CASE REPORTS

Treatment of Ibuprofen Toxicosis in a Dog with IV Lipid Emulsion Luiz Bolfer, DVM, Maureen McMichael, DVM, DACVECC, Thandeka R. Ngwenyama, DVM, Mauria A. O’Brien, DVM, DACVECC

ABSTRACT A 3 yr old spayed female mixed-breed dog weighing 19.4 kg was evaluated for ingestion of 1,856 mg/kg (180 tablets) of ibuprofen, a human formulated nonsteroidal anti-inflammatory drug (NSAID). At the time of presentation, the patient was alert and hypersalivating, but her mental status rapidly declined to obtunded, stuporous, and then comatose within 30 min of presentation. Initial treatment included supportive therapy with prostaglandin analogs and antiemetics. An IV lipid emulsion (ILE) was administered as a bolus, followed by a constant rate infusion. Clinical signs began to improve approximately 3 hr after completion of the lipid infusion. The patient required supportive care for 3 days before discharge. This case report demonstrates the use of ILE for treatment of ibuprofen toxicosis in a dog. ILE infusion may be a therapeutic option for patients with toxicosis due to lipid-soluble drugs. (J Am Anim Hosp Assoc 2014; 50:136–140. DOI 10.5326/JAAHA-MS-5979)

Introduction

of prostaglandin analogs (e.g., misoprostol), IV fluids, anti-

IV lipid emulsion (ILE) infusions have been used as a treatment

emetics, and other gastric protectants.9

of various intoxications, such as tricyclic antidepressants, Ca

This report describes a case of a 3 yr old spayed female

channel blockers, and b-blockers in both humans and animal

mixed-breed dog that was presented after ingesting 1,856 mg/kg

models.1–4 Recently, ILE was used to treat moxidectin toxicosis

(180 tablets) of ibuprofena, a human formulated nonsteroidal

in a dog and lidocaine toxicity in a cat.5,6 Rapid ILE infusion may

anti-inflammatory drug (NSAID). The dog developed severe neu-

be a therapeutic option for patients with toxicosis due to other

rologic signs, thrombocytopenia, anemia, and coagulopathy. ILE

lipid-soluble drugs, like ibuprofen. Ibuprofen is the most pop-

therapy was used to treat ibuprofen toxicosis in a dog.

ular over-the-counter pain reliever in the United States, and the National Animal Poison Control Center has noted a corre-

Case Report

sponding increase in the number of calls related to canine

A 3 yr old spayed female mixed-breed dog weighing 19.4 kg

exposures to ibuprofen.

7,8

was presented to the Veterinary Teaching Hospital, University of

Ibuprofen reversibly inhibits cyclo-oxygenase (COX) by com-

Illinois.for ingestion of 1,856 mg/kg of ibuprofen, a human for-

peting with the substrate arachidonic acid for the active site of the

mulated NSAID. According to the owner, the dog ate the contents

enzyme. The majority of toxicoses involve the gastrointestinal

of an entire bottle (180 tablets) of ibuprofen between 1 hr and

(GI) tract, kidneys, hematopoietic system, and, in higher dosages,

6 hr before presentation.

the central nervous system. Treatment of ibuprofen toxicosis has

The owner had contacted the American Society for the

traditionally been limited to symptomatic care, including the use

Prevention of the Cruelty to Animals Animal Poison Control

From the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL (L.B.); and Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL (M.M., T.N., M.O.).

CBC complete blood count; COX cyclo-oxygenase; CRI constant rate infusion; GI gastrointestinal; HR heart rate; ILE IV lipid emulsion; NSAID nonsteroidal anti-inflammatory drug; RR respiratory rate; PCV packed cell volume; POC point-of-care; TS total solids

Correspondence: [email protected] (M.M.)

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ILE to Treat Ibuprofen Toxicosis

Center prior to presentation and was advised to administer 30 mL

of protein. Urine cytology revealed moderate blood, few WBCs,

of hydrogen peroxide per os to induce emesis. The dog vomited

red blood cells, epithelial cells, and no bacteria. Moderate granular

three times, and the presence of scant pills in the emesis was

casts and moderate amorphous crystals were present.

noted, but the number of pills was unable to be quantitated.

