19Th Annual Small Animal Symposium

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19TH ANNUAL SMALL ANIMAL SYMPOSIUM

SUNDAY, MARCH 18, 2018 9 A.M. TO 6:30 P.M.

SAN FRANCISCO AIRPORT MARRIOTT

How do you I keep How do I create a What are some of clients from using dedicated the top conditions Google as their isolation space in geriatric pets? veterinarian? where there is none?

Welcome to this full day of learning! We work in a dynamic field where we have the opportunity to make an impact every day. Excellence requires continual study, and SAGE Centers for Veterinary Specialty and Emergency Care is proud to provide this full day of education to Bay Area veterinarians, technicians, managers, and client service staff. We hope you will enjoy the program and use the day to foster ties within our veterinary community. Following the event, please complete our online evaluation and let us know your thoughts. Your suggestions are welcome and essential to ensuring that this event is the best it can be year after year! What’s new at SAGE  In August 2017, we launched a new collaboration with PetCure Oncology at our Camp- bell facility to deliver stereotactic radiotherapy, along with other more traditional forms of radiation therapy. SAGE was the first veterinary hospital to deliver these treatments using Varian Medical Systems’ newest linear accelerator, the Halcyon Treatment System.

 We welcomed 11 new veterinarians to our growing team since last year—several of them will be speaking at this year’s event. We hope you get a chance to meet with those who are in attendance. Meet our new SAGE veterinarians

Sarah Silverman Cardiology Redwood City Zachary Wilcox Emergency/Critical Care Redwood City Kiera Steele Emergency/Critical Care Concord Noelani Reinker Internal Medicine Redwood City/Campbell Vivian Lau Neurology Redwood City Sara Lefman Emergency/Critical Care Redwood City Christine Wong Emergency/Critical Care Campbell Moria Borys Internal Medicine Dublin Kelly Fishman Physical Rehabilitation Redwood City Zuhal Elhan Emergency/Critical Care Dublin Shyla Myrick Emergency/Critical Care Campbell Sage Philosophy

We believe animals Our Mission are amazing. We are here because we appreciate and love animals. We will give pets and their families the best possible To set the highest standard of care with kindness and respect. compassionate, collaborative veterinary care that improves the We believe in lives of pets and people. continual learning. Our profession is based on scientific knowledge. Our success depends upon creative problem solving, up-to-date training, and the finest skills. We are committed to advancing veterinary medicine and Our Values improving pet care throughout the Bay Area. Compassion We believe in collaboration. Service We work in partnership with referring veterinarians Integrity and one another, knowing it is fundamental to our integrated approach and to continuity of care. All Collaboration of us are responsible for maintaining the high Sustainability standards and positive attitude that make Sage a great place to work. Innovation We believe we are part of a greater whole. In pursuing our mission, we have both opportunities and an obligation to contribute to our communities, to minimize our environmental impact, and to model sustainability. SAGE would like to thank the sponsors of our 19th Annual Small Animal Symposium

Track Sponsors

Lunch Sponsor

A&E Medical Imaging, Inc. Animal Arts Animal Memorial Service AnimalScan Diamondback Drugs DVM Multimedia Elanco Epic Golden Gate Pharmacy JP Morgan Chase Just Food for Dogs Henry Schein Hill’s Pet Jurox KindredBio Medicus Biosciences Nova Biomedical Radiocat rVetlink San Mateo Neighborhood Pharmacy Servetusa Trupanion Umpqua Bank VDx VISC Shamrock Office Solutions TABLE OF CONTENTS . TRACK 1 — Clinical 1

What is Minimally Invasive Surgery, and Why Is It Important?...... 1 Dr. Chuck Walls Dr. Leigh Glerum

Movement Disorders...... 7 Dr. Vivian Lau

When Is the Right Time to Spay/Neuter?...... 15 Dr. Lissa Richardson Intra-Articular Therapies for Osteoarthritis Management...... 29 Dr. Margot Daly

Geriatric Patient Care...... 33 Dr. Kelly Fishman

The Highs and Lows of Cannabis...... 39 Dr. Micki McCabe

Dermatology: Avoiding the Pitfalls of Pruritits...... 43 Dr. Stacey Holz TRACK 2 – Clinical 2

Bacteria Resistance...... 49 Dr. Christine Wong

Common Toxicities...... 87 Dr. Sara Lefman

Shock and Fluid Management...... 92 Dr. Terence Krentz Immune Suppressant Medications...... 94 Dr. Moria Borys Review of and Updates on Diabetes...... 106 Dr. Kris Bruskiewicz Dr. Heidi McClain

Probiotics...... 107 Dr. Noelani Reinker Syncope...... 109 Dr. Sarah Silverman TRACK 3 – Clinical 3

Feline Oral Inflammation Differentiation...... 125 Dr. Kevin Stepaniuk

Ophthalmological and Maxillofacial Manifestations of Dental Disease...... 130 Dr. Kevin Stepaniuk

Understanding Fractured Teeth and the Appropriate Treatment Recommendations...... 134 Dr. Kevin Stepaniuk

Tick-borne Diseases...... 140 Dr. Annette Litster

Reading a Biopsy Report...... 145 Dr. Beki Regan

Incomplete Margins: Now What?...... 190 Dr. Wendi Velando Rankin Stereotactic Radiotherapy: What We Can Do for Pets...... 237 Dr. Kelsey Pohlmann

TRACK 4 – Nursing

Feline Heartworm Disease: An Update...... 244 Dr. Annette Litster

The Window to the Wall...... 251 Kim Adams, RVT

Back to Basics with Bloodwork...... 284 Dr. Monie Yee Anemia: What Does the CBC and Blood Smear Show Us?...... 285 Jo Woodison, RVT

Point of Care Diagnostics in the ER...... 296 Jo Woodison, RVT

Clandestine Oral Pathology Missed on Examination...... 307 Dr. Kevin Stepaniuk

Anesthetic Drugs: How Do They Work?...... 312 Liza Morales, RVT Judy Kpa, RVT

TRACK 5 – NURSING

Assessment of the Critically Ill Patient...... 316 Kristin Frietas, RVT, VTS

Evans Syndrome: A Technicians Role...... 323 Yvonne Brandenburg, RVT, VTS Techniques for Postop Success...... 333 Liz Hughston, RVT, VTS Stephen Cital, RVT, VTS

Dermatology: Joining Forces with the Microscope...... 357 Dr. Stacey Holz

Clandestine Oral Pathology Missed on Examination...... 360 Dr. Kevin Stepaniuk

Managing Respiratory Cases...... 365 Jo Woodison, RVT

Polytrauma: Where to Start?...... 366 Jo Woodison, RVT TRACK 6 – Management/Client Care

What if We Applied the Ritz Carlton Model in Our Practice?...... 374 Robin Brogdon, MA

What are Your Clients Turning to Dr. Google For?...... 374 Robin Brogdon, MA

Pet Nutrition & Profitability: Evolve and Grow...... 376 Jeff Wineke Compassion Fatigue...... 379 Julie Squires

How to Feel Better in Veterinary Medicine Part 1...... 382 Julie Squires

How to Feel Better in Veterinary Medicine Part 2...... 386 Julie Squires

Boundaries: The Missing Ingredient in Veterinary Medicine...... 390 Julie Squires Track 1 What is minimally invasive surgery and why is it important? Arthroscopy and MIPO

Charles M. Walls, DVM, DACVS Sage Centers

Minimally invasive arthroscopic treatment of joint disease has been a mainstay in human surgery for over 30 years. In human surgery, one would not think of an open arthrotomy to treat a meniscal tear of the knee or a rotator cuff tear in the shoulder. There have been tremendous advances in minimally invasive arthroscopy as well as in fracture management that have lead to less patient pain, morbidity and complications with earlier return to function and work. In veterinary medicine, these advances have been met with mixed reviews as to the benefits, mostly due to lack of proper equipment, instrumentation and technical expertise. Basically, we in veterinary medicine are 25 years behind our human counter parts in both these arenas, but this is currently changing.

Fortunately for our animal patients, through the availability of newer and more cost effective minimally invasive equipment, specialized instrumentation for small animal procedures and advent of evolving minimally invasive training programs for surgeons, minimally invasive surgery is becoming a more prevalent option for treatment of a variety of surgical diseases. The following is a brief description of the diseases that can benefit from arthroscopy and MIPO fracture management.

Arthroscopic Procedures in Small Animal Surgery:

1) Elbow: The elbow was probably the first joint to benefit from arthroscopic evaluation and treatment over open arthrotomy. The mainstay in veterinary arthroscopic surgery of the elbow is the diagnosis and treatment of elbow dysplasia in it’s various forms. The most common indication is the diagnosis and treatment of medial coronoid disease. In the young dog without significant joint incongruity and articular cartilage wear, arthroscopic treatment can be quite effective in identification of medial coronoid disease and treatment (subtotal or axial subtotal medial coronoidectomy). OCD, which is fortunately much less common, can at least be initially treated with debridement, abrasion +/- microfracture techniques. a. Elbow arthroscopy may also be used to help assess articular fracture reduction to ensure proper joint surface alignment to help minimize progressive osteoarthritis. b. Arthroscopy can also aid in the grading of articular cartilage lesions, as well as help diagnosis the more rare inflammatory or neoplastic disease processes.

2) Shoulder: Shoulder arthroscopy has been the mainstay for treatment of caudal humeral OCD for the past 10 years. The treatment is highly effective in being able to remove the chondral flap and achieve successful debridement of the sclerotic subchondral bone (calcified layer) with the use of a high speed bur to promote vascular in-growth and

Back to Table of Contents 1 fibrocartilage formation. In the shoulder, this has resulted in less short-term morbidity vs. open arthrotomy as well as successful long-term outcomes. Other uses of shoulder arthroscopy are in aiding the often-difficult diagnosis of biceps tendon disease and medial shoulder instability (with disruption or tearing of the subscapularis muscle, medial glenohumeral ligament, joint capsule tearing or joint capsule laxity). Less common, but clinically important, lateral shoulder compartment laxity and tearing of the lateral glenohumeral ligamentous structures can also be identified.

3) Stifle: Stifle arthroscopy has significantly aided in the improved visualization of intra- articular structures and disease. Improved visualization aids in characterizing and grading the degree of synovitis, articular cartilage wear, type and extent of cruciate ligament tearing (cranial vs. caudal or both) as well as the type and character of medial and, less frequently, lateral meniscal pathology that is not possible through open arthrotomies. Arthroscopic cruciate ligament debridement and treatment of medial meniscal tears now is common place in veterinary surgery. In addition, with the aid of this type of visualization, we as surgeons are able to make better decisions as to the types of treatment options available by knowing information such as whether or not a partial cranial cruciate ligament tear is competent vs. incompetent. Additionally, arthroscopy can help determine whether an intact medial meniscus with associated cranial cruciate ligament tear is stable or unstable. This has helped us more accurately determine whether a medial meniscal release is appropriate or not. Ideally an intact, stable medial meniscus is an important stabilizer of the joint and helps lessen the degree of secondary OA in the joint if left intact. Occasionally however even in the best of cases, a medial meniscus can subsequent to surgical stabilization become torn and arthroscopic meniscectomy is the treatment of choice over open arthrotomy. Stifle arthroscopy can also be helpful is defining and debriding OCD lesions of the femoral condyle as well as aid in the diagnosis of difficult to diagnose lymphocytic/plasmacytic synovitis or less commonly synovial cell sarcoma or other neoplastic disease processes without a significant lytic bone component. Arthroscopically assisted intra-articular cruciate ligament graft placement in conjunction with TPLO or CBLO procedures are also possible to perform.

4) Hip joint: Though less commonly performed, hip arthroscopy can be very useful in helping determine the degree of articular cartilage wear and labral rim wear in the young dog with hip dysplasia prior to considering a pelvic osteotomy. More recently, arthroscopic, minimally invasive toggle-pin fixation has been described for the treatment of hip luxation in dogs. It is also helpful for diagnosing occult neoplastic and inflammatory diseases of the hip which are otherwise difficult to diagnose.

5) Carpus and Tarsus; Due to the small size or these joints, arthroscopy is possible but often not to the extent of the other major joints of the body. With the advent of smaller 1.9mm scope however, tarsal OCD abrasion is possible.

Minimally Invasive Plate Osteosynthesis (MIPO):

2 1) As with human arthroscopic procedures, MIPO fracture management has gained increased popularity in human fracture management. There have been tremendous advances in specialized plates and locking plating systems specifically designed for MIPO implantation. This is especially true with the common use of C-arm fluoroscopy which has allowed for this advancement. MIPO in humans has greatly reduced the soft tissue trauma and infection rates that occurred as a result of previous “open” procedures.

2) In veterinary surgery, MIPO is still in its infancy primarily due to the lack of specialized instrumentation and the lack of widely available C-arm fluoroscopy. This however is quickly changing with more university and private training programs aimed at teaching the surgical resident and surgeons fluoroscopic and MIPO techniques for fracture management.

3) Technique and case presented.

3 What is minimally invasive surgery and why is it important? Introduction, Laparoscopy, and Thoracoscopy

Leigh E. Glerum, DVM, DACVS Sage Centers

“Minimally invasive surgery (MIS)” is a ubiquitous phrase used in the human, and increasingly, the veterinary medical fields. MIS provides an alternative approach—via several small incisions—to anatomical sites that were previously accessed by more aggressive means (i.e.- single large incisions and retraction). MIS generally provides the patient with less postoperative discomfort, less surgical morbidity, and more rapid recovery time.

MIS does require specialized equipment and a specific surgical skill set. Basic equipment and instrumentation include endoscopes, camera, monitor, light source, insufflator(CO2), fluid pump, access ports, hand instruments, and vessel sealing device. The surgeon and support staff must undergo advanced training, and skills are ideally honed and maintained through repetition with clinical patients.

The benefits of MIS are numerous. However, in order to run a successful MIS program, there are several investments that must be made. There is an initial financial investment for advanced training and equipment. The surgeon and support staff must be committed to caring for the equipment and ongoing skill development. Patients must be recruited through referring veterinarian and client education.

Laparoscopic Procedures in Small Animal Surgery:

Urogenital

Ovariectomy may be performed via 3 small ventral midline incisions, umbilicus and caudal. A vessel sealing device is utilized to mobilize the ovaries, then they are extracted through a slightly enlarged port incision.

Cryptorchid neuter may be performed via 3 small ventral midline incisions, umbilicus and caudal. A vessel sealing device is utilized to mobilize the testicle(s), then it/they are extracted through a slightly enlarged port incision.

Gastropexy

Prophylactic gastropexy may be performed via 1 small umbilical incision and an ultimately 2- 3cm incision in the right cranial abdominal quadrant. The pyloric antrum is visualized and grapsed, then exteriorized through the right cranial quadrant port incision. Incisional gastropexy is thus accomplished in a laparoscopic assisted fashion through a much smaller than laparotomy sized incision. Prophylactic gastropexy is often performed in combination with ovariectomy or neuter.

4 DIagnostic Procedures

Abdominal exploration may be accomplished via 2-3 ventral port incisions. The peritoneum, omentum, liver, gall bladder, stomach, pancreas, kidneys, bladder, adrenal glands, and fixed lymph nodes may be visualized. The entirety of the intestinal tract is a bit more challenging to inspect, but the bowel may be “run” via methodical instrument use or via alternative port that allows the surgeon to exteriorize and handle to bowel directly. Liver, pancreas, kidney, and peritoneal biopsies are readily obtainable. Intestinal biopsies may be obtained in an assisted fashion. Lymph node biopsy is also possible.

Therapeutic Procedures

Cholecystecomy and adrenalectomy may both be performed via MIS technique. Case selection is crucial to surgical success. The ideal laparoscopic cholecystectomy candidate is a mid to larger size dog with a non-obstructive gall bladder mucocele. Please contact one of the Sage surgeons to discuss any potential candidates for these procedures.

Thoracoscopic Procedures in Small Animal Surgery:

Diagnostic Procedures

Thoracic exploration may be performed via 2-3 subxyphoid and intercostal port incisions. The pleural surfaces, lungs, pericardium/heart, and cranial mediastinal region may be visualized. Lymph nodes can be more challenging to visualize. Pleural surface and pericardial biopsies are readily obtainable. Lung biopsies may be obtained with the aid of a stapling device or pre-tied ligature. Mediastinal, heart base, and cardiac mass biopsies may be obtained in appropriate cases where the risks of major vessel penetration and/or hemorrhage are not too great. Lymph node biopsy is also possible.

Therapeutic Procedures

Partial pericardiectomy is the most common indication for thoracoscopy at Sage. 3-4 subxyphoid and intercostal ports are established. A portion of the pericardium is excised, and the remaining pericardium may be “released” via radial incisions. Cardiac tamponade is durably relieved for patients with a variety of conditions such as right auricular hemangiosarcoma, heart base mass, mesothelioma, and idiopathic pericardial effusion.

Lung mass excision is feasible in select cases. The ideal candidate would have a mass of a size that could be extracted through an intercostal space. The mass would ideally be located in the mid to peripheral portion of a lobe. Please contact a Sage surgeon to discuss any potential candidate for this procedure.

5 Thoracic duct ligation may be performed via thoracoscopy in dogs to address idiopathic chylothorax. Duct ligation is combined with thoracoscopic partial pericardiectomy to increase the probability of surgical success.

6 Beyond Seizures: Disorders of Involuntary Movement Vivian Lau DVM MS DACVIM (Neurology)

Disorders involving the muscle -Myotonia (congenital vs acquired)

Disorders involving the neuron -Tetanus -Tetany -Tremors -Movement disorders

Due to time, this talk is focused on Tremors and Movement Disorders only.

Tremors -Formerly classified as various forms of myoclonus, more recently accepted terminology is tremors -Sudden contraction then immediate relaxation of a group of muscles -Rhythmic/oscillatory involuntary contraction and relaxation of a group of muscles

Resting tremors - only reported in ppl. Similar to humans with Parkinson disease- degeneration of substantia nigra, not seen in horses with yellow star thistle (degen of substantia nigra and globus pallidus). No tremor in kerry blue terrier or chinese crested dogs with cerebellar cortical abiotrophy and degeneration of substantia nigra, caudate, and olivary nuclei

Back to Table of Contents Constant repetitive myoclonus -Continuous rhythmic contractions, most obvious in resting animal -Usually focal (usually 1-2 limbs, jaw), less often whole body -No change in group of muscles -Etiology –Neural Injury –Canine Distemper –Drug-induced: Morphine, etomidate, propofol, alfaxalone, lead toxicity -Pathophysiology: -Functional disruption of lower motor neuron (LMN) cell bodies -Pacemaker mechanism -Persists despite transection of cranial cord -Minimal microscopic lesions on histopathology -Treatment -Na+ channel blockers: Ia- Procainamide, Ib- Mexiletine and lidocaine

Action-Related Repetitive Myoclonus (Intention Tremor) -Action-related kinetic tremors -Diffuse and rapid -Worse with activity, disappears at rest - Diffusely affects skeletal muscle- rapid (many contraction/relaxations per second) - More active patient is, more recruiting of LMNs and more rapid myoclonus or tremor -Disappears in still patient -Causes -Cerebellar -Congenital -Idiopathic (“Little white shakers”)/Toxic (tremorgenic mycotoxins, etc) Can be associated with cerebellar lesion but need diffuse myelin or neuronal lesions or may be functional, caused by toxicity or NT disorder

Postural-Related Repetitive Tremor -Involves muscle activity but … –limited to postural muscles (muscles used for weight support) –absent during voluntary movements -2 forms: –Old dogs- pelvic limbs –Young dogs- limbs or head

Orthostatic tremors -Young dogs- limbs -Great Danes and Scottish Deerhounds -Standing or attempting to lie down -Gone when recumbent or exercising

8 -Present when stands at rest or attempting to lie down or posture for intake or excretion -Becomes severe during efforts to lie down -Gone when running or walking -Functional CNS disorder involving supraspinal generator -All diagnostics normal (except EMG), disorder of stretch reflex mechanism -Slowly increase in intensity with time -Can auscult with stethoscope -Does not fatigue when running -Gone at rest -Can be seen with a dyskinesia -Suspected inheritance in great dane- hereditary? -Drug therapies limited -Pheno and gaba give some temporary relief

Idiopathic Head Tremors -Young dogs- head -English bulldog, Doberman pinscher -Possible stretch reflex mechanism involved- need tension in limb muscles -Depends on a specific degree of muscle tension in neck- only when head and neck are in a supporting position -Boxer dogs, French bulldogs, Labradors, Beagles too -Not associated with stress (although can be seen after stressful events in some patients) -Happens in relaxed dogs -Disappears with distraction in 87% of patients (Shell. Vet Med Intl 2015) -Sporadic occurrence with no pattern -Normal imaging and csf -No EMG studies -No effective drugs -Some improvement with time (67% of patients- Shell. Vet Med Intl 2015)

Episodic Nonpostural Repetitive Myoclonus -Episodes of severe myoclonus -Peripheral Nerve Hyperexcitability (PNH) -Variable frequency and amplitude -Myokymia and Neuromyotonia -Congenital or Acquired –Jack Russell Terriers- spinocerebellar ataxia –Neural Injury -Jack Russell Terriers- spinocerebellar ataxia -Myokymia is part of this disorder -Abnormality in genes encoding potassium channel on glial cells (high extracellular K+ makes hyperexcitable and impedes glutamate reuptake) or

9 calcium-dependent cysteine protease (neuronal maintenance and remodeling)- spinocerebellar ataxia, poor prognosis -Neuromyotonia: -Can be associated with falling, rigid extended limbs and delayed muscle relaxation (Quantal squander aka Isaacs syndrome or Isaacs-Mertens syndrome in ppl) -Underlying axonal disorder poorly understood -Hyperthermia -Continuous muscle fiber activity- human medicine term -Hyperexcitable general somatic efferent axons to affected muscle groups -Can see this post-radiation - suspect persistent conduction block caused by delayed demyelination secondary to radiation -Non-specific findings on nerve and muscle biopsies -EMG- “marching soldiers” and “pings” -Treatment: –Membrane stabilizing drugs (phenytoin, procainamide, mexiletine) –Cold water bath and anesthesia

Movement Disorders -Episodic sudden involuntary skeletal muscle contraction - Not rhythmic - Dystonia/Dyskinesia - Conscious patient with normal sensorium -Hereditary, drug-related, or unknown -Poorly understood -Disruption of central pattern generator of LMN - Ion channels - neurotransmitters -Diagnosis- pattern recognition

10 Episodic Falling -aka Hypertonicity and ‘Deer Stalking’ -Cavalier King Charles Spaniel -Young dogs (<1yr) -Heritable -Deletion in BCAN gene- gene codes for brevican -Brevican: brain-specific extracellular matrix-proteoglycan brevican Found near nodes of Ranvier- stabilizes in face of major ion flux. cell adhesion, migration, axon guidance, and neuronal plasticity -Improves with age -Treatment -Clonazepam (BZD) -Acetazolamide (CAI)

Scotty Cramp -Young Scottish terriers (<1yr) -Autosomal recessive -Female>male -Normal BCAN gene -Excitement/stress -EMG/Histo- normal -Serotonin levels may play role -Treatment -Fluoxetine (SSRI)- trazodone? -Diazepam -Valerian root and vitamin E -Improves with time

Canine Epileptoid Cramping Syndrome -Border Terriers -aka “Spike’s disease” -Variable age of onset 6 weeks to 7 years -Can be triggered by stress -Non-responsive to AEDs (anti-epileptic drugs) -Can last for much longer than a seizure -Associated GI signs -Responsive to diet change (Lowrie et al JVIM 2015) -Almost half study population had borborygmi or vomiting/diarrhea immediately preceding or after an episode -Gluten- gliadin and glutenin -Increased antitransglutaminase 2 and antigliadin antibodies -Transglutaminase breaks down gliadin -Improvement in half of BTs with a hypoallergenic diet in one report -Improvement in all six in a more recent study with gluten-free diet

11 PNKD in Chinook dogs -Paroxysmal Nonkinesigenic Dyskinesia –Not triggered by movement -aka “Chinook seizures” -Normal EEG, MRI and CSF and chem and UA -Normal T4, negative for lead -No comments on tx or outcome -Most under 3yrs -Variable age of onset –Most <3yrs -Suspected autosomal recessive -Last up to 1hr -Unknown pathophysiology –Basal nuclei? -Some dogs also had seizures -Unknown outcome

Other Paroxysmal Dyskinesias -Drug-related -Phenobarbital (single case report- resolved with cessation of PB administration) -May be heritable -Boxer pups, Bichon frise, Wheatons, GSP, Dalmatian, etc. -Boxer pups -Females less affected than males -1-5 minute episodes at 8weeks of age -normal male dog MRI -2 unrelated litters -Treatments -Phenobarbital -Acetazolamide -Diazepam -Gabapentin -Variable outcome

Dancing Dobermans -Young Doberman pinschers (<7yrs) -Both sexes -+/-Progressive -Neuromyopathy affecting gastrocnemius -EMG changes can be noted -No known treatment, generally benign condition

12 Summary of Myoclonus/Tremors -Most now considered tremors -Etiology: –Infectious –Toxic –Radiation/Injury –Heritable –Unknown -Pathophysiology –Change in environment of LMN cell body –Poorly understood -Diagnosis –Pattern recognition –EMG changes -Treatment –Membrane stabilizers –Cold water bath –Anesthesia –Do nothing -Prognosis –Variable

Summary of Movement Disorders -Etiology –Heritable -BCAN deletion/other –Drug-related –Unknown -Pathophysiology –Ion channelopathy? –Serotonin? –Unknown -Diagnosis –Pattern recognition –Exclusion -Treatment –SSRIs –Benzodiazepines –Acetazolamide –Phenobarbital -Prognosis –Variable –Unknown

13 Additional resources: -Lowrie et al. J Vet Intern Med 2015;29:1564–1568. The Clinical and Serological Effect of a Gluten-Free Diet in Border Terriers with Epileptoid Cramping Syndrome -Lowrie and Garosi. The Veterinary Journal 214 (2016) 109–116. Review- Classification of involuntary movements in dogs: Tremors and twitches -Urkasemsin and Olby. Vet Clin of North America 2014. Canine Paroxysmal Movement Disorders -de Lahunta, Glass, and Kent. Compendium 2006. Classifying Involuntary Muscle Contractions -Shell et al. Veterinary Medicine International 2015. Clinical and Breed Characteristics of Idiopathic Head Tremor Syndrome in 291 Dogs: A Retrospective Study

Many of the videos are available online at: http://neurovideos.vet.cornell.edu/

14 Factors to Consider in Timing of Gonadectomy for Privately Owned Dogs and Cats

Lissa Richardson, DVM Dip ACVS

In the past it was fairly straightforward: spay or neuter around 6 months, ideally for female dogs before their first heat to have the lowest risk of developing mammary neoplasia.

