Successful Treatment With Intravenous Lipid Emulsion of Accidental Amantadine Overdose: A Case Report

ABSTRACT

A 2.5‐year‐old, 4.9 kg, Chinese Crested was accidentally administered a dose of 43.5 mg/kg of amantadine, resulting in the rapid onset of tremors, agitation, vertical nystagmus, and lack of pupillary light reflex in one eye. After unsuccessful treatment with methocarbamol, a 1.5 mL/kg bolus of 20% intravenous lipid emulsion therapy was initiated followed by a 0.25 mL/kg/min continuous rate infusion. All clinical signs secondary to the amantadine toxicity resolved following intravenous lipid emulsion therapy and remained normal on 24 h, day 5, day 18, and day 50. This represents the first report of amantadine toxicity in a clinical setting and is the first case showing that intravenous lipid emulsion therapy could be an effective treatment for amantadine toxicity.

Intravenous lipid emulsion therapy may be an appropriate treatment for amantadine toxicity. While amantadine levels were not performed, clinical signs improved following intravenous lipid emulsions. Additional studies recommend evaluating direct changes to amantadine levels with this therapy in the future.

1. Case Description

A 2.5‐year‐old female spayed Chinese Crested was presented to the emergency department of the multispecialty hospital for progressive non‐ambulatory paraparesis. The owners reported that she was painful with stiff back legs and a tense abdomen the day prior to presentation to the emergency department. The morning of the presentation, the dog was administered a 0.1 mg/kg dose of meloxicam at the recommendation of their primary veterinarian. The owners reported that the patient developed ataxia in the hind limbs which progressed to being non‐ambulatory. Unfortunately, the exact times of the onset of clinical signs, administration of meloxicam, development of ataxia, and progression to becoming non‐ambulatory were not provided by the owner. She was presented to the multispecialty hospital approximately 2 h after the development of her non‐ambulatory status.

Initial physical examination showed her to be bright and alert. She was noted to be non‐ambulatory with absent nociception in the left hindlimb and a markedly blunted nociception response in the right. She also had discomfort with palpation over the thoracolumbar junction of the spine. A haematology and biochemistry panel showed no clinically significant abnormalities other than mild elevation of blood urea nitrogen (31 mg/dL, reference range 7–25 mg/dL).

The patient was started on intravenous crystalloids (Lactated Ringer's solution—LRS) at a rate of 50 mL/kg/day. Gabapentin (10.4 mg/kg) and a fentanyl bolus (3 µg/kg) followed by a continuous rate infusion (CRI) of 3 µg/kg/hr were used for analgesia throughout the night. Seven hours later she was transferred to the surgical service for evaluation, magnetic resonance imaging (MRI), and possible surgery. Her fentanyl CRI was discontinued 1 h prior to transfer so as not to alter physical exam findings. The physical exam findings were noted to be similar to the presentation. The patient was premedicated with midazolam 0.2 mg/kg, methadone 0.22 mg/kg, ketamine 4 mg/kg, and dexmedetomidine 1 µg/kg intravenously (IV) and intubated. The patient was maintained on 100% oxygen with sevoflurane gas inhalant anaesthesia.

Magnetic resonance imaging (MRI) showed diffuse degenerative intervertebral disc disease with an acute‐on‐chronic rupture at the first and second lumbar (L1‐L2) disc space, and cranial spread through the ninth to twelfth thoracic (T9‐T12) disc space causing associated compression. Suspected epidural haemorrhage was also noted to be extending through the T9‐T12 disc spaces.

The patient underwent a routine left dorsolateral hemilaminectomy at T9‐11 and T13‐L2. No complications were noted, and the patient recovered uneventfully from anaesthesia. Postoperative analgesia was provided with fentanyl (3 µg/kg/hr), ketamine (4 µg/kg/min), oral meloxicam (0.1 mg/kg q24h), and oral gabapentin (10.4 mg/kg PO q24h). Prazosin (0.43 mg/kg PO q12h) was administered to assist with bladder expression. Two days following surgery the patient was weaned off the CRI of fentanyl and ketamine. Oral amantadine was added to the electronic treatment sheet to continue multimodal analgesia. The dose ordered was accidentally dosed as 43.5 mg/kg instead of the intended 4.35 mg/kg.

The electronic treatment system did not contain a safety warning for this excessively high dose, and the mistake was not caught by a doctor or technician prior to administration. One hour following administration, the patient was noted to have generalised tremors, hyperaesthesia to light and sound, vertical nystagmus bilaterally and reduced pupillary light response of the right eye. A dose of midazolam (0.5 mg/kg) was administered IV due to suspicion of seizure activity. A venous blood gas showed a mixed acid/base disorder with metabolic acidosis and respiratory alkalosis, mild hypernatraemia, hyperlactatemia (Table 1).

