Intravenous lipid emulsion to treat suspected cocaine toxicosis in a dog

Abstract

A 6-month-old puppy was treated for suspected cocaine toxicosis. Supportive care was initiated but clinical signs worsened and treatment with intravenous lipid emulsion (ILE) was instituted. Clinical signs rapidly resolved in response to treatment with ILE.

Intravenous lipid emulsion (ILE) has been used to treat a variety of toxicoses in both humans and animals. These toxicants include local anesthetics and other lipophilic drugs, such as lidocaine, bupivacaine, ivermectin, baclofen, synthetic cannabinoid, bromethalin, moxidectin, ibuprofen, naproxen, permethrin, diltiazem, and 25 hydroxyvitamin D (1–12).

Cocaine is both a local anesthetic and a lipophilic drug, with a log P of 2.28 (13). Given these properties it is reasonable to think that ILE would be beneficial in cases of cocaine toxicosis. Log P is the octanol water partition coefficient of a drug in the neutral form. This has been shown, in humans and in animal models, to be a good predictor of the efficacy of ILE to treat a drug overdose. Generally, drugs with Log P > 1 are thought to be lipophilic. Other factors that are thought to contribute to the partitioning effect and lipophilicity of a drug include the pH of the drug and electrostatic interactions with the negatively charged phospholipid layer of the ILE. Intravenous lipid emulsion has been shown to be helpful in toxicities caused by drugs with a low log P (such as baclofen and N-methylamphetamine) so these alternative factors determining the lipophilicity of a drug as well as some of the other mechanisms of action of ILE are also important in determining whether ILE would be beneficial (2,14).

To the authors’ knowledge, there are no previous reports on the use of ILE in domestic animals in a case of cocaine toxicosis.

Case description

A 6-month-old male intact German shepherd cross dog weighing 18.2 kg was presented to the emergency service for suspected illicit drug toxicosis. The patient was described to be previously healthy. He had been out on a walk approximately 30 min before presentation. He was not observed to have ingested anything on the walk, but he is a scavenger and there was a history of needles and syringes with suspected illicit drugs in the area in which he was walked. On arriving home from the walk he became restless and was pacing and panting excessively. He was presented to the emergency service.

On presentation he was pyrexic (40.1°C), mildly tachycardic (heart rate 160 beats/min) and hypertensive [blood pressure 181/153 (166) mmHg] (Cardell Veterinary Monitor; Midmark, Tampa, Florida, USA). He was bright and alert but was noted to be agitated and restless. Mild ptyalism was present. Neurological examination revealed bilateral mydriasis with decreased pupillary light reflexes; there was no ataxia and no other neurological deficits. No tremors were observed. Urine was collected via a urinary catheter for a urine drug screen (Rapid Response, 1 panel, Drugs of Abuse; BTNX, Markham, Ontario). The urine drug screen was positive for cocaine and phencyclidine (PCP). A complete blood (cell) count (CBC), chemistry panel, electrolytes, and blood gas were found to be within normal limits (True North Veterinary Diagnostics, Langley, British Columbia; ABL 800 Flex; Radiometer, London, Ontario). An 18-gauge IV catheter was placed (18GA 1.16IN; Becton Dickinson Infusion Therapy Systems, Sandy, Utah, USA) and the dog was started on balanced isotonic crystalloid solution (Isolyte S; B. Braun of Canada, Scarborough, Ontario) at 62 mL/h [after a 10 mL/kg body weight (BW) fluid bolus]. Emesis was not induced due to the severity of his agitation. Maropitant citrate (Cerenia; Zoetis, Kirkland, Quebec), 1 mg/kg BW, IV, was given to prevent vomiting associated with activated charcoal administration. The dog was offered 2 g/kg BW activated charcoal, mixed with a few tablespoons of food (Charac-50; Omega Laboratories, Montreal, Quebec) which he readily ingested. This was repeated every 6 h for 2 additional doses. The pyrexia resolved after 3 h of fluids. His heart rate improved to 132 beats/min at this time, but he remained hypertensive with a blood pressure of 186/118 (132) mmHg. At this time he seemed less agitated and had settled in a dark and quiet environment.

