Toxicology Brief: Successful treatment of baclofen overdose with intravenous lipid emulsion

A previously healthy, 6-month-old 17.7-lb (7.7-kg) neutered male Shetland sheepdog was presented to a veterinary facility after being found nonresponsive at home by the owners.

HISTORY

Before presentation, the owners had found evidence that the dog had ingested the contents of a pill vial containing 10-mg baclofen tablets sometime in the previous six hours. The dog had consumed about 16 tablets, giving it a dose of 20.7 mg/kg of baclofen.

PHYSICAL EXAMINATION

At presentation, the dog was in unresponsive lateral recumbency, although intermittently vocalizing. A physical examination revealed mild hypothermia (99.6 F; normal = 101 to 102 F), moderate hypersalivation, and moderate bradycardia (70 beats/min; normal = 110 to 120 beats/min), but the patient was normotensive. The results of a baseline electrocardiogram, complete blood count (CBC), and serum chemistry profile were all normal. A single tablet of baclofen was found adhered to the coat of the dog's forelimb, reducing the possibly ingested dose to 19.4 mg/kg.

CASE MANAGEMENT

Based on the physical examination findings and evidence of access to the agent, baclofen toxicosis was presumptively diagnosed.

Initial measures

Initial treatment included administration of intravenous fluids (0.9% saline solution 60 ml/kg/day) and, because the dog had an altered state of consciousness, an antiemetic (maropitant 1 mg/kg subcutaneously) to reduce the risk of vomiting and secondary aspiration pneumonia.

Decontamination by giving activated charcoal was initially considered but was eventually rejected because of the risk of aspiration. Instead, intralipid emulsion therapy was instituted, as previous experience had suggested its benefit in shortening the length of clinical signs in cases of baclofen toxicosis.1

Before the administration of the first dose of intravenous lipid emulsion (ILE), the dog experienced a seizure, which was quickly controlled with a single dose of diazepam (0.5 mg/kg intravenously). It was also noted that the dog's bradycardia had worsened to an average of 40 beats/min with serial auscultations over several minutes with intermittent ventricular escape beats. Giving the dog a single 0.5-ml dose of atropine (0.03 mg/kg intravenously) immediately improved the bradycardia and resolved the escape beats. An attempt was made to place an endotracheal tube, but placement was prevented by a strong swallowing reflex and chewing at the tube.

First ILE administration

Three hours after presentation, the dog experienced an episode of sudden respiratory arrest. The dog began receiving conventional mechanical ventilation with 80% oxygen supplementation at a rate of 12 breaths/min. Shortly thereafter, an initial bolus (1.5 ml/kg) of 20% ILE was administered, followed 15 minutes later by a 0.25 ml/kg/min dose given over an hour.

Over the next four hours, the dog's heart rate stabilized at 80 beats/min with no additional abnormal beats. An episode of regurgitation was seen with gastric contents exiting through the nares; thus, prophylactic antibiotic administration was initiated (cefazolin 26 mg/kg intravenously). Also, the dog became more alert and responsive to handling, so isoflurane (1% to 1.5%) was administered intermittently to minimize agitation and anxiety and facilitate mechanical ventilation. A blood sample taken four hours after the initial ILE administration showed moderate lipemia, so the second administration of ILE was delayed to allow the serum to clear.

Second and third ILE administrations

Eight hours after the first ILE administration, the serum had become sufficiently clear to proceed with the second delivery. Again, an initial bolus (1.5 ml/kg) of a 20% ILE was administered followed by a more protracted delivery (0.25 mg/kg/min) given over an hour. Four hours after the second ILE administration, the dog was sufficiently recovered to be removed from assisted ventilation (a total of 15 hours receiving ventilation).

Despite this improvement in clinical status, the dog was still profoundly sedate and only moderately responsive to stimuli. After confirming the absence of lipemia via blood sample, a third dose of ILE was given to assist with further recovery. As with the previous doses, an initial bolus was supported by subsequent extended administration over an hour.