TABLE 1.

venous blood gas results obtained from an epoc blood analysis machine showing a mixed acid‐base disorder with metabolic acidosis and respiratory alkalosis.

Label	Results	Reference	Unit
pO2	66.5	24.0‐54.0	mmHg
cSO2	93.9	40.0‐90.0	%
pCO2	22.8	30.0‐47.0	mmHg
HCO3‐	15.0	16.0‐28.0	mmol/L
TCO2	14.9	17.0‐26.0	mmol/L
pH	7.427	7.360‐7.460
BE, ECF	−9.3	−5.0‐5.0	mmol/L
Sodium	157	140‐151	mmol/L
Potassium	4.1	3.5‐5.0	mmol/L
Chloride	122	106‐127	mmol/L
iCa	1.10	1.13‐1.42	mmol/L
Anion Gap	25	5‐22	mmol/L
Lactate	3.90	0.60‐3.0	mmol/L
BUN	13	7‐26	mg/dL
Creatinine	0.57	0.40‐1.50	mg/dL
Glucose	80	63‐124	mg/dL
HCT	38	36‐55	%

Notes: Hyperlactatemia and hypernatremia also noted.

Abbreviations: BE, base excess; BUN, blood urea nitrogen; HCO3‐, bicarbonate; HCT, hematocrit; iCa, ionized calcium.

After the incorrect dose administration was noted, the ASPCA Animal Poison Control Center (APCC) was contacted. At their recommendation, that patient was administered an initial injection of 45.7 mg/kg of methocarbamol IV, approximately 2 h following intoxication. Mild improvement was noted in the tremors following the dose of methocarbamol but moderate tremors were still present. Due to continued clinical signs, it was elected to administer a dose of intravenous lipid emulsion (ILE), approximately 3 h following intoxication. A typical dose of 1.5 mL/kg bolus over 10–15 min followed by a dose of 0.25 mg/kg/min for 45 min was administered (Gwaltney‐Brant and Meadows 2012; Markert et al. 2023). Marked improvement of the hyperesthesia and resolution of her nystagmus, and reduced pupillary light response was noted immediately following completion of the ILE administration. Recheck blood work was not performed following ILE administration.

The patient was hospitalized for an additional 72 h with cyproheptadine (1.13 mg/kg PO q8h), methocarbamol (34 mg/kg IV q12h), and acepromazine (0.02 mg/kg IV q8h) as needed for agitation. She was noted to be free of all clinical signs 8 h following ILE administration and 12 h following onset of signs. She remained in the hospital to recover from her neurosurgery. She was discharged on day 5 with gabapentin and meloxicam. Recheck examination on day 15 and day 50 following discharge (day 18 and 53 following onset of signs respectively) did not show any recurrence of clinical signs related to amantadine toxicity.

2. Discussion

This is, to the authors' knowledge, the first report of canine amantadine toxicity in a clinical setting and successful treatment of clinical signs most likely associated with amantadine toxicity with intravenous lipid emulsion therapy. Amantadine Hydrochloride is a common noncompetitive N‐methyl‐D‐aspartate (NDMA) receptor antagonist and dopamine agonist that is becoming commonly used in multimodal analgesia within the veterinary field (Lascelles et al. 2008). Unfortunately, medical errors are not an uncommon occurrence. One study of 606 veterinarians found that over a 12‐month period either a near miss (389 individuals) or an adverse event (179 individuals) had occurred. However, this study also included other medical errors other than medication errors, such as wrong surgery sites and anaesthetic complication (Kogan et al. 2018).

This dog was accidentally administered 43.5 mg/kg of amantadine orally. This is close to 10 times the currently recommended dose of 3–5 mg/kg PO q12‐24 h (Madden et al. 2014). Clinical signs were seen to have developed approximately 1 h following ingestion. Previous studies have shown that maximum plasma concentration occurs within 1 to 4 h in dogs administered a dose of 2.8 mg/kg (Norkus et al. 2015). This is also similar to other experimental studies which showed adverse effects within an hour of administration (Vernier et al. 1969).

Common adverse effects secondary to amantadine toxicity in dogs have been reported as vomiting, agitation, hypersalivation, anorexia, mydriasis, tremors, intermittent clonic convulsions, myoclonic jerks, increased sensitivity to stimuli, and loss of pupillary light reflex (Vernier et al. 1969). Our patient demonstrated the majority of these signs except for the vomiting, hypersalivation, and anorexia. In one study central nervous system stimulation was noted at doses of 37 mg/kg with death occurring at 93 mg/kg (Vernier et al. 1969). Amantadine intoxication appears to be infrequently encountered in human patients; however a few case reports exist. The literature reports similar CNS symptoms as seen in dogs (disorientation and sensitivity to stimulation), as well as hallucinations secondary to acute toxicity (Cattoni and Parekh 2014; Pimentel and Hughes 1991; Snoey and Bessen 1990). It is difficult to ascertain the doses leading to these signs, as many of the reports do not report the weight of the patients.