Recent studies, mostly retrospective, have shown some association of prepubital spay with cancer and orthopedic problems. Veterinarians need to discuss the relative risk of timing the procedure…or even whether or not to do it.

Many studies bring up a plethora of associations and potential risk factors but do not really show causation. This really is the next area of research that needs to occur so we can understand the connection between genetics and environment to make better recommendations.

Age, breed, and proposed purpose all will factor into the decisions in a way that is very complicated to present. Even a systematic review of the literature leaves a lot of questions. I have referenced AMVA statements and included statement from the American College of Veterinary Theriogenologists at the end of this paper for reference. The later helps very much in simply listing benefits and risks.

A few landmark studies are mentioned below.

The Hoffman Study 1 was done in 2013 and used the Veterinary Medical Data Base (VMDB, http://www.vmdb.org) which contains abstracted medical records of animals presented to North American veterinary teaching hospitals since 1964. They had 40,000 dogs older than 1 year with cause of death recorded. They found that gonadectomized dogs had longer life spans but had higher rates of cancer. Many more studies were done around this.

The Hart studies were done close to home, one looked at rates of the most common cancers and rate of cruciate disease and hip dysplasia in goldens and labs seen at UC Davis2. They did not include dogs older than 8 however. As stated in the abstract: The

- Labrador Retrievers: 5 percent of gonadally intact males and females had one or more joint disorders, neutering at <6 mo. doubled the incidence of one or more joint disorders in both sexes. - Golden Retrievers: 5 percent rate of joint disorders in intact dogs, neutering at <6 mo. increased the incidence of a joint disorder to 4–5 times that of intact dogs. - Female Labrador Retrievers cancer rate increased slightly above the 3 percent level of intact females with neutering. - Female Golden Retrievers neutering at all periods through 8 years of age increased the rate of at least one of the cancers by 3–4 times. - Male Golden and Labrador Retrievers neutering had relatively minor effects in increasing the occurrence of cancers.

1 Hoffman JM, Creevy KE, Promislow DE. Reproductive capability is associated with lifespan and cause of death in companion dogs. PLOS ONE. 2013;8(4):e61082. pmid:23613790 2 Hart BL, Hart LA, Thigpen AP, et al. Long-term health effects of neutering dogs: comparison of Labrador Retrievers with Golden Retrievers. PLoS One 2014;9:e102241.

Back to Table of Contents 15 The association of gonadectomy as a risk factor for hip dysplasia/elbow dysplasia may be flipped. In our practice, the diagnosis of hip dysplasia in a young dog, often leads to gonadectomy. The diagnosis of moderate to severe hip and elbow dysplasia can be made before 6 months. I look forward to seeing the results of the Golden Retriever Lifetime Study, which closed recently which is prospective.

A new study, just published this February has a different finding with respect to cancer. Kent et al3 looked at golden retrievers that were necropsied at UC Davis, so this was the same cohort in the Hart study that showed higher risk of 3 forms of cancer in gonadectomized golden retrievers. They included all dogs, not just dogs less than older than 1 but younger than 9 yrs as was done in the Hart study. There was no significant difference in the proportion of intact males and castrated males dying of cancer (p = 0.43). But more spayed females died of cancer than intact females. Intact female dogs had shorter life spans than spayed female dogs. There were no differences between intact and castrated males. The study showed that being spayed or neutered did not affect the risk of a cancer related death but increasing age did. They concluded that golden retriever dogs have a substantial risk of cancer related mortality in a referral population and age appears to have a larger effect on cancer related mortality than reproductive status. They found 424 of the 652 dogs necropsied (65.0%) were determined to have died because of cancer. The median age for dying of a cause other than cancer was 6.93 years while those dying of cancer had a median age of 9.8 yrs.

At Sage, we encounter more requests for alternatives for castration and ovariohysterectomy. We routinely do ovariectomy alone when doing a laprascopic spay. Done well (no remnant), there is no increase in uterine or vaginal pathology. In large breed dogs, we will perform a lap assisted gastropexy. No one has done a tubal ligation and only one surgeon has done vasectomies.

AMVA published a paper by Kendall E. Houlihan DVM, A literature review on the welfare implications of gonadectomy of dogs in May 2017 with 162 references. It is very detailed but does not present a simple summary:

AVMA article

PDF version of AVMA Summary article This is the position paper pulled from the website on February 2018 and is a very straighforward summary of the risks:

The Boards of Directors of the Society for Theriogenology and the American College of Theriogenologists Montgomery, AL

Basis for Position on Mandatory Spay-Neuter in the Canine and Feline

3 Michael S. Kent, Jenna H. Burton, Gillian Dank, Danika L. Bannasch, Robert B. Rebhun Association of cancer- related mortality, age and gonadectomy in golden retriever dogs at a veterinary academic center (1989-2016) Article | published 06 Feb 2018 PLOS ONE

16 The American College of Theriogenologists (ACT) is the certifying college for veterinarians board certified in reproduction (specialists) and the Society for Theriogenology (SFT) is an organization of veterinarians with a special interest in reproduction in veterinary medicine. The ACT and SFT believe that companion animals not intended for breeding should be spayed or neutered; however, both organizations believe that the decision to spay or neuter a pet must be made on a case by case basis, taking into consideration the pet’s age, breed, sex, intended use, household environment and temperament. The use of generalized rules concerning gonadectomy (removal of the ovaries or testes) is not in the best interest of the health or well-being of the pets or their owners. Each of the following considerations must be assessed for each individual animal and household.

1) Health concerns a. Research has shown that there can be positive effects of the sex steroid hormones. The sex steroids are hormones produced by the ovaries and testes, and are only present in intact males and females. Gonadectomy at any age deprives the body of the positive health effects of these hormones. Although in most cases, the benefits of spay-neuter outweigh the benefits of exposure to the sex steroids, this is not true in all cases. Since gonadectomy prior to puberty or sexual maturity may make the risks of some diseases higher in certain breeds or individuals, the option to leave an animal intact must be available to the pet owner. i. Advantages of remaining intact: 1. There is a decreased incidence of hemangiosarcoma in intact bitches and dogs. 2. There is a decreased incidence of osteosarcoma in intact male and female dogs. 3. There is a decreased risk of transitional cell carcinoma in intact dogs and bitches. 4. There is a decreased risk of prostatic adenocarcinoma in intact male dogs compared to gonadectomized male dogs. 5. There is a decreased incidence of obesity in intact male and female dogs and cats, which may be due at least partly to increased metabolic rate. 6. There is a decreased incidence of urinary incontinence in intact bitches (equivocal if bitches are spayed after 5 months but before their first heat). 7. There may be a reduced incidence of urinary tract infection in intact bitches. 8. There may be a reduced incidence of feline lower urinary tract disease (FLUTD) in intact male and female cats which may be partly due to decreased obesity in these animals. 9. There may be a reduced incidence of autoimmune thyroiditis and hypothyroidism in intact male and female dogs. 10. There is a decreased incidence of diabetes mellitus in intact female cats and a possibly reduced incidence in diabetes mellitus in intact male dogs. 11. There is a reduced incidence of cranial cruciate rupture in intact male and female dogs. 12. There may be a reduced incidence of hip dysplasia in male and female dogs that are not gonadectomized before 5 months of age. 13. There may be an increased incidence of capital physeal fractures in castrated male cats that may be partially due to increased weight gain in gonadectomized males.

b. Research has shown that there are a number of detrimental effects of the sex steroid hormones. Spaying and neutering will remove these hormones and thus lower the risk of these conditions. i. Advantages of being spayed or castrated:

17 1. There is an increased risk of mammary, testicular, and ovarian neoplasia in intact male and female dogs and cats. a. There is an increased risk of mammary cancer with each subsequent cycle and the benefit of spaying does not disappear until the animal reaches old age. i. Mammary cancer is one of the most common types of neoplasia in small animals. 1. Mammary neoplasia is malignant 60% of the time in dogs and 90% of the time in cats. b. The incidence and mortality risk for ovarian cancer are very low c. The incidence for testicular cancer is more common but malignancy and mortality are very low. 2. There is an increased risk of pyometra in both intact female dogs and cats and this risk increases with increasing age. 3. There is an increased risk of prostatitis, benign prostatic hyperplasia, prostatic cysts and squamous metaplasia of the prostate in intact male dogs. 4. There is a decreased incidence of perineal and inguinal hernia and perineal adenoma in neutered male dogs. c. Based on the research available, it is clear there are a number of health benefits of the sex steroid hormones and that this benefit varies with age, sex, and breed. Therefore, although spay- neuter is the responsible choice for most pets, it is in the best interest of each individual patient for its veterinarian to assess the risks and benefits of gonadectomy and to advise his/her clients on what is appropriate for each individual pet at each stage of its life.

2) Behavioral concerns a. Research has shown that there are positive effects of the sex steroid hormones on behavior. i. Advantages of remaining intact: 1. There is a decrease in shyness and hiding behavior in intact male and female cats. 2. There may be less aggression towards people and animals in intact bitches. 3. There may be a decreased incidence of cognitive dysfunction in intact male and female dogs. b. Research has shown that there are negative effects of the sex steroid hormones on behavior. i. Advantages of being spayed or castrated: 1. Inter-dog aggression may be due to competition for available territory or availability of cycling animals. 2. Urine spraying and inter-animal aggression is increased in intact male cats. 3. There is a decreased risk of wandering and being hit by a car in neutered animals. 3) Provision of quality medical care a. It is not in the animals’ best interest to have the legislature dictate the time or need for surgical treatment. i. This does not allow for medical decisions based on the individual animal’s needs, its owners’ needs or the needs of the household. 1. Animals with medical conditions that may result in complications during anesthesia or surgery (i.e. heart murmurs, bleeding disorders). 2. Providing appropriate aftercare for surgical patients may not be feasible in some home situations. b. Restricting and reducing the pool of purebred animals will greatly hinder medical research of conditions that are particular to specific breeds, slowing down advances in medical and surgical knowledge. This may in turn impact the research available concerning health conditions common to both animals and people. 4) Public Health concerns a. Making spay/neuter mandatory for licensure may make the public more hesitant to seek veterinary assistance because they are afraid of fines and legal repercussions as a result of failing to spay or neuter their pets by the prescribed time. By avoiding veterinary care for their pets, animals will be at increased risk of inadequate routine vaccination (including rabies) and

18 inadequate deworming programs which may in turn result in increased transmission of disease to the public.

The ACT and SFT make the following recommendations to continue moving toward effective methods of reducing the number of abandoned, unwanted and euthanized dogs and cats in the US and other countries where similar problems exist. a. Provide increased jurisdictional control to the AVMA Governmental Relations division, Animal Welfare Committee, and the APHIS-Animal Care division. b. Ensure suppliers to pet stores are providing adequate care for breeding stock and offspring. c. Support programs to expand the public awareness of pet overpopulation, acceptable breeding standards, and responsibilities of pet ownership. Provide the public a means to access assistance with concerns of pet health, ownership, behavior and management issues. d. Work with state and local rescue and humane societies to assemble accurate data on causes for relinquishment of dogs and cats to enable these organizations, federal and local governments, and veterinary organizations to address the fundamental causes of abandonment. e. Provide low cost spay/neuter facilities for economically disadvantaged persons and communities. f. Continue to work on reduction of feral cat populations. g. Establish programs to ensure access of breeders to proper reproductive care and counseling. h. Provide local or federal governmental assistance to registered rescue organizations to facilitate placement of unwanted pets.

The ACT and SFT do not believe that mandatory spay/neuter programs will significantly reduce the pet overpopulation problems, since most animals that are abandoned are relinquished because of behavior, health, economic and life changing conditions and not due to their reproductive status. In fact, in some European Union countries where gonadectomy is illegal unless deemed medically necessary (such as Norway) there are no significant problems with pet overpopulation, indicating that the pet overpopulation problem that exists in the United States is due to cultural differences on the importance of pets, the responsibility of pet owners, and the ability of the government and national agencies to properly educate the public. Although both organizations believe that most companion animals should be spayed or neutered, the ACT and SFT also strongly believe that it is not in the best interest of the animals to produce legislation regarding medical treatments, Therefore, both organizations oppose mandatory spay/neuter programs.

There are hundreds of references which provide scientific information on the effects of spay and neuter in both dogs and cats. We chose to provide the reader with a selected list of them.

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137) Salman MD, Hutchison J, Ruch-Gallie R, et al. Behavioral reasons for relinquishment of dogs and cats to 12 shelters. J Appl Anim Welf Sci 2000;3:93-106.

138) Salmeri KR, Bloomberg MS, Scruggs SL, Shille V. Gonadectomy in immature dogs: Effects on skeletal, physical and behavioral development. J Amer Vet Med Assoc 1991;198:1193-1203.

139) Salmeri KR, Olson PN, Bloomberg MS. Elective gonadectomy in dogs: A review. J Amer Vet Med Assoc 1991;198:1183-1192.

140) Scarlett JM, Salman MD, New JC, Kass PH. The role of veterinary practitioners in reducing dog and cat relinquishments and euthanasias. J Amer Vet Med Assoc 2002;220:306-311.

141) Scarlett JM, Salman MD, New JC, Kass PH. Reasons for relinquishment of companion animals in US animal shelters: Selected health and personal issues. J Appl Anim Welf Sci 1999;2:41-57.

142) Schneider R, Dorn CR, Taylor DON. Factors influencing canine mammary cancer development and postsurgical survival. J Nat Canc Inst 1969;43:1249-1261.

143) Seguin MA, Vaden SL, Altier C, et al. Persistent urinary tract infections and reinfections in 100 dogs (1989-1999). J Vet Intern Med 2003;17:622-631.

144) Shen V, Dempster DW, Birchman R, et al. Lack of changes in histomorphometric, bone mass, and biochemical parameters in ovariohysterectomized dogs. Bone 1992;13:311-316.

145) Shoemaker NJ, Schuurmans M, Moorman H, Lumeij JT. Correlation between age at neutering and age at onset of hyperadrenocorticism in ferrets. J Amer Vet Med Assoc 2000;216:195-197.

146) Slauterbeck JR, Pankratz K, Xu KT, et al. Canine ovariohysterectomy and orchiectomy increases the prevalence of ACL injury. Clin Orthop 2004;429:301-305.

147) Sloth C. Practical management of obesity in dogs and cats. J Sm Anim Prac 1992;33:178-182.

148) Sorenmo KU, Goldschmidt M, Shofer F, et al. Immunohistochemical characterization of canine prostatic carcinoma and correlation with castration status and castration time. Vet Comp Oncol 2003;1:48-56.

149) Spain CV, Scarlett JM, Houpt KA. Long-term risks and benefits of early-age gonadectomy in cats. J Amer Vet Med Assoc 2004;224:372-379.

150) Spain CV, Scarlett JM, Houpt KA. Long-term risks and benefits of early-age gonadectomy in dogs. J Amer Vet Med Assoc 2004;224:380-387.

151) Spain CV, Scarlett JM, Cully SM. When to neuter dogs and cats: A survey of New York state veterinarians’ practices and beliefs. J Amer Anim Hosp Assoc 2002;38:482-488.

152) Stocklin-Gautschi NM, Hassig M, Reichler IM, et al. The relationship of urinary incontinence to early spaying in bitches. J Rep Fert 2001;Suppl 57:233-236.

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27 156) Thrusfield MV, Holt PE, Muirhead RH. Acquired urinary incontinence in bitches: Its incidence and relationship to neutering practices. J Sm Anim Prac 1998;39:559-566.

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28 Intra-articular Injections for Chronic Pain Management Margot Daly, DVM, CCRP SAGE Campbell - Physical Rehabilitation

- What is Multi-Modal Pain Management? Multi-Modal pain management is the use of a variety of medications, physical modalities, and local or regional techniques to effectively combat pain from a variety of pathways. Approaching pain management from several angles, rather than relying on NSAIDs and tramadol, can provide significant advantages, particularly in chronic or wind-up pain cases. Generally a synergistic combination of pharmaceuticals, neutraceuticals, and non- pharmaceutical analgesics such as low-level laser therapy, manual therapy, acupuncture, and pulsed electromagnetic field therapy (PEMF) are utilized. Intra-articular injections can in some cases be an extremely useful, and often underutilized, part of a multimodal pain management program.

- Local vs. systemic treatment of pain While systemic treatment with NSAIDs, gabapentin, opiates, Adequan, and neutraceuticals like Cosequin can and do improve pain scores and gait analysis measurements, some dogs will experience pain flare ups, or may be intolerant of some oral medications. Owners who struggle with compliance for multiple daily medications may be able to reduce their pet’s daily medication list, or prevent increases in the number or strength of medications as osteoarthritis progresses. Another excellent use of intra-articular injections is for pets who continue to have persistent effusion, pain, or lameness in a joint post-operatively, despite adequate medical and physical rehabilitation management.

- Indications for IA injection * As part of a multimodal approach to osteoarthritis * Intra-articular tendon/ligament injury (partial CCLR, low grade MSI, etc) * Joint blocking for lameness workups (common in equine, less common in canine) * Patients intolerant or nonresponsive to pharmaceutical pain management * Episodes of acute exacerbation of lameness

- Technical Aspects * Commonly injected joints and landmarks Shoulder - lateral approach, distal to the point of the acromion, patient in lateral, let leg hang off table Elbow - medial approach, distal to medial malleolus, patient in lateral, rolled towel under elbow Hip - proximal and cranial to greater trochanter, patient in lateral, externally rotate and distract the limb Stifle - cranial approach, just lateral to patellar tendon, stay perpendicular to avoid fat pad! * Injection supplies and techniques

Back to Table of Contents 29 22g needles (1-1.5” depending on the joint) Clippers, sterile scrub, sterile gloves Injectables Radiographs - it can be helpful to radiograph first to note location of any major osteophytes or anatomical abnormalities that may change the accuracy of your landmarks. Sedation - awake with light sedation/analgesia on board is fine if you have good restraint and are comfortable with the approach. I often use 0.2mg/kg butorphanol as it will have both a mild analgesic and sedative effect, or a standard dexdomitor/torb cocktail for more challenging patients or patients who need multiple injections. It is never wrong to use heavier sedation or brief anesthesia for very painful patients, joints you are less comfortable with or that may be challenging to inject due to marked osteophytes.

- What to inject? * Hyaluronic Acids - improved physiochemical properties within the joint, inhibition of inflammatory mediators, decreased degenerative changes (gross and microscopic). Up to 6 months of pain relief after three weekly consecutive injections. 80% respond well, 10% fair, 10% do not respond. * Steroids - recommended only in end-stage joints, with no more than 4 injections per year. Often the dog will respond very well to the first injection, with less response to future injections. I have had dogs improve for up to four months with HA/steroid alone. Triamcinolone is preferred, but depomedrol can be used as well. * Opiates - generally only used in the context of a “cocktail.” injection * "Cocktails" - A recipe I like for intra-articular OA relief specifically, was recommeded to me originally by a rehab vet who is also a Certified Veterinary Pain Practitioner. It includes: HA 3-5mg/joint Triamcinolone 6mg/joint (can substitute 20mg depomedrol if needed) Morphine 0.1mg/kg/joint

- Regenerative Medicine Options * Pros and cons This is an emerging field and in many ways there are still more questions than answers. Pros - autologous and therefore unlikely to cause major negative side effects if used correctly; in-house processing systems are now available for both PRP and Stem Cells; there is an emerging body of literature demonstrating the anti-inflammatory, anti-apoptotic, anti-fibrotic, and angiogenesis inducing efficacy of these treatments; for low grade CCLR and MSI cases and small OCD lesions, we may eventually be able to actually heal the injured ligament using these therapies. Cons - not inexpensive therapies: PRP generally $500 and up per treatment, stem cell therapy can be more depending on the system you are using; the legal status of collecting, shipping, and processing stem cells is a point of contention at the FDA and some veterinarians are concerned that off-site stem cell companies may become a legal gray area; lots of different PRP and SC machines out there, not all are validated for use in dogs, we are still learning what cell counts, culture techniques, etc. are needed in order to have consistent, positive effects. * Platelet Rich Plasma

30 Always processed in-house. Patient’s blood can be drawn and spun/filtered prior to, or at the time of injection. Most systems provide anticoagulant, if not, generally a 30 minute window to use the product. You can run the whole blood, and then the PRP through your CBC machine to see how well your system is concentrating the platelets and whether it is appropriately eliminating RBCs and WBCs. Processing is generally simple and takes approximately 15 minutes regardless of the system used. A small percentage of patients (20-25%) will have a painful flare up for the 24-48 hours following the injection - higher RBC counts in the PRP and higher proportions of certain WBCs are thought to increase the risk of flare ups. Patients with flare ups do not have negative outcomes once the flare has subsided. For mild synovitis, mild OA, or postoperative pain, a single injection is often sufficient. For moderate OA, two consecutive weekly inejctions or combination therapy is recommended. For severe OA, three injections every other week or combination therapy, or steroids are recommended. * Stem Cells / Combination therapy Progenitor cells that can differentiate into bone, cartilage, fat, or connective tissue. Can be processed in house or off-site. Adipose vs. Bone-Marrow derived. Studies have shown that in the acidic environment of an inflamed joint, stem cells will often die. However, when injected in combination with PRP, the PRP proved to have a protective effect on the stem cells, improving the time of response to therapy from <3 months to >6 months. There has also been a study confirming that stem cells were able to home to cartilage defects when injected IA - however some normal cartilage needs to be available for this to be successful, so may be better for joints with focal defects such as OCD lesions. In human medicine and in one VOSM case study, regeneration of partially ruptured CCLR was confirmed on second-look scope following PRP/SC combination therapy. Best used for severe OA, OCD lesions, and partial ligament tears. Medical, nutritional, and rehabilitation management is still needed for these patients. Improvements can be seen for up to 9 months following a single injection.

- References Ayhan, Egemen, Hayrettin Kesmezacar, and Isik Akgun. "Intraarticular injections (corticosteroid, hyaluronic acid, platelet rich plasma) for the knee osteoarthritis." World journal of orthopedics 5.3 (2014): 351. Sundman, Emily A., et al. "The anti-inflammatory and matrix restorative mechanisms of platelet-rich plasma in osteoarthritis." The American journal of sports medicine 42.1 (2014): 35-41. Jean, Yen‐ Hsuan, et al. "Hyaluronic acid attenuates osteoarthritis development in the anterior cruciate ligament‐ transected knee: Association with excitatory amino acid release in the joint dialysate." Journal of Orthopaedic Research 24.5 (2006): 1052-1061. Brandt, Kenneth D., Gerald N. Smith, and Lee S. Simon. "Intraarticular injection of hyaluronan as treatment for knee osteoarthritis: what is the evidence?." Arthritis & Rheumatology 43.6 (2000): 1192- 1203. Mokbel, A., et al. "Homing and efficacy of intra-articular injection of autologous mesenchymal stem cells in experimental chondral defects in dogs." Clinical and Experimental Rheumatology-Incl Supplements 29.2 (2011): 275. Vilar, Jose M., et al. "Controlled, blinded force platform analysis of the effect of intraarticular injection of autologous adipose-derived mesenchymal stem cells associated to PRGF-Endoret in osteoarthritic dogs." BMC veterinary research 9.1 (2013): 131.

