Suspected synthetic cannabinoid toxicosis in a dog

Introduction

An increase in the availability of marijuana and synthetic cannabinoids (SC) has led to an increase in pet exposure and inadvertent cases of toxicosis in veterinary medicine. At the time of this manuscript preparation, 20 states and the District of Columbia have legalized the sale and possession of marijuana for medical use according to the National Conference of State Legislatures.1 Additionally, Colorado and Washington State have legalized the sale and possession of marijuana for recreational use.1 A recent publication reported a concurrent increase in the number of canine delta 9 tetrahydrocannabinol (Δ9-THC) toxicosis cases presenting to Colorado veterinary emergency hospitals with the increased numbers of marijuana distribution licenses issued.2 The ingredient responsible for clinical signs associated with toxicosis in marijuana, and possibly SC, is Δ9-THC although other psychotropic compounds have been implicated.

Cannabinoids have gained in popularity as a complementary medical therapy, in part due to their beneficial effects seen with treatment for some diseases in human medicine.3 They have been implicated in the inhibition of growth in some cancers, used to relieve inflammation from inflammatory bowel disease, alleviate abdominal pain, decrease nausea, and improve quality of life for various human medical ailments.3 Synthetic cannabinoids are designer illicit drugs typically dissolved in a solvent, applied to dried plant material, and smoked as an alternative to marijuana.4 Some common names of SC include “K2,” “Spice,” and “Potpourri.” The mechanism of action is thought to involve activation of cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), located in the central nervous system (CNS) and peripherally. Cannabinoid receptor 1 in the brain is particularly concentrated in anatomical regions associated with cognition, memory, reward, anxiety, pain sensory perception, motor co-ordination, and endocrine function.5 The reported feelings of euphoria, paranoia, aggression, and relaxation are likely associated with the CB1 receptor. Cannabinoid receptor 2 has been noted in the GI tract, inflammatory, and epithelial cells.6 Synthetic cannabinoids have a higher affinity for these receptors than natural cannabinoids.7

There is not a routinely utilized rapid test to detect SC presence in human biological samples. Supportive care with intravenous fluid therapy has been the predominately reported treatment for cases of Δ9-THC and now SC toxicity. Activated charcoal administration is rarely recommended by veterinary toxicologists for marijuana ingestion in small animals.

The purpose of this case report is to describe the clinical signs associated with SC toxicosis, and the use of intravenous lipid emulsion (ILE) therapy as a treatment option in a dog. To date, no known reports of treatment with ILE therapy for SC toxicosis have been reported in small animals. This case report highlights the potential therapeutic effects of ILE in severe toxicosis of SC.

Case Description

A 2-year-8-month-old male Boxer dog presented to an emergency veterinary hospital after a rapid decline in mentation, decreased respiratory rate, and progressive ataxia with generalized twitching were noted by the owner at home over a duration of 4 hours. The dog was found in its kennel with vomitus nearby. The vomitus contained paper tissue of unknown origin. No known toxin exposure was reported at the time of presentation. The dog was previously healthy and not on any medications.

On physical examination, the dog was laterally recumbent, aggressive when stimulated, hypothermic (32.7°C [90.9°F]), had intermittent episodes of alternating sinus bradycardia and tachycardia (60–160/min), and bright pink mucous membranes with a capillary refill time <2 seconds. Neurological examination found stuporous mentation, hyperesthesia, intermittent full body muscle fasciculations, and intermittent opisthotonos. Baseline CBC, electrolytes, venous blood gas, and biochemistry panel were evaluated. The CBC revealed an automated platelet count of 110.0 × 10⁹/L or 110.0 × 10³/μL (reference interval 200–500 × 10⁹/L or 200–500 × 10³/μL). All other values for the CBC, electrolytes, and blood biochemistry were within the reference interval. The blood gas at admission (time = 0) revealed a respiratory acidosis (Table 1) and a mild hyperlactatemia at 2.7 mmol/L [reference interval <2.5 mmol/L].

Initial supportive care consisted of intravenous fluid therapy with a Plasmalyte1 bolus (8.4 mL/kg), then 2.5 mL/kg/h. Activated charcoal was not administered at this time due to a perceived risk of aspiration. An external forced warm air device was utilized for heat support. The patient's neurological status deteriorated within 2 hours of presentation to comatose, with an absent gag reflex and periods of apnea. Persistent sinus bradycardia (40/min) and hypothermia (34.4°C [94.0°F]) were noted. A venous blood gas and electrolyte panel were repeated an hour following initial treatment, revealing persistent respiratory acidosis and mild hypokalemia (Table 1). Mannitol2 (1 g/kg) was administered intravenously to treat a presumptive increase in intracranial pressure. The airway was protected with a nonsterile endotracheal intubation followed by flow by oxygen supplementation with an estimated FiO₂ of 40%. Mechanical ventilation was recommended as a supportive treatment for respiratory acidosis and intermittent apnea, but was initially declined by the owner.