Six hours after presentation he became agitated again. This coincided with shift change and the ICU becoming much busier and louder. He developed ataxia and fine head tremors and some facial twitching was noted. Bilateral mydriasis remained. The dog developed a marked sinus tachycardia, especially when stimulated (up to 190 beats/min). His rectal temperature increased to 39°C. A urine drug screen was repeated and remained positive for cocaine, but was now negative for PCP. His intravenous fluid rate was increased to 120 mL/h. He was given 1 dose of methocarbamol (Methocarbamol 100 mg/mL; Summit Veterinary Pharmacy, Aurora, Ontario), 50 mg/kg BW, IV, with no improvement in his clinical signs. Given the progressive clinical signs, treatment with ILE (Intralipid 20%; Fresenius Kabi Canada, Toronto, Ontario) was started. He was administered a bolus of ILE, 2 mL/kg BW over 1 min, followed by a constant rate infusion of 0.25 mL/kg BW per min for 30 min. Within 15 min of starting the ILE the dog was noted to have normal mentation and resolution of the agitation. No lipemia was noted in the serum after treatment with ILE. A few hours after starting the ILE he was noted to be normal with no further ataxia or tremors. He was discharged a few hours later with no ongoing concerns.

Discussion

Cocaine is an illicit drug that has previously been reported to cause toxicosis in domestic pets (15–17). It is a Schedule 1 drug under the Canadian Controlled Drugs and Substances Act (18). Results from the Canadian Tobacco and Alcohol Drugs Survey reveal that cocaine is the third most commonly abused substance after alcohol and marijuana (18). The reported incidence of cocaine use in the survey was 2% of the population in 2017 (this is increased from 1% of the population in the 2015 survey) (19). Cocaine is available as a white powder that is insufflated or injected, or as a freebase form, known as “crack” cocaine, which can be smoked or injected (18). At lower doses cocaine inhibits catecholamine reuptake at sympathetic nerve terminals causing stimulation of the sympathetic nervous system. At higher doses cocaine acts like a local anesthetic (class I anti-arrhythmic agent) by blocking myocardial sodium and potassium (adenosine triphosphate) channels causing cardiovascular depression and vasodilation (13,20,21). It also causes cardiovascular mitochondrial dysfunction and long-term cardiovascular damage (22).

The half-life of cocaine in a dog model after oral administration of 4 mg/kg BW of cocaine was 85.2 min with peak plasma levels seen at 83.6 min post-ingestion. Cocaine has been shown to have poor systemic bioavailability when given orally. In this study comparing oral and intravenous administration of cocaine the area under the plasma time concentration curve was 4 times higher for intravenous compared to oral administration (23).

Treatment for cocaine toxicosis is supportive, there is no reversal agent. Treatments used in the management of cocaine toxicosis are varied and include benzodiazepines, calcium channel blockers, nitric oxide-mediated vasodilators, α and β-blockers, α2-agonists, antipsychotics, ILE, and sedatives, such as propofol (15,24).

Despite the common usage reported in humans there are only infrequent reports of cocaine toxicosis in domestic pets in the literature (15–17). There are some published studies of experimental canine models of cocaine toxicosis (25,26).

The largest case series evaluating suspected cocaine toxicosis in domestic animals included 19 dogs. The prevalence of suspected cocaine toxicosis in that study was 0.03% of total cases presenting to the ER. In these cases, similar clinical signs were reported and included hyperexcitability, muscle tremors, seizures, ataxia, altered mentation, excessive vocalisation, mydriasis, hypersalivation, vomiting, tachycardia, hyperthermia, and hypertension. Sixteen of the 19 dogs were hospitalized for treatment, which included fluid therapy, activated charcoal, benzodiazepines, phenobarbital (1 patient received a loading dose), acepromazine, mannitol, esmolol, and propofol (2 patients received constant rate infusions). All patients survived to discharge, although 1 was discharged against medical advice. The median length of hospitalization was 15 h (range: 10 to 30 h). Two patients still had clinical signs at the time of discharge (15).

Intravenous lipid emulsion has been described with increasing frequency for use in multiple toxicoses in human and veterinary medicine. The mechanisms of action of ILE have been previously described in detail elsewhere and are thought to be multifactorial. These include the creation of a “lipid sink” which sequesters lipophilic drugs into this lipid compartment, improves cardiovascular function via the provision of an energy substrate for the myocardium, and increases intracellular calcium levels (2,3,9,12–14). Intravenous lipid emulsion has previously been documented for use with local anesthetic toxicoses causing cardiovascular instability (9,10,12) as well as other lipophilic drugs previously listed. Myocardial mitochondria are known to be impaired with cocaine toxicosis so this increase in energy substrate for the mitochondria may be an important component of how ILE works in cocaine toxicosis (22).