31 Upchurch, David A., et al. "Effects of administration of adipose-derived stromal vascular fraction and platelet-rich plasma to dogs with osteoarthritis of the hip joints." American journal of veterinary research 77.9 (2016): 940-951. Yun, Sungho, Sae-Kwang Ku, and Young-Sam Kwon. "Adipose-derived mesenchymal stem cells and platelet-rich plasma synergistically ameliorate the surgical-induced osteoarthritis in Beagle dogs." Journal of orthopaedic surgery and research 11.1 (2016): 9. ArthroDynamic Technologies YouTube Channel for IA Injection Videos: https://www.youtube.com/channel/UCb5dvVm6bBEfA9tsC67ReMA

32 Geriatric Patient Care

Kelly Fishman, DVM, CVA, CCRT (in progress)

Department of Physical Rehabilitation SAGE Redwood City

Objective: To provide the general practitioner with knowledge specific to diagnosis and care of geriatric patients.

• Defining the geriatric patient o The term geriatric relates to people and there are no groupings to define what is geriatric in a dog . Due to difference in body size and mass in breeds of dogs, there is a sliding scale for designating what age a dog may be considered geriatric o So what is the typical age at which various sizes of dogs are considered geriatric . Table 35-1 (Millis)1 2 o IGF-1 pathway for ageing Kenyan demonstrated that small dogs have lower concentrations of the growth hormone IGF-1 in their blood than larger dogs. High levels of IGF-1 have been shown in a wide variety of organisms to be associated with increased risk of death from age-related diseases such as cancer2 o Estimated (>) that 14% to 43% of the pet population is moving into the second half of their life span, so understanding this group is important so that adjustments can be made to accommodate the changes in older patients (>>>)3 o The worlds oldest living dog, a Labrador named Bells, who died at 29 • Age is not a disease, but what are the effects of the aging process? o The body endures physiological changes as it ages, those important to physical rehabilitation are associated with the musculoskeletal and neurologic systems . Bone • The cortex thins and fat infiltrates the bone marrow • Fractures take longer to heal as callus formation is slower and geriatric patients with fractures are good (>) rehabilitation candidates (>>>) . Muscle • Loss of muscle fibers, reduced oxygenation to the muscles, or the development of muscle fibrosis.4 • Muscle atrophy is result • Less support for the joints leads to increased stress on cartilage and bone . Cartilage • Decreases in the number of chondrocytes, water content of the cartilage declines with age, leading to thinning of the cartilage layer.3 • Age-related thinning of cartilage and increased stress on the joints due to loss of muscle strength predispose the patient (>) to arthritis, which is the most common condition seen in geriatric patients.3

Back to Table of Contents 33 . Muscle spindle mechanoreceptors provide proprioceptive input. . With aging muscle spindle cells become less sensitive and joint mechanoreceptors volume decline, which contribute to a decline in proprioception.5 One of a combination of reasons geriatric patients experience increased falls • Geriatric Wellness Workup o Presence of concurrent neurologic, musculoskeletal, or metabolic disease should also be considered. o The increased likelihood of multiple conditions being present in a geriatric dog warrants a thorough medical evaluation before a rehabilitation program is designed. . Need to identify any concurrent diseases that may affect the success of rehabilitation . CBC, Chem, UA as baseline in all patients o Good history to identifying pain and lameness . Key questions to ask in a history • What is current exercise level and clients goals for their pet • For weakness: (>>>) o Dog slipping? o Trouble holding self up for defecation/urination? o Difficulty rising • For pain: (>>>) o Slowing down on walks? . Unique features of the physical exam • Check for toe nail wear • Joint pain o Slowly flex and extend joints, watch for signs of discomfort, feel for crepitus and tension • Muscle pain o Painful on palpation of muscle groups o Additional diagnostics (>>>) . Radiographs of affected joint . MRI o It is important that the client make regular appointments yearly. . A geriatric screen program should be implemented as part of a general wellness program for animals 8 and older. • Educate clients on normal process of aging, common conditions, nutrition, exercises o Communication between the veterinarian, rehabilitation therapist, and client is important so the best plan (tailored to the needs of the patient) is developed • Geriatric Rehabilitation Plan o Use of a questionnaire or notes (<<<) to establish a baseline and monitor

34 o Pain . Focus first on treating pain and then, when pain is controlled start focusing on rehabilitation . Multimodal pain management • Amantadine (>>> DOSE) • Gabapentin 7-10 mg/kg PO q8hr . Therapeutic modalities • Ice • Heat • Laser • TENS • Massage • Acupuncture . Several modalities, rather then one, are required in geriatric rehabilitation to produce notable results and improvements o Maintaining an ideal body weight . Obesity is one of the most common conditions in geriatric patients . Excess weight may predispose aging dogs to….. o Exercise . Low impact exercise • Short leash walks frequently • Controlled swims with a life vest, and for dogs with a history of swimming o Nutrition . Protein o Environmental Modification . Relatively simple and can make huge difference in the patients comfort and mobility . Warmth especially water circulating blankets will help reduce morning stiffness . Bedding should be padded . Non slip flooring . Ramps in place of stairs . Avoiding overdoing activities on weekends and excessive play which may result in more injury o What is offered at a physical rehabilitation center . Shockwave . Hydrotherapy . Manual therapy . Acupuncture . Advanced exercises programs that focus on strength, proprioception, endurance • Osteoarthritis is the most common problem of the MS system in geriatric dogs

35 o Estimated to affect 20% of adult dogs and we are approached frequently to treat arthritic patients1 o Clinical signs include muscle atrophy, decreased range of motion (joint stiffness), pain, limited activity and lameness6 o A vicious cycle of pain, reduced activity level, joint stiffness and loss of strength occurs as OA progresses.1 o Traditional management of dogs with OA included anti-inflammatory drugs and surgical management o More recent advances include weight loss, physical rehabilitation techniques (for joint ROM>) modalities, exercises for strength and endurance 1 . Helps to reduce the severity of clinical signs . Reduce the reliance on medications or reduce the dose of medication o Maintain IBW . Obesity contributes to the progression of OA in dogs (Marshall 2009) o Chondroprotectants . Omega-3 fatty acids 7 o Reduce inflammatory mediators (>) . Injectable polysulfated glycosaminoglycans (PSGAGs) • Increase production of hyaluronic acid and cartilage GAGs . Hyaluronic acid • Major component of synovial fluid and cartilage and injections of HA can increase synovial fluid viscosity, reduce inflammation and prostaglandin production . Glucosamine • Precursor to a part of the articular cartilage matrix • Studies and shown the glucosamine helps to improve cartilage metabolism and up regulates PG synthesis8 . Chondroitin sulfate • Predominant GAG found in articular cartilage o Laser . protocol for OA (>>>) o Exercises . Muscles act as shock absorbers for joints so strengthening these muscles will help support the joints. . Mild weight bearing exercises stimulate the metabolism . Low impact exercise that target muscles that support the spine, TL and PL (>) • Abdominal core exercise (>>>) • Forelimb exercises (>>>) • Pelvic limb exercises (>>>) • Endurance o Walk, swim

36 . Do not force exercise with unstable joint or with effused, painful joints . Warm up period and cool down o Veterinarians must impress on owners that the management of chronic OA is a lifelong Commitment and is hard work. Critical to re-evaluate on a regular basis and provide feedback and encouragement to clients. • OA Case Study o Clinical signs . Stiff in the mornings . Many older patients come to rehabilitation center with a suspected diagnosis of OA but no radiographs to diagnosis this. In some cases, owners decline radiographs because of the expense. o Laser o Exercise . Warm up: Warm pack to joints 10-15 min . Short walks with breaks. Gradually increasing time and watching and stopping with signs of fatigue . Cool down: 5 min slow walk followed by massage and gentle passive stretches or ROM and ice to control effusion . Strengthening exercises with the clients goals to help guide the exercises • Ramp work o UWTM or swimming . Minimal impact on joints • Determining quality of life and focusing on healthspan not lifespan o Health span is the period of life during which one is generally healthy and free from serious disease. We should be less interested in lifespan and more interested in healthspan o A mindset still exists that, when dogs grow old, “old age” is a medical condition rather than a stage of life during which some common medical conditions may occur. o How to manage client expectations o Help with end of life discussion

37 1 TALYOR, RA, MILLIS DL, LEVINE D, ADAMSON CP, BEVAN J & MARCELLIN-LITTLE, D. 2004. Physical rehabilitation for geriatric and arthritic patients. In: Millis, D.L., Levine, D., & Taylor, R.A. (eds) Canine Rehabilitation and Physical Therapy. St Louis, MO: Saunders-Elsevier, 411-425 2 Kenyon C. 3 STARR L. 2013. Rehabilitation for geriatric patients. In: ZINK, C., Van DYKE J. Canine Sports Medicine and Rehabilitation John Wiley & Sons, Inc., 349-369

4 METZGER, FL 2005. Senior and geriatric care programs for veterinarians. Vet Clin North Am Small Anim Pract, 35, 743-753 5 Shaffer 2007 6 Millis The role of exercise and physical modalities in the treatment of osteoarthritis. Vet Clin North Am Small Anim Pract 27:913-930, 1997 7 Roush 2010 8 Derfoul 2010 9 – Marshall 2009

38 The Highs and Lows of Cannabis

Micki McCabe, DVM, DACVIM (internal medicine), CVA,

Graduate Diploma of Veterinary Chinese Herbal Medicine

Integrative Medicine SAGE Centers for Veterinary Specialty and Emergency Care

Objective: To discuss updates on the use of medicinal cannabis and its legal implications as marijuana has become legalized in California for recreational use: how do we advise our clients? – Because they are asking!

Present legal climate as of the time of this writing

California Veterinary Medical Board meeting October 2017:

Current VMB position: the recommendation, approval, administration and/or dispensation of cannabis to animal patients by veterinarians is unlawful. However, the legal opinion could not conclude with certainty that discussing cannabis with clients is admissible.

The VMB directed the executive officer to pursue legislation which would allow the University of California to research the efficacy, safety, and indications of marijuana use in animals.

-California Veterinarian Nov-Dec 2017

Cannabis sativa (L.)

Cannabis sativa (L.) is the botanical name for what we call both hemp and marijuana. The plant has been utilized historically for the making of ropes, clothing (the stems and stalks are high in fiber), and as a food source and supplement, as the seeds are high in protein and omega 3 fatty acids. Cannabis has been cultivated for at least 10,000 years. The roots, leaves and flowers have been used as far back as Neolithic times for medicine and rituals. There are hundreds of different compounds in the plant, many of which are beneficial from a medical standpoint.

Early American literature at the time of Washington and Jefferson shows the use of cannabis for making sails but also references to likely smoking the plant. The plant, known simply as hemp at that time, was a vital crop to early settlers of the US. In the mid1800’s, the plant was noted by doctors for its mood enhancement, appetite stimulation, and interestingly, its safety.

Hemp vs. Marijuana: CBD vs. THC

The two compounds in cannabis that have received the most attention to date are THC and CBD. In 1964, the structure of Δ-9- tetrahydrocannabinol (Δ-9-THC) was identified as the primary psychoactive property of marijuana. In contrast, Cannabidiol, or CBD, has no psychoactive effects, but it can be very helpful medicinally for a variety of conditions that we will get to later. There are at least 421 other compounds in cannabis, including other cannabinoids, terpenes and terpenoids, flavonoids, non-cannabinoid phenols, nitrogenous compounds, etc. Interestingly, THC and CBD are almost odorless. The characteristic smell of marijuana comes from some of the terpenes and terpenoids in the plant.

Hemp, which is high in CBD and very low in THC, enjoys a more relaxed legal status than ‘marijuana,’ though it is still complicated. ‘Marijuana,’ by contrast, is cultivated for a multitude of concentrations of THC and CBD. The distinction between the two is confusing at best. For our intents and purposes, the public can purchase hemp products on line, in health food stores, and now even in pet stores. In California as of January 2018, adults

Back to Table of Contents 39 purchasing marijuana products, even those low in THC, will be buying from a marijuana dispensary. This is where the VMB’s position puts veterinarians in a difficult situation. The public is very interested in and able to access these products. It is imperative that we as trained professionals become legally able to guide the use of these products in our patients. Our patients are uniquely sensitive and their needs can be different than humans, as we all know.

Legalities

Marijuana prohibition started in the US in 1937, shortly after alcohol prohibition ended. This included the growing of industrial hemp, despite widespread cultivation of cannabis in the 1800’s and 1900’s as an efficient and sustainable crop for cloth, ropes, etc. Since 1970, the federal government has considered marijuana a schedule I drug. Schedule I drugs are those with ‘no currently accepted medical use in the United States, a lack of accepted safety for use under medical supervision, and a high potential for abuse,’ and include heroin, LSD, marijuana, peyote, quaaludes, and ecstasy. In contrast, cocaine and fentanyl are Schedule II drugs, buprenorphine a Schedule III, and the benzodiazapines are Schedule IV. There is work going on in Congress to try to lower the Schedule level of cannabis, but progress has been slow.

Despite its illegal federal status, marijuana has been approved in 29 states plus Washington D.C. for its medicinal use, and 9 states plus Washington D.C. for its recreational use. The medical marijuana laws protect human physicians when they counsel their patients on the use of marijuana. However, veterinarians are not allowed to prescribe or dispense cannabis to palliate an animal suffering from, among other illnesses terminal cancer and its associated pain, or breakthrough cluster seizures, in the case of refractory epilepsy. In 2014, the US Farm Bill was an act of Congress which defined industrial hemp as "any Cannabis sativa (L.) that produces naturally less than .3% THC on a dry weight basis." This has increased availability of hemp products to a large degree, though the laws remain murky. In January, Jeff Sessions rescinded the federal ‘relaxation’ on enforcement of cannabis laws in states where it is considered legal at present.

The Endocannabinoid system

Shortly after identifying the THC molecule in the sixties, the body’s own endocannaibinoid system was identified and in fact, makes its own cannabinoids. The first cannabinoid receptor, CB-1 was identified in the rat brain using a radio-labeled THC molecule. It has been identified to be present in vertebrates and invertebrates, so is evolutionarily ancient. The first endocannabinoid neurotransmitter was identified as anandamide, which is mimicked by THC. CB-1 is the most prevalent protein-based receptor in the CNS. It can also be found in fat cells, liver, and in muscles, skin, hair follicles, and skeletal tissue. The second cannabinoid receptor is known as CB-2, and its neurotransmitter is 2-Arachidonoylglycerol (2-AG), which is mimicked by CBD. CB-2 is found in cells of the immune system, as well as the peripheral nervous system. The endocannabinoid system’s major effects are homeostasis: they have been described as “Relax, Eat, Sleep, Forget and Protect.” The endocannabinoid system affects embryological development to apoptosis, and just about every system in between.

Entourage Effect

One area of tremendous interest is the Entourage effect, which basically shows the benefit of the entire plant as opposed to an isolated component, for instance Marinol (isolated THC) vs. marijuana. It has been clearly shown to have superior benefits than the isolated version.

Research on the use of Cannabis:

40 Over 23,000 published studies exist on the use of cannabinoids for multiple human medical conditions. In veterinary medicine, many studies have been retrospective or anecdotal. There are more and more being reported each year, but more information is vital. Potential benefits have been found in many areas including inappetance, seizures, cancer, arthritis, anxiety, antifungal, diabetes control, to name a few. There is little funding and access to good prospective studies to date, however, there is much anecdotal and historic evidence of good effect with the use of cannabis in a variety of situations.

Potential Clinical Applications for Cannabis (Boothe, 2015)

Pain, Inflammation and Immunomodulation • Effective for both acute and chronic pain by centrally and peripherally modulating nocioception • CBD affects T-cells resulting in a mild generalized immunosuppressive effect • CBD has been found to have potential benefit for arthritis and psoriasis in humans Epilepsy • CBD attentuates seizures in experimental models of epilepsy in animals • THCV inhibits CB1 receptor activity resulting some anticonvulsant activity

Anxiolytic • CBD exerts benzodiazepam-independent activity, postulated to be via post-synaptic 5-HT1A receptors Neuroprotection • CBD acts as an antioxidant and as such has been suggested for Alzheimer’s, Parkinson’s and Huntington’s diseases. Anti-emesis • CBD in animal models has been found to be effective for the control of vomiting that is unresponsive to 5-HT-3 agonists such as metoclopramide or ondansetron Diabetes Mellitus • CBD inhibits development of diabetes in experimental models of diabetes in mice. Reduction of pancreatic inflammation and antioxidant effects are credited with this benefit Bone formation • Cannabinoids stimulate the stem cells responsible for fracture healing and bone formation, as well as reducing bone loss by controlling bone reabsorption Cancer • Many of the cannabinoids have anti-apoptotic effects and reduce neoplastic proliferation in selected tumor cell lines • Anecdotal reports from both human and veterinary patients indicate the potential for complete remission and possibly even cure of a number of different neoplastic diseases Anti-microbial • Both CBC and CBG have potent anti-bacterial effects including against MRSA

Risk factors

Dogs have been found to have 200 times more cannabinoid receptors as compared to humans, with a much higher percentage in the cerebellum. This creates a more susceptible population to accidental overdose, especially with access to recreational products such as brownies (add to that additional toxicity of chocolate and butter) and the like. Dogs have a very specific reaction to overdose of THC called static ataxia, where they stand and can’t seem to walk or move, and sometimes fall over. They frequently dribble urine and can be very sedate. Generally, with supportive care, sometimes including intralipids to more rapidly pull the drug from the body’s fat, they do well, however, with the added ingestion of butter or chocolate, more serious injury can occur. Sometimes sensory depression can be profound. Interestingly, there is no known LD 50 for cannabis in dogs (tested to > 3000mg/kg THC). The safety margin is higher than most medications we prescribe. Having said that, in states where marijuana

41 has been legalized, trips to the ER for children and pets has increased significantly, mostly due to ingestion of marijuana edibles, which are typically high in fat (increasing absorption) and often having toxic ingredients in them (chocolate, raisins, etc).

Dosing ranges

Doses that tend to be effective and helpful would typically be a starting dose of 0. 05 mg/kg BID of THC products, increasing gradually to 0.5 mg/kg/day, sometimes higher over time. CBD dosing tends to be safe at 0.25 mg/kg BID to start, increasing to 0.5 mg/kg BID, and possibly higher as needed. More isn’t always better: it can be more effective to a point, then lose effectiveness if the dose is too high.

What’s the conversation?

Technically, veterinarians are not yet able to recommend or prescribe cannabis until the laws change. We can legally counsel people on the potential dangers of accidental ingestion. Owners can seek their own trusted sources, of which you may have an opinion on who to ask.

References

1. Boothe, DM. The High Points of Medical Marijuana. Western States Veterinary Conference Proceedings, February 2015. 2. Campora L, Miragliotta V, Ricci E, Cristino L, DiMarzo V, Albanese F, della Valle MF, Abramo F. Cannabinoid receptor type 1 and 2 expression in the skin of healthy dogs and dogs with atopic dermatitis. Am J Vet Res 2012;73:988-995. 3. https://www.deadiversion.usdoj.gov/schedules/ 4. Izzo AA, Borelli F, Capasso, R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends in Pharmacological Sciences; 2009;30(10):515-527. 5. McMillan DE, Dewey WL and Harris LS. Characteristics of Tetrahydrocannabinol tolerance. Annals NY Acad Sci. (1971)191:83-99. 6. McParland JM, Guy GW and Di Marzo V. Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System.(2014)PLoS ONE (9)3:e89566. doi:10.1371/journal.pone.0089566.

7. HTTP://WWW.NCSL.ORG/RESEARCH/AGRICULTURE-AND-RURAL-DEVELOPMENT/STATE-INDUSTRIAL-HEMP- STATUTES.ASPXSTATE INDUSTRIAL HEMP STATUTES 12/13/2017 8. https://medicalmarijuana.procon.org/view.resource.php?resourceID=000881 9. http://norml.org/states

10. Richter G Ultimate Pet Health Guide Hay House, Inc. 2017. 91-102. 11. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Brit J Pharmacol 2011;163:1344-64. 12. Silver RS Medicinal Cannabis sativa L: A Plant That Has Changed The World. VBMA Webinar December 2017

13. Silver, RJ. Medical Marijuana & Your Pet The Definitive Guide. Lulu Publishing Services. 2015.

14. Svizenska I, Dubovy P, Sulcova A. Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligandsand functional involvement in nervous system structures: A short review. Pham Biochem Beha 2008; 90: 501-511

42 Dermatology: Avoiding the Pitfalls of Pruritus

Stacey N. Holz, DVM

Dermatology

SAGE Centers - Dublin

Pruritic Pitfalls

We all may know a pruritic patient that comes to see us and leaves us scratching our heads as well. The keys to avoiding pruritic pitfalls reside in a systematic approach coupled with some patience and endurance. While many patients that present with pruritus are indeed atopic individuals, there are many other concurrent infectious diseases that may go overlooked and often contribute to the inflammation and pruritus of the patient. Many atopic animals may also have defects in skin and barrier function that can result in increase adherence by bacteria and promote growth of Malassezia. Identifying these will benefit the patient and improve the patient’s outcome.

The most common concurrent disorders with atopic patients that the author sees in dermatology practice are:

• Flea Allergic Dermatitis

• Food Allergy/Cutaneous Food Adverse Reaction

• Demodicosis

• Sarcoptes/Scabies Hypersensitivity

• Malassezia dermatitis

• Bacterial Pyoderma

Steps to avoid the pruritic pitfalls

Some of the clues to help the patient still reside in the history and the key to a good history is making sure you and your staff know the right questions to ask. For example: If asking a pet owner about flea control for their dog, do not simply ask “Do you use flea control?” and end with a yes or no answer. Instead ask more detailed and more insightful questions such as “What flea control product do you use ? When did you last use this for your pet? How often do you usually use this? Do the other pets in the household receive flea control? Does your pet swim?”

Some of the clues to help the pruritic patient are of course apparent during the examination. Look at the lesions and patterns of the lesions or pruritus (i.e. what areas of the body are pruritic). For example if a pruritic dog is mainly chewing their tail and pelvic limbs, do not overlook this pattern of flea allergic dermatitis in the dog. Secondary lesions on an animal comprised of pustules and crust or scale are often due to secondary bacterial infections. Secondary lesions on an animal comprised of brown waxy debris are often due to Malassezia. Further inspection using the microscope is warranted for any of these to confirm and outline a

Back to Table of Contents 43 plan. Also note if the lesions are on haired or non haired skin (ex: dermatophytes can affect haired skin whereas immune-mediated disorders can affect the nasal planum which is not haired) or Mucocutaneous junctions. Take note of if the lesions are symmetrical or asymmetrical (symmetrical lesions often occur with inflammation and asymmetry with infection and neoplasia).

Concurrent disorder contributing to pruritus Key to identiﬁcation and management

Flea Allergic Dermatitis Look for the pattern of pruritus (in dogs) and look more into the ﬂea control for the pet and the household as well as the lifestyle of the pet (i.e. swimmer or outdoors more)

Food Allergy / Cutaneous Food Adverse Reaction A good 8 week (in dogs) and 12 weeks (in cats) novel protein food trial remains the gold standard for diagnosing. Remember the other ﬂavored medications, toys, pill pockets, treats, etc.

Demodicosis Skin scrapings and trichograms and utilize some of the new ﬂea and tick control products we have that can eliminate mites.

Sarcoptes / Scabies Hypersensitivity Skin scrapings may occasionally reveal this more elusive mite. Look out for the pattern of extreme pruritus involving the pinna, lateral elbows, ventrum, etc.

Malassezia dermatitis Cytology is key in not missing this yeast!

Bacterial pyoderma Cytology and often bacterial cultures are key in identifying and establishing a plan to treat these.

Diagnostics

Virtually all pruritic patients should have a dermatology minimum data base with a good history, dermatological exam, as well as cytology and skin scrapings. The use of cytology in practice is still lower than it should be as this simple diagnostic tool is often under utilized. The Microscope is the most important piece of diagnostic equipment we use in dermatology and it’s use will help you raise your level of medicine to a higher standard.

Management Options for Pruritus

We start with a thorough exam including cytology (microscopic examination of surface material of the skin) and/or skin scrapings to determine concurrent infections. Any concurrent bacterial or Malassezia infections are treated.

Utilize excellent flea control to prevent flea allergy as many atopic animals can have a predisposition to flea allergy.

High potency fatty acid supplementation can decrease inflammation and may help some pets (especially those with dry skin).

44 Avoid any allergens when possible (including food allergens or indoor/outdoor allergens). A food trial is recommended for dogs with non-seasonal pruritus as food allergens can be flare factors for dogs with atopic dermatitis.

Bathing can be very helpful for infections, itch relief, and removing pollen or other allergens.

For short-term or symptomatic relief of itch:

• Steroid containing sprays or medications may be needed to break the itch/scratch cycle. Oral Prednisone or Prednisolone is usually administered at 0.5mg/kg SID - BID and tapered. Temaril-P may be given according to manufacturer label.

• Antihistamines are symptomatic and are very safe but do not help very many pets with acute allergies. These can be used if helpful (usually most helpful when used consistently daily) long-term.