Potpourri,3 an SC containing Damiana leaf, Marshmallow leaf, and Athaea leaf was reported as a possible toxin exposure after repeated conversation with the owner and recommendations for advanced diagnostics to investigate the cause of CNS signs. The American Society for the Prevention of Cruelty to Animals (ASPCA) National Animal Poison Control Center (NAPCC) was then consulted. Activated charcoal with sorbitol4 (2 g/kg) via orogastric intubation, and a warm water enema were administered using 240 mL of warm water via 14 fr red rubber feeding tube to facilitate gastrointestinal decontamination. A moderate amount of normal formed feces was evacuated. Intravenous lipid emulsion therapy was initiated with 20% Intralipid5 (1.5 mL/kg, followed by 0.5 mL/kg/h). Plasmalyte^a with potassium chloride6 supplementation (20 mmol/L [20 mEq/L]) and metoclopramide7 (1 mg/kg/24 h) were initiated. Metoclopramide^g was initiated in an effort to increase gastric emptying. An immediate change in mentation was not appreciated following the ILE bolus infusion. After an hour of continuous ILE infusion, however, the patient began to respond to noxious stimuli. After 5 hours of treatment, the owners gave consent to initiate mechanical ventilation due to persistent hypoventilation, episodic apnea, and continued respiratory acidosis (Table 1).

A sterile endotracheal tube was placed transorally and the patient was transitioned to mechanical ventilation. Propofol,8 at 1.1 mg/kg, was administered to effect as needed, and used as an intravenous anesthetic agent to facilitate mechanical ventilation. The ventilation strategies were as follows: initial FiO₂ was set at 100%, rapidly decreasing to 40%, using pressure controlled, assist-control with 5 cm H₂O positive end expiratory pressure. Machine-delivered breaths were adjusted to achieve minute volume sufficient to resolve the hypercapnea. Standard nursing care ensued for care of a recumbent patient on the ventilator. Urine output was monitored via a urinary catheter attached to a sterile, closed collection set. Electrocardiogam, pulse oximetry, capnography, indirect arterial blood pressure, and body temperature were continuously monitored.

Four hours after initiation of the ILE infusion, the patient's serum inspected grossly lipemic. The ILE infusion was temporarily discontinued. The total dose of ILE infusion was 2 mL/kg at this time. Ten hours after presentation, the patient became steadily more rousable and required increasing amounts of propofol,^h to effect as needed, allowing maintenance of endotracheal intubation. The serum inspected grossly clear 4 hours after temporary ILE discontinuation, and the ILE was initiated again at 0.5 mL/kg/h for 2 additional hours. Arterial blood gas measurement confirmed improvement of the respiratory acidosis 8 hours after initiation of mechanical ventilation (hour 15). Approximately 15 hours after presentation, the dog became acutely rousable and was rapidly weaned from mechanical ventilation and extubated. Venous blood gas revealed resolution of the respiratory acidosis (Table 1). The dog's mentation was delirious and he demonstrated aggressive behavior immediately following the weaning process. The ILE infusion was permanently discontinued at this time. The delirium steadily improved over the next 8 hours, and the dog appeared to be of normal mentation by hour 30 following presentation. A cytology of the sputum from his endotracheal tube revealed septic suppurative inflammation. An aerobic bacterial culture and sensitivity was submitted. A CBC, biochemical profile, and venous blood gas were repeated, with mild hypokalemia and a very mild respiratory acidosis (Table 1) as the only abnormalities just prior to discharge.

The dog was discharged to home 33 hours following presentation on a 7-day course of amoxicillin trihydrate/clavulanate potassium9 (6.3 mg/kg) for potential hospital acquired pneumonia pending culture of the endotracheal tube. The culture from the endotracheal tube revealed growth of the following: nonhemolytic Staphlococcus species, Beta hemolytic Streptococcus species, Ewingella Americana, and normal naso-oropharyngeal flora. All species identified were sensitive to the prescribed antimicrobial (amoxicillin trihydrate/clavulanate potassium).ⁱ The dog never developed clinical signs of pneumonia.

Follow-up with the owner 5 days postdischarge revealed that the dog was apparently healthy at home, with no further signs of SC toxicity. The remaining potpourri product was submitted to an independent lab10 for SC testing. The SC Panel confirmed the submitted sample contained Δ9-THC, and AM-2201, and JWH-122, two SC in the naphthoylindole chemical family.