Within 30 min of presentation, the patient’s level of con-

At the time of presentation, the patient was bright, alert,

sciousness rapidly progressed to coma. The HR increased to

responsive, and hypersalivating. Heart rate (HR, 102 beats/min),

180 beats/min, the RR increased to 42 breaths/min, and the body

respiratory rate (RR, 24 breaths/min), and temperature (37.98C)

temperature dropped to 35.58C. Naloxonef was given, at the

were within normal limits. The mucous membranes were pink

suggestion of the American Society for the Prevention of Cruelty

and moist, with a capillary refill time of , 2 sec. Neither murmurs

to Animals Poison Control Center at a dose of .01 mg/kg IV,

nor arrhythmias were present on cardiac auscultation. Femoral

and the dog became briefly aroused. The naloxone was repeated,

pulses were strong and synchronous, and normal bronchove-

but the dog rapidly progressed back to a comatose state. Naloxone

sicular lung sounds were ausculted in all lung fields. Abdominal

administration may be beneficial in cases of ibuprofen intoxication

palpation was soft and nonpainful, and the remainder of the

and signs of central nervous system dysfunction as NSAIDs may

physical examination was unremarkable.

share a common mechanism of action with opioids.10

After the initial physical examination, an IV catheterb was

The systolic blood pressure dropped to 60 mm Hg, and

placed in the right cephalic vein. Maropitantc (1 mg/kg) was sub-

a bolus of 20 mL/kg of isotonic crystalloidsg was administered

cutaneously administered for nausea and vomiting. Blood pres-

followed by a 5 mL/kg bolus of a synthetic colloid solutionh.

sure was 90 mm Hg systolic using indirect Doppler measurement,

Forced warm air was used to maintain normal body temperature,

electrocardiography revealed normal sinus rhythm, and O2 satu-

and an endotracheal tube was placed to protect the airway. Se-

ration was 98%. A limited abdominal ultrasound screening was

dation was not needed. Ventilation and oxygenation were assessed

performed, and free abdominal fluid was not observed.

by monitoring end-tidal CO2 and O2 saturation.

A point-of-care (POC) venous blood gasd and electrolyte analysis

Due to the patient’s rapid deterioration, an IV lipid so-

was performed that revealed metabolic acidosis, hypokalemia,

lutioni was administered at 1.5 mL/kg over 15 min, followed by

hyperglycemia, and hyperlactatemia. Packed cell volume (PCV)

a constant rate infusion (CRI) at .5 mL/kg/min for 2 hr. Blood

and total solids (TS) were both normal (Table 1). Blood

was collected 2 hr after completion of lipid infusion, and serum

was collected for a complete blood count (CBC) and serum

was frozen at 228.88C for future analysis. Serum ibuprofen

biochemical profile (Table 2). The CBC revealed leukopenia

analysis detected a baseline (preILE) concentration of 190 mg/mL,

with neutropenia, hemoconcentration, and adequate platelet

and an undetectable postILE concentration. In humans, thera-

count. The manual differential revealed rare polychromasia,

peutic concentrations of ibuprofen range from 10 mg/mL to

poikilocytosis, and anisocytosis. Serum biochemical analysis

50 mg/mL.11

revealed hypokalemia, hypoglobulinemia, and hypotriglycer-

The patient was admitted to the intensive care unit for con-

idemia. The serum was immediately frozen at 228.88C for

tinued monitoring and supportive care. A urinary catheter and

further testinge.

a double-lumen jugular catheter were placed. A peripheral catheter

Urinalysis (obtained by cystocentesis) revealed cloudy, yellow-

was placed in the right dorsal pedal artery for direct blood pressure

orange urine with a specific gravity of 1.026, pH of 8, and 300/gL

monitoring and arterial blood gas sampling. IV crystalloid fluids

TABLE 1 Abnormal POC Blood Work at Presentation and During Treatment Mg (0.47–0.62 mmol/L)

TS (53–80 g/L)

pH (7.39–7.49)

HCO3 (17–24 mmol/L)

Na (144–151 mmol/L)

K (3.7–4.91 mmol/L)

Glu (3.8–8.3 mmol/L)