• Oclacitinib is a new non-steroidal medication that may be used short term as it usually provides relief within days of starting. *see below for more information

For long-term management (allergies cannot be cured!) - non-steroidal therapies include:

• Allergen Specific Immunotherapy (ASIT) involves allergy testing to identify the environmental allergens that may be flare factors. This information is used (along with a good history, etc.) to develop a recipe for oral (SLIT/sublingual immunotherapy) or injectable (SCIT/subcutaneous immunotherapy) allergen specific immunotherapy. The response to this therapy is appreciated slowly over time and usually ~50-60% effective with the maximum benefit apparent in 6-12 months of starting. Side effects are rare with ASIT in dogs and cats. This is a very safe therapy and some patients can certainly respond more quickly (in the initial months) allowing them to use less concurrent medications.

• Cyclosporine (Atopica): is a non-steroidal oral medication used to modulate the immune response at ~5mg/kg SID in dogs and ~7mg/kg SID for cats. This helps the majority of dogs and cats that use this therapy within 1-2 months. If a patient responds to Cyclosporine therapy within the first 30-60 days of use, it is usually continued long-term. Often the frequency can be reduced to some degree over time. Side effects can include vomiting and diarrhea and giving this medication with food (or freezing capsules) often helps to prevent this. Usually annual CBC/Chemistry panel/Urinalysis are recommended with long-term use.

• Oclacitinib (Apoquel): is a new non-steroidal fairly fast acting oral medication (FDA approved for dogs only). Treatment doses are 0.4-0.6mg/kg once daily long-term (up to twice daily for short period of up to 14 days). Response is usually seen within days of initiating this therapy. It is a JAK inhibitor and is specific for JAK 1 and JAK 3 rather than JAK 2. The inhibition of JAK enzyme pathways, inhibits cytokines including inflammatory cytokines such as IL-31 (pruritogenic). Side effects can include vomiting or diarrhea and this medication is contraindicated in patients with infections or current or historical demodicosis. Currently many of us in dermatology are monitoring CBC/Chemistry panels regularly (every 6 months) with it’s chronic use.

45 • Monoclonal Antibody targeting IL-31 (Canine Atopic Dermatitis Immunotherapeutic/ Cytopoint): is a non-steroidal injectable medication (dogs only). This canine monoclonal antibody targets and neutralizes IL-31 (a inflammatory and pruritogenic cytokine). Treatment doses are a minimum dose of 2 mg/kg body weight. The full volume from each vial (comes in 10mg, 20mg, 30mg, and 40mg dose vials) is to be drawn into one syringe. The dose is administered subcutaneously as a single injection in hospital up to every 28-30 days (every 4-8 weeks as needed). Response if often seen within 24 hours. This can be given to dogs of any age. Side effects can include lethargy during the first 24 hours.

Summary of therapy options for Atopic Dermatitis

Therapy Dose Route Efficacy Time until range maximum benefit Bathing varies topical low to minutes but moderate may not last Antihistamines varies PO low can be weeks

Fatty Acids 18-20 mg/lb. PO low can be 2 SID of EPA months Steroids 0.5mg/kg SID PO moderate to days (prednisone) high Cyclosporine 5(dog)-7(cat) PO moderate to typically 1-2 mg/kg SID high months ASIT (SCIT or build up and SC or PO moderate to up to 6-12 SLIT) maintenance high months Oclacitinib 0.4-0.6mg/kg PO moderate to days SID* *dogs high mAb targeting ~2 mg/kg once SC moderate to hours to days canine IL-31 q 4-8 weeks *dogs high (Cytopoint)

*Remember*: we cannot cure allergies but we can manage them to help our patients lead a more comfortable and happier life.

Beast Bacteria

Those of you that are football fans may be familiar with the term “Beast Mode” during a successful play by a former Seattle Seahawks running back. Unfortunately, bacteria (particularly Staphylococcus) are increasingly taking on their own ability to operate in a “beast mode” of mutation and adaptation and successfully survive and resist antibiotics.

46 Bacterial pyoderma in dogs is usually caused by Staphylococcus pseudintermedius and is not usually considered contagious. More recently, however, antibiotic resistant and potentially contagious bacterial skin infections are being diagnosed with greater frequency in animals. Bacteria will not usually invade normal skin. Rather, skin damaged or inflamed as a result of allergic skin disease or another underlying disorder is a good environment for bacteria to invade, overgrow, and result in an infection. The inflammation of the skin changes the microclimate of the skin (increases humidity and temperature) which favors bacterial growth. A pet who swims frequently may also be predisposed to bacterial skin infections. Animals with allergic skin disease (particularly underlying atopic dermatitis), parasitic skin disease, immunosuppression, Hypothyroidism, Cushing’s disease, cancer, Pemphigus, etc. can be at risk for bacterial pyoderma. Bacteria may have increased adherence ability in pets with underlying atopic dermatitis.

Clinical Signs Common clinical signs can consist of pruritus, pustules, bullae, ulcers, fistula, epidermal collarettes, erythema, partial alopecia, scale, crust, fistulae (furunculosis/deep), and odor.

Diagnosis The diagnosis is based upon both examination and microscopic examination of an impression slide cytology demonstrating bacteria and neutrophils (direct slide cytology is usually better to find bacteria than tape). Bacterial cultures (culture and sensitivity) are needed to determine exact species and effective antibiotics, especially in more severe or refractory infections.

Resistant Bacterial Infections More and more we are seeing forms of bacteria that are resistant to many antibiotics including methicillin resistant forms and multi-drug resistant E.coli. Multi-drug resistance incidence has significantly increased. Treatment with low concentrations of a bactericidal agent can generate multi-drug resistance via increase in mutation rate. In “reactive resistance” bactericidal antibiotics function as mutagens.

The MRS (methicillin resistant strains) are resistant to all B-lactams and may be resistant to Fluoroquinolones, Sulfas, Clindamycin, etc. Do not use Cephalosporins or Clavamox regardless of susceptibility.

Methicillin Resistant Staph. Pseudintermedius (MRSP): This species is commonly cultured from patients and can cause a variety of ear/skin infections in pets. While it can be spread from animals to people, this is very rare and there is much less concern about MRSP compared to MRSA in terms of risk to humans.

Methicillin Resistant Staph. aureus (MRSA): This species is usually more concerning as MRSA is a cause of disease in people and an increasing problem in pets (cats, dogs, and horses). It can be transmitted between animals and people (in both directions).

Methicillin Resistant Staph. schleiferi (MRSS): This species is closely related to S. pseudintermedius. It is most commonly found in skin and ear infections. Transmission to people from pets is very unlikely.

MRSA is the main concern with regard to Staph. infections, and warrants particular attention when it causes infection in a pet. However, any bacterial infection in a pet should compel owners and veterinarians to use excellent hand hygiene principles. For other Staph. species (MRSP), the risks of transmission to people are much lower, but it is still essential to implement measures to further reduce the spread. In cases such as MRSA, it is even more important to take precautions including washing hands frequently, avoiding contact with the

47 infected part of the animal's body (plus the nose, where MRSA can be), keeping the infected site(s) bandaged (if possible), keeping infected pets off the bed, and restricting contact with high risk people (young children, elderly, people who are immunocompromised). For the other Staph. species, the risks to people are much lower, but it is still reasonable to implement these measures to reduce risk. Please see Worms and Germs handouts at wormsandgermsblog.com. *KEY POINT: WASHING HANDS/GOOD HAND HYGIENE IS PARAMOUNT*

Treatment of MRS and other resistant bacteria require appropriate drug, dose, and duration based upon culture and avoid use of antibiotics when possible and use topical antimicrobials that do not promote resistance. Key attributes of topical ingredients are in the table below.

Topical Ingredient Available in/ Key attributes Forms Acetic Acid Cleaners, acidic, antibacterial, anti-fungal Shampoo, Spray, Wipe Benzoyl Peroxide Shampoo, antibacterial and follicular flushing as well gel as keratoplastic and keratolytic, drying, “bleaching” Ceramides Spot on, lipids important for barrier function Shampoos Chlorhexidine Shampoo, antibacterial and anti-fungal at higher Spray, concentrations Mousse DMSO solvent enhances absorption of other substances

Topical Fatty acids Spray, keratolytic, can be moisturizing Shampoo Ketoconazole Spray, Wipe, anti-fungal Shampoo Miconazole Solution, anti-fungal and antibacterial (including Shampoo MRS) Topical Oatmeal Spray, humectant, increase water content of (colloidal) Shampoo stratum corneum = moisturize, antipruritic Phytosphingosine Spot on, lipids important for barrier function Shampoo, Spray, Wipe, Mousse Pramoxine Spray, anti-pruritic Shampoo Selenium Sulfide Shampoo keratolytic, keratoplastic, degreasing

Sulfur Shampoo, antibacterial and keratolytic, keratoplastic Dip

Vetericyn VF Spray, antibacterial and anti-fungal, promotes 48 Hydrogel healing/re-epithealization Track 2 Antimicrobial Resistance

An approachable team of specialists providing advanced, collaborative, and compassionate care.

Christine Wong DVM, DACVECC Back to Table of Contents This document is intended for confidential use by the SAGE organization and/or its affiliates. 3/18/2018 49 Any review, dissemination, distribution, or copying of this document is strictly prohibited. Outline

• Antimicrobial resistance – Defined – Contributors to emergence – Challenges to new therapy • California antimicrobial stewardship legislation • Judicious use of antimicrobials – Index of suspicion – Selection • Hospital antibiotic stewardship programs • Novel approaches to address AMR

50 Antimicrobial Resistance

A measure of an antimicrobial agent’s decreased ability to kill or inhibit growth of a microorganism

• Multidrug resistance – organism is resistant to 1 agent in ≥3 separate antimicrobial categories in which the wild type would normally be susceptible

• Extensive drug resistance – organism is susceptible to 1 or 2 classes

• Pandrug resistance – organism is not susceptible to all known or licensed antimicrobials

51 Antimicrobial Resistance

• Veterinary data is limited – Lack of funding – Surveillance based on organ systems or disease state – Limited regulations on reporting 52 AMR: Veterinary

Journal of Antimicrobial Chemotherapy (JAC) (Schwarz, 2016) 53 AMR: Veterinary

54 AMR: Veterinary

55 AMR: Veterinary

56 Emergence of Antimicrobial Resistance

• Natural/ Intrinsic resistance • Acquired resistance – change in phenotype compared with wild type, which confers decreased effectiveness of an antimicrobial

57 Emergence of Antimicrobial Resistance

• Antimicrobials are the most used and abused • Over prescription driven by: – Patient demand – Time pressure on clinicians – Diagnostic uncertainty – Resistance recognized nationally, but not on the individual level

58 Emergence of Antimicrobial Resistance

59 Risk Factors for AMR

Humans: • Prior antimicrobial use • Admission to an ICU • Prolonged length of hospital stay • Recent surgery • Mechanical ventilation • Infection control lapses • Exposure to patient with colonization of MDR pathogen

60 Risk Factors for AMR

Dogs: • Predisposing disease • Prior antimicrobial use • Duration of hospitalization • Duration of ICU hospitalization • Surgical procedure • Mechanical ventilation

61 Challenges to Development of New Therapeutics

• Antimicrobial resistance is small compared to other disease states – Impact is greatest in serious and life-threatening diseases, which are rare • Competition amongst antimicrobials already on the market • Relatively low price per dose • Rapid emergence of resistance • Stewardship efforts limit access to new drugs

62 63 Antimicrobial Stewardship Legislation

• Antimicrobial stewardship may no longer be voluntary • Since 2014, human hospitals are required to adopt and implement an antimicrobial stewardship policy • Since 2017, similar requirements applied to skilled nursing facilities • SB 361: act to amend section 4846.5 on antimicrobial stewardship: education and policies

• https://leginfo.legislature.ca.gov/faces/billTextClient.xhtml?bill_id=201520160 SB361

64 Antimicrobial Stewardship Legislation • SB 361, Hill. Antimicrobial stewardship: education and policies. • This bill would require a veterinarian who renews his or her license on or after January 1, 2018, to complete a minimum of one credit hour of continuing education on the judicious use of medically important antimicrobial drugs, as defined, every 4 years as part of the continuing education requirement.

65 66 Veterinary Antimicrobial Use Monitoring

• Section 105 Animal Drug User Fee Act Revision in 2016 • FDA releases an annual report on antimicrobials sold and distributed for use in food-producing animals • Sponsors of approved or conditionally approved antimicrobial new animal drug products are required to report species-specific estimates • “…to improve the efficiency of the reporting process …so that we could more effectively address the problem of resistance associated with the use of antimicrobial drugs in food animal production.”

• https://www.federalregister.gov/documents/2016/05/11/2016- 11082/antimicrobial-animal-drug-sales-and-distribution-reporting

67 Judicious Use of Antimicrobials

68 Index of Suspicion

• Are there systemic signs? – Blood smear: Bands, toxic change – Signs of sepsis: hyperemic mucous membranes, tachycardia, hypotension, fever – Evidence of a nidus of infection: open wounds, abscess, malodorous abnormal effusion/ discharge • What are the consequences of not starting antimicrobials? – Timely implementation vs awaiting culture

69 Timely Implementation

• Administration of effective antimicrobial within the first hour of documented septic shock was associated with a 79.9% survival rate • For every hour that an antimicrobial is delayed in the first identification of septic shock, mortality is increased by 7.6%

70 Timely Implementation

Time to antimicrobial implementation • Preprotocol 6h • Protocol 1h Survival to discharge revealed no difference (p=0.425) • Preprotocol 60% • Protocol 70%

71 Timely Implementation

• Empirical choice appropriate 52.6% of the time • Appropriate selection not associated with outcome • Previous antimicrobial use had no association with outcome – Associated with subsequent inappropriate empirical selection • Previous abdominal surgery was associated with inappropriate empirical selection

72 Timely Implementation

Humans • Timely implementation only shown to apply to septic shock • Scarce evidence to support timely implementation in milder forms of critical illness-related infections Dogs • Evidence to support early and aggressive use in all patients with critical illness-related bacterial infections is lacking

73 Selection

Intracellular bacteria on FNA or other sample • Source of sample (eg urine, skin) • Morphology – rods, cocci, spirochete, presence of endospores • Gram staining Culture and susceptibility interpretation • Minimum inhibitory concentration (MIC) – lowest concentration of an antimicrobial that inhibits growth of the microorganism • Breakpoints – highest MIC achievable in serum given standard route of an antimicrobial that inhibits growth of the organism – Circumstantial resistance – in vitro test predicts susceptibility, but in vivo antimicrobial lacks efficacy

74 Selection

75 Selection

Pharmacokinetic factors • Breakpoints reflect achievable serum concentrations – Diffusion rate-limited: diffusion from plasma to tissues can be limited by available blood flow • eg abscess, cavitated mass, hypotension – Perfusion rate-limited: membrane may present a barrier to drug diffusion • eg CNS, prostate, eye, bronchial epithelium • Circumstantial resistance – in vitro test predicts susceptibility, but in vivo antimicrobial lacks efficacy

76 Selection

Host factors • Functional state defense – Immune suppression • Functional state metabolism during illness – Absorption, distribution, metabolism and elimination • Presence of foreign body or prosthetic material – Biofilm

77 Optimization

78 Escalation vs De-escalation Escalation – selecting an antimicrobial with a narrow spectrum of activity that likely covers the pathogen causing the suspected infection • Used in the stable patient that can await culture De-escalation – empiric administration of broad-spectrum antimicrobials aimed to cover all pathogens • Usually reserved for critical patients • Culture and suspectibility before implementation mandatory – Modify and step down treatment after results

79 Duration

Prolonged therapy may: • Amplify resistant strains • Induce development of chronic infections Reduce duration by: • Frequent reassessment to consider discontinuation of therapy after resolution of clinical signs • Repeat cytologic evaluation or negative culture

80 Practicing Antimicrobial Stewardship

• Judicious use of antimicrobials • Data monitoring • Transparency • Stewardship infrastructure • Availability of expertise in infectious disease

81 CDC Core Elements of Antimicrobial Steward Programs

• Leadership Commitment • Accountability • Drug Expertise • Implementation or action • Tracking and reporting • Education

82 Novel Approaches to Address AMR

• Harnessing the immune system • Manipulating microbial communities • Antivirulence strategies • Rapid Diagnostics

83 Communication – you are the expert

84 References 1. Epstein S. Multidrug-Resistant Infections. Hopper, K. & Silverstein, D. C., editors. In: Small Animal Critical Care Medicine, 2nd ed. St. Louis: Saunders; 2015: 537-540 2. Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2012;18(3):268-281. 3. https://www.cdc.gov/drugresistance/about.html 4. Schwarz S, Enne VI, van Duijkeren E. 40 years of veterinary papers in JAC - what have we learnt? The Journal of antimicrobial chemotherapy. 2016;71(10):2681-2690. 5. Marques C, Belas A, Franco A, Aboim C, Gama LT, Pomba C. Increase in antimicrobial resistance and emergence of major international high-risk clonal lineages in dogs and cats with urinary tract infection: 16 year retrospective study. The Journal of antimicrobial chemotherapy. 2018;73(2):377-384. 6. Couto N, Monchique C, Belas A, Marques C, Gama LT, Pomba C. Trends and molecular mechanisms of antimicrobial resistance in clinical staphylococci isolated from companion animals over a 16 year period. The Journal of antimicrobial chemotherapy. 2016;71(6):1479-1487. 7. Marston HD, Dixon DM, Knisely JM, Palmore TN, Fauci AS. Antimicrobial Resistance. Jama. 2016;316(11):1193-1204. 8. Powers JH. Antimicrobial drug development--the past, the present, and the future. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2004;10 Suppl 4:23-31.

85 References 9. https://leginfo.legislature.ca.gov/faces/billTextClient.xhtml?bill_id=201520160SB361 10. https://www.federalregister.gov/documents/2016/05/11/2016-11082/antimicrobial-animal-drug-sales-and-distribution-reporting 11. https://me.me/t/smokey-bear 12. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Critical care medicine. 2006;34(6):1589-1596. 13. Abelson AL, Buckley GJ, Rozanski EA. Positive impact of an emergency department protocol on time to antimicrobial administration in dogs with septic peritonitis. Journal of veterinary emergency and critical care (San Antonio, Tex : 2001). 2013;23(5):551-556. 14. Dickinson AE, Summers JF, Wignal J, Boag AK, Keir I. Impact of appropriate empirical antimicrobial therapy on outcome of dogs with septic peritonitis. Journal of veterinary emergency and critical care (San Antonio, Tex : 2001). 2015;25(1):152-159. 15. Keir I, Dickinson AE. The role of antimicrobials in the treatment of sepsis and critical illness-related bacterial infections: examination of the evidence. Journal of veterinary emergency and critical care (San Antonio, Tex : 2001). 2015;25(1):55-62. 16. Papich MG. Strategies for Treating Infections in Critically Ill Patients. Hopper, K. & Silverstein, D. C., editors. In: Small Animal Critical Care Medicine, 2nd ed. St. Louis: Saunders; 2015 949-955 17. https://www.mercurynews.com/2018/01/11/canine-flu-has-bay-area-dog-owners-worried/

86 Common Toxicities Sara Lefman DVM, DACVECC

DECONTAMINATION

• Emesis induction o Most effective within 3-4 hours of ingestion o Canine . Apomorphine 0.03mg/kg IV or 0.04mg/kg IM, 0.08mg/kg SQ, 0.25mg/kg in conjunctival sac . 3% hydrogen peroxide 1tsp/10lb . Morphine 0.2-0.5mg/kg IM o Feline . Dexdomitor 3.5mcg/kg IV or 7mcg/kg IM . Hydromorphone 0.05-0.1mg/kg IM with or without midazolam 0.2mg/kg IM . Xylazine 0.44mg/kg IM • Activated charcoal o 1-3g/kg body weight; first dose may or may not include a cathartic • Gastric lavage o For caustic or petroleum distillate ingestions o Should be intubated! • Enemas • 20% Intralipid therapies o 1.5ml/kg bolus over 5-15 minutes followed by a CRI at 0.25ml/kg/min for 30-120 minutes

TOXINS

• Grapes/Raisins o Method of toxicity: unknown but causes damage to proximal renal epithelium o Time to toxic effect: up to 72 hours post ingestion o Target organs: kidneys o Clinical signs: none, or signs related to renal failure o Duration of clinical signs: variable o Emesis? Yes o Charcoal? Yes, although questionable o Supportive care: . Aggressive fluid diuresis for a minimum of 48 hr is recommended

Back to Table of Contents 87 • NSAIDs o Method of toxicity: blockade of COX enzymes inhibiting the production of prostaglandins; directly irritate GI mucosa o Target organs: gastrointestinal tract, kidneys, CNS o Clinical signs: dose dependent but can cause vomiting, diarrhea, GI ulceration, renal failure, seizures, coma, idiosyncratic hepatic toxicity o Duration of clinical signs: dependent on t1/2 of drug; species specific o Emesis? Yes o Charcoal? Yes, repeated q4-6 for 3 doses o Supportive care: . IV fluids for 3 half lives of drug (usually 48-72 hrs) . Misoprostol 1-5mcg/kg PO q8-12 x 3-5d . Pantoprazole/Omeprazole 1mg/kg IV q24 x 5-10d . Sucralfate 0.5-1g PO q8 x 5-10 days 30 minutes before other drugs . Maropitant 1mg/kg IV q24 . Naloxone for neurologic signs such as coma . Sodium bicarbonate for metabolic acidosis . With massive ingestions, total plasma exchange can be considered

• Xylitol o Method of toxicity: sugar alcohols result in the release of insulin (rapid and dose dependent) . Doses >75-100mg/kg for hypoglycemia . Doses greater than 500mg/kg may develop severe hepatic insufficiency or failure o Time to toxic effect: 30 minutes to 24 hours for hypoglycemia, 12-72 hours for liver failure o Target organs: pancreas, liver o Clinical signs: ataxia, dullness, collapse, seizures; signs of liver failure with high exposures o Duration of clinical signs: 24 hours for hypoglycemia, transient liver value increase within 72 hours or sustained signs of liver failure o Emesis? Not usually helpful; may have minimal effect if >30 minutes after ingestion o Charcoal? No, does not appreciably bind o Supportive care: . Dextrose PRN; usually only needed for first 12 hours . Hepatoprotectants (N-acetylcysteine, SAM-e, silymarin) for dogs with large exposures

• Marijuana o Method of toxicity: THC causes release of acetylcholine, dopamine, NE and serotonin in brain

88 o Time to toxic effect: usually 30 minutes or greater but depends on the product with edibles having a longer onset o Target organs: brain o Clinical signs: ataxia, hyperesthesia, mental dullness, urinary incontinence, mydriasis, respiratory depression, hyper or hypothermia, tachy/bradycardia o Duration of clinical signs: in some forms, up to 36 hours; 18-24 hour average o Emesis? Only if recent ingestion and patient not neurologic o Charcoal? Yes, can give repeated doses if not neurologic o Supportive care: . Anti-emetics . IV fluid therapy . Heat support . Intralipid with severe cases

• Acetaminophen (Tylenol) o Method of toxicity: metabolized in liver to toxic and non-toxic metabolites; some metabolites cause oxidative damage o Time to toxic effect: 30-60 minutes o Target organs: gastrointestinal tract, red blood cells, liver, CNS o Clinical signs: vomiting, diarrhea, methemoglobinemia, facial edema, KCS, hepatic failure/dysfunction, neuro toxicity o Emesis? Yes o Charcoal? Yes, within 2 hours of ingestion o Supportive care: . SAMe 40mg/kg PO then 20mgkg PO q24 in canine SAMe 180mg PO then 90mg q12-24 or 30-50mg/kg q24 in felines . N-acetylcysteine 140mg/kg IV once followed by 70mg/kg IV q6 for 7 doses (about 72 hours)

• Bromethalin o Method of toxicity: uncouples oxidative phosphorylation in brain o Toxic dose: 0.46mg/kg in dogs, 0.24mg/kg in cats; LD50= 3.65mg/kg in dogs, 0.54mg/kg in cats o Time to toxic effect: 24-72 hours o Target organs: CNS o Clinical signs: high dose: convulsant syndrome or low dose: paralytic syndrome o Emesis? Yes o Charcoal? Yes, repeated q8 for 3-6 doses o Supportive care: . Anti-convulsants if clinical . Mannitol or hypertonic saline to reduce cerebral edema if clinical

89 • Anticoagulant rodenticides o Method of toxicity: inhibit vitamin K epoxide reductase leading to deficiency of vitamin K dependent coagulation factors (2, 7, 9, 10) o Time to toxic effect: 48-72 hours o Target organs: coagulation system o Clinical signs: none or signs of coagulopathy (bleeding into body cavities, pharynx, etc) o Duration of clinical signs: either no clinical signs or coagulopathy until treated o Emesis? Yes o Charcoal? Yes o Supportive care: . Vitamin K 3-5mg/kg/d PO/SQ if not able to decontaminate or need treatment; must continue for 30 days . Plasma at 10-20ml/kg IV for coagulopathic patients

• Metaldehyde o Method of toxicity: reduction in CNS GABA levels and serotonin and norepinephrine, increased monoamine oxidase activity o Toxic dose: 2mg/kg or > in dogs o Time to toxic effect: CNS signs within 1-3 hours, hepatic failure possible 3-5 days post exposure o Target organs: CNS, liver o Clinical signs: tremoring, seizures, hyperthermia, ataxia, tachycardia, depression, tachypnea, nystagmus, mydriasis o Emesis? Yes, within 30-60 minutes of ingetion o Charcoal? Yes, repeated every 6-8 hours o Supportive care: . Methocarbamol 55-220mg/kg IV slowly until relaxation achieved, then to effect; can be repeated but not to exceed 330mg/kg/day . Diazepam 0.5-1mg/kg IV, can be repeated . IV fluids . Anti-convulsant therapy (use barbituates cautiously) . Intralipid for specific compouds such as Penitrem A if other therapies not effective

• Chocolate o Method of toxicity: theobromine and caffeine cause GI, cardiac and CNS stimulation o Toxic dose: depends on type of chocolate; refer to ASPCA chocolate wheel! In general, GI at 20mg/kg, cardiac at 40-50mg/kg, CNS at >60mg/kg o Time to toxic effect: 6-12 hours of ingestion o Target organs: GI, heart, CNS

90 o Clinical signs: vomiting, diarrhea, tachycardia, arrhythmias, hyperthermia, seizures o Duration of clinical signs: up to 72 hours in severe ingestions o Emesis? Yes o Charcoal? Yes, repeated every 8-12 hours o Supportive care: o IV fluid therapy o Anti-emetics o ECG monitoring with treatment of arrhythmias o Methocarbamol or anticonvulsant therapy PRN

• Ant bait o Non-toxic as the ingredients are specific to the insect and are present in small amounts o Plastic ingestion

91 Shock: Updates in Diagnosis and Management

Terence Krentz, DVM

I. Shock a. Defined: inadequate cellular energy production. b. Most commonly occurs secondary to poor tissue perfusion from low or unevenly distributed blood flow. c. This leads to critical decrease in oxygen delivery (DO2) compared to oxygen consumption (VO2) in tissues. d. Major classification scheme: i. Hypovolemic, distributive, cardiogenic. ii. Also metabolic, hypoxic. e. Hypovolemic i. Internal/external hemorrhage or excessive loss of other bodily fluids (polyuria, vomiting, diarrhea, third-spacing). f. Distributive i. Maldistribution of blood flow. ii. Sepsis/SIRS: initial hyperdynamic phase or vasodilatory shock (vasodialation) progressing to hypodynamic (decreased cardiac output). iii. Gastric dilatation-volvulus (GDV): often normal circulating blood volume, compression of major vessels leads to decreased venous return and reduced cardiac output. 1. Secondary hypovolemic shock from rupture of short gastric and splenic vessels. g. Cardiogenic i. Inadequate cellular metabolism secondary to cardiac dysfunction despite adequate intravascular volume. 1. Systolic/diastolic dysfunction or arrhythmias, cardiac tamponade. II. Diagnosis a. Minimum database: CBC/Chem/UA. b. Coagulation panel, blood typing, cross matching (all cats, canine with prior transfusion). c. Venous/arterial blood gas analysis with lactate. d. Blood pressure: indirect (Doppler, oscillometric), direct (arterial). e. Pulse oximetry. f. When patient more stable: i. Thoracic/abdominal radiographs. ii. Abdominal ultrasound/FAST scan. iii. Echocardiography. III. Therapy a. All forms except cardiogenic, recommend rapid IV access and administration large volumes isotonic crystalloid solutions. i. No proven benefit of one fluid type over another. ii. Inadequate fluid administration can contribute to mortality. iii. Use of balanced, isotonic crystalloids (LRS, NormR, Plasmalyte).

