2016 WINTER: Toxicities | E-cigarettes | Marijuana | Potential Toxicity: MDR1 Mutation? | ECG Monitoring | Adderall® Toxicity
Medical Director’s Notes
We hope everyone had a wonderful holiday season. Our emergency team is only too aware that in addition to cheer, the holiday season usually brings with it an increase in the number of pet toxicity cases. From fatty foods, like chocolate and ham, to ribbon and tinsel, pets are great at getting into trouble around the holidays. Spring brings its own slew of toxins, like blooming plants, mushrooms, fertilizers and pesticides. Here is Trupanion’s top ten list of poison and toxicity claims from 2015:
- Rat poison
- Common household drugs
- Grapes and raisins
- Onions and garlic
Emergency Team: Dr. Caleb Murphy, Dr. Ariane Goerlich, Dr. Amy Goldstein, Dr. Jamie Resnick, Dr. Heather Chalfant, Dr. Kristina DePaula
It’s a toxic world if you think about it, and it is our job as veterinarians to look at it that way in order to protect our patients. Even the most mundane items can be toxic if patients are exposed to large enough quantities.
Toxicity is a relative thing. The amount, rate of exposure and the ability of the patient to metabolize and excrete the chemical all need to be taken into consideration. The medications we prescribe to our patients have the potential to be toxic if the pet can’t metabolize the chemical adequately. See what happens when you give a normal dose of ivermectin to an Australian shepherd with an MDR1 gene mutation, or an NSAID to a dehydrated dog.
We are fortunate to have a large database of well documented cases and studies concerning environmental and household chemical toxicities. The challenge for us is educating pet owners on the dangers of these substances in order to prevent toxin exposure. We must also be able to rapidly recognize and treat an ill patient demonstrating toxicity.
We hope you enjoy the toxicity articles provided by our emergency team and, as always, we stand by our commitment to you:
- We will treat you as a partner.
- We will treat your patients as we would treat our own pet.
- We will treat your clients as we would treat a family friend.
We thank you for relying on us and wish you a happy and healthy new year!
Kristina DePaula, DVM, DACVECC
The Dangers of E-cigarettes
With the increased popularity of the e-cigarette, as an alternative to the more popular and conventional cigarette, has also come an increase in the number of hospital admissions to many veterinary emergency clinics. E-cigarette ingestion/exposure poses a serious risk to pets, but unfortunately outside of the veterinary world, this information may be relatively new or unheard of to many pet owners. The primary concern with the ingestion of e-cigarettes has to do with the ingestion of its ingredient, nicotine. While the e-cigarette may seem relatively harmless, each cartridge packs a powerful punch, containing anywhere from 6 to 24 mg of nicotine; in contrast the average cigarette only contains approximately 9 mg of nicotine.
Although the e-cigarette resembles the traditional cigarette, e-cigarettes work by atomizing liquid (containing nicotine) into a vapor that can be inhaled. Many people who use these products also enjoy the different flavors and varieties that these products come in, ranging from peppermint to cherry. The aroma or scent of these e-cigarette cartridges is what makes them a popular target among pets. Pets are drawn to these different scents and in many reported cases ingest the flavored nicotine liquid.
In addition to the increased nicotine content of these products, vials of liquid nicotine, called “e-juice,” are often available to refill cartridges. Moreover, pre-filled cartridges are often sold in packs containing up to 20 or more individual cartridges. This added danger makes intoxication almost guaranteed, whereby pets are likely to show severe clinical signs up to and even including death. According to Pet Poison Helpline, a 50-lb dog ingesting a single cartridge will often show clinical signs; whereas consumption of the same quantity by a 10-lb dog will often result in death. On the other hand, signs may vary with partial consumption. In addition, consumption of e-cigarettes, and or any of their parts may result in severe gastroenteritis or gastrointestinal obstruction.
The onset of clinical signs is rapid, with pets showing signs such as vomiting, diarrhea, tachycardia, tachypnea, neurologic signs like tremors, ataxia, weakness, and seizures, in as little as 15 minutes. Cardiac arrest and even death is observed as well. Delayed signs have been documented especially with cutaneous exposures. Below is a listing of clinical signs by the system affected:
- Gastrointestinal: vomiting, hypersalivation, diarrhea, abdominal pain/discomfort
- Cardiovascular: hypertension, cardiac arrhythmias
- Neurologic: ataxia, weakness, mydriasis, seizures
- Pulmonary: initial tachypnea followed by respiratory depression
The diagnosis is often made possible by a history inclusive of exposure to nicotine and is often suggested by the combination of clinical signs with their acute onset. Differential diagnoses should include other potential toxicants with similar clinical signs. Metaldehyde, bromethalin and methylxanthine products; insecticides (carbamates, organophosphates), strychnine, mycotoxins, and toxic mushrooms are among the most common. Bloodwork is often non-specific, with some pets showing hyperkalemia. More advanced laboratory analysis of blood and vomitus, such as HPLC, or mass spectrometry is possible, although often not feasible given the time it takes to send off these samples to a reference laboratory.