Lac (0.435–2.93 mmol/L)

pCO2 (31–55 mm Hg)

47%

69

7.28

14.8

146

3.26

7.7

7.1

30.7

— —

— —

7.35 7.40

18 20

145 145

3.80 3.75

6.9 7.1

6.8 2.3

32 35

0.42 0.40

30 hr

—

—

7.38

22

138

3.55

6.9

2.0

34

0.58

48 hr

16%

32

—

—

—

—

—

PCV (35–52%)* At presentation 6 hr 13 hr

—

—

—

—

*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 BUN (2.5–7 mmol/L)

aPTT (9–15 sec)

ALT (0.2–1.4 mkat/L)

—

—

—

14.9

21.3

—

—

2.5

PT (6–10 sec)

WBC (6.0–17.0 3 109/L)*

Neut (3.0–11.5 3 109/L )

HCT (35–52%)

Plt (200–900 3 109/L)

Tri (0.2–1.8 mmol/L)

Glob (27–44 g/L)

At presentation

3.9

2.7

53.7%

212

0.23

21

7

30 hr

7.0

5.4

36%

100

0.34

28

11

1 wk after discharge

—

—

—

220

—

23

7

—

*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.

with 20 mEq/L potassium chloride was administered at a rate of

bleeding from the suture site. Abnormalities on POC blood gas

8 mL/kg/hr and colloids were administered at 1 mL/kg/hr. Sys-

revealed hyponatremia and hypokalemia (Table 1). A CBC revealed

tolic blood pressure remained low at 80 mm Hg despite crys-

thrombocytopenia and serum biochemical analysis revealed ele-

talloid and colloid support, and a CRI of vasopressinj was started

vated blood urea nitrogen. All other parameters were within

at .07 mg/kg/hr.

normal limits. Prolonged prothrombin time and activated par-

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 (36.38C) and became tachycardic (HR was 158

tial thromboplastin time were identified on the coagulation profile (Table 2). IV fluids, omeprazole (1 mg/kg q 24 hr), and misoprostol (3 mg/kg q 6 hr) were continued, and sucralfateo (1 g q 8 hr) was started. The benefits of plasma transfusion were discussed with the owner but declined due to financial constraints.

beats/min) and tachypneic (RR was 48 breaths/min). Systolic

At approximately 48 hrs after presentation, the patient’s

blood pressure was 110 mm Hg. A nasogastric tube was placed to

mucous membranes, sclera and ventral abdomen became icteric,

administer omeprazolek (1 mg/kg q 24 hr), misoprostoll (3 mg/kg q

anemia was noted with a PCV of 16%, and TS of 3.2 g/dL. A

6 hr), and for enteral nutrition. A POC blood gas revealed per-

reticulocyte count revealed 0.4% reticulocytes with an absolute

sistent hyperlactemia and the development of hypomagnesemia

count of 9.8 3 109/L. N-acetylcysteinep (50 mg/kg IV q 6 hr) was

(Table 1).

started. Tests of hepatic function (e.g., bile acids) and blood and

Approximately 13hr after presentation, the patient was alert and responsive. Bleeding was present at the site of the nasogastric

plasma transfusions were declined by the owner. N-acetylcysteine (50 mg/kg q 6 hr IV) was started.

tube sutures on the left side. Topical epinephrinem and ice packs

On days 3 and 4, the IV fluids, N-acetylcysteine, misoprostol,

were used to try to stop the bleeding. Bleeding would stop tran-

omeprazole, and sucralfate were continued. Monitoring included

siently and then resume when the patient moved. Due to financial

electrolytes; venous blood gas daily; temperature, pulse, and res-

concerns, tests to evaluate primary hemostasis (e.g., PFA-100) were

piration; and indirect blood pressure q 6 hr.