Back to Table of Contents 92 1. 90mL/kg dogs, 50mL/kg cats given in ¼ increments with re-evaluation of perfusion parameters. 2. Hypotensive resuscitation (target MAP 60 mm Hg) for hemorrhagic shock. iv. Hyperoncotic solutions. 1. Hypertonic saline 7.5%: 4mL/kg IV v. Synthetic colloids/hydroxyethyl starches not recommended given concern for acute kidney injury and increased mortality associated with their use. vi. Blood component therapy. 1. Packed red blood cells 10-20 mL/kg. 2. Fresh whole blood 20-30 mL/kg. 3. Fresh frozen plasma 10-20 mL/kg. 4. Human serum albumin or lyophilized canine albumin depending on availability. b. Cardiogenic shock: oxygen therapy and avoidance of stress. i. Diuretic and vasodilator therapy. ii. Positive inotrope therapy: dobutamine, pimobendan. iii. Sedation and intubation/positive-pressure ventilation. c. End-points of therapy. i. Normalization of heart rate, blood pressure (MAP 70-120 mm Hg). ii. Improved pulse quality, appropriate mentation, mucus membrane pallor. iii. Urine output: UOP > 0.5mL/kg/hr iv. Resolution lactic acidosis: Lac < 2.5 mmol/L. v. Pulse-oximetry: SpO2 >95% vi. Central venous pressure: 0-5 mm H2O vii. Mixed venous oxygen saturation: SvO2 >70%

Resources:

Cazzoli C, Prittie J. The crystalloid-colloid debate: consequences of resuscitation fluid selection in veterinary critical care. JVECC 2015, 25: 6-19.

Silverstein DC et al. Effectiveness of intravenous fluids resuscitation in the emergency room for treatment of hypotension in dogs: 35 cases (2000-2010). JVECC 2012, 22: 666-673.

Haskins S. Shock: In: Small Animal Critical Care Medicine, 2nd Ed. Ed Silverstein DC, Hopper K. Elsevier. St. Louis, MO. 2015. Pp 26-30.

93 Sunday, March 18, 2018 Immunosuppressive Therapies

Moria Borys, DVM, MS Sage Small Animal Symposium 2018

Subject Basic review of Immunology: 1. Innate vs Adaptive immunity a. Innate: Immediate defense i. No prior exposure/sensitization required 1. No lasting immunity ii.Physical and chemical barriers 1. Skin, epithelial surfaces (GI, respiratory, urogenital) 2. Normal flora, fatty acids, pH 3. Enzymes (saliva, gastrointestinal, tears) iii. Many components 1. Neutrophils 2. Macrophages/dendritic cells 3. Eosinophils and basophils 4. NK Cells 5. Complement activation 6. Cytokines: IL-1, IL-6, TNF-alpha 7. Chemokines: IL-8, CXCL1 8. Interferons – IFN-alpha a. Interfere with viral replication 9. Defensins 10.Toll-like receptors and NOD-like receptors b. Adaptive immunity i. Primary component: B and T lymphocytes ii.Humoral and Cell-Mediated immunity 2. Humoral vs Cell-Mediated Immunity a. Humoral: i. B cells – recognize Ag through surface-bound Ig 1. Become plasma cells or memory B cells 2. Secrete large amounts of their specific Ig a. Binding/opsonization of extracellular pathogens and destruction vs phagocytosis, complement binding b. Cell-mediated immunity i. T cells – T cells recognize pathogens through interaction with antigen-presenting cells 1. Do not recognize free-floating antigen (needs to be pre- processed) 2. Presented in the major histocompatibility complex (MHC) 3. Differentiate into Cytotoxic (CD8+) or Helper (CD4+) T cells

Back to Table of Contents 94 Sunday, March 18, 2018 ii.Antigen-presenting cells: Macrophages, dendritic cells, B cells 1. Antigen presentation occurs in peripheral or secondary lymph organs (LNs, spleen, GALT, BALT) 3. Immune dysregulation a. Not well understood b. Likely multifactorial i. Inherent genetic factors ii.Environmental (Infectious agents, drugs, vaccines, neoplasia) c. Autoimmune disease: i. Inappropriately stimulated ii. Marked local or systemic inﬂammatory response iii. Tissue destruction, clinical disease d. Immunosuppressants i. Many not well studied in veterinary medicine ii. Use and dosages often extracted from human studies

IMMUNE SUPPRESSANTS 1. Glucocorticoids 1. MOA: 1. Indirect effects: 1. Bind to intracellular cytoplasmic glucocorticoid receptor 2. GC-receptor complex translocates to nucleus 3. Binds to DNA response elements 4. Influences gene transcription 1. Suppress cytokine activity, alter macrophage function 2. Direct effects: 1. Stabilize cell membrane of endothelial cells 1. Inhibit production of local chemotactic factors 2. Inhibit release of arachidonic acid (prevent production of prostaglandins, thromboxanes, and leukotrienes) 3. Inhibit release of collagenase, elastase, tissue plasminogen activator 4. Redistribute monocytes and lymphocytes from peripheral circulation to lymphatics and bone marrow (primarily T cells) 2. Affect most (possibly all) cells of the body 3. Effects are dose-dependent 1. Physiologic 2. Anti-inflammatory: 1. Inhibit phospholipase A2 and release of proinflammatory cytokines 2. Stabilize granulocyte membranes 3. Immune suppressive: 1. Downregulate macrophage Fc receptor expression (decrease responsiveness to antibody-sensitized cells, decreased antigen processing)

95 Sunday, March 18, 2018 2. Suppress T cell function 1. Induce apoptosis of T cells 3. B cell antibody production downregulated with chronic use 4. Adverse effects: 1. Signiﬁcant systemic side effects unavoidable 2. Iatrogenic hyperadrenocorticism with adrenal gland suppression 1. PU, PD, PP, panting, weight gain 3. Gastrointestinal ulceration 4. Insulin resistance (+/- development of overt DM) 5. Muscle catabolism 6. Delayed wound healing 7. Opportunistic infections 8. Behavioral changes 9. Liver enzyme elevations 1. ALP (steroid isoenzyme) +/- ALT 10. Thromboembolic disease 5. Advantages 1. Rapid onset of action 2. Inexpensive 3. Lots of clinical experience 6. Clinical use: 1. Remain a mainstay or ﬁrst-line therapy for many autoimmune diseases 2. Combination therapy with many other agents 1. NOT NSAIDS – increased risk of GI ulceration 7. Available forms - vary greatly in potency, route of administration, and duration of action 1. Prednisone/prednisolone 1. Prednisone = prodrug 1. Metabolized to active form, prednisolone, in the body 2. Cats – 5x higher plasma concentrations achieved with predniSOLONE vs prednisone 1. Lower prednisone absorption vs decreased conversion? 2. Dexamethasone sodium phosphate 1. Injectable 2. Patients with severe malabsorption 1. Increased bioavailability, improved clinical response 3. Lacks mineralocorticoid activity 1. Minimize sodium/water retention 2. Cardiac disease, hypoalbuminemia, hypertension 4. Potency: 4-10x prednisone 3. Budesonide 1. Oral formulation 2. High potency 3. Exploits pH differential between proximal and distal small intestine – targets action to distal SI

96 Sunday, March 18, 2018 4. Absorbed at the level of the enterocyte and delivered to liver via portal system 1. 80-90% ﬁrst pass metabolism 2. Minimizes systemic bioavailability 3. Despite “minimal” absorption, blunted ACTH stimulation results in dogs treated for 30 days 5. Commonly used for canine IBD 4. Fluticasone 1. Locally delivered (inhaled) for respiratory disease 1. Minimize systemic adverse effects 2. Expensive! 2. Myelotoxic agents: Cyclophosphamide 1. MOA: 1. Alkylation of DNA during S phase of cell cycle 1. Lethal, or produce miscoding errors that inhibit replication or DNA transcription 2. Suppresses both B- and T-cell activity and antibody production 2. Adverse effects: 1. Myelosuppression 2. Gastrointestinal upset 3. Alopecia 4. Hemorrhagic cystitis 3. Clinical uses: 1. IMHA 2. ITP 3. Rheumatoid arthritis 4. Feline IMHA, RA 3. Myelotoxic agents: Azathioprine 1. Thiopurine (purine analog), prodrug of 6-mercaptopurine 1. Liver and other peripheral tissues (including in erythrocytes): 1. Enzymatically oxidized to 6-thiouric acid (via xanthine oxidase) or 6- methylmercaptopurine (via thiopurine methyltransferase, TMPT) 1. These are both inactive metabolites 2. Active metabolite: 6-thioguanine nucleotides (6-TGNs) – via hypoxanthine phosphoribosyl transferase (HPRT) 1. Responsible for both therapeutic and cytotoxic effects of azathioprine 2. MOA: 1. Once generated, 6-TGNs compete with endogenous purines for incorporation into RNA and DNA 1. Creates nonfunctional DNA/RNA 2. Disruption of DNA and RNA synthesis and mitosis 3. Targets humoral and cell-mediated immunity (lymphocytes) 1. Lymphocytes: lack of salvage pathway for purine biosynthesis

97 Sunday, March 18, 2018 2. Interferes with lymphocyte proliferation, reduces lymphocyte numbers, and decreases t cell-dependent antibody synthesis 2. Adverse effects: 1. Myelosuppression 1. Dose-dependent neutropenia, thrombocytopenia 2. Delayed response – 1-2 weeks of therapy 3. Reversible after drug withdrawal 4. 13% prevalence in one study 2. Gastrointestinal upset (vomiting, diarrhea) 3. Hepatitis, hepatic necrosis 1. Monitoring of liver enzymes strongly recommended (ALT) 4. Pancreatitis 5. Cats – AVOID! Or significant dose reduction. 1. Highly myelotoxic 3. Clinical use: 1. Delayed efficacy (days to weeks) makes clinical utility more limited 2. Organ transplant 3. GC-sparing effects 1. IMHA, ITP, autoimmune skin diseases, myasthenia gravis, SLE, IBD 2. Recent study: Azathioprine combined with prednisolone not more effective than prednisolone alone 4. Perianal fistulas: only moderately effective (monotherapy) 4. Pharmacokinetics 1. Humans: TMPT activity highly variable and correlates with outcomes 1. Both efficacy and toxicity 2. Decreased activity—> Increased toxicity due to increased availability of substrate for HRPT, increased 6-TGNs 3. 9-fold difference in TMPT activity reported in dogs 1. Lowest: Giant Schnauzers 2. Highest: Alaskan Malamutes 4. Cats: Decreased TMPT compared to humans, dogs 2. Allopurinol – xanthine oxidase inhibitor 1. Significant increase in 6-TGN concentrations 2. Increased risk of toxicity 3. Generally avoid using together 4. Has been exploited in some humans with nonresponsive IBD 4. Myelotoxic agents: Methotrexate 1. MOA: Competitive inhibition of folic acid reductase 1. Necessary for dihydrofolate —> tetrahydrofolate 2. Affects production of purines and pyrimidines 3. S phase of cell cycle 2. Uses: limited

98 Sunday, March 18, 2018 1. Antineoplastic 2. Rheumatoid arthritis (humans), psoriasis 5. Calcineurin Inhibitors: Cyclosporine (Atopica) 1. Polypeptide derived from Norwegian soil fungus, Tolypocladium inflatum 2. MOA: Calcineurin inhibitor 1. Cyclosporine binds to cytoplasmic protein cyclophilin 1. T lymphocytes express cyclophilin in high concentrations 2. Highly conserved protein that acts as protein isomerase (protein- folding enzyme) 2. Cyclosporine-cyclophilin complex binds to and blocks function of calcineurin 1. Calcineurin = Serine/threonine phosphatase activated by increased intracellular calcium concentrations 1. Dephosphorylates nuclear factor of activated T cells (NFAT) 2. Translocates into nucleus, binds to nuclear transcription factor (activator protein 1) and induces transcription of genes for T-cell activation 3. Final consequences of calcineurin inactivation: 1. Decreased expression of IL-2 and other cytokines 1. Prevention of further t-cell activation 2. Attenuation of clonal proliferation of T- and B-cells 2. Decreased production of IL-3, IL-4, TNF-alpha 1. Altered function of granulocytes, macrophages, NK cells, eosinophils, mast cells 3. Reported to decrease lymphocyte cytokine production in feline lymphocytes in vitro, canine lymphocytes both in vitro and in vivo 3. Advantages 1. Glucocorticoid-sparing effects – many combination protocols 2. Rapid onset of immune suppression 3. Fewer systemic side effects vs glucocorticoids 4. Adverse effects: 1. Gastrointestinal upset 1. Most common side effect reported 2. Often transient or responsive to dose reduction 2. Gingival hyperplasia 3. Opportunistic infections 4. Hepatotoxicity 5. Lymphoproliferative disorders 6. Reported case of anaphylaxis secondary to parenteral administration in a cat 7. Thromboembolic complications 5. Clinical uses: 1. Initial use: management of transplant recipients 2. Perianal fistulas – first line therapy 1. Topical tacrolimus – very closely related

99 Sunday, March 18, 2018 1. Binds to cytoplasmic immunophilin FKBP12 2. Limited usage due to severe systemic side effects 1. Topical: perianal fistulas, KCS, dermatitis 3. Keratoconjunctivitis sicca (KCS, dry eye) 4. Atopic dermatitis 5. IBD 6. IMHA 7. Pure red cell aplasia (PRCA) 8. ITP 6. Pharmacokinetics: 1. Substrate of Cy P450, family 3, subfamily A (CYP3A) and of drug transporter P-glycoprotein 1. INCREASED levels: 1. Azole antifungals - Coadministration with ketoconazole sometimes used to reduce dose/cost of cyclosporine 2. Clarithromycin 3. Grapefruit juice 2. Significantly impacted by formulation (oil-based vs microemulsion), species, liver function, concurrent medications 3. Blood levels: Assay method essential 1. Plasma vs whole blood 2. Immunoassay vs HPLC 3. Target levels not as clearly established in veterinary medicine 1. Humans: whole-blood trough 150-250 ng/mL 2. Dogs/cats: Whole blood trough 400-600 ng/mL routinely used 1. Trough levels do not reliably predict clinical response 4. Other markers: 1. T-cell cytokine expression 2. Drug exposure 3. Lymphocyte-specific proliferation 6. Chlorambucil 1. Nitrogen mustard derivative 2. Prodrug: converted in liver to active metabolite, phenylacetic acid 3. MOA: 1. Cell-cycle nonspecific, cytotoxic alkylating agent 1. Cross-links DNA at random 2. Targets B cells 4. Slow acting – may take 2 weeks to reach therapeutic efficacy 5. Adverse effects: 1. Less adverse effects in cats vs azathioprine 2. Myelosuppression 1. Mild, typically 7-14d after initiation 3. Gastrointestinal toxicity 4. Neurotoxicity (reversible myoclonus) 1. Reported in a single cat after overdose

100 Sunday, March 18, 2018 6. Clinical use: 1. Prospective studies lacking 2. Alimentary lymphoma – cats 3. Feline ITP – second line drug, successful in one case report 7. Intravenous Immunoglobulin (IVIg) 1. Purified pooled human plasma product, multiple healthy donors 1. 90% purified IgG, trace IgA, IgM, CD4, CD8, and HLA 2. MOA: Not well-understood 1. Fc receptor blockade 2. Autoantibody elimination 3. Cytokine modulation 4. Complement inhibition 5. Fas-Fas ligand blockade 3. Considered adjunctive therapy in acute management 1. Not typically useful for single-agent therapy 2. Potential for acute disease stabilization due to fast disease response 1. Prevention of further tissue injury 2. Provides time for long-term immunomodulatory therapies to become clinically effective 3. Shortens hospitalization 4. Decreases need for repeated transfusions 4. Low likelihood of adverse events 1. None reported in clinically ill dogs/cats. 1. Complicated by diphenhydramine administration in some dogs prior to use. 2. Inflammatory/hypercoaguable state in healthy Beagles after administration. 3. Reported in humans: 1. Acute hypersensitivity reactions (foreign protein administration) 2. Hypotension 3. Thromboembolism 4. Renal insufficiency 5. Dose-dependent aseptic meningitis 5. Clinical use: 1. Severe/refractory ITP, IMHA 1. No consensus in veterinary medicine 2. Most data limited to retrospective studies 3. ITP: Prospective randomized double-blinded, placebo controlled clinical trial 1. All dogs treated with immune suppressive doses of corticosteroids 2. Randomized: placebo vs IVIg 3. Significant reduction in resolution of thrombocytopenia (3.7 vs 7.5 days) and days hospitalized (4 vs 8 days). 4. No difference in number of blood transfusions, cost, mortality. 4. IMHA: Blinded clinical trial.

101 Sunday, March 18, 2018 1. 28 dogs, IVIg vs placebo during initial stabilization in addition to prednisone and low-weight molecular heparin 2. No difference in days to stabilization of PCV or duration of hospitalization 5. 7 approved uses in humans: 1. Kawasaki disease 2. Bone marrow transplantation 3. ITP 4. Chronic B-cell lymphocytic leukemia 5. Pediatric HIV 6. Chronic inflammatory demyelinating polyneuropathy 7. Primary immunoglobulin deficiency 8. Vincristine 1. Alkaloid, derived from periwinkle plant 2. Increases platelet counts in ITP 3. Proposed MOA: 1. Stimulates megakaryocyte fragmentation 2. Impairs microtubule assembly within macrophages to interfere with platelet phagocytosis 1. Single agent in humans: only increases platelet counts in subset of refractory ITP patients 4. Adverse effects 1. Clinically significant myelosuppression 1. Theoretically possible 2. Not reported at these dosages (0.02 mg/kg) 2. Gastrointestinal upset (anorexia, vomiting, diarrhea) 3. Peripheral neuropathy (rare) 4. Extravasation/perivascular tissue sloughing 5. Effects on platelet function not documented 1. Reportedly stimulates thrombopoesis in normal dogs, with no effect on in vivo platelet function 2. Dogs with lymphoma: results in abnormal platelet aggregation 6. Clinical use 1. Actively bleeding patients w/ ITP 2. Initial patient stabilization or salvage therapy 3. 24 dogs with severe ITP: 1. Prednisone alone: platelet count >40k 6.8 days, mean hospitalization 7.3 days 2. Prednisone + vincristine: platelet count >40k 4.9 days, mean hospitalization 5.4 days 9. Mycophenolate mofetil 1. Prodrug – active metabolite is mycophenolic acid (MPA) 2. Rapid onset of action (maximal effect 2-4 hours post administration) 3. MOA:

102 Sunday, March 18, 2018 1. Potent, selective, noncompetitive, reversible inhibitor of type II isoform of inosine-5’-monophosphate dehydrogenase (IMPDH) 1. IMPDH catalyzes rate-limiting step of de novo synthesis of guanosine nucleotides (IMP —> GMP) 2. Lymphocytes (B and T) entirely dependent on de novo pathway for purine synthesis, differentiation, proliferation, and Ig production 2. Type II isoform of IMPDH more abundant in activated lymphocytes 1. Type II is 5x more susceptible to MPA vs type I isoform (which is expressed in many cell types) 3. MPA cytotoxicity thus selective to lymphocytes via depletion of guanosine and deoxyguanosine nucleotides 1. Suppresses dendritic cell maturation 2. Reduces monocyte recruitment to sites of inflammation 3. May be antifibrotic 1. Ability to inhibit proliferation of non-immune cells (including smooth muscle, renal tubular, mesangial cells) 4. Adverse effects: 1. Limited information available in dogs/cats. 2. Gastrointestinal upset (diarrhea, weight loss) 3. Mild allergic reactions 4. Opportunistic infections 5. Allergic reactions 6. Neutropenia 7. Lymphoma 5. Pharmacokinetics: 1. Multiple drug interactions 2. Fluoroquinolones, metronidazole: 1. Reduce enterohepatic circulation of MMF, reduce efficacy 3. Proton pump inhibitors (PPIs) 1. Reduced dissolution of MMF in stomach, decreased drug exposure 1. Effect negated with enteric-coated formulations 4. Cyclosporine 1. Inhibition of enterohepatic recirculation, reduced efficacy 5. Glucocorticoids 1. Increase metabolism of MMF (reduced efficacy) 6. Azathioprine 1. Similar MOAs, similar risks of bone marrow suppression 2. Concurrent administration not recommended 6. Clinical use: 1. Canine aplastic anemia 2. Subepidermal blistering autoimmune skin disease 3. Feline refractory IMHA (case report – 2 cats) 4. Acquired myasthenia gravis 1. Small retrospective case series 2. Combination therapy not more effective than pyridostigmine alone

103 Sunday, March 18, 2018 10. Leflunomide 1. Synthetic isoxazole derivative 2. Active metabolite: malononitrilamide or teriflunomide 3. MOA: 1. Teriflunomide – selective pyrimidine synthesis inhibitor via reversible inhibition of dihydroorotate dehydrogenase 1. This is a mitochondrial enzyme required for de novo pyrimidine biosynthesis 2. B and T lymphocytes lack a pyrimidine salvage pathway 2. Proposed – inhibition of tyrosine kinase activity 1. Alters cytokine and growth factor receptors 3. Malononitrilamide: inhibits mitogen-stimulated proliferation of feline lymphocytes in vivo. 4. Adverse effects: 1. Lethargy 2. GI upset 3. Bone marrow suppression 1. Leukopenia, thrombocytopenia – generally mild 2. Severe myelosuppression and bone marrow necrosis anecdotally reported 4. Humans: Severe idiosyncratic reactions 1. Myelosuppression, hepatotoxicosis, toxic epidermal necrolysis 5. Clinical use: 1. Humans: 1. Rheumatoid arthritis 2. Crohn’s disease 3. Systemic lupus erythematosus 4. Transplant recipients 2. Canine 1. Evan’s syndrome 2. Reactive histiocytosis 3. IMPA 1. 8/14 dogs had resolution of clinical signs after initiation of leflunomide (retrospective) 3. Feline 1. Rheumatoid arthritis – marked improvement with leflunomide and methotrexate in 50% cats that had been nonresponsive to “standard” therapy

104 Drug Active metabolite MOA Adverse effects Onset of action Notes Dose + Indications

Glucocorticoids Prednisolone Many - binds to Iatrogenic Rapid Dexamethasone 2 mg/kg/day (-solone vs - sone intracellular GC hyperadrenocorticis SP - No immune achieves 4-5x receptor, nuclear m Many mineralocorticoid suppressive (pred) higher blood levels response autoimmune dzs effects in cats, no elements to alter Water/sodium DexSP 4-10x conversion protein synthesis retention Budesonide - high more potent needed) (affects ALL (congestive heart ﬁrst-pass CELLS OF THE failure) metabolism BODY) (80-90%) so less - Decrease GI ulceration/perf systemic effects. activity of (NSAIDS) Concentrated local phospholipase effects (converted A2 (&production Induction of ALP to lipophilic esters of arachidonic steroid isoenzyme in cells) acids) - Stabilize Fluticasone = granulocyte inhaled “topical” membranes for asthma. - T-cell apoptosis Extensive ﬁrst- pass metabolism

105 Review of and Updates on Diabetes in Dogs and Cats

Kris Bruskiewicz, DVM, DACVIM

SAGE Centers (Concord)

Heidi McClain, DVM, DACVIM

SAGE Centers (Redwood City)

To discuss current management and monitoring strategies for dogs and cats with diabetes using case studies for examples.

