Treatment and outcome following substantial ketamine overdose in a dog

Abstract

A 9-year-old, 3.7 kg (8.14 lb) neutered male Yorkshire terrier mix was treated following a ketamine overdose after subcutaneous ureteral bypass surgery. Due to an error in communication and misinterpretation of an electronic treatment sheet, the dog was inadvertently placed on a continuous rate infusion (CRI) of ketamine at 67.6 mg/kg per hour, rather than the intended 0.2 mg/kg per hour rate. Four hours after initiation of the ketamine CRI, the dog developed signs indicative of a ketamine overdose including tachycardia, hyperthermia, anisocoria, and hypoglycemia. It was determined the dog had received an iatrogenic overdose of ketamine; the infusion had been running at 67.6 mg/kg per hour, resulting in 270 mg/kg of ketamine over 4 h. Aggressive supportive measures were undertaken, and the dog gradually recovered over an 18-hour period, without lasting consequences of the overdose.

To the authors’ knowledge, there are no current published reports of a ketamine overdose of this magnitude in a dog. This case report documents an iatrogenic 338 times intravenous ketamine overdose in a dog, which was successfully managed with supportive care. In addition, it highlights the importance of doctor-technician communication and the potential errors in using electronic treatment sheets.

Case description

A 9-year-old, 3.7 kg (8.14 lb) neutered male Yorkshire terrier mix dog was brought to a tertiary referral center for evaluation and treatment of right hydronephrosis and hydroureter. Pre-anesthetic bloodwork including quick assessment tests (PCV/TP, lactate, BUN, and glucose) and renal biochemistry profile were overall unremarkable, with only minor electrolyte abnormalities. A unilateral subcutaneous ureteral bypass (SUB) procedure was performed in the right kidney without complication. The dog recovered from anesthesia uneventfully, and post-operative analgesia was requested via electronic treatment sheet with fentanyl (Sandoz Canada, Boucherville, Quebec) and ketamine (Ketaset, Zoetis Canada, Kirkland, Quebec) continuous rate infusions (CRIs). The analgesic orders were also verbally communicated to the intensive care unit (ICU) technicians. On separate syringe pumps, fentanyl was dosed at 3 μg/kg per hour, and ketamine was prescribed at 0.2 mg/kg per hour following an intravenous loading dose of each medication (3 μg/kg and 0.2 mg/kg, respectively). Following the loading doses, the dog became sedate and was subjectively less painful on abdominal palpation. Additional supportive care included Lactated Ringers Solution (Lactated Ringers Solution, USP; Hospira, Lake Forest, Illinois, USA) (LRS), intravenous (IV) fluids with 20 mEq/L of KCl at 60 mL/kg per day, maropitant (Cerenia, Zoetis Canada), 1 mg/kg, IV q24h, ampicillin (Fresnius Kabi Canada, Toronto, Ontario), 22 mg/kg, IV, q8h, and pantoprazole (Fresnius Kabi Canada), 1 mg/kg, IV, q12h. Over the course of the evening, the dog remained sedated, and vital parameters including heart rate, respiratory rate, and temperature, were within normal limits.

Approximately 4 h after initiation of the ketamine CRI, it was determined that a medical error had occurred. Although the syringe pump was programed to deliver the ketamine using a 0.3 mg/mL dilution, the ketamine was administered undiluted (100 mg/mL). With the undiluted ketamine concentration programmed to run at 0.2 mg/kg per hour using the intended 0.3 mg/mL programed concentration, the dog had inadvertently received a 67.6 mg/kg per hour rate of ketamine. This equates to a total amount of 270 mg/kg over a 4-hour period. At the time of the discovery of the medical error, the dog’s vital parameters remained within normal limits. The ketamine CRI was discontinued, and the fentanyl continued at a rate of 3 μg/kg per hour, as the dog was still in the early post-operative period. The ASPCA Animal Poison Control Center (APCC) was contacted for information on ketamine overdose management, as literature review revealed limited information. The veterinary toxicologist was unable to offer more insight into what to expect with regard to prognosis but indicated that clinical signs from the sympathomimetic medication could develop and recommended continued supportive care. Supportive care was provided including intravenous fluids (120 mL/kg per day) to promote diuresis and drug elimination, and regular eye lubrication (every 30 min) to limit the development of corneal ulceration secondary to lack of palpebral reflex. Cardiorespiratory parameters were monitored using continuous telemetry, non-invasive blood pressure, and pulse oximetry.