Adverse effects related to ILE are uncommon. Reported adverse effects include hyperlipidemia, pancreatitis, corneal lipidosis, hemolysis, fluid overload, hypersensitivity, and phlebitis. In humans, other adverse effects include Acute Respiratory Distress Syndrome (ARDS), acute kidney injury, embolism, fat overload syndrome (hyperlipidemia, hemolysis, jaundice, seizures, prolonged clotting time, thrombocytopenia), and sepsis secondary to contamination of the bag or delivery system. It is also possible that ILE may interfere with the activity of lipid soluble medications that the patient is receiving (2,3).

There are several rat models in which the effect of ILE on cocaine toxicosis was investigated (13,27,28). One study of ILE treatment for cocaine toxicosis showed decreased cocaine-induced cardiovascular collapse and decreased hypotensive effects with pre-treatment with ILE. The mortality rates were also significantly lower in the ILE group compared to a control group (13). In another rat model of treatment with ILE after cardiac arrest induced by intravenous cocaine there was no improvement in outcome after treatment with ILE (27). A third study, also looking at pre-treatment with ILE prior to intravenous cocaine overdose, found that ILE attenuated the severe hypotension noted after injection of cocaine, and reduced cocaine-induced cardiac toxicosis in isolated rat hearts (28).

There are a few case reports in humans describing the use of ILE for treatment of cardiovascular instability secondary to cocaine toxicosis. One patient was presented in a comatose state with seizures and marked cardiovascular instability. The patient was treated with ILE and showed rapid improvement in cardiovascular parameters (29). Another report also describes the use of ILE in the case of a patient who was comatose with status epilepticus after smoking a large amount of crack cocaine. The wide complex tachycardia and hypotension present were unresponsive to magnesium sulphate and sodium bicarbonate. Treatment with ILE was instituted and within 10 min resolution of the tachycardia and hypotension was seen (30). Both of these patients survived to discharge. However, there is 1 case report of unsuccessful treatment with ILE in another severe cocaine overdose with wide complex tachycardia (31).

The urine multidrug screen used in this patient evaluates for the presence of benzoylecgonine, an inactive metabolite of cocaine. This drug test has good sensitivity and specificity in humans but has not been validated for use in animals (15). False positive results are rarely reported with cocaine toxicosis, but could include coco leaf tea, salicylates, and fluconazole (15,32). The clinical signs in this case were consistent with cocaine toxicosis. Phencyclidine (PCP) is reported to have a higher incidence of false positive results on urine drug screens. Substances reported to cause false positive results more commonly include dextromethorphan, tramadol, venlafaxine, and 3,4-methylenedioxypyrovalerone (MDPV, otherwise known as “bath salts”) (33,34). Phencyclidine can be positive in urine drug screens for 2 wk after exposure, so the second negative screen for PCP most likely indicates that the initial result was a false positive (35). Clinical signs seen with PCP toxicosis include muscle rigidity, erratic walking, ptyalism, nystagmus, and at higher doses loss of consciousness, miosis, and hypertension (21). Following the second urine drug screen, clinical signs at this time were most consistent with cocaine toxicosis, although other toxicants causing similar clinical signs could not be ruled out. Blood or urine tests (using gas chromatography-mass spectrometry) to confirm the cocaine ingestion were not submitted in this case due to cost constraints.

Although there are some published data to support the use of ILE in cocaine toxicosis, these include only a few case reports and rat models; therefore, the use of ILE as treatment for cocaine toxicosis is not currently recommended in humans. Further data are required to assess the efficacy of this treatment and to determine whether it may interfere with other standard treatments (24).

Intravenous lipid emulsion has been an effective treatment in humans and animals for local anesthetic systemic toxicosis (LAST) and has also been used as part of the treatment for many different lipophilic toxicants. Some previous studies and reports suggest that ILE may be helpful with cocaine toxicosis. The patient described herein was suspected to have clinical signs related to cocaine toxicosis, although other toxins cannot be ruled out. The dog responded quickly to treatment with ILE with no adverse effects noted and complete resolution of all clinical signs with no further drug therapy required.

In conclusion, cocaine toxicosis has been previously shown to have an excellent prognosis. However, strong sedatives, beta-blockers, and anti-epileptic therapy, sometimes at very high doses, may be required to manage the clinical signs. Intravenous lipid emulsion may be a useful alternative or adjunctive treatment for patients with severe clinical signs associated with suspected cocaine toxicosis, and in patients which either do not respond to traditional therapy, or, in which these traditional therapies may be contraindicated due to pre-existing disease. Intravenous lipid emulsion may also help to decrease the incidence of myocardial damage in severe cases of cocaine toxicosis. CVJ