To the authors' knowledge there is a paucity of human literature and no veterinary literature describing treatment options for amantadine toxicity. The previous veterinary studies evaluating safety with higher doses listed the common adverse effects but did not list any specific treatments (Vernier et al. 1969). As there is no known antidote for amantadine intoxication, the traditional treatment for these patients is a combination of removal of the toxin via gastric decontamination (emesis or gastric lavage) prior to the onset of clinical signs. (Pimentel and Hughes 1991). Emesis was not pursued in this case due to her already affected central nervous system. It is unclear why gastric lavage was not pursued. Since there is such a paucity of literature, the recommendation made by the ASPCA APCC was to continue to treat her clinical signs symptomatically. This was the reason that methocarbamol was administered for her tremor activity and acepromazine and cyproheptadine were administered for her agitation and hyperaesthesia. Use of activated charcoal has been reported in a few human studies; however amantadine is rapidly and completely absorbed following oral ingestion and is excreted primarily by the kidneys; thus, the efficacy of this treatment is unknown (Aoki and Sitar 1988; Pimentel and Hughes 1991; Kogan et al. 2018; Snoey & Bessen 1990).

Amantadine has a log P of 2.44 and is therefore lipophilic and a good candidate for treatment with ILE, even though it was not directly recommended by the ASPCA APCC. For this reason, the patient was administered a standard dose of ILE. The use of ILE for amantadine overdose has not been reported in either the human or veterinary literature to the authors’ knowledge (Gwaltney‐Brant and Meadows 2012; Markert et al. 2023). Intravenous lipid emulsion is being increasingly used for the treatment of certain toxicities in veterinary medicine. The exact mechanism of action of ILE is still unknown, although several suspected mechanisms such as lipid sink and lipid shuttle have been proposed (Akyol et al. 2023; Bolfer et al. 2014; Fernandez et al. 2011; Gwaltney‐Brant and Meadows 2012; Markert et al. 2023). The lipid sink mechanism is where the ILE acts as a sink for lipid‐soluble drugs. This allows the lipid‐soluble drug to pass from the tissue into the lipid phase of the vessels (Akyol et al. 2023; Fernandez et al. 2011; Bolfer et al. 2014; Gwaltney‐Brant and Meadows 2012; Markert et al. 2023). The ‘lipid shuttle’ mechanism proposes that the lipid‐soluble drug gets taken to the liver or kidneys for metabolisation or excretion, preventing the drug from ever reaching its target tissue (Markert et al. 2023). Intravenous lipid emulsion may also have protective effects on cardiac myocytes (Akyol et al. 2023; Gwaltney‐Brant and Meadows 2012; Markert et al. 2023). The efficacy of ILE is dependent on the log P value of the substance being targeted. The log P value of any given substance describes its lipophilicity. The higher the log P value, the more lipophilic a substance is; therefore, any substance with a log P > 1 is considered to be lipophilic. Intravenous lipid emulsion is more effective in decontaminating toxins with a log P > 1 (Gwaltney‐Brant and Meadows 2012; Markert et al. 2023). The clinical signs had markedly improved following the first administration of ILE, so repeating the dose was not performed.

The terminal half‐life of amantadine is 5.9 h in the greyhound dog, so the majority of the drug should be metabolised or excreted within 24 h (Norkus et al. 2015). In humans the drug is eliminated mostly unchanged via the urinary system (Aoki and Sitar 1988). Thus, care must be taken with patients that have renal disease.

Plasma levels for amantadine were not obtained in this patient; marked improvement in the clinical signs was observed following ILE administration. For this reason, along with the relative safety of ILE therapy, ILE is a viable treatment option for patients that receive a toxic dose of amantadine. One limitation of this case report was that serum plasma levels of amantadine were not obtained. Amantadine levels before, during, and after administration of ILE would have directly revealed the effect of ILE on amantadine toxicity in this patient.

Amantadine toxicity may become more frequently encountered in the veterinary field as its use as an analgesic increases. Intravenous lipid emulsion appears to be an effective treatment for acute amantadine toxicity. This is important for veterinarians to remember, as life‐threatening changes can occur with the administration of toxic doses.

Author Contributions

Brett Hogberg: writing ‐ original draft, writing ‐ review and editing. Kristen Marshall: writing ‐ review and editing. Mark Vardanega: conceptualisation, writing ‐ review and editing.

Peer Review

The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer‐review/10.1002/vms3.70402.

Data Availability Statement

Data sharing is not applicable to this article, as no new data were created or analysed in this study.