One hour after discontinuing the ketamine CRI, the dog began to develop clinical signs indicative of a ketamine overdose including tachycardia (200 beats/min), loss of palpebral reflex, hyperthermia (41.3°C), and increased upper respiratory noise suspected to be due to increased tracheal secretions. Respiratory rate and non-invasive blood pressure remained within normal limits. Venous blood gas revealed mild hypoglycemia (3.2 mmol/L; reference range: 3.3 to 6.2 mmol/L). Active cooling measures with ice packs placed onto fluid lines and around the dog’s body continued until normothermia was confirmed on rectal temperature. The dog developed an acute dystonic reaction, a characteristic of ketamine toxicity, and thus recumbency care and physiotherapy were initiated. Two hours after discontinuing the ketamine, severe anisocoria was observed with left miosis. In addition, the pupillary light reflex was markedly delayed to absent bilaterally suggesting a possible increase in intracranial pressure. Mannitol (Fresnius Kabi Canada) was administered as a bolus (257 mg/kg, IV, over 20 min) and towels were used to elevate the head to help reduce intracranial pressure. Although the anisocoria persisted, the dog’s overall mentation improved, and the dog was able to lift its head. A second mannitol bolus was administered 3 h later due to recurrent depressed mentation; however, there was no improvement in neurological status following the second bolus and the mannitol was discontinued. Corneal fluorescein staining revealed a left superficial corneal ulceration, attributed to the anisocoria; this was treated with topical Tobramycin (Fresnius Kabi) and ofloxacin (0.3%: Ocuflox; Akorn, Lake Forest, Illinois, USA), q2h, tropicamide (Mydriacyl; Alcon Laboratories, Fort Worth, Texas, USA), q4h, and serum q2h. Intraocular pressures were normal bilaterally. Repeat venous blood gas analysis revealed progressive hypoglycemia (1.5 mmol/L), which resolved following an intravenous dextrose bolus (0.5 mL/kg). Hypoglycemia did not reoccur; therefore, a dextrose CRI was not prescribed. Intravenous fluids were continued at 120 mL/kg per day, with 20 mEq/L KCl added as supplementation. Three-view thoracic radiographs, an abdominal ultrasound, and echocardiography did not reveal any abnormal findings. A renal biochemistry profile, urinalysis, and urine culture were submitted. Other than hyposthenuria likely secondary to the increased fluid rate, the laboratory results were within normal limits and the culture was negative.

The dog continued to improve over the following 18 h. The anisocoria subsequently resolved after 3 d of ocular treatment. At ~18 h after discontinuing the ketamine, the dog was alert with normal vital parameters and had coordinated motor control. Daily serial laboratory tests and examinations including Abdominal Focused Assessment with Sonography in Trauma (AFAST), urine specific gravity, and quick assessment tests (including PCV/TP, BUN, lactate, and glucose) were performed. The residual free fluid noted on AFAST gradually resolved and was deemed likely due to lingering intra-operative lavage, and the renal pelvis of the right kidney remained similarly dilated compared to pre-operative measurements. The quick assessment tests remained within normal limits, and the urine specific gravity remained hyposthenuric, which was most likely secondary to fluid diuresis as the dog previously had isosthenuria. Two days after surgery, a nasogastric tube was placed and enteral nutrition with Emeraid (EmerAid, LLC; Cornell, Illinois,USA) formula was prescribed (70 kcal/feeding, q8h) and the dog tolerated the feedings well. Ondansetron (Zofran; Novartis Pharmaceuticals Canada), 0.2 mg/kg, IV, q8h was prescribed at initiation of nasogastric feedings to reduce nausea. The fentanyl CRI was tapered and intravenous buprenorphine (Par Pharmaceutical, Chestnut Ridge, New York, USA), 0.01 mg/kg, q8h was prescribed. The buprenorphine dose was decreased to 0.005 mg/kg due to a moderate degree of sedation associated with the initial dose. Weekly complete blood (cell) counts (CBC), biochemistry profile, and repeat abdominal ultrasound were performed to monitor the dog after SUB placement. Seven days after surgery the dog continued to be inappetent and an abdominal ultrasound confirmed pancreatitis. As the dog continued to have normal renal values, meloxicam (Metacam; Boehringer Ingelheim Vetmedica, St. Joseph, Missouri, USA), 0.05 mg/kg, SQ was prescribed q24h.

Throughout the remainder of hospitalization, the dog did not exhibit any additional clinical signs attributable to the ketamine overdose. He remained dependent on the nasogastric tube for nutrition and would only eat small amounts of canned food when offered meals despite receiving 1 mg/kg per day oral mirtazepine (Remeron; Merck Canada, Kirkland, Quebec). The intravenous medications were gradually discontinued or transitioned to oral variations as the dog continued to improve. The dog was discharged 12 d after surgery with 7.4 mg/kg gabapentin (Teva Canada, Toronto, Ontario), 14 mg/kg, q12h, amoxicillin-clavulanic acid (Clavamox; Zoetis Canada), 0.07 mg/kg, q12h, omeprazole (Losec; Astrazeneca, Mississauga, Ontario), 1 mg/kg, q12h, mirtazapine q24h, and topical tobramycin, tropicamide, ofloxacin, and eye lubricant. Twenty-four days after surgery, the dog was anesthetized for SUB flush and placement of an esophageal feeding tube for continued nutritional support due to lethargy and inappetence from suspected recurrence of pancreatitis. The esophageal feeding tube was removed by the family veterinarian when the dog began eating regularly and voluntarily. At a 5-month recheck, the dog continued to be free of side effects from the ketamine overdose and was considered to have made a full recovery.

Discussion

In the dog described in this case report, fentanyl administration did not provide adequate analgesia after unilateral SUB placement and therefore ketamine was added for additional analgesia. Following a loading dose of ketamine before initiating the CRI, the dog clinically appeared to have greatly improved analgesia based on vital parameters and examination (i.e., abdominal palpation). However, several hours later it was discovered that the ketamine used in the CRI was undiluted (100 mg/mL) and was administered on a syringe pump at a rate calculated for a 0.3 mg/mL concentration, resulting in a 338 times overdose. Typically, the reported dose range when using ketamine as a CRI is a loading dose of 0.5 to 2 mg/kg, followed by a CRI of 0.1 to 0.6 mg/kg per hour for post-operative analgesia (1).

Ketamine is a phencyclidine derivative that is classified as a dissociative anesthetic due to its ability to dissociate the thalamocortical and limbic systems via antagonistic action on the N-methyl-D-aspartate (NMDA) receptors (1,2). This dissociation results in cataleptic consciousness, during which the recipient appears to remain awake with open eyes but is non-communicative and may have a slow nystagmic gaze (2). Ketamine is a relatively short-acting dissociative anesthetic drug that rapidly establishes plasma concentration when administered intravenously, with a clearance rate of 58.2 ± 17.3 mL/min per kilogram and a terminal half-life of 63.6 ± 23.9 min of the active metabolite norketamine (3). Ketamine is primarily metabolized by the liver via demethylation and hydroxylation and is excreted via the kidneys (1). Although the manufacturer cautions against use of ketamine in animals with underlying liver or renal insufficiency, the duration of action does not appear to be prolonged in these animals (1). The properties of ketamine make it a unique anesthetic and analgesic agent; however, due to varying degrees of hypertonicity exhibited when administered as a sole analgesic, ketamine is often combined with other analgesics, sedatives, or muscle relaxants to limit this side effect (1). Although other anesthetics decrease heart rate and respiratory rate, ketamine has minimal cardiovascular depression and acts as only a mild respiratory depressant (1,2). However, at increased dosages ketamine may cause apneustic breathing (1). Secondary to its sympathomimetic effects, ketamine tends to increase cardiac output, mean arterial blood pressure, and heart rate (1). Ketamine also maintains pharyngeal and laryngeal function, in addition to having a bronchodilatory effect and aiding in maintenance of airway secretions (2).

The use of ketamine as an adjunctive analgesic agent in veterinary medicine has been well-established. When administered at the appropriate dosages, ketamine is a potent anesthetic and analgesic, by modulating nociceptor signaling at the level of the spinal cord with NMDA antagonism (1). Reported overdoses of ketamine appear to be the most common in children and cats, ranging from 10 to 20 times the intended dose (4–6). Although prolonged recoveries have been reported with ketamine overdoses, in children and cats, most human patients in published ketamine overdose reports experienced a full recovery without report of permanent adverse effects attributable to the overdose (5–7). Ketamine overdoses have been published as the cause of death in 3 human patients, but ketamine fatalities are still considered an unusual cause of death in human medicine (8–10). In veterinary medicine, there is a single report of a cat experiencing cardiopulmonary arrest secondary to a 20× overdose of ketamine administered as an intravenous bolus for induction of anesthesia (4). The cat survived following cardiopulmonary resuscitation efforts, including manual and mechanical ventilation, drug reversal, closed chest compressions, emergency drug administration, and intravenous fluids (4). Moreover, yohimbine was used in this case report (0.1 mg/kg, IV, q4h for total of 3 doses) and the authors suggested that the α-2 antagonist may offer partial antagonism of ketamine in cats and shorten recovery time associated with ketamine overdoses (4,11). Yohimbine alone increased alertness, decreased time to arousal, and decreased ketamine-induced anesthesia time in a feline research study (11). To date, there is no further investigative research on the use of yohimbine or other α-2 antagonists in the use as a ketamine reversal agent.

Ketamine is a relatively safe drug with a wide therapeutic index (1). For acute toxicity following intravenous administration, the LD₅₀ of ketamine in rats was 58.9 mg/kg and 55.9 mg/kg in mice (12). Neither a TD₅₀, nor an LD₅₀, for acute toxicity has been established in the dog for intravenous ketamine. The dog herein received an overdose of intravenous ketamine at a rate of 67.6 mg/kg per hour, equating to a total of 270 mg/kg over a 4-hour infusion. This dog was dosed at a rate that was 338× higher than the intended rate listed in the electronic treatment sheet. The dog did not exhibit signs of toxicity until approximately 1 h after discontinuation of ketamine CRI, suggesting some degree of compensation through metabolism and excretion despite the dog having just undergone a unilateral SUB procedure.

Although further studies are needed to establish true ketamine TD₅₀ and LD₅₀ in dogs, this case report suggests that a 270 mg/kg total intravenous dose of ketamine running at a CRI rate of 67.6 mg/kg per hour is non-lethal in dogs. As ketamine has no reversal agent, prompt supportive care as highlighted in this report should be initiated as soon as a ketamine overdose has been discovered. In addition, this case report highlights the importance of communication between veterinarians and veterinary technicians to avoid medical errors. Systematic verification of all drug dosages and volumes by at least 2 different trained personnel before drug administering may aid in preventing future overdoses (4). CVJ