not performed at that time. After the patient became responsive,

On day 5 of hospitalization, body temperature was 38.58C

the systolic blood pressure (110 mm Hg) and body temperature

HR was 120 beats/min, and RR was 24 breaths/min. Recheck

(37.88C) normalized. Vasopressin, colloids, direct blood pressure

PCV was 18% and TS were 3.5 g/dL. The central line was re-

monitoring, and active warming were discontinued. Repeat uri-

moved, and the site monitored for bleeding. The patient was

nalysis was normal, and no casts were observed. A POC blood

discharged with S-adenosylmethionineq, omeprazole, misoprostol,

gas revealed a normal lactate concentration with persistent hy-

and instructions to have additional testing (i.e., CBC, serum bio-

pomagnesemia (Table 1). Magnesiumn was added to the IV fluids

chemical analysis, urinalysis, and coagulation panel) performed at

at a rate of 1 mEq/kg/day.

the primary veterinarian in 1 wk. At the referring veterinarian 1 wk

Approximately 30 hr after presentation, the patient was quiet,

after discharge, the patient had completely recovered. Blood work

alert, and responsive. Body temperature was 38.28C, HR was 148

and urinalysis performed at that time revealed slightly elevated al-

beats/min and RR was 24 breaths/min. The patient developed

anine aminotransferase and hypoglobulinemia. All other values

hematemesis, mild melena, hematuria, and persistent unilateral

were unremarkable.

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Discussion

In humans, mild depression of the nervous system can occur

To the authors’ knowledge, this is the first documented use of

at lower doses. Dizziness, depression, headache, and nausea are

ILE for the treatment of ibuprofen intoxication in a dog. Docu-

the most common signs. Doses higher than 400–500 mg/kg are

mentation of undetectable concentrations of ibuprofen postlipid

reportedly associated with seizures and coma in dogs intoxicated

infusion is suggestive, but not indicative, of successful detoxifi-

with ibuprofen, and secondary effects of hypoxia, acidosis, and

cation. In humans, there are several case reports demonstrating

pyrexia can be associated with prolonged seizures.17 Higher doses

concentrations as high as four times the therapeutic range, and

can cause coma and severe respiratory distress leading to me-

concentrations , 180 mg/L are associated with seizures, respira-

chanical ventilation in people.11

tory failure, and acidosis.

11–13

The dog described in this case re-

Bleeding developed on the second day of hospitalization,

port had serum concentrations approximately four times the

but tests of primary hemostasis (e.g., PFA-100) were not per-

highest end of the therapeutic range for humans.

formed due to financial concerns. Inhibition of thromboxane A2

According to the owner, the dog ingested the ibuprofen be-

by NSAIDs is known to induce a platelet dysfunction that can

tween 1 hr and 6 hr before presentation. Because emesis was

lead to bruising and bleeding. An underlying hepatic dysfunc-

partially successful, it is impossible to know the amount absorbed.

tion (i.e., icterus, coagulopathy) was suspected, but additional

In dogs, ibuprofen is rapidly absorbed after oral administration

tests of hepatic function (e.g., bile acids) were not performed

attaining maximal plasma concentrations from 30 min to 3 hr after

due to financial concerns. Hepatic dysfunction has been re-

ingestion. Ibuprofen is 96% protein bound, has reported elimi-

ported in people with NSAID toxicity.14

nation half-lives of 2.5 hr and 5.8 hr, and undergoes enterohepatic 14

recycling.

Treatment of ibuprofen toxicosis has traditionally been limited to symptomatic care, including the use of prostaglandin

Ibuprofen is the most popular over-the-counter pain reliever

analogs (e.g., misoprostol), IV fluids, antiemetics, and other gastric

in the United States, and a search of medical records at the Georgia

protectants.9 Intervention to treat the intoxication should occur

Animal Poison Center over a 19 mo period revealed 240 cases

as early as possible and has the benefit of timely administration

of dog and cat exposure to NSAIDs. The most common NSAID

that may be life saving if the owner lives far from a veterinary

was ibuprofen.15

facility. However, centrally acting emetics, administered by a vet-

Ibuprofen inhibits COX, the enzyme that converts arachidonic acid to prostaglandin H2. In turn, prostaglandin H2 is

erinarian, are far more reliable for induction of emesis than hydrogen peroxide used at home.

converted by other enzymes to various prostaglandins and throm-

Lipid emulsions are most commonly used in IV parenteral

boxane A2. Ibuprofen is thought to be a nonselective COX in-

nutrition as well as a delivery vehicle for hydrophobic drugs such as

hibitor, inhibiting both COX-1 and COX-2. Inhibition of COX-1

propofol. There are several studies showing the successful use of

prevents prostaglandin’s biologic benefits, including gastric mucosal

lipid emulsions in the treatment of acute local anesthetic toxicity in

protection and preservation of adequate renal perfusion and glo-

humans and animals and they have recently been reviewed.5,6,18–21

merular filtration. Consequently, ibuprofen exposure reduces renal

Briefly, the most commonly accepted mechanism of action in the

blood flow leading to acute kidney injury, acute interstitial ne-

treatment of toxicity with lipid emulsion is the lipid sink theory.

phritis, hyperkalemia, and GI ulceration. Although renal dysfunc-

The administration of lipid solutions is thought to bind lipid

tion is often reversible after discontinuation of the drug, severe and

soluble drugs and compartmentalize them into the newly created

prolonged renal hypoperfusion secondary to prostaglandin in-

lipid compartment. It is impossible to know if the lipid infusion was

hibition could lead to acute cortical necrosis and irreversible acute

responsible for the rapid improvement in the level of consciousness

renal failure.16 The patient described in this report did not develop

in the patient described in this report, but the patient had ingested

either azotemia or oliguria, and although proteinuria and casts were

a massive dose of ibuprofen and made a complete recovery. Com-

observed on presentation, they resolved with supportive care.

plications associated with the lipid infusion were not observed.

Inhibition of prostaglandin synthesis also interferes with

Dosage recommendations for lipid infusion are varied and

the maintenance of gastric mucosal integrity. Dogs are more

mostly anecdotal. Most reports suggest a bolus of 1.5–4 mL/kg

predisposed than humans to ibuprofen’s ulcerogenic effects due to

followed by .25–.5 mL/kg/min for 1 hr.4–6 The dog described

higher GI absorption rates and a longer drug half-life, which leads

in this case report received a bolus of 1.5 mL/kg followed by a CRI

to slower drug elimination and higher blood concentrations.14

of .5 mL/kg/min for 120 min.

Those pharmacokinetic factors narrow the margin of safety of ibuprofen in dogs.

Lipid emulsion therapy is not without potential complications. Those emulsions can promote bacterial growth requiring

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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. FOOTNOTES a Motrin; McNeil Healthcare, Lake Forest, IL b Venocath 20G; Hospira Inc., Lake Forest, IL c Cerenia; Pfizer Animal Health, New York, NY d Nova Biomedical; Critical Care Xpress, Waltham, MA e High-Performance Liquid Chromatography; NMS Labs, Willow Grove, PA f Narcan; Endo Pharmaceuticals Inc., Chadds Ford, PA g Lactated Ringer’s solution; Hospira Inc., Lake Forest, IL h Hetastarch; Teva Parental Medicines Inc., Irvine, CA i Intralipid 20% solution; Hospira Inc., Lake Forest, IL j Vasopressin; Cerner Multum, Denver, CO k Prilosec; AstraZeneca, Wilmington, DE l Cytotec; Pfizer, New York, NY m Epinephrine; America Regent Laboratories, Shirley, NY n Magnesium sulfate; America Regent Laboratories, Shirley, NY o Sucralfate; TEVA, North Wale, PA p N-acetylcytsteine; Hospira Inc., Lake Forest, IL q Denosyl; Nutramax Laboratories, Edgewood, MD REFERENCES 1. Cave G, Harvey M. Intravenous lipid emulsion as antidote beyond local anesthetic toxicity: a systematic review. Acad Emerg Med 2009; 16(9):815–24. 2. Tebbutt S, Harvey M, Nicholson T, et al. Intralipid prolongs survival in a rat model of verapamil toxicity. Acad Emerg Med 2006;13(2): 134–9. 3. Cave G, Harvey MG, Castle CD. The role of fat emulsion therapy in a rodent model of propranolol toxicity: a preliminary study. J Med Toxicol 2006;2(1):4–7. 4. Harvey M, Cave G. Intralipid outperforms sodium bicarbonate in a rabbit model of clomipramine toxicity. Ann Emerg Med 2007;49(2): 178–85, e1–4.

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