Although there is no specific antagonist treatment for nicotine intoxication, treatment is aimed at controlling signs of respiratory distress, cardiac arrhythmias, cardiovascular collapse, shock and general supportive care with intravenous fluids, gastroprotectants, anti-emetics and oxygen therapy. Cutaneous or ocular exposure should include decontamination of the affected surface with copious amounts of a lavage solution (ocular), or bathing with soap and water (cutaneous).
If a known ingestion occurs, immediate veterinary care is recommended. At-home care is not recommended due to the rapid onset of clinical signs and severity of symptoms. It is recommended that owners take their pets to the closest emergency clinic and or contact either, Pet Poison Helpline (800.213.6680) or the ASPCA Animal Poison Control Center (888.426.4435) for further advice.
A Growing Toxicity
Marijuana is one of the most commonly used illicit drugs in the United States. With its legalization for human medical use in numerous states, including Massachusetts, and its recent decriminalization in Colorado and Washington, the frequency with which pets are being exposed to marijuana or one of its derivatives is increasing. Here at BluePearl in Waltham we have seen several marijuana intoxications in the past year (dogs and one ferret).
The toxic chemical in marijuana is delta 9-tetrahydrocannabinol or THC. Dried leaves and flowers of the hemp plant Cannabis sativa contain 1-8% THC. Hashish, compressed resin produced from the flowering tops of the plants, contains 10% THC. Hash oil or butter, a concentrated form of hashish or marijuana in which the cannabinoids are extracted into the fat of oil or butter, can have a THC concentration exceeding 50%.
The most common means by which dogs and, uncommonly, cats are exposed to marijuana is by ingestion of home cooked or commercial products containing THC. THC is stored in the tissues of the brain, liver and kidneys. Being highly lipid soluble the chemical is also stored in fat deposits where it can remain for days. The majority of the THC is excreted via the biliary system and eliminated via the feces.
Signs of marijuana intoxication typically occur within 60 minutes of exposure and can last several days. The THC binds to cannabinoid receptors in the brain where it interacts with the neurotransmitters norepinephrine, dopamine, serotonin and gamma-aminobutyric acid inducing various stimulatory and inhibitory signs involving the gastrointestinal, cardiovascular and neurologic systems.
Signs of marijuana intoxication
- Depression or dysphoria
- Hyperstartle response
- Urine dribbling (very common)
Is it marijuana?
The challenge in diagnosing marijuana toxicity is getting the pet owner to confirm the pet’s potential exposure. Routine blood testing is typically non-remarkable. Over-the-counter drug tests as well as laboratory tests for THC have not yet been proven effective in pets (they were designed for humans). False negative results are prevalent, but a positive result is reliable. Luckily the most common signs of THC toxicity, i.e. dysphoria, drowsiness, a hyperstartle response and especially urine dribbling, are pretty recognizable.
What’s the best treatment?
Treatment after immediate exposure to marijuana could include induction of emesis and the administration of activated charcoal. Both would be contraindicated if the clinician feels the patient’s mental state predisposes the pet to the possibility of aspiration pneumonia. Interestingly, induction of emesis may not be effective as one of the marijuana’s medical uses is to inhibit nausea and vomiting in human cancer patients. The repeat administration of activated charcoal (without sorbitol and at ½ the original dose), 6-8 hours after an initial administration should be considered to reduce GI absorption of the THC as it goes through enterohepatic recirculation.
Symptomatic/supportive care should be individualized to the patient and typically includes IV fluids to ensure hydration and perfusion, supplemental heating or cooling as indicated, and anti-anxiety therapy (i.e. diazepam). More severely affected patients may require cardiovascular medications, oxygen supplementation or even ventilation. Intravenous lipid emulsion (ILE) should be considered in more severely affected patients and those with prolonged duration of signs. THC is lipid soluble, thus ILE can act as a reservoir and bind the THC. Here at BluePearl in Waltham we have used ILE on some of our marijuana intoxications, including the aforementioned ferret. Close monitoring patients intoxicated with THC is important. Generally, the prognosis for THC intoxication is good, and most dogs recover with symptomatic/supportive care as the LD50 in dogs is high at 3 gm/kg. However, severe toxicosis can be fatal, as is rarely seen with the high potency forms of THC (i.e. hash oil, marijuana butter).
Reports of marijuana’s effectiveness for treating ill pets are very limited. Marijuana is a schedule I drug. Even though medical marijuana is sanctioned for humans in Massachusetts, as a veterinarian it remains illegal for you to prescribe or recommend it to treat a patient.