Back to Table of Contents 106 Probiotics

L. Noelani Reinker, DVM, DACVIM (Internal Medicine)

Probiotics are increasing in popularity as a treatment for patients with chronic gastrointestinal disease. When dealing with patients with chronic gastrointestinal disease, it can be difficult to critically evaluate and choose between the myriad of options available (i.e. probiotics vs. antibiotics) and within the classes of probiotics themselves (brand, strain, etc.).

First, a number of definitions:

- Prebiotic – Non-digestible substances that provide a beneficial physiological effect for the host by selectively stimulating the favorable growth or activity of a limited number of indigenous bacteria

- Probiotic - Live microorganisms which, when administered in adequate amounts, confer a health benefit on the host

- Synbiotic - Products that contain both probiotics and prebiotics

- Microbiota – Collection of all microorganisms residing in the GI tract.

- Microbiome – collection of all microbial genes in the sample, including host, bacteria, fungi, viruses, etc.

More and more attention is being paid to the microbiome because the sum of all the organisms in the gut (and their subsequent metabolic actions) is likely what influences the overall health of the GI tract. Bacteria specifically can be part of the overall host immunity, have immunomodulating effects, and provide food sources for enterocytes (vitamins, short chain fatty acids). They can also change the pH of the ingesta. Modulation of the pH reduces growth of pathogens and decreases solubility of bile acids, decreasing reabsorption and enterohepatic circulation of bile acids, increased absorption of minerals, and reduced absorption of ammonia.

Dysbiosis occurs when the bacterial populations within the GI tract become imbalanced. It has been shown to be present in many different types of gastrointestinal disease.b Recently, a dysbiosis index was developed at Texas A&M GI Lab, which targets the bacterial groups that seem to be the most altered in diseased dogs. An index of 0 is normal, with elevations above 0 being abnormal.

From a clinical perspective, it’s very important to critically evaluate a probiotic product before recommending it to your client. Questions to consider are:

- Quantity of bacteria present - Number of strains present, and are they grown together or separately - Sensitive to specific antibiotics (for example, concurrent administration of metronidazole) - Other additives such as prebiotics or flavorings - Literature available on the product or strain

In previous studies, many products have failed critical evaluation. These products are not regulated by the FDA so this is not illegal. Some ways that they can fall short include:

- Incorrect labeling (misspelling, inaccuracies, incomplete) - Incorrect quantity of CFU (colony-forming units) and incorrect strain of bacteria

Back to Table of Contents 107 - The bacteria have died or are are not stable in the package

The frustration with administration of probiotics is that there is not enough information about what may work best for a given condition and not enough regulation of probiotic products. This combination makes probiotics a relatively weak tool for the use in gastrointestinal disease.

Fecal microbiotia transplantation is considered a new method for restoring GI flora. In humans, there is good evidence to support the use of fecal transplantation for certain conditions such as diarrhea due to Clostridium difficile (success rates 87-90%). In some studies in humans, the success rates do seem higher with specific donors. In veterinary medicine, not much information is available, and most evidence is anecdotal. We suspect that the success of fecal transplantation depends on several factors such as the optimal GI flora in the donor, the disease process being treated, as well as factors involved in the FMT process. In the future this may become a valuable tool in veterinary medicine.

Further reading:

Redfern et al. Role of the gastrointestinal microbiota in small animal health and disease. Veterinary Record 181:14, 2017.

JAVMA Probiotics in Veterinary Medicine, Mar 2017, Vol. 250, No. 5, Pages 519-528

108 2/1/18

I’ve fallen…and I got up! SYNCOPE

An approachable team of specialists providing advanced, collaborative, and compassionate care.

Sarah Silverman March 18, 2018 This document is intended for confidential use by the SAGE organization and/or its affiliates. Any review, dissemination, distribution, or copying of this document is strictly prohibited.

Syncope

Summary • Definition • What to expect when you’re expecting syncope • Causes of syncope • Diagnostic approach • Treatment

What is syncope?

Syncope or fainting – Short loss of consciousness and muscle strength – Due to transient decrease in blood flow to the entire brain Pre-syncope – State consisting of lightheadedness, muscular weakness, and “feeling faint”

Back to Table of Contents 109 2/1/18

What to expect when you’re expecting syncope

Timing – Fast onset • If repeated episodes, pets may recognize feeling of lightheadedness – Short duration – seconds – Spontaneous recovery: “as if nothing ever happened” • Some pets may act “clingy” or briefly confused

What to expect when you’re expecting syncope

Stimulus – Exercise – Excitement – Coughing – Standing up from sleeping/laying

What to expect when you’re expecting syncope

The episode – Completely limp – Rigid limbs +/- opisthotonus or outstretched neck – May urinate and/or defecate – Unconscious/unresponsive – May vocalize early in episode

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Causes of Syncope

• Primary cardiac – Structural – Electrical • Pulmonary hypertension • Vasovagal (neurocardiogenic) • Orthostatic hypotension • Other

Causes - Structural

Obstructive Lesions – Subaortic Stenosis – Pulmonic Stenosis – Poorly placed tumor or clot – HOCM

Causes - Structural

Mitral Valve Endocardiosis – Congestive Heart Failure • Reactive PH • Decreased oxygenation – Without CHF • Increase in sympathetic modulation of HR • Transient increase in BP

– Arrhythmia J Vet Intern Med 2014;28:363–370 Holter Monitoring of Small Breed Dogs with Advanced – LA rupture Myxomatous Mitral Valve Disease with and without a History of Syncope

C.E. Rasmussen, T. Falk, A. Domanjko Petric, M. Schaldemose, N.E. Zois, S.G. Moesgaard, B. Ablad, H.Y. Nilsen, I. Ljungvall, K. Hoglund,€ J. H€aggstrom,€ H.D. Pedersen, J.M. Bland, and L.H. Olsen

Background: Syncope is a transient loss of consciousness occasionally occurring in dogs with advanced myxomatous mitral valve disease (MMVD). Objective: (1) To study ECG changes during syncopal episodes in dogs with advanced MMVD and (2) to compare the occurrence of arrhythmias and changes in heart rate variability (HRV) between dogs with advanced MMVD with and without a history of syncope. Animals: Forty-three privately owned dogs (<15 kg) with advanced MMVD: 21 with and 22 without a history of syncope. Methods: Prospective study with dogs recruited for an evaluation including history, physical examination, echocardiography, and arrhythmia and HRV analysis performed on 24-hour Holter recordings. Results: A syncopal episode was observed during Holter monitoring in 4 dogs: 3 dogs had sinus rhythm and 1 dog had sinus arrest followed by escape rhythm. An arrhythmia variable representing sinus arrhythmia was significantly lower in dogs with a history of syncope than in those without (P=.008). Eight of 26 HRV variables were significantly different between dogs with and without a history of syncope. Conclusions and Clinical Importance: Compared with dogs without a history of syncope, dogs with advanced MMVD and a history of syncope did not have a higher occurrence of arrhythmias, but had less sinus arrhythmia, and had changes in HRV variables representing decreased overall HRV, decreased parasympathetic, and increased sympathetic modulation of heart rate. Key words: Arrhythmia; Collapse; Heart rate variability.

yncope is a transient loss of consciousness because Sof a decreased delivery of essential nutrients to the Abbreviations: 1,2 brain. A syncopal episode has a sudden onset, is of ACE-I angiotensin-converting enzyme inhibitor short duration (usually a few seconds), and is followed APC atrial premature complex 3 by spontaneous complete recovery. In dogs, the cause AV atrioventricular of syncope is often divided into 3 categories: cardiac, bpm beats per minute noncardiac, and unknown. A cardiac-related cause of CKCS Cavalier King Charles Spaniel syncope is suggested to be the most common cause of Dig digoxin syncope in dogs.2 Decreased cardiac output leading to F furosemide cerebral hypoperfusion has been suggested as the cause HF high frequency HFn normalized high frequency HR heart rate 111 HRV heart rate variability From the Department of Veterinary Clinical and Animal Sciences (Rasmussen, Zois, Schaldemose); the Department of Veterinary IVSd interventricular septal thickness in diastole Disease Biology, Faculty of Health and Medical Sciences, University IVSs interventricular septal thickness in systole of Copenhagen, Frederiksberg, Denmark (Falk, Olsen); the Clinic LA/Ao left atrium-to-aortic root ratio for Small Animal Medicine and Surgery, University of Ljubljana, LF low frequency Ljubljana, Slovenia (Domanjko-Petric); Novo Nordisk A/S, LFn normalized low frequency Maløv, Denmark (Moesgaard, Pedersen); the Bla Stjarnans€ Animal LVIDd left ventricular internal dimension in diastole Hospital, Gothenburg, Sweden (Ablad, Nilsen); the Department of LVIDs left ventricular internal dimension in systole Clinical Sciences, (Ljungvall, Haggstr€ om);€ the Department of LVPWd left ventricular free wall thickness in diastole Anatomy, Physiology and Biochemistry, Swedish University of LVPWs left ventricular free wall thickness in systole Agricultural Sciences, Uppsala, Sweden (Hoglund);€ and the Department of Health Sciences, University of York, York, UK MEAN mean of all NN intervals (Bland). Preliminary results of this study were presented as a MMVD myxomatous mitral valve disease research abstract at the European College of Veterinary Internal MR mitral regurgitation Medicine(ECVIM)Congress in Porto, Portugal, 2009. NN interval interval between two QRS complex of sinus or Corresponding author: L.H. Olsen, Department of Veterinary supraventricular origin Disease Biology, Faculty of Health and Medical Sciences, Univer- PAH pulmonary hypertension sity of Copenhagen, Ridebanevej 9, 1870 Frederiksberg C, PCA principal component analysis Denmark; e-mail: [email protected]. Pimo pimobendan Submitted October 5, 2012; Revised October 8, 2013; PISA proximal isovelocity surface area Accepted November 26, 2013. pNN50 % of successive NN intervals that diﬀer more than Copyright © 2014 by the American College of Veterinary Internal 50 ms Medicine 10.1111/jvim.12290 2/1/18

Causes - Electrical

Bradyarrhythmia – High grade 2nd degree AV block • 3:1 conduction • can be intermittent – 3rd degree AV block – Causes • Idiopathic • Degenerative process (nodal fibrosis) • Electrolyte abnormalities (K) • Myocarditis (inflammatory, infectious) • Neoplasia • Congenital

Causes - Electrical

High grade 2nd degree AV block

Intermittent AV block

Causes - Electrical

3rd degree AV block

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Causes - Electrical

Sick Sinus Syndrome – Sinus arrest with failure of subsidiary pacemakers – Can involve AV dysfunction – Can present with inappropriate sinus arrhythmia or sinus bradycardia, periods of sinus arrest – Can have periods of supraventricular tachycardia (brady-tachy syndrome)

Causes - Electrical

Sick Sinus Syndrome or Sinus Node Dysfunction – Intrinsic sinus node dysfunction – Secondary to autonomic dysfunction • Suggests medical management • 44% atropine responsive (partial and adequate responses) Journal of Veterinary Cardiology (2016) -, -e- – Miniature schnauzer, miniature dachshund, WHWT, cocker spaniel; females > males www.elsevier.com/locate/jvc – Sudden death rare Outcome and survival in canine sick sinus syndrome and sinus node dysfunction: 93 cases (2002e2014)

J.L. Ward, DVM , T.C. DeFrancesco, DVM , S.P. Tou, DVM , C.E. Atkins, DVM , E.H. Grifﬁth, PhD , B.W. Keene, DVM, MS*

North Carolina State University Veterinary Hospital, 1052 William Moore Dr, Raleigh, NC 27607, USA

Received 27 August 2015; received in revised form 29 March 2016; accepted 8 April 2016

KEYWORDS Abstract Introduction: To evaluate the clinical presentation, diagnosis, treat- Dog; ment, and outcomes of a group of dogs with sinoatrial node abnormalities. Arrhythmia; Animals: Ninety-three client-owned dogs at a referral institution. Bradycardia; Materials and Methods: Medical records were reviewed for clinical history, diagnos- Sinus arrest; tic testing, and medical or permanent artiﬁcial pacemaker (PAP) treatment. Own- Pacemaker ers or veterinarians were contacted for long-term follow-up. Results: Sixty-one dogs were symptomatic for their bradyarrhythmia and were diagnosed with sick sinus syndrome (SSS). Thirty-two dogs were asymptomatic for their bradyarrhythmia and were diagnosed with sinus node dysfunction (SND). Miniature Schnauzers, West Highland White terriers, Cocker spaniels, and female dogs were overrepresented. Medical management with positive chronotropic drugs success- Causes - Electrical fully controlled syncope long-term in 54% of SSS dogs, and acted as a bridge to PAP in 20%. Positive atropine response predicted medical treatment success. Forty-six percent of SSS dogs eventually underwent PAP implantation. Median survival time was approximately 18 months in SND and SSS dogs regardless of treatment strategy. Congestive heart failure (CHF) associated with progressive valvular heart disease occurred commonly in all groups, particularly in dogs with bradycardiaetachycardia syndrome. Sick Sinus Syndrome Conclusions: Sinus node dysfunction and SSS represent a spectrum of sinoatrial node disease, which for some dogs may also involve a component of autonomic Sick Sinus Syndromedysfunction. Dogs with SND do not require treatment. Dogs with SSS often require treatment to reduce the frequency of syncope; medical management is

* Corresponding author. E-mail address: [email protected] (B.W. Keene).

Please cite this article in press as: Ward JL, et al., Outcome and survival in canine sick sinus syndrome and sinus node dysfunction: 93 cases (2002e2014), Journal of Veterinary Cardiology (2016), http://dx.doi.org/10.1016/j.jvc.2016.04.004

Collapsed

Sinus arrest with failure of the subsidiary pacemaker cells

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Causes - Electrical

Sick Sinus Syndrome

Causes - Electrical

Atrial Standstill – Dilated, thin, and fibrotic atria – English springer spaniel – Poor prognosis

Causes - Electrical

Tachyarrhythmia – Ventricular tachycardia • ARVC • DCM • Myocarditis • Adrenal disease – pheochromocytoma • Toxins – Supraventricular tachycardia rarely causes syncope - can cause extreme weakness/collapse

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Causes - Electrical

Ventricular Tachycardia

Causes – Pulmonary Hypertension

Pulmonary Hypertension – Primary disease process (idiopathic) – Obstructive • PTE • Heartworm – Left sided heart enlargement +/- CHF

Causes – Pulmonary Hypertension

Pulmonary Hypertension – Pulmonary disease • Fibrosis, pneumonia, neoplasia – Left to right shunt (VSD, PDA, ASD) – Reactive • Hypoxia, high altitude, pulmonary edema – Hyperviscosity

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Causes – Vasovagal

Vasovagal Syncope – Exaggerated response to normal stimulus • Exaggerated vagal input secondary to high sympathetic tone • Exaggerated sympathetic recovery after period of bradycardia and hypotension – Cough drop – Boxers may be predisposed

J Vet Intern Med 2008;22:931–936 Bradycardia-Associated Syncope in 7 Boxers with Ventricular Tachycardia (2002–2005)

J.D. Thomason, M.S. Kraus, K.K. Surdyk, T. Fallaw, and C.A. Calvert

Background: Syncope is a recognized problem in Boxers and often is the result of rapid ventricular tachycardia (VT). Affected dogs may have echocardiographic evidence of dilated cardiomyopathy, but frequently have normal echocardiograms. Although VT is probably the most common cause of syncope in Boxers, neurocardiogenic bradycardia can also occur. Objective: We describe 7 Boxers with comorbid VT and neurocardiogenic bradycardia, wherein the syncope was secondary to bradycardia rather than VT. Animals: Seven Boxers were selected from a larger population of Boxers with Holter-documented VT because these dogs had documented bradycardia at the time of syncope. Methods: Retrospective study. Results: Although all dogs had Holter-documented VT, the etiology of the syncopal episodes was consistent with neurocardiogenic bradycardia. Clinical Importance: Neurocardiogenic bradycardia or VT can occur as isolated problems in Boxers. In some Boxers, VT and potential or manifest neurocardiogenic bradycardia coexist. The administration of a b-blocker or sotalol to such dogs can aggravate or precipitate neurocardiogenic bradycardia-related syncope. Key words: Cardiomyopathy; Event recording; Holter recording; Neurocardiogenic bradycardia.

yncope is a common problem in Boxers. Two com- documented VT, because these Boxers had documented brady- Smon causes of syncope in this breed are ventricular cardia at the time of syncope. There were 4 males and 3 females tachycardia (VT) associated with cardiomyopathy and ranging in age from 3 to 7 years. neurocardiogenic bradycardia. The former is more common and is usually associated with many ventricular Case Examples premature complexes (VPC) when a Holter recording is Case 1 performed within a day or two of the syncopal event. It is potentially lethal and is usually treated with mexiletine or A 6-year-old male, 39-kg Boxer was presented with the sotalol.Causes Neurocardiogenic bradycardia – Other is less common chief complaint of syncope. The dog had experienced and is not necessarily associated with cardiomyopathy. several syncopal episodes between 1 and 5 years of age. Syncope typically occurs infrequently and may not re- Each episode was associated with exertion coupled with quire treatment. When a Holter recording performed excitement. Recently, the dog had experienced 3 episodes soon after a syncopal event in a Boxer contains no or over a span of approximately 2 weeks. One episode was fewOrthostatic VPC, syncope secondary toHypotension bradycardia should be associated with exertion and 2 episodes occurred when strongly considered. Neurocardiogenic bradycardia can the dog arose after awakening. coexist with cardiomyopathy in Boxers because both On physical examination, an arrhythmia was ausculta- conditions are– common. Standingb-blocker or sotalolup treatment,from lyingted, which down was thought to be consistent with the occur- unlike mexiletine, administered for VPC may uncover or rence of VPC. Cardiac ultrasound examination identified aggravate neurocardiogenic bradycardia. a left ventricular end-diastolic dimension of 52 mm (nor- – Pooling of blood èmal, Decreased48 mm), left ventricular venous end-systolic dimension return of è 40 mm (normal, 38 mm), left ventricular fractional MaterialsDecreased and Methods cardiacshortening output of 23% è (normal, Drop30%), andin anarterial E-point to blood septal separation of 10 mm (normal, 8 mm) consistent Seven Boxers were retrospectively selected from a larger population of Boxers evaluatedpressure between 2002 and 2005 with Holter- with mild dilated cardiomyopathy (DCM). The heart rhythm was further evaluated. A static ECG From the Department of Veterinary Clinical Sciences, Center for was performed and the only abnormalities identified Veterinary Health Sciences, Oklahoma State University, Stillwater, were isolated VPC. The morphology of these VPC was OK (Thomason); and the Department of Small Animal Medicine and consistent with a right ventricular origin.1,2,a An ambu- Surgery,Medically College of Veterinary Medicine,induced Cornell University, Ithaca, latory ECG (Holter) recorderb was fitted to the dog. NY (Kraus); Department of Small Animal Medicine and Surgery, During the ensuing 24 hours, the dog was normally College of Veterinary Medicine, University of Georgia, Athens, GA (Surdyk, Fallaw,– Calvert). Negative Presented as an abstract chronotropic at the 2007 AC- active in drugs the home environment. with underlying On 1 occasion, the VIM Forum, Seattle, WA. dog collapsed immediately on arising from sleep and Corresponding author: Justin D. Thomason, DVM, DACVIM, standing up. Department of Veterinarybradycardia Clinical Sciences, Center for Veterinary Clinically relevant Holter analysisc results included Health Sciences, Oklahoma State University, Stillwater, OK 74078; 9,583 VPC, VT, and an episode of bradycardia. The e-mail: [email protected]. VPC comprised approximately 183 couplets, 68 triplets, Submitted November– Positive 15, 2007; Revised Februaryinotropic 5, 2008; Ac- drugs with underlying outflow tract and 27 episodes of nonsustained (6–26 beats) VT at rates cepted March 10 2008. Copyright r 2008obstruction by the American College of Veterinary Internal of 250–300 beats/min (bpm) (Fig 1A). According to the Medicine patient diary, the episodes of VT were not associated 10.1111/j.1939-1676.2008.0119.x with overt clinical signs.

Diagnostic Approach

• Use history, signalment and physical exam to prioritize • Thoracic radiographs • Echocardiogram • Blood pressure (acute; treatment) • ECG – Atropine response test • Holter • Event or loop recorder

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Diagnostic Approach - Radiographs

Why What to look for – History of coughing – Pulmonary edema – Heart murmur – Cardiac enlargement – Crackles or wheezes – Parenchyma disease – Airway disease

Diagnostic Approach - Radiographs

Syncope with new cough

Diagnostic Approach - Radiographs

Syncope with coughing

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DiagnosticMisty: Approach Radiographs - Radiographs Misty: Radiographs Syncope with crackles, no murmur

Diagnostic Approach - Echocardiogram

Why – Signalment – Heart murmur • Basilar murmur • Right-sided murmur – Cardiac enlargement – Concern for PH

Diagnostic Approach - Echocardiogram

Severity of valvular disease – Larger regurgitant fraction – Systolic function – May be more susceptible to changes in heart rate and blood pressure – Consider treatment

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Diagnostic Approach - Echocardiogram

Pulmonary hypertension • Tricuspid Insufficiency to estimate pulmonary pressures • Treatment: – Oxygen if dyspnea – Sildenafil – Tadalafil – Pimobendan

Diagnostic Approach - Echocardiogram

Outflow Tract Obstruction • Subaortic stenosis • Pulmonic stenosis • HOCM • Tumor within outflow tract • Treatment – Atenolol – PS – balloon valvuloplasty

Diagnostic Approach - ECG

Why What to look for – Breed – P without QRS • Boxer, bulldog, – Pauses doberman – VPCs • Schnauzer, – Overall heart rate dachshund, cocker, WHWT – No heart murmur – No resp signs – Irregular rhythm

119 2/1/18

Diagnostic Approach - ECG

Low heart rate – QRS for every P? – Pauses – Inappropriate or excessive bradycardia (including sinus arrhythmia)

Diagnostic Approach - ECG

Atropine Response Test – 0.04 mg/kg subcutaneously – Recheck ECG in 30 minutes • Adequate or full response: HR > 160 bpm and regular • Partial: >25% increase but <160 bpm • Negative: failed to increase by 25% – Likely to respond to medical therapy

Diagnostic Approach - ECG

Negative Atropine Response Test – Continue workup: concurrent disease • Radiographs • CBC, chemistry, UA and culture • +/- Abdominal ultrasound – Continue workup: underlying cause • Cardiac troponin I – inflammatory/infectious cause • Echocardiogram – tumors, cardiac enlargement – Pacemaker

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Diagnostic Approach - Holter

• Sick Sinus Syndrome – Sinus arrhythmia but no overt pauses identified • Intermittent AV block • Capture an event

Treatment - Bradyarrhythmia

Positive Atropine Response Test – Medical therapy: • Theophylline • Terbutaline • Propantheline • Hyoscyamine – Underlying disease may progress and/or develop tolerance to oral therapy

Treatment - Bradyarrhythmia

Transvenous Pacemaker – AV block – SSS – Severe vasovagal syncope

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Treatment - Bradyarrhythmia

Epicardial Pacemaker • Small dogs, cats, myocardial changes, myocarditis, pro-coaguable

Diagnostic Approach - ECG

Ventricular Tachycardia – Lidocaine bolus 2 mg/kg – Lidocaine CRI 40 – 80 mcg/kg/min

Diagnostic Approach - ECG

Ventricular Tachycardia – Continue workup • Echocardiogram – tumors, cardiac enlargement, systolic dysfunction • Radiographs - CHF • Abdominal Ultrasound – splenic disease, adrenal disease • CBC/chemistry – systemic illness, electrolytes

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Diagnostic Approach - Holter

Ventricular Premature Complexes – Not definitively severe enough to be the cause – Baseline prior to treatment – Ensure no concurrent pauses – Identify intermittent arrhythmia DIAGNOSIS OF ARVC

• Holter monitor is the only antemortem gold standard for diagnosis of ARVC

• >300 VPCs of RV origin in 24hrs or complex RV ectopy • <100 VPCs normal for Boxer dogs • 100-300 VPCs Equivocal • Diagnostic conﬁdence Diagnosticgained by genetic Approach mutation -testing; Event/Loop breed predisposition and response to therapy • Event Recorder – About 1 week – Must witness episode – Not continuous recording • Zio Patch – Continuous up to 2 weeks • Implantable Loop Recorder – Minor procedure – Multiple months – Requires interrogator to obtain recordings – Can set parameters to record or initiate with remote activator

Treatment – Ventricular Ectopy

Sotalol – Can contribute to collapse if concurrent pause • i.e. Boxers – Can contribute to weakness, collapse, CHF if severe systolic dysfunction Mexiletine – GI upset – Capsules – Not as effective as single agent

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Diagnostic Approach - Vasovagal

• Diagnosis of exclusion • Capture an event • Holter • Event Recorder • Loop Recorder (implantable)

Treatment - Vasovagal

• Avoid stimulus • Trial and error? • Digoxin • Pacemaker

• Single– study center, retrospective! • Transvenous, single chamber pacing! • Median age 7yrs (6mos to 13yrs), Labradors most common! • Vasovagal syncope - improved with pacing in 6 of 8 dogs! • Major complications: 15 dogs, 3 deaths! • Minor complications: 23 dogs! • Survival: One year - 86%;Three year - 65%; Five year - 39% ! • Cardiac related mortality - 21 dogs! • Negative prognostic indicators - concurrent heart disease and used pulse generators

Questions?