Case outcome

Four hours after the third administration of ILE, the dog was sternal yet moderately ataxic when encouraged to walk. Its appetite was reported to be good, with normalization in vital parameters. Presumably because of the regurgitation, the dog developed a moderate purulent nasal discharge, so it was given a combination of amoxicillin and sulbactam (Unasyn—Pfizer; 25 mg/kg intravenously). The dog continued to receive intravenous fluids (0.9% sodium chloride at maintenance rates) and was monitored for the next six hours for additional signs relative to the possible aspiration.

The dog was discharged to the owners later that night still receiving antibiotics and still slightly ataxic, but otherwise stable. The owners reported that the next day (48 hours after exposure) the dog was ambulating normally with complete resolution of the nasal discharge.

Serum or plasma baclofen concentrations were not measured before, during, or after ILE treatment.

DISCUSSION

Baclofen is a centrally acting skeletal muscle relaxant. Prescribed in people to alleviate muscle spasticity associated with multiple sclerosis and spinal disorders, it has been recently used in treating the side effects of alcohol withdrawal and is also becoming a common drug of abuse.2

Its administration in dogs has been intermittent, specifically for the relief of urinary retention secondary to urethral muscle spasticity. Dosages for this purpose are reported to be 1 to 2 mg/kg orally three times a day, though even at therapeutic doses, adverse drug effects such as ataxia or weakness are frequently noted. Baclofen administration in cats is not recommended.3

Toxicokinetics

Baclofen acts as a mimic of gamma-aminobutyric acid at the spinal end of upper motor neurons, functionally inhibiting monosynaptic and polysynaptic reflexes at the spinal level. The inhibition results in a flaccid paralysis of skeletal muscles. Poor penetration of the blood-brain barrier limits central nervous system (CNS) signs at therapeutic doses, but in overdose situations, CNS signs can be significant.4

The dose of baclofen an animal ingests appears to affect the pharmacokinetic profile. At or near therapeutic doses, absorption is rapid and complete, with peak plasma concentrations occurring roughly three hours after ingestion. With higher doses, the absorption is more incomplete and has been shown to be prolonged.2 The presence of food in the gastrointestinal tract does not appear to affect bioavailability.5 In people, the half-life shows similar dose variations, with half-life increasing from 2.5 hours to six hours for therapeutic doses. In cases of significant overdose, the half-life has been noted to increase to more than 34 hours.2

Baclofen is primarily eliminated unchanged by the kidneys, though fluid diuresis alone has not been shown to enhance excretion. Small amounts are metabolized through deamination in the liver and excreted in the bile.2

Toxicity

Baclofen toxicosis is potentially lethal because of respiratory arrest from the paralytic effect on intercostal and diaphragm muscles. No LD50 has been established in dogs. However, according to preliminary information retrieved from the toxicology database at the ASPCA Animal Poison Control Center (APCC), fatal events have been noted with baclofen doses as low as 4 mg/kg and more consistently with doses > 10 mg/kg.1

Independent of dose, clinical signs have generally been noted within two hours of exposure, with a few cases showing signs in as little as 15 minutes and as late as seven hours. Once they develop, clinical signs can persist for several hours; clinical signs from larger doses potentially last several days because of slow clearance from the CNS.4

Exposure to baclofen can result in a constellation of clinical signs. In the cases reported to the ASPCA APCC, the most common clinical signs were ataxia, vomiting, and vocalizing. Vocalization was noted frequently in cases that were otherwise nonresponsive. Other frequently reported clinical signs were dyspnea, seizures, depression, tachypnea, hypothermia, and hypotension.1,4 Hypokalemia and hypoglycemia are frequent findings in human exposures but were not consistently reported in animal cases.2

Differential diagnoses

When diagnosing baclofen toxicosis, it is important to rule out other possible causes of the clinical signs, including:

• An overdose of other skeletal muscle relaxants (e.g. cyclobenzaprine), amphetamines, avermectins, barbiturates, benzodiazepines, 5-hydroxytryptophan, opioids, propofol, tricyclic antidepressants, selective serotonin reuptake inhibitors, zaleplon, zolpidem, zopiclone, and botulinum toxin

• Ionophore toxicosis

• Coonhound paralysis

• Tick paralysis

• CNS trauma.