If you feel you may be dealing with a pet who has a potential toxicity, or desire 24 hours or after-hours monitoring of your patient, please don’t hesitate to give us a call. Our emergency and critical care services have extensive experience dealing with toxicities.
Potential Toxicity? Don’t Forget the Patient
When it comes to being suspicious for the presence of a toxic reaction, you shouldn’t just look at the potential chemical exposure. You also have to consider the health status of the patient. The presence of an underlying problem in a pet can change what would typically be a safe chemical exposure into a life threatening exposure. One important example of this complication is the possible presence of a MDR1 gene mutation in some herder breeds who are treated with or otherwise exposed to routine doses of common drugs.
What is the MDR1 gene mutation?
The development of ivermectin to prevent heartworm disease and treat other parasites was a tremendous step forward for the veterinary profession. It did not take long, however, to realize that in collies recommended doses of ivermectin, found to be safe in other breeds, caused severe neurologic signs. Subsequent research determined that many collies carried an inherited defect in their multi-drug resistance (MDR1) gene. This gene encodes for P-glycoprotein. P-glycoprotein is located in the cell membranes of the liver, pancreas, intestines, kidney and brain capillary endothelium. It functions to bind and actively transport certain chemicals that have leaked into the cell cytoplasm out of the cell. Collies who possessed the MDR1 gene mutation did not produce adequate P-glycoprotein concentrations needed to remove the ivermectin that leaked into their brain cells. The excessively high concentration of intracellular ivermectin was responsible for the abnormal neurologic signs.
P-glycoproteins are responsible for clearing a number of other chemicals and drugs from within susceptible cells. A list of drugs to be concerned about can be found on the Washington State University college of veterinary medicine’s website. The administration of these drugs to dogs with the MDR1 gene mutation has been reported to cause variable and potentially severe side effects including neurologic signs, gastrointestinal signs and myelosuppression (decreased blood cell counts):
- Ivermectin, as well as milbemycin, selamectin, and moxidectin: These drugs are considered safe in MDR1 dogs when used at the prescribed doses for heartworm preventative, but are toxic at higher doses or with accidental ingestion of multiple heartworm pills
These drugs may cause adverse reactions and may be pumped out of the brain by P-glycoprotein, but data is not available:
These drugs are known to be pumped out of the brain by P-glycoprotein, but appear to be safely tolerated by dogs with known MDR1 mutation:
A number of breeds have been shown to potentially carry the MDR1 gene mutation, namely collies (70% frequency), Australian shepherds and miniature Aussies (50%), Shetland sheepdogs (15%), and long-haired whippets (65%). Infrequently, the defect has been found in other breeds. The disorder is inherited as an autosomal recessive gene.
There is a screening test to confirm the presence of the mutated MDR1 gene available at Washington State University’s college of veterinary medicine. Test results indicate if the dog carries two, one or no copies of the mutated gene. Even heterozygous dogs may show some susceptibility to toxicity. A cheek swab sample can be submitted by owners, or a blood sample drawn by a veterinarian.
What should you do if you have a breed that carries the MDR1 gene mutation?
It is safest to avoid the drugs to which the dog may be sensitive. If you must use a potentially toxic drug, the dose should be decreased by 50% in homozygous dogs and 25% in heterozygous pets. Pet owners should be informed of the associated risks of treating the patient.
Did you know?
The presence of P-glycoprotein in some cancer cells is likely responsible for rendering them multidrug resistant. Researchers are looking for ways to inhibit the action of P-glycoproteins in cancer cells to improve the efficacy of anticancer medications.
Electrical impulses within the heart are responsible for the coordinated contraction of the cardiac chambers, i.e. the atria and the ventricles. The SA node, also known as the pacemaker of the heart, is responsible for initiating the electrical impulse. The electrical impulse travels along special nerves in the heart wall stimulating the right and left atrial chambers to contract. After a fraction of a second delay at a nerve bundle called the AV node, the electrical impulse then travels along additional nerve pathways into the walls of the ventricles stimulating the ventricular muscles to contract. This directed flow of electrical impulses through special nerve pathways causes a coordinated contraction of first the atria and then the ventricles pumping blood rhythmically out into the arteries of the body.
These electrical impulses also travel beyond the heart into the surrounding body in a predictable direction. Wired electrodes, attached to the body in predetermined locations, will detect the electrical impulses. An electrocardiograph (ECG) machine, to which the electrodes are attached, displays the strength and direction of the impulses on a monitor as they are produced. A printout of the tracing can also be produced by many machines.