Discussion

The dog in this case report developed severe acute clinical signs associated with likely ingestion of SC. Mechanical ventilation was required as the dog became comatose and hypercapneic. Intravenous lipid emulsion was administered in an attempt to hasten resolution of clinical signs. Noticeable response to stimuli was observed after the ILE infusion was initiated.

An LD50 for Δ9-THC or SC has not been established in dogs or cats.8 Research in dogs and monkeys revealed that oral doses of Δ9-THC and Δ8-THC ranging from 3,000 to 9,000 mg/kg were not lethal, and all dogs recovered within 24 hours of ingestion.9 The potpourri that was relinquished by the owner for analysis tested positive for ∆9-THC, AM-2201, and JWH 122. Delta-9 tetrahydrocannabinol, AM-2201, and JWH 122 are agonists for CB1 and CB2 receptors and are responsible for clinical signs of toxicosis in veterinary patients. According to the ASPCA NAPCC, the expected half-life of the SC in dogs was 72–96 hours. The serum concentration of these compounds was not determined in this patient. A presumptive diagnosis of SC toxicosis was made based upon known exposure and clinical signs.

A review of unpublished data from the ASPCA NAPCC database collected between January 2008 to December 2012 resulted in 865 reported canine exposures to cannabinoids. The most common clinical signs reported included: ataxia (61%; n = 526), lethargy/depression (50%; n = 436), vomiting (22%; n = 188), hyperesthesia (17%; n = 144), bradycardia (14%; n = 121), disorientation (14%; n = 118), urinary incontinence (13%; n = 112), and hypothermia (11%; n = 96). Of the 62 canine exposures to suspected SC, the most common clinical signs reported were similar and included: ataxia (66%; n = 41), lethargy/depression (39%; n = 24), bradycardia (26%; n = 16), hypothermia (26%; n = 16), vomiting (24%; n = 15), urinary incontinence (21%; n = 13), hyperesthesia (16%; n = 10), and mydriasis (15%; n = 9).11 Other signs in dogs exposed to SC that have been recorded in the NAPCC database include agitation, vocalization, diarrhea, hypersalivation, tachycardia, seizures, and coma.^k Ocular side effects in people included photophobia, nystagmus, blepharospasm, and diplopia (ie, double vision).10 In people, indirect acute kidney injury has been reported in SC exposure cases.4 There have also been reports of toxicosis in chronic SC users. A diagnosis of cannabinoid hyperemesis syndrome is considered in human patients who present with chronic severe nausea and vomiting that can sometimes be accompanied by abdominal pain and compulsive hot bathing behavior, in the absence of other obvious causes.11 In veterinary medicine, only acute toxicosis has been described.

Treatment for SC toxicosis is similar in human and veterinary medicine. Management of suspected SC toxicity is symptomatic and supportive; no antidote exists.12 Supportive care and discontinuation of the drug are the mainstays of therapy. Activated charcoal can also be administered to aid in decontamination of the GI tract.13 According to the ASPCA NAPCC activated charcoal is rarely recommended, but was in this case because of the severity of the dogs’ clinical signs. Seizures and aggression may be manageable with benzodiazepines or other sedative agents. In this case, mechanical ventilation was recommended due to persistent hypoventilation and periods of apnea, although it is not typically required in treatment of SC toxicosis.

Injectable lipid emulsions consist of a mixture of soy oil, glycerol, and egg phospholipids, and are commonly the major components of parenteral nutrition, providing calories and essential fatty acids.14 Several theories are postulated for the mechanism of lipid emulsion therapy for select toxicosis. It has been proposed that an expanded intravascular lipid phase acts to sequester lipophilic toxin within it, thus reducing the effect site concentration and toxicity until the compound is metabolized and excreted.15 Another theory considers the effect on the myocardium. Potential direct effects include enhanced utilization of free fatty acids as an energy source by the myocardium, an increase in intracellular calcium, α-adrenergic receptor mediated increased vasopressor effect, and the reduction of nitrous oxide and insulin induced vasodilation by ILE.16 Lipid emulsion is also the vehicle for the general anesthetic propofol.14 A drug is deemed lipophilic if its log P value is >1.0.16 The log P is the partition coefficient of a drug in a solvent and theorizes how quickly a drug will dissolve into the tissues. Delta-9 tetrahydrocannabinol, and presumably SC, have a high octanol/water partition coefficient (log P > 4.5) and rapidly distribute into lipophilic substrates.17

Intravenous lipid emulsion therapy was administered with speculation that it may minimize CB1 and CB2 receptor activation by binding free SC in the lipid phase, preventing CNS binding, and thus improving the patient's clinical signs. The concurrent administration of propofol anesthesia made the assessment of clinical response to the ILE therapy a challenge. It could be argued that the propofol contributed an additive affect to the ILE therapy, thus enhancing the lipid sink. The patient did, however, show signs of improving mentation shortly after a continuous infusion of ILE was initiated and prior to propofol administration. Intravenous lipid emulsion therapy was not constant throughout the dog's hospitalization, as serum lipemia did occur. Lipemia is an established risk of ILE therapy, and temporary discontinuation until the serum clears is the recommended response to this complication.18 Delayed or subacute reactions to ILE may occur, and are commonly referred to as “fat overload syndrome” (FOS).16 In people, FOS can result in fat embolism, hyperlipidemia, hepatomegaly, icterus, splenomegaly, thrombocytopenia, increased clotting times, and hemolysis.16 This dog did not develop any other known complications while receiving ILE therapy. Overall, in people the frequency of complications with the use of lipid infusion has been low, especially with short-term use.14 According to the Food Drug Administration the complication rate for ILE has been less than 1%.19

The administration of ILE in veterinary medicine can be considered for certain lipophilic toxicities associated with a high morbidity, particularly where traditional therapies (including ventilator management) have failed or are cost prohibitive.16 The persistent hypoventilation and progressive decline in mentation in the face of supplemental oxygen and IV fluid therapy stimulated the recommendation to pursue mechanical ventilation in addition to the ILE therapy.

To the authors’ knowledge, there are no known reports of patients requiring mechanical ventilation due to SC intoxication. There are also no known case reports of dogs receiving ILE therapy as a treatment for SC ingestion. One retrospective study that described a relative rate of increase of marijuana ingestion in dogs living in Colorado after legalization mentioned that 3 dogs of 125 client owned dogs were treated with ILE therapy for Δ9-THC toxicosis, one of which died.2

In human medicine, the use of ILE is generally reserved for severe toxicosis and life-threatening conditions (eg, cardiopulmonary arrest, nonresponsive hypotension, and local anesthetic overdose) and when conventional therapies have failed to improve physiological parameters.16 If using a 20% ILE, a total volume of 10 mL/kg/day should not be exceeded, as has been extrapolated based on doses recommended in human medicine.16 There are no reports of the use of ILE to treat Δ9-THC or SC toxicosis in people. Treatment is symptomatic and supportive, with discontinuation of the drug until clinical signs resolve.

Intravenous lipid emulsion therapy may have a role in the management of severe refractory SC and marijuana toxicosis. Further investigation is necessary to determine effectiveness of ILE therapy in SC and marijuana toxicity. Use of propofol anesthesia should be avoided if possible in future cases of ILE therapy, as it may interfere with the ability to assess clinical response. Potentially the lipid component of propofol in this case was additive to the ILE, and enhanced toxin clearance. It is also possible that the ILE therapy made no difference in this patient's time to clinical recovery. One drawback to this case study is that the patient was sent home on a subtherapeutic dose of amoxicillin trihydrate/clavulanate potassiumⁱ for potential hospital-acquired pneumonia. This was a medication dosing error that was not detected at the time of patient discharge. The antimicrobial should have been adjusted to an appropriate dose or discontinued. Another limitation to this report was that serum concentration of the SC was not determined in this patient. Quantifying the concentration of systemic SC before, during, and after ILE therapy could have been able to demonstrate the effects of ILE on SC toxicity in this patient. A mild respiratory acidosis returned after mechanical ventilation was discontinued. It is possible that the ILE and propofol provided an energy substrate, resulting in higher metabolic production of CO₂, as reported in people receiving parenteral nutrition with varying percentage of lipid and carbohydrate energy sources.20 Since the dog continued to breathe normally with no observed periods of apnea or abnormal mentation, repeat blood gas measurement was not performed. It is reasonable to assume this patient may have recovered with mechanical ventilation alone, and that ILE therapy did not hasten recovery. The serum half-life of SC in dogs was estimated to be 72–96 h by the consulting NAPCC representative. Since fewer than 3 half-lives of SC elapsed between presentation and discharge with normal mentation, the authors suggest that ILE therapy may have expedited the resolution of clinical signs by as much as 180 hours. Considering the relative safety of ILE therapy, and potential complications of long-term mechanical ventilation such as ventilator-associated pneumonia, ventilator-induced lung injury, and multiple organ dysfunction syndrome, it is the authors’ opinion that ILE therapy was justified and may have been beneficial in this case.