Diagnosis and treatment

Diagnosis is based on evidence of or a history of exposure to the medication and rapid development of typical CNS signs. In addition, tests are available—although not widely—that can determine the presence of baclofen in serum or urine.2

Suspected cases should be treated aggressively with the goal of mitigating the progression of the respiratory depression. In asymptomatic dogs, emesis can be induced with either hydrogen peroxide (2.2 ml/kg orally with a potential additional dose if the first dose is unsuccessful) or apomorphine (0.03 mg/kg intravenously, 0.04 mg/kg intramuscularly, or 0.25 mg/kg into the conjunctival sac). If it can be safely administered, a dose of activated charcoal (2 to 4 g/kg) should also be given. Repeated doses of charcoal are not beneficial.2,4 Gastric lavage can be considered, though anesthesia may compound the depressive effects of baclofen.4

For symptomatic cases, hemodialysis with hemoperfusion is effective at removing the agent from circulation.6 Alternatively, fluid diuresis combined with ILE therapy has shown promise in reducing the severity and duration of clinical signs.

Based on observations regarding similar baclofen toxicosis cases presented to the ASPCA APCC, ILE administration appears to shorten the clinical duration or severity of clinical signs. However, no controlled data regarding the efficacy and safety of ILE administration in treating baclofen toxicosis are available to back up this observation.

The exact mechanism of action of ILE in treating baclofen toxicosis is unknown, though it is hypothesized that it acts as a reservoir for fat-soluble agents, binding them and allowing removal through normal metabolic pathways (i.e. macrophages).7

Adverse effects reported after ILE administration include persistent lipemia, hypersensitivity reactions, interference with concurrent drug therapy, interference with laboratory tests because of lipemia, pancreatitis secondary to persistent lipemia, hemolysis, and lipid emboli in neonates.8

Diazepam (0.5 to 1 mg/kg intravenously to effect) has been effective in treating baclofen-induced seizures. Cyproheptadine (1.1 mg/kg orally or rectally) has had variable effect in treating vocalization and disorientation. In human studies, flumazenil and physostigmine have both proven ineffective in treating signs consistent with baclofen overdose.2

Monitoring

Performing baseline serum chemistry profiles and CBCs is recommended to identify underlying conditions, which may complicate treatment. In severe cases, repeat evaluation of serum potassium and blood glucose concentrations may be warranted. Patients with marked respiratory signs will require blood gas monitoring.

CLINICAL RELEVANCE

Because of the increasing use of baclofen as a palliative treatment and as a drug of abuse, the number of animal exposures is rising rapidly. With the potential for respiratory arrest in overdose situations, early identification and rapid decontamination and treatment are paramount for a positive outcome. In addition, with few veterinary facilities capable of performing hemoperfusion or hemodialysis, ILE therapy may prove an affordable, accessible alternative therapy to successfully treat baclofen toxicosis. More research is needed to show that ILE is an effective and safe treatment option for treating baclofen overdose cases.

Jarrod Butler, DVM ASPCA Animal Poison Control Center 1717 S. Philo Road, Suite 36 Urbana, IL 61802

REFERENCES

1. AnTox Database. Urbana, Ill: ASPCA Animal Poison Control Center, 2013.

2. POISINDEX editorial staff: Baclofen. POISINDEX System. Micromedex, Englewood, Colo., 2012.

3. Plumb DC. Veterinary drug handbook. 7th ed. Ames, Iowa: Blackwell, 2011.

4. Wismer T. Baclofen overdose in dogs. Vet Med 2004;4:406-410.

5. Peterson GM, McLean S, Millingen KS. Food does not affect the bioavailability of baclofen. Med J Aust 1985;13:689-690.

6. Scott N. Baclofen intoxication in a dog successfully treated with hemodialysis and hemoperfusion coupled with intensive supportive care. J Vet Emerg Crit Care 2007;17(2):191-196.

7. Fernandez AL, Lee JA, Rahilly L, et al. The use of intravenous lipid emulsions as an antidote in veterinary toxicology: a review. J Vet Emerg Crit Care 2011;21(4):309-320.

8. Gwaltney-Brant S, Meadows I. Use of intravenous lipid emulsions for treating certain poisoning cases in small animals. Vet Clin North Am Small Anim Pract 2012;42(2):258-259.