Electrocardiography is an excellent means of monitoring the heart rhythm and rate in anesthetized patients. A change in the heart rate can alert technicians and clinicians to the depth of anesthesia or the adequacy of blood perfusion. The presence of abnormal tracings may reflect an underlying heart condition, electrolyte imbalances, or excessive neurologic tone. Many medications can also adversely alter the rate and rhythm of the heart. When observing a patient’s ECG, it is important to be cognizant of trends. The changes observed on an ECG monitor during an anesthetic procedure provide early visual clues that a problem may be developing.
It is important to realize that the electrocardiograph reading only reflects the electrical activity of the heart. It provides no information about the pumping ability of the heart. The effectiveness with which the heart is pumping blood through the body can better be assessed using other monitoring parameters such as blood pressure or pulse strength, oxygen saturation (pulse oximetry), and end tidal CO2 concentrations (capnography). That being said, an excessively low heart rate, excessively high heart rate, or asynchronous stimulation of the cardiac chambers, as noted by an abnormal heart rhythm on an ECG tracing, can interfere with the ability of the heart to efficiently pump blood through the body. Electrocardiography can identify when an abnormal heart rate or rhythm is contributing to poor perfusion.
How to connect an ECG
Electrocardiograph electrodes are conventionally placed in a standard position on the patient so that abnormalities are easier to detect.
Red electrode – left hindlimb
Green electrode – right hindlimb
White electrode – right forelimb
Black electrode – left forelimb
Lead II is the most commonly used setting for evaluating the heart rate and rhythm. Lead II (which measures directional electrical impulses between the right forelimb and left hindlimb) correlates best with the direction of electrical impulse flow in the heart resulting in the best view of the P wave and QRS complex.
To reduce the loss of electrical signal as the electrical impulse travels between the skin and the electrodes, medical jelly is applied between the two surfaces.
What should you do if you note an abnormal rate or rhythm on the ECG of an anesthetized patient?
- Inform the veterinarian.
- Make sure that the airway is patent and oxygen flow is satisfactory. Adjust oxygen levels as deemed appropriate.
- Assess whether the patient is breathing (or being ventilated) adequately. Check end tidal CO2 (capnography).
- Check the patient’s circulatory status. Helpful monitoring parameters include evaluating the patient’s blood pressure, oxygen saturation (pulse oximetry), pulse strength, and alignment of pulse with the ECG heart beat.
- Consider treatments to reverse hypotension, if present.
- Consider the patient’s depth of anesthesia.
- Consider whether the surgeon is stimulating the vagal nerve.
- Consider medications that may be affecting the heart.
Many arrhythmias and alterations in heart rate will respond to adjustments made to improve oxygenation, ventilation and circulation. If an arrhythmia that is causing hemodynamic instability persists despite such therapy, then specific drug treatments may be required.
Note: It is beyond the scope of this article to describe all the abnormal heart rhythms that can occur in a patient, how to recognize them and what treatments should be considered. It is recommended that individuals responsible for ECG monitoring learn to recognize normal and abnormal ECG readings, so they can bring abnormal readings to the attention of the veterinarian.
Adderall® (Dextroamphetamine) Toxicity
Adderall® is an amphetamine that causes release of endogenous catecholamines leading to central nervous system and cardiovascular stimulation. Examples of other amphetamines include Ritalin® (methylphenidate), methamphetamine, Dexedrine® (dextroamphetamine) and Vyvanse® (lisdexamfetamine). Amphetamine toxicity in dogs has become common due to increased availability with use for treatment of attention deficit disorder.
Clinical signs and physical examination
Clinical signs from toxicity develop rapidly and are typically seen 2- 4 hours after exposure (up to 8 hours with extended release). Adderall toxicity will cause restlessness, hyperactivity, panting, shaking, seizures, ataxia, head bobbing, circling, weakness and collapse. With severe cases sudden death is possible. On physical examination we can also diagnose tachypnea, bilateral mydriasis, hyperthermia, cardiac arrhythmias and tachycardia. Clinical signs can last between 12 and 48 hours. Clinical signs tend to be longer with extended release formulas.
If no clinical signs are present with recent exposure emesis induction should be performed and activated charcoal administered. Once clinical signs develop agitation should be managed with acepromazine. Diazepam should be avoided as it can worsen dysphoria and central nervous system signs. Serotonin syndrome can be treated with cyproheptadine (oral or rectal). With severe tachycardia propranolol can be considered if the blood pressure is normal. If severe tachycardia and hypertension are present esmolol should be considered. Hospitalization with supportive care including fluid diuresis, monitoring vitals, minimizing sensory stimuli and thermoregulation is commonly needed.
Many patients with minimal clinical signs or aggressive care will make a full recovery. A poor prognosis is present with severe hyperthermia, head bobbing, severe tachycardia and seizures. Complications can include disseminated intravascular coagulation and rhabdomylosis leading to renal failure.