124 Track 3 FELINE ORAL INFLAMMATION AND TREATMENT UPDATES

Sage Symposium 2018

Kevin S. Stepaniuk, B.Sc., DVM, FAVD Diplomate, American Veterinary Dental College

Veterinary Dental Education Consulting Services, LLC www.veterinarydentisryeducation.com [email protected] Columbia River Veterinary Specialists

Introduction

Until recently there has been no consistent description of inflammatory lesions and patterns in the oral cavity of cats. The historical veterinary literature, textbooks, and lecturers have not used consistent descriptions of oral inflammatory patterns in the oral cavity. The generic description of “stomatitis” often leads to misdiagnosis, prognosis, and treatment planning. Stomatitis is inflammation of the entire mouth and arise from many etiologies. See www.avdc.org nomenclature for a description of different regions of inflammation in the oral cavity. The following definitions for oropharyngeal inflammation are approved by the American Veterinary Dental College (AVDC) and used with permission from the www.avdc.org website.

Gingivitis: Inflammation of the gingiva Periodontitis: Inflammation of the non-gingival periodontal tissues (e.g., periodontal ligament and alveolar bone) Alveolar mucositis: Inflammation of alveolar mucositis: inflammation of alveolar mucosa (i.e., mucosa overlying the alveolar process and extending from the mucogingival junction without obvious demarcation to the vestibular sulcus and to the floor of the mouth) Sublingual mucositis: Inflammation of mucosa on the floor of the mouth Labial/buccal mucositis: Inflammation of the lip/cheek mucosa Caudal mucositis: inflammation of the mucosa of the caudal oral cavity, bordered medially by the palatoglossal folds and fauces, dorsally by the hard and soft palate, and rostrally by alveolar and buccal mucosa Contact mucositis and contact mucosal ulceration: lesions in susceptible individuals that are secondary to mucosal contact with a tooth surface bearing the responsible irritant, allergen, or antigen. They have been called “contact ulcers” and “kissing ulcers”. Palatitis: inflammation of mucosa covering the hard and/or soft palate Glossitis: inflammation of mucosa of the dorsal and/or ventral tongue surface Cheilitis: inflammation of the lip (including the mucocutaneous junction area and skin of the lip) Osteomyelitis: inflammation of the bone and bone marrow Stomatitis: inflammation of the mucous lining of any of the structures in the mouth; in clinical use the term should be reserved to describe wide-spread oral inflammation (beyond gingivitis and periodontitis) that may also extend in submucosal tissues (e.g., marked caudal mucositis extending into submucosal tissues may be termed caudal mucositis) Tonsillitis: inflammation of the palatine tonsil Pharyngitis: inflammation of the pharynx

Feline caudal mucositis (a.k.a. “stomatitis”) is a frustrating oral condition for clients and veterinarians. The pathogenesis of the disease is not fully understood but it appears that an immunological mechanism

Back to Table of Contents 125 is involved. However, this true immunological “stomatitis” needs to be differentiated from common other conditions such as periodontitis, aggressive periodontitis, pyogenic granuloma and diseases such as epitheliotropic lymphoma, autoimmune conditions, eosinophilic granulomas, etc.

Particularly, aggressive periodontitis and adult onset periodontitis secondary to a plaque and bacterial biofilm and the inflammation, may be mistaken and mistreated as “stomatitis”. It is important to recognize that “stomatitis” involves extension of the inflammation beyond the gingiva and mucogingival junction and involves the caudal pharynx, palatoglossal folds, the palatal mucosa, and the buccal mucosa. In some cases, it just involves the caudal oral mucosa (caudal mucositis). Caudal mucositis is a defining clinical pattern of inflammation for the consideration of “stomatitis”. Severe periodontitis, juvenile gingivitis, juvenile onset periodontitis, and aggressive periodontitis often only involve the gingiva (gingivitis) with or without extension past the mucogingival junction into the mucosa (buccal mucositis). Biopsy of the gingiva in these conditions results in a similar histopathological diagnosis of a cat with immune dysregulated stomatitis. Differentiation of severe periodontitis, juvenile gingivitis, juvenile onset periodontitis, and aggressive periodontitis early in the clinical presentation is necessary for appropriate treatment planning.

Pathophysiology of Periodontitis

Periodontitis is active inflammation of the periodontium secondary to a bacterial biofilm. It begins with the accumulation of the dental pellicle (e.g., salivary glycoproteins) that occurs within seconds of a tooth being cleaned. Within hours, first colonizing oral bacterial colonize the pellicle and the plaque biofilm is formed. The plaque biofilm matures within days. Gingivitis (inflammation of the gingiva) is the first clinical sign of the starting inflammatory cascade. Mineralization of the plaque biofilm results in calculus (tarter). Periodontal disease is caused by the bacterial biofilm (plaque) and the associated host inflammatory response. Significant periodontal disease can be present without calculus. Calculus is not the cause of periodontal disease.

As the plaque biofilm matures, early bacterial colonizers, gram-positive aerobic cocci, become less predominant. The biofilm shifts to gram-negative anaerobes and spirochetes located more apical in the periodontal pockets. Bacterial products such as ammonia, volatile sulfur compounds, and proteolytic enzymes contribute to the destruction of the periodontium. The host inflammatory response, matrix metalloproteinases that degrade collagen of the periodontal ligament, elastase (break down collagen and elastin), and prostaglandins (PGE2) are directly responsible for tissue damage and/or stimulate osteoclastic bone resorption (PGE2, IL-1β, TNF-α). The calcium carbonate in the saliva of cats combines with the plaque to form calculus. Calculus increases surface area for bacterial attachment and can mechanically disrupt and damage the gingiva.

Variations of Periodontitis

Adult onset periodontitis is a chronic common condition affecting the entire population. There is no specific breed predilection of this chronic disease that is managed with annual periodontal cleanings and home care. However, if left untreated it will lead to significant inflammation in the oral cavity and tooth loss. Juvenile onset and Aggressive periodontitis may occur more commonly in the domestic short hair, Siamese breeds, and Maine Coon breeds. Significant inflammation begins as early 6-9 months of age with abundant plaque and calculus present. This aggressive inflammation leads to gingival recession, bone loss, pocket formation, furcation exposures and rapid tooth loss. Often these cats require full mouth extractions at a young age but can have a very good long-term prognosis with full mouth extractions. Feline juvenile gingivitis reported in Abyssinians, Persians and DSH, begins around 5 to 6 months of age with hyperemic PROLIFERATIVE gingivitis. There is little plaque and calculus present. The proliferative gingiva engulfs the crowns and results in pseudopockets and the start of periodontitis.

126 Management of Periodontitis

Management of periodontal disease is not a once in a lifetime event for the patient but rather an ongoing program throughout continued life stages of the patient. Gingivitis is the start of the inflammatory cascade and may progress to periodontitis and loss of periodontal attachment. The goal with periodontitis is to stop the disease, minimize further attachment loss, and treat compromised teeth (e.g., periodontal surgery, guided tissue regeneration, and extraction as indicated). Therefore, education and prevention of disease (daily brushing, dentifrices, and frequent professional dental care) are the best defenses.

A professional dental cleaning, to return the tooth to a clean surface, followed by daily home care, to remove the plaque biofilm, is the gold standard to prevent and control periodontal disease. If pockets are eliminated and the plaque biofilm is removed on a daily basis, then the maturation of plaque and further pocket formation can be controlled and minimized. Expired dentition will require surgical extraction.

Feline Pyogenic Granuloma

A region in the caudal mandible that may become inflamed and misdiagnosed, particularly in Persian, brachycephalic, cats as well as following surgical extraction of the first mandibular molar and/or secondary to periodontal disease of the first mandibular molar, is a feline pyogenic granuloma. Unless the underlying cause is identified and treated, the clinician can be frustrated, the lesions will re-occur after resection, and the cat will suffer with chronic pain. They often start buccal to the mandibular 1st molars as a result from the occluding maxillary 4th premolar, periodontitis, and the perpetuated traumatic inflammatory cycle. It may continue following extraction of the 1st molar if the surgical site is not sutured closed correctly and atraumatically and/or the maxillary 4th premolar is not treated with odontoplasty and sealant or alternatively surgical extraction in some cases. Congenital or acquired malocclusions may also lead to the development of these lesions. Finally, inappropriate surgical closure and inappropriate transposition of the molar salivary gland into a traumatic occlusion during extraction of the 1st molar, in any cat, may cause these lesions to develop.

Caudal Mucositis Feline “stomatitis” (gingivitis with buccal mucositis and caudal oral mucositis) is an immune dysregulation of the feline’s local and systemic immune system. The initial trigger of the dysregulation is unknown. There are continued theories, debate, confounding factors, and additional disease entities concurrent with the inflammation, and a lack of standard diagnosis and description of oral inflammatory lesions. A prevalence study concluded approximately 0.7% of cats in British general practices have “gingivostomatitis”.

Pathogenesis

The common dermal-epidermal inflammatory reaction of predominately plasma cells and lymphocytes is suggestive of an immunoreactive condition. The retrovirus status (FeLV and FIV) should be determined in all patients from an overall health management standpoint. However, these immunosuppressive viruses are not the etiology of the immune dysregulation stomatitis. Immunosuppressive conditions can increase periodontitis and secondary oral inflammation due to lack of control of the plaque biofilm. Once again periodontitis and the associated gingival and mucosal inflammation must be differentiated from a “true stomatitis”.

With a dysregulated immune stomatitis there are changes in cellular and humoral immunity. T- lymphocyte subset ratios are low (CD4+/CD8+) due to high numbers of CD8+ (suppressor-cytotoxic T-

127 Cells). CD4+ (TH-1 and TH-2 – helper induced T-cells) recognize MHC II on surface antigen presenting cells, other T-cells, B-cells, some mesenchymal cells, and osteoblasts where as CD8+ cells recognize MHC I universally exhibited on all cell types. The levels of salivary IgA are low and IgG and IgM are high in stomatitis patients. It is not known if the low IgA is from the disease, prior to the disease, the result of decreased immunoglobulin secretion, changes in salivary flow, or and/or increased destruction. Additionally, and not surprisingly, there are increased mast cells in the tissues compared to specific pathogen-free cats. Mast cells are also increased in inflamed gingiva secondary to periodontal disease and tooth resorption.

What is the inciting cause of the dysregulated immune system? Bacteria, oral food antigens, environmental antigens, and viruses have all been suggested as inciting causes. Bacterial persistence (plaque) is the most likely inciting cause at this time. It is known that many cats with stomatitis test positive for feline calicivirus and may have increased concurrent shedding of feline calicivirus (recognize this may not indicate active infection but just presence of biological makers such as DNA and RNA). However, other studies have found no association with feline herpes virus, feline calicivirus, and Bartonella species. Do the viruses and/or bacteria disrupt the oral epithelium and subsequently deeper tissues are exposed too oral bacterial, food, and environmental antigens resulting in a dysregulated immune response? Or, are the viruses’ opportunistic colonizers of inflamed tissue and an abnormal functioning immune response? Currently, many Diplomates of the AVDC accept that the shedding of viruses may contribute to the overall clinical morbidity of the patient. To my knowledge, no control patients have been experimentally infected with the feline calicivirus resulting in a stomatitis (Koch’s Postulates). There may be a defect in the patient’s cell mediated immunity resulting in presentation of auto-antigens to infiltrating CD4+ cells and/or damage to mucosa allowing presentation of auto-antigens and subsequent auto-antibody production. Bacteria associated with the plaque biofilm may be the major triggering factor.

It is worth mentioning Bartonella henselae due to its zoonotic significance and the suggestion of its link to “gingivostomatitis”. Positive serological testing for the organism suggests exposure and not active infection. Many normal healthy cats test positive serologically. In cats with “gingivostomatitis” that are positive for Bartonella, appropriate treatment for elimination of the organism does not often result in resolution of the “gingivostomatitis”. Current studies are unable to associate feline herpes virus 1, FeLV, FIV, and Bartonella with chronic “gingivostomatitis” in the cat. Calicivirus was not associated in that study but other studies suggest a comorbidity.

At this time, the elimination of bacteria/plaque from the teeth, sulci, and periodontal ligament space, via surgical extractions, is the treatment that results in the best resolution of clinical signs.

Diagnosis and Treatment

Each patient has to be assessed and treated individually. A comprehensive evaluation is necessary. A complete history of signalment, onset, duration, environment, chronic illness, systemic illness, vaccination, etc. must be obtained. Diagnostic testing includes CBC/Chemistry/UA, T4, FeLV, FIV, +/- Bartonella testing, and +/- calicivirus for many patients. Not every patient is recommended every test initially but each test should be considered on a case-by-case management basis. Although in current practice, Bartonella and calicivirus testing are rarely done, if at all.

Definitive treatment recommendations may differ depending on the consulting specialist and specialty. In many boarded veterinary dentists’ opinion, at this time, full mouth extractions provide the best long-term resolution. However, not every specialist may recommend the same treatment plan for each case. In some cases, every tooth will be extracted whereas in others, every tooth except the canine teeth will be extracted. Intraoral radiographs and clinical disease help determine the plan in each case. Ultimately,

128 most cats with “stomatitis” end up with all the dentition completely extracted and many veterinary dentists will extract all the dentition in one surgical procedure.

Professional periodontal cleanings and home care cannot control the clinical inflammation and pain. Anecdotally, many patients who present refractory to chronic immunosuppression (long-term steroid use) also may have concurrent endocrine disease (diabetes mellitus) and seem to have cross-reacted to additional dietary, environmental, and auto-antigens resulting in poorer surgical outcomes to full mouth extractions. However, a complete assessment and individual treatment plan must be made with each client and patient in order to meet the needs of the patient, the client, and to achieve the best possible outcome for each situation. Not every client can afford or can grasp the concept of removing all the teeth with oral surgery, initially. However long term medical therapy is expensive and may be more expensive, over time, with office visits, blood monitoring, and medications compared to surgery.

Referral for full mouth extractions to a veterinary dentist should be considered due the time it takes to remove all of the teeth and roots if your hospital is not equipped with multimodal analgesia/anesthesia, intraoral radiographs and can complete the procedure in a timely fashion to minimize the duration of general anesthesia. Clients are always advised that the full mouth extractions may not completely resolve all the inflammation and adjunctive therapy may be necessary. Intraoral radiographs and aggressive multimodal pain control are necessary.

Published results from exodontics are favorable: • 60% complete remission • 20% no medical treatment necessary other than plaque control • 13% required continued medical management • 7% no response

If continued medical management is necessary, fatty acids, appropriate lowest dose possible prednisolone treatment, and possibly cyclosporine, with appropriate clinical, blood, and drug monitoring, has been effective in some cases. After removal of all the teeth, corticosteroids may still be necessary in some cases. However, the dosage and frequency, along with their side effects, is greatly reduced. Veterinary dentists in Europe, and some veterinary dentists with special FDA import permits in the USA and Canada, investigated/investigating the use of Omega-Interferon, which is not currently available in North America with questionable results. Laser ablation therapy to remove chronically inflamed tissue and create scar formation (hence less blood supply and potential immunological response) with carbon dioxide and Nd:YAG lasers have seen some success. Novel antigen diets and Omega-3 fatty acids may be of benefit in some refractory cases. Certain antimicrobial combinations and/or additional immunosuppressive therapy may be necessary post-extraction for the partial and non-responders. However, chronic long-term therapy with antibiotics is never indicated as a monotherapy for this condition or any condition of the oral cavity.

Currently, UC Davis stem cell treatment holds the most promising future for non-responding cats. However, it is VERY IMPORTANT to understand that the cultured stem cell treatment takes 10-14 days to harvest the appropriate stem cells and this is NOT the weekend stem cell course, the several day stromal fraction that some “stem cell” veterinarians offer.

129 OPHTHALMOLOGICAL AND MAXILLOFACIAL MANIFESTATIONS OF DENTAL DISEASE

Sage Symposium 2018

Kevin S. Stepaniuk, B.Sc., DVM, FAVD Diplomate, American Veterinary Dental College Veterinary Dental Education Consulting Services, LLC www.veterinarydentisryeducation.com [email protected] Columbia River Veterinary Specialists

Introduction

Patients often present with maxillofacial swellings, periorbital swellings, periocular swellings, and difficulty and/or pain opening and closing the mouth. There are many causes including odontogenic (dental), ophthalmological, skeletal and soft tissue pathologies that must be considered. Obvious causes may or may not be clinically evident and what may seem the “obvious”, may be hidden odontogenic infection. Particularly when the patient presents with acute ophthalmological manifestations. With acute maxillofacial and ocular swellings and inflammation the patient pain and temperament often precludes an obvious diagnosis without sedation or general anesthesia. Obtaining a correct diagnosis is required to plan and begin appropriate treatment.

Ocular Manifestations

Chemosis may occur with orbital and periorbital inflammation drawing attention to ocular pathology as the primary cause. However, the swelling may be secondary to odontogenic infection resulting in the periorbital/orbital pathology. Exophthalmus, which may have orbital causes, must be differentiated from buphthalmia from primarily intraocular causes (e.g. glaucoma). Draining tracts and ventral periocular mass effects can occur secondary to odontogenic infection. Likewise, a chronic smoldering retrobulbar cellulitis/abscess may lead to many ocular changes.

Ocular Complications Related to Anesthetic and Dental Procedures

Regional nerve blocks (i.e. local anesthesia) in the maxillofacial skeleton may result in periocular and intraocular damage and loss of an eye if performed incorrectly. Both the maxillary and infraorbital nerve blocks can be incriminating. Placing the needle too deep in the dorsal direction for an intraoral maxillary block, too dorsal over the zygomatic arch for an intraoral infraorbital block, and/or entering the infraorbital canal and not remaining parallel to the dental arcade can lead to ocular penetration. Additionally, regional hematoma is a common and anticipated finding of nerve blocks. A hematoma secondary to the maxillary nerve block may lead to a temporary exophthalmus.

Spring loaded mouth gags or any mouth gag resulting in the feline oral cavity being widely opened for any extended period of time diminishes the only perfusion, maxillary blood flow, to the brain in the cat. Death, central nervous system, and/or neurological blindness may result.

Unfortunately retained tooth roots are a very common finding in veterinary medicine. Infected/inflamed retained tooth roots of the caudal maxillary dentition can result in regional inflammation. Likewise, hidden periodontal disease of the maxillary molars, particularly smaller breeds and brachycephalic dogs, can be a source of regional infection/inflammation.

Back to Table of Contents 130 Orbital Disease Differential Diagnosis

The clinician must have a complete differential diagnosis list and plan when evaluating patients in order to differentiate orbital disease from odontogenic or ophthalmological causes. Ophthalmological and non- odontogenic causes including, but not limited to, retrobulbar neoplasia or neoplasia invading from juxtaposed anatomy, scleritis, pseudotumors, extraocular myositis, foreign body abscess/cellulitis, trauma, zygomatic sialoadenitis, and coagulopathies are considered. An ocular and dental examination are necessary.

Maxillofacial swellings and draining tracts

Odontogenic infection (e.g. periodontal disease, endodontic disease) in dogs and cats are chronic, insidious, yet very common. Most patients suffer silently with chronic infection, chronic pain, and chronic systemic inflammation until end-stages of the disease. Chronicity, immunosenescence, comorbidity of systemic diseases (e.g., diabetes mellitus, hyperadrenocorticism) and administration of medications for other medical conditions (e.g., corticosteroids, cyclosporine, oclacitinib) may unmask the chronic infection and result an acute on chronic infection resulting in an emergency presentation.

The draining tracts are often located rostral-ventral to the eye in the caudal portion of the maxilla but may occur anywhere. Maxillary draining tracts and swellings should be investigated for odontogenic infections such as periodontal disease or endodontic disease prior to extensive dermatological or neoplastic work ups including advanced imaging and biopsy. Teeth should be a primary differential diagnosis for any maxillofacial swellings and draining tracts. The pathology is easily diagnosed with an appropriate anesthetized examination and intraoral radiographs, if the veterinarian knows the knowledge of the pathophysiology. If an odontogenic infection is not the cause, then evaluation for neoplasia, dermatological conditions, etc. can be pursued. Often if it is neoplasia, a tooth is involved and surgical extraction and deep biopsy via the extraction site will provide a histological diagnosis.

Differentiation and Diagnosis

In many cases, periodontal probing and intraoral radiographs during anesthesia are necessary. Intraoral radiographs are also more detailed and useful even when the necessary computed tomography (CT) and/or magnetic resonance imaging (MRI) are performed. Viewing CT in a window not specific for the teeth and bone and/or having slices that are too large to identify very small hidden periodontal and endodontic changes will miss what can be picked up with a periodontal probing examination and intraoral radiographs of the distal maxillary dentition. MRI is useful for presumptive retrobulbar tumors, non- responding retrobulbar cellulitis, foreign bodies, and zygomatic salivary pathology. CT is more helpful with bone and teeth but a more accessible faster alternative with contrast enhancement to additionally evaluate for inflammation and tumors.

Urgent Medical Management

Having an accurate diagnosis is necessary for a targeted long-term plan. However, urgent treatment to protect the cornea with a temporary tarsorrhaphy and sterile ophthalmic lubricant may be necessary with exophthalmus. Antibiotic coverage for retrobulbar infection should include anaerobic bacteria arising from the environment or oral cavity. Hence, amoxicillin/clavulanic acid or clindamycin is often a first choice. In the case of retrobulbar cellulitis secondary to an oropharyngeal puncture or foreign body, it may be necessary for several weeks of antibiotic treatment and the addition of additional spectrums of activity in some cases. If no contraindication exists, the use of systemic non-steroidal anti-inflammatories is helpful for inflammation and pain control. Likewise, additional analgesia from opioids or gabapentin

131 should be considered pending work up for a definitive diagnosis. Systemic corticosteroids should be avoided until a diagnosis is made as inappropriate use can lead to worsening of infection resulting in severe maxillofacial cellulitis and death.

Clinical Sings of Pain and/or Difficulty Opening the Mouth

Differentials

1. Retrobulbar Abscess/Cellulitis (Odontogenic and Non-odontogenic) 2. Masticatory Muscle Myositis 3. Zygomatic Salivary Mucocele/sialadenitis 4. Neoplasia 5. Maxillary Fracture 6. Craniomandibular Osteopathy (e.g. Terrier Breeds) 7. TMJ Ankylosis (Previous Trauma) 8. Zygomatic Arch Fracture/Healing (Previous Trauma) 9. Tetanus (Clostridium tetani) 10. Osteoarthritis of TMJ (uncommon)

Zygomatic mucocele/sialadenitis:

Inflammation or trauma of the zygomatic salivary gland may lead to leakage of saliva resulting in pressure and inflammation in the retrobulbar tissues. Thick, tenacious saliva/blood tinged saliva may be identified if ruptured in the pterygopalatine fossa. MRI is helpful in challenging cases. Treatment may include medical (NSAIDS and appropriate antibiotics). In chronic cases, sialoadenectomy of the gland may be necessary. Sialoadenectomy of the zygomatic salivary gland is challenging due to the regional anatomy of the eye, zygomatic arch, and friable salivary gland tissue.

