tube was placed to administer omeprazole^k (1 mg/kg q 24 hr), misoprostol^l (3 μg/kg q 6 hr), and for enteral nutrition. A POC blood gas revealed persistent hyperlactemia and the development of hypomagnesemia (Table 1).

Approximately 13hr after presentation, the patient was alert and responsive. Bleeding was present at the site of the nasogastric tube sutures on the left side. Topical epinephrine^m and ice packs were used to try to stop the bleeding. Bleeding would stop transiently and then resume when the patient moved. Due to financial concerns, tests to evaluate primary hemostasis (e.g., PFA-100) were not performed at that time. After the patient became responsive, the systolic blood pressure (110 mm Hg) and body temperature (37.8°C) normalized. Vasopressin, colloids, direct blood pressure monitoring, and active warming were discontinued. Repeat urinalysis was normal, and no casts were observed. A POC blood gas revealed a normal lactate concentration with persistent hypomagnesemia (Table 1). Magnesiumⁿ was added to the IV fluids at a rate of 1 mEq/kg/day.

Approximately 30 hr after presentation, the patient was quiet, alert, and responsive. Body temperature was 38.2°C, HR was 148 beats/min and RR was 24 breaths/min. The patient developed hematemesis, mild melena, hematuria, and persistent unilateral bleeding from the suture site. Abnormalities on POC blood gas revealed hyponatremia and hypokalemia (Table 1). A CBC revealed thrombocytopenia and serum biochemical analysis revealed elevated blood urea nitrogen. All other parameters were within normal limits. Prolonged prothrombin time and activated partial thromboplastin time were identified on the coagulation profile (Table 2).

IV fluids, omeprazole (1 mg/kg q 24 hr), and misoprostol (3 μg/kg q 6 hr) were continued, and sucralfate^o (1 g q 8 hr) was started. The benefits of plasma transfusion were discussed with the owner but declined due to financial constraints.

At approximately 48 hrs after presentation, the patient’s mucous membranes, sclera and ventral abdomen became icteric, anemia was noted with a PCV of 16%, and TS of 3.2 g/dL. A reticulocyte count revealed 0.4% reticulocytes with an absolute count of 9.8 × 10⁹/L. N-acetylcysteine^p (50 mg/kg IV q 6 hr) was started. Tests of hepatic function (e.g., bile acids) and blood and plasma transfusions were declined by the owner. N-acetylcysteine (50 mg/kg q 6 hr IV) was started.

On days 3 and 4, the IV fluids, N-acetylcysteine, misoprostol, omeprazole, and sucralfate were continued. Monitoring included electrolytes; venous blood gas daily; temperature, pulse, and respiration; and indirect blood pressure q 6 hr.

On day 5 of hospitalization, body temperature was 38.5°C HR was 120 beats/min, and RR was 24 breaths/min. Recheck PCV was 18% and TS were 3.5 g/dL. The central line was removed, and the site monitored for bleeding. The patient was discharged with S-adenosylmethionine^q, omeprazole, misoprostol, and instructions to have additional testing (i.e., CBC, serum biochemical analysis, urinalysis, and coagulation panel) performed at the primary veterinarian in 1 wk. At the referring veterinarian 1 wk after discharge, the patient had completely recovered. Blood work and urinalysis performed at that time revealed slightly elevated alanine aminotransferase and hypoglobulinemia. All other values were unremarkable.

Discussion

To the authors’ knowledge, this is the first documented use of ILE for the treatment of ibuprofen intoxication in a dog. Documentation of undetectable concentrations of ibuprofen postlipid infusion is suggestive, but not indicative, of successful detoxification. In humans, there are several case reports demonstrating concentrations as high as four times the therapeutic range, and concentrations < 180 μg/L are associated with seizures, respiratory failure, and acidosis.^11–13 The dog described in this case report had serum concentrations approximately four times the highest end of the therapeutic range for humans.

According to the owner, the dog ingested the ibuprofen between 1 hr and 6 hr before presentation. Because emesis was partially successful, it is impossible to know the amount absorbed. In dogs, ibuprofen is rapidly absorbed after oral administration attaining maximal plasma concentrations from 30 min to 3 hr after ingestion. Ibuprofen is 96% protein bound, has reported elimination half-lives of 2.5 hr and 5.8 hr, and undergoes enterohepatic recycling.¹⁴

Ibuprofen is the most popular over-the-counter pain reliever in the United States, and a search of medical records at the Georgia Animal Poison Center over a 19 mo period revealed 240 cases of dog and cat exposure to NSAIDs. The most common NSAID was ibuprofen.¹⁵

Ibuprofen inhibits COX, the enzyme that converts arachidonic acid to prostaglandin H2. In turn, prostaglandin H2 is converted by other enzymes to various prostaglandins and thromboxane A2. Ibuprofen is thought to be a nonselective COX inhibitor, inhibiting both COX-1 and COX-2. Inhibition of COX-1 prevents prostaglandin’s biologic benefits, including gastric mucosal protection and preservation of adequate renal perfusion and glomerular filtration. Consequently, ibuprofen exposure reduces renal blood flow leading to acute kidney injury, acute interstitial nephritis, hyperkalemia, and GI ulceration. Although renal dysfunction is often reversible after discontinuation of the drug, severe and prolonged renal hypoperfusion secondary to prostaglandin inhibition could lead to acute cortical necrosis and irreversible acute renal failure.¹⁶ The patient described in this report did not develop either azotemia or oliguria, and although proteinuria and casts were observed on presentation, they resolved with supportive care.

Inhibition of prostaglandin synthesis also interferes with the maintenance of gastric mucosal integrity. Dogs are more predisposed than humans to ibuprofen’s ulcerogenic effects due to higher GI absorption rates and a longer drug half-life, which leads to slower drug elimination and higher blood concentrations.¹⁴ Those pharmacokinetic factors narrow the margin of safety of ibuprofen in dogs.

In humans, mild depression of the nervous system can occur at lower doses. Dizziness, depression, headache, and nausea are the most common signs. Doses higher than 400–500 mg/kg are reportedly associated with seizures and coma in dogs intoxicated with ibuprofen, and secondary effects of hypoxia, acidosis, and pyrexia can be associated with prolonged seizures.¹⁷ Higher doses can cause coma and severe respiratory distress leading to mechanical ventilation in people.¹¹

Bleeding developed on the second day of hospitalization, but tests of primary hemostasis (e.g., PFA-100) were not performed due to financial concerns. Inhibition of thromboxane A₂ by NSAIDs is known to induce a platelet dysfunction that can lead to bruising and bleeding. An underlying hepatic dysfunction (i.e., icterus, coagulopathy) was suspected, but additional tests of hepatic function (e.g., bile acids) were not performed due to financial concerns. Hepatic dysfunction has been reported in people with NSAID toxicity.¹⁴

Treatment of ibuprofen toxicosis has traditionally been limited to symptomatic care, including the use of prostaglandin analogs (e.g., misoprostol), IV fluids, antiemetics, and other gastric protectants.⁹ Intervention to treat the intoxication should occur as early as possible and has the benefit of timely administration that may be life saving if the owner lives far from a veterinary facility. However, centrally acting emetics, administered by a veterinarian, are far more reliable for induction of emesis than hydrogen peroxide used at home.

Lipid emulsions are most commonly used in IV parenteral nutrition as well as a delivery vehicle for hydrophobic drugs such as propofol. There are several studies showing the successful use of lipid emulsions in the treatment of acute local anesthetic toxicity in humans and animals and they have recently been reviewed.^5,6,18–21 Briefly, the most commonly accepted mechanism of action in the treatment of toxicity with lipid emulsion is the lipid sink theory. The administration of lipid solutions is thought to bind lipid soluble drugs and compartmentalize them into the newly created lipid compartment. It is impossible to know if the lipid infusion was responsible for the rapid improvement in the level of consciousness in the patient described in this report, but the patient had ingested a massive dose of ibuprofen and made a complete recovery. Complications associated with the lipid infusion were not observed.

Dosage recommendations for lipid infusion are varied and mostly anecdotal. Most reports suggest a bolus of 1.5–4 mL/kg followed by .25–.5 mL/kg/min for 1 hr.^4–6 The dog described in this case report received a bolus of 1.5 mL/kg followed by a CRI of .5 mL/kg/min for 120 min.

Lipid emulsion therapy is not without potential complications. Those emulsions can promote bacterial growth requiring aseptic procedures when administering them to prevent contamination and possible sepsis. IV lipid administration may cause immunosuppression through immune cell dysfunction. Other potential side effects that may occur include phlebitis, thrombosis, hypertriglyceridemia, and hepatic lipidosis.

Conclusion

This case report describes a patient with a massive ibuprofen overdose treated with lipid infusion. No complications were seen and the dog made a full recovery.