Retrobulbar Abscess/Cellulitis (Infection) vs. Masticatory Myositis (Autoimmune) –

Conditions that Require Rapid and Accurate Differentiation

Retrobulbar/Maxillofacial Abscess/Cellulitis:

Infection and inflammation in the retrobulbar and caudal maxillofacial region are common. Puncture wounds from sticks, plant material, and oral foreign bodies traumatize and inoculate the soft tissues of the caudal oropharyngeal region. Regional hidden periodontal and endodontic disease (odontogenic infection) can lead to inflammation and infection in the retrobulbar space due to the close proximity (millimeters) and incomplete ventral orbit of dogs and cats. Ubiquitous environmental bacteria such as Actinomyces and Nocardia cause chronic pyogranulomatous inflammation resulting in swellings and draining tracts of the head and neck.

The clinical signs of acute injury are often missed (e.g., pain and ptyalism). Chronically, pain on opening the mouth and resistance to opening during the examination are common. Retropulsion of the ipsilateral eye is painful and an intraoral swelling or region of trauma may be identified in the pterygopalatine fossa. The ipsilateral eye may have chemosis and prolapse of the third eyelid. In severe cases, maxillofacial swelling and exophthalmus on the ipsilateral side occurs.

Diagnosis includes intraoral dental radiographs and advanced imaging as indicated. Exploration of the pterygopalatine fossa and caudal oropharynx may be both diagnostic and therapeutic. However, the tissue must be carefully and minimally explored to look for regions of abscess, sialocele, and cellulitis if

132 indicated. However, blind stab incisions are NOT recommended as the vital maxillary artery and its branches, maxillary and optic nerves, and the eye are in close proximity (millimeters). Instead, a superficial mucosal incision can be made and the area bluntly (only once or twice) evaluated with blunt hemostatic forceps. Advanced imaging (e.g. CT, MRI) are very helpful to quickly rule out differential diagnosis. Intraoral radiographs are necessary to assess the maxillary dentition. Close clinical examination of the dentition is necessary to find hidden endodontic or periodontal disease.

Treatment involves surgical extraction of the offending tooth, if it is related to an odontogenic infection (intraoral radiographs are required to make the diagnosis). If it is not odontogenic infection or a zygomatic mucocele, then the patient is treated with antibiotics that cover the aforementioned pathogens, NSAIDS, and additional analgesics as indicated. The owners are advised if the condition resolves, then reoccurs following cessation of medical therapy, that investigation for a hidden plant/wood foreign body may be necessary (ocular/periocular ultrasound) and/or prolonged treatment (4-6 weeks) for Actinomyces and Nocardia may be necessary. If imaging has ruled out differential diagnosis and pathology, in some cases, treatment with amoxicillin/clavulanic acid and a fluoroquinolone antibiotic for 4-6 weeks is necessary.

Masticatory Myositis (MM):

In the acute presentation, the patient and the clinician cannot open the mouth. Even with heavy sedation and general anesthesia the mouth will not open due to severe muscle inflammation in the acute phase. The masticatory muscles (masseter, pterygoids, and temporalis muscles) are swollen and firm. It may be unilateral or bilateral. In the chronic presentation, the muscles are severely atrophied and fibrosed making opening the mouth problematic. An autoimmune attack of the type-2M muscle fibers results in inflammation, destruction, and replacement with fibrous tissue. The diagnosis is confirmed by ruling out other differentials (advanced imaging), type-2M antibody titer, and masticatory muscle biopsy while anesthetized. Presumptive treatment may start following collection of blood for type-2M antibody (corticosteroid treatment prior to collection may result in false negatives). If aggressive corticosteroid therapy results in severe drug related side effects, additional immunotherapy with azathioprine, etc. may be added to allow decreasing the corticosteroid dose.

Clinical note:

DO NOT place a patient on immunosuppressive corticosteroids for a presumptive diagnosis of masticatory myositis until retrobulbar/maxillofacial abscess/cellulitis is ruled out. Immunosuppression of an infection can lead too severe regional and systemic infection and death in many patients due to a misdiagnosis or inappropriate presumptive diagnosis. Remember many patients with retrobulbar cellulitis/abscess will resist opening the mouth during a conscious examination due to pain. Therefore, placing an intravenous catheter and administering multimodal analgesia and/or anesthesia will allow you to assess the range of motion of the TMJ as well as evaluate the pterygopalatine fossa for evidence of trauma and swelling – the mouth can be opened; in these cases, treat with antibiotics, anti-inflammatory NSAIDS, if not contraindicated, and other analgesics. In an acute masticatory myositis case, the mouth cannot be opened, in the anesthetized patient, due to the extreme inflammation of the muscles. In these cases, draw blood for a Type 2M antibody titer and obtain a muscle biopsy. Then administer immunosuppressive medications.

133 UNDERSTANDING FRACTURED TEETH AND THE APPROPRIATE TREATMENT RECOMMENDATIONS Sage Symposium 2018

Kevin S. Stepaniuk, B.Sc., DVM, FAVD Diplomate, American Veterinary Dental College

Veterinary Dental Education Consulting Services, LLC www.veterinarydentisryeducation.com [email protected] Columbia River Veterinary Specialists

ENDODONTIC DISEASE

Endodontic Anatomical Structures The tooth is composed of organic and inorganic material. The 3 hard tissues of the tooth include the enamel (crown only), dentin (root and crown) and cementum (root only). The cementum and enamel meet at the cementoenamel junction (CEJ). The cementum attaches to the periodontal ligament to the tooth. Dentin is continually produced throughout the life of an animal in a vital tooth. Dentin comprises the majority of the mineralized substance of the tooth and is comprised of 45, 000 - 70 000 +/- dentin tubules/mm2 of surface area. Within the dentin tubules are the odontoblastic processes of the odontoblasts. The odontoblast cell body is adjacent to the dentin and compromises one of the four (4) histological cell layers of the pulp. Odontoblasts produce primary dentin prior to tooth eruption, secondary dentin throughout life, and tertiary dentin (reactionary and reparative dentin) in response to dentin irritation. Odontoblasts that produce dentin are located in the pulp with the blood vessels, lymphatics, and nerves. The pulp (endodontic system) is divided into the root (pulp) canal (in the root), the pulp chamber (in the crown), and the pulp horns (in the cusps of the crown). The four (4) histological layers of the pulp include the odontoblasts layer, the cell free zone of Weil, cell rich layer, and the central neurovascular center. Acutely exposed dentin tubules (enamel and uncomplicated crown and crown-root fractures) and pulp (complicated crown and crown-root fractures) are very painful and allows access of oral bacteria and toxins into the pulp resulting in pulpitis. The concussive forces of trauma and/or uncomplicated crown and crown root fractures can lead to reversible and irreversible pulpitis depending on the extent of dentin tubular injury, dentin thickness, and nature of insult. Endodontic Disease Fractured teeth, non-vital teeth, caries, developmental anomalies, concussed teeth, luxated teeth, and perio-endodontic lesions result in inflammation and infection of the endodontic system (i.e., pulp). Endodontically compromised teeth REQUIRE intraoral dental radiographs. All fractured teeth with pulp exposure require endodontic treatment or extraction. “Wait and see” is a negligent and an inappropriate option. Even if there is no pulp exposure the tooth may have irreversible pulpitis due to the concussive trauma or the exposure of the porous dentin tubules. The tooth may become infected and require treatment. Even if there is a large radiographic periapical lucency around a chronically fractured tooth with pulp exposure, the tooth is still treatable with endodontic therapy and can be saved. Referral to a veterinary dentist is recommended as indicated.

Back to Table of Contents 134 Traumatized (concussed) teeth may become discolored, and infected from the same trauma (concussive pulpitis) that did or did not fracture the tooth. Intraoral radiographs, monitoring, and/or treatment are necessary. Discolored teeth need intraoral dental radiographs followed by endodontic treatment or extraction.

Fractured Teeth and Non-Vital Teeth Intraoral dental radiographs for assessment and treatment are required. All fractured teeth with pulp exposure require endodontic treatment or extraction. Many teeth with uncomplicated crown fractures and enamel fractures may also have endodontic disease requiring treatment that can only be found via intraoral radiographs.

Classification of tooth fractures can be found at www.avdc.org (nomenclature). Enamel infraction (an incomplete fracture of the enamel without loss of tooth substance), enamel fracture (a fracture with loss of crown substance confined to the enamel), uncomplicated crown fracture (a fracture of the crown that does not expose the pulp), complicated crown fracture (a fracture of the crown that does expose the pulp), uncomplicated crown-root fracture (a fracture of the crown and root that does not expose the pulp), complicated crown root-fracture (a fracture of the crown and root that does expose the pulp), and a root fracture (a fracture involving the root). Uncomplicated crown fractures may lead to the death of the tooth by translocation of bacteria and toxins across exposed dentin tubules or the force that fractured the tooth (concussive pulpitis). Complicated and uncomplicated crown root fractures may lead to periodontal disease since the normal anatomical structures of the subgingival periodontium are altered.

Decision Making of Fractured Teeth

Endodontically compromised and/or infected teeth require endodontic treatment or exodontic treatment. If the client does not elect endodontic treatment, the patient signalment and concurrent disease processes preclude endodontic treatment, or the tooth cannot be maintained with endodontic treatment, extraction is indicated and necessary.

Endodontic Pathology and Treatments

Non-Vital/Discolored Teeth Localized intrinsic staining is consistent with a non-vital tooth. Total or partial pulp necrosis was found in 92.2% of intrinsically stained teeth. Radiographic signs consistent with endodontic disease were absent in 42.9% of the teeth. The intrinsic stain is the result of pulpitis and pulp hemorrhage resulting in hemoglobin and the subsequent breakdown products in the dentin tubules. Often the patient suffers

135 quietly in silence with only subtle clinical signs of chronic pain being noticed by an astute owner. Clients often remark the improved change in behavior following treatment of a non-vital tooth. Complicated Crown Fractures in Young Adult Teeth The pulp has good resilient potential at this age and endodontic treatment should be pursued in a timely fashion. If the patient is <12 months of age, a vital pulpotomy (partial coronal pulpectomy and direct pulp capping)/apexogenesis should be performed as soon as possible. If the tooth is not vital, apexification or apexification like procedures are necessary to create an apical portion of the tooth followed by standard endodontic treatment.

Vital pulp endodontic treatments Younger teeth less than 18 months of age* have additional endodontic treatment options beyond standard normograde root canal treatment. Young teeth have large pulp canals and less secondary dentin. They may not have a completely formed root and closed apex, which preclude root canal treatment (< 10-12 months of age depending on signalment). Therefore, treatment options to save the tooth include a partial coronal pulpectomy with direct pulp capping [vital pulpotomy (VP)], apexogenesis (guided continued maturation of the root apex) or apexification (apical hard tissue barrier establishment, if the tooth is non- vital). Arbitrary times for intervention and treatment, in relation to the complicated crown fracture, have been suggested. Timely intervention is necessary. If the patient is <12 months of age, a VP/apexogenesis should be performed as soon as possible but at least within 2 weeks, if the tooth is still vital. If the patient is 12-18 months of age, a VP within 1-2 days, is recommended. Arguably a root canal treatment could be done in this age group if the apex is formed. The owner is always advised follow up and root canal treatment may be necessary in these teeth. Statistically many teeth may die and require root canal treatment in the future. However, the tooth also matures to produce a complete apex and increased secondary dentin making it a better candidate for standard root canal treatment.

Total pulpectomy (root canal treatment) – normograde endodontics Teeth with complicated crown or crown-root fractures require endodontic treatment if not extracted. Often root canal treatment is chosen for strategic teeth (mandibular and maxillary canine teeth, maxillary 4th premolars, mandibular 1st molars) and esthetic teeth (incisors). However, root canal treatment may be elected for any tooth depending on the purpose of the patient and the client’s desires. The dental discipline of normograde endodontics is a broad topic. The different methods to prepare, sterilize, and obturate the various sizes and shapes of root canal systems are extensive. In veterinary endodontics, the variation of species, canal shapes, canal sizes, and tooth morphology make veterinary endodontics both fun and challenging. These notes are not meant to be comprehensive and the reader is referred elsewhere for broader information. Veterinary endodontic procedures are not simple. It is a tactile discipline that requires training and experience as well as a consistent caseload to maintain the skills to deal with the anatomical variations that are presented. The veterinarian must first understand the basic principles of endodontics, endodontic complications and challenges, and the use of basic instrumentation (hand file and cold gutta percha techniques). Many hours of lectures and labs, and additional specimen training, etc., is necessary prior to attempting root canal treatment on a patient. Additionally, there is significant expense of equipment and supplies, with expiration dates that must be respected. Root canal treatment includes mechanical and chemical removal of pulp, bacteria, dentin, and toxins while shaping the canal for a 3-dimensional obturation. The canal is obturated with endodontic sealants and core materials. Finally, a restoration or crown, as indicated, is to complete the procedure and restore the tooth.

136 Basic concepts Preparation of the canal includes mechanical and chemical removal of pulp, bacteria, dentin, and toxins while shaping the canal for a 3-dimensional obturation. The veterinarian must learn various techniques to clean, prepare, and obturate a canal. In fact, many techniques can be combined to disinfect, shape, and obturate the endodontic systems of veterinary species. There are endodontic studies testing the various instrumentation and obturation techniques. Dye leakage studies, which may not correspond to clinical outcome, are used to test the various materials. It should be noted that one technique in the hands of a skilled individual might be clinically successful whereas, in the hands of another may be disastrous. Technology allows us to increase efficiency and effectiveness of endodontic procedures. However, the experienced veterinary dentist needs to be familiar with several techniques as one technique may not be ideal for every situation. There is no “perfect system” for every patient and every case. There are positives and negatives of each technique and the veterinary dentist should have more than one approach to resolve an endodontic challenge. Surgical endodontics

Surgical endodontics is not the solution for all failed endodontic procedures. If re-instrumentation, disinfection, and obturation of a poorly performed or problematic endodontic procedure can resolve the endodontic lesion, then standard endodontics should be considered first. Additionally, two stage endodontic procedures should also be considered prior to electing a surgical endodontic procedure when presented with chronically infected canals or open apices. Indications for surgical endodontics include failed-skillfully performed standard root canal treatment, procedural blockage that cannot be resolved, open apex [apexogenesis, apexification, apical stop, and/or normograde apical mineral trioxide aggregate (MTA®) placement is not possible], apical fenestration, periradicular drainage, or damaged, severely infected apex requiring removal and debridement. The objective is to remove severely damaged apical and periapical tissue and seal the endodontic canal with a retrograde filling. The commonly treated teeth are the canine and carnassial teeth in the dog. Dental sealants/resins

There is some discussion and controversy when to “seal” uncomplicated crown fractures and enamel fractures. The vital tooth (odontoblasts) can occlude the dentin tubules with mineral during reversible pulpitis. As with all assessments, intraoral radiographs are required. Dental sealants are recommended with known acute uncomplicated fractures exposing the dentin tubules in young animals (<18-24 months of age*). By sealing the dentin tubules, the dental pain from the exposed odontoblastic processes can be controlled and the translocation of bacteria and oral solutions resulting in pulp necrosis can be prevented. The sealing of older uncomplicated crown fractures in older teeth and animals without a known recent fracture history remains controversial and lacks good scientific evidence to justify the treatment and associated expense. Dental sealants may be unfilled resins, resins with filler particles, glass ionomers, and/or combinations with or without fluoride used mostly as pit and fissure sealants for human teeth.

If unsupported enamel or dentin tooth structure is contoured via odontoplasty (white stone or fine diamond bur) in order to create a less plaque retentive surface, then a sealant product will need to be placed because dentin tubules, previously repaired, will be opened during the procedure. Depending on the product utilized, an acid etch is necessary to prepare the tooth surface. Depending on the product, a one-step or multiple-step procedure is necessary to correctly bond the restorative material to the tooth. The user must be familiar with each product because steps are often different depending on the materials, manufactures, and evolution of the restorative material.

137 Restorative Dentistry

Discussion and teaching restoratives and endodontics is a controversial topic in the veterinary dentistry world. There are entire 1000 +/- page text books each dedicated to endodontics, restorative dentistry, and dentistry materials each, in human dentistry. Understanding each of those disciplines and demonstrating proficiency in that knowledge is required in order to become a Diplomate in the American Veterinary Dental College. There are entire courses for human dentistry and entire surgery courses for a veterinary surgeon. A human M.D. is not licensed to provide restorative dentistry on a human patient nor is a D.D.S licensed to perform and appendectomy on a human. However, a veterinary practitioner (DVM/VMD) functions as a surgeon, dentist, internal medicine doctor. Once again, veterinary dentistry and oral surgery is this grey, twilight zone of practice and clearly the practice acts for veterinarians. We are jack of all trades and masters of none. So, first do no harm.

Understand fractured teeth relates to endodontic disease. Understand the basic anatomy. Understand the thought process. Understand intraoral radiographs and the necessity. Understand what is the best for the patient. Then utilize the skills and skill sets you acquire in the best interest of the patient and the clients.

Bonded Sealant The term in itself is confusing. The term is used loosely in human dentistry and even looser in veterinary dentistry. I remain confused, but accept when talking with colleagues that many times we are talking about the same thing when using different terms. Not to mention, the reality from a chemical aspect, they do not actually chemically “bond” rather they micromechanically interlock or micromechanically “bond” with enamel and dentin. The Sealants may be resin based, glass ionomer based, have filler particles, not have filler particles, be used to as bonding layer for layers of restorative or be a true pit and fissure sealant. Hours could be spent on discussing dental materials alone. I will be talking essentially about unfilled resins that are commonly used as dental adhesives/bonding agents for composite restorations that are used to “seal” the dentin tubules.

Recall the tooth crown is made of enamel and dentin. Enamel in approximately 96% mineralized (i.e. primarily hydroxyapatite crystals organized into rods/prisms) with water and organic material (e.g. protein other than collagen). Dentin is approximately 70% mineral (hydroxyapatite) 20% organic material (e.g. collagen) and 10% water. Dentin contains tubules containing odontoblastic processes, there is an outward movement of fluid, and there is inter-tubular, intra-tubular and peri-tubular dentin.

The ideal bonding agent in human dentistry needs to bond well to enamel and dentin must resist biting forces, have flexural and mechanical forces similar forces properties similar to the tooth, resist degradation in the oral cavity over time, and decrease sensitivity. STOP! That is a human tooth! Dogs and cats have a different bite! They have a different oral environment (e.g. oral pH, microbiome, proteome)! They have dietary substrate! Dogs dentin tubular anatomy is different (e.g., more dense and oval shaped)! Dogs and cats have thinner enamel!

Therefore, I prefer to be conservative with the use of bonded sealants. I tend to be realistic and ethical in my decision making.

Elementary Understanding of Resin Bonding Agents It is impossible to discuss the chemical bond of glass ionomer, the fills of various composite materials, etc. and my intention is only to introduce participants to these concepts in this course. Bonding agents, resins, composites, and glass ionomers are part of restorative dentistry but are used as part of protecting and treatment of the endodontic system.

138 Dental adhesives/bonding agents must have a secure foundation to tooth structure whether that is to provide occlusion of dentin tubules or provide attachment for other restorative materials in order to prevent microleakage, restoration retention, and maintain the restorative bond. These bonding agents bond to unprepared enamel, prepared enamel, and prepared dentin.

There is some discussion and controversy when to “seal” uncomplicated crown fractures and enamel fractures in animals. The reality is there is very little to no science other than opinions and the bully pulpit.

The vital tooth (odontoblasts) can occlude the dentin tubules with mineral during reversible pulpitis. As with all assessments, intraoral radiographs are required. Dental sealants are recommended with known acute uncomplicated fractures exposing the dentin tubules in young animals (<18-24 months of age*). By sealing the dentin tubules, the dental pain from the exposed odontoblastic processes can be controlled and the translocation of bacteria and oral solutions resulting in pulp necrosis can be prevented. The sealing of older uncomplicated crown fractures in older teeth and animals without a known recent fracture history remains controversial and lacks good scientific evidence to justify the treatment and associated expense. Nomenclature is confusing. Dental resins/composites may be unfilled resins, resins with filler particles, glass ionomers, and/or combinations with or without fluoride used mostly as pit and fissure sealants for human teeth. Dental bonding agents are often unfilled resins. Veterinary dentistry often uses the old human generation classification system. The bonding agent I prefer is technically an “eight generation” universal adhesive. I use 3M ESPE Scotchbond Universal Adhesive that may be used in a total-etch (32% phosphoric acid) and self-etch technique.

If unsupported enamel or dentin tooth structure is contoured via odontoplasty (e.g., white stone, fine diamond bur, 3M finishing discs, Super Snap Shofu) in order to create a less plaque retentive surface, then a sealant product will need to be placed because dentin tubules, previously repaired, will be opened during the procedure. Depending on the product utilized, an acid etch is necessary to prepare the tooth surface. Depending on the product, a one-step or multiple-step procedure is necessary to correctly bond the restorative material to the tooth. Over etching of dentin can cause tooth sensitivity. The animal may not show signs of pain. The user must be familiar with each product because steps are often different depending on the materials, manufactures, and evolution of the restorative material. Understanding the product in use is crucial as they may be total-etch, self-etch, they may allow both etching techniques, they may multiple steps or one step. If instructions are not exactly followed it will fail or cause harm. The first step is bonding. In some cases, composites or fluoride glass ionomers may be necessary. Then learning fillers such as nanofilled, hybrid, etc. and finishing discs is necessary.

Finally, if there is near pulp exposure, an indirect pulp capping with a hard setting calcium hydroxide followed by a composite restoration is necessary. The calcium hydroxide stimulates the odontoblasts to produce reparative dentin. Recheck intraoral radiographs of the tooth in 6 months is necessary.

Conclusion It is important to understand that endodontic infection is hidden subgingivally and intraoral radiographs of discolored teeth, fractured teeth, malformed teeth, enamel defects, etc. is required to identify, diagnose, and treat veterinary patients with the understanding radiographic changes can be absent or minimal in many cases. Endodontic treatment can remove infection and preserve function of many teeth thereby eliminating chronic pain, infection, and inflammation.

139 TICK-BORNE DISEASE – KEY QUESTIONS ANSWERED

Annette Litster, BVSc PhD FANZCVS (Feline Medicine) MMedSci (Clinical Epidemiology) Senior Veterinary Specialist, Focus Areas in Infectious Diseases, Feline Medicine, and Shelter Medicine Zoetis US CAD Veterinary Specialty Operations

1. Which ticks, which pathogens, which areas? Hard bodied (Ixodid) ticks (Kidd, 2003)  Ixodes scapularis, Ixodes pacificus – Transmits Anaplasma phagocytophilum and Borrelia burgdorferi  Amblyomma americanum – Transmits Ehrlichia ewingii  Dermacentor variabilis – Transmits Ehrlichia canis  Rhipicephalus sanguineus – Transmits Ehrlichia canis, Anaplasma platys  Life stages – egg, larva, nymph, adult

2. What are the transmission times for each pathogen and why do they vary? (Kidd, 2003)  A window of opportunity generally exists between tick attachment and the transmission of a disease-causing agent from the tick to the host. During this window, transmission can be prevented by repelling, removing or killing the tick.  Pathogen factors – o Organisms that exist in the salivary glands of unfed ticks (e.g. Anaplasma) can be transmitted faster than those that do not (e.g. Borrelia burgdorferi). Some pathogens undergo reactivation, multiplication, or migration before they are transmitted to the mammalian host o There can be different transmission times for different species of the same pathogenic genus.  Host factors - There can be different transmission times according to the host species.  Immunological factors - Host immunity against Borrelia burgdorferi can prevent tick transmission because antibodies are ingested with the blood meal and kill Borrelia burgdorferi in the midgut. If the tick vector is partially fed and interrupted, it can transmit Borrelia burgdorferi much faster to a second host on which it attaches. The outer membrane of B. burgdorferi is composed of outer surface proteins (Osp). Osp are expressed by B. burgdorferi at different stages of the life cycle. Outer surface protein A (OspA) is required for the tick vector to become infected and is expressed during the part of the Borrelia life cycle that occurs in the midgut of the tick. The next stage of the Borrelia life cycle occurs when the bacteria move from the midgut of the tick to the salivary glands. At this stage, outer surface protein expression moves from Osp A to OspC. Once B. burgdorferi has been transmitted to a susceptible mammal, expression of OspA is minimal or absent and another outer surface protein, OspC, dominates. OspC is required for B. burgdorferi to infect mammals. Anti-Osp C antibodies are capable of killing Borrelia, while anti-Osp A antibodies can only prevent transmission. Natural infection with B. burgdorferi does not induce long-lasting protective immunity. Vaccination provides protection against infection by inducing antibodies against Borrelia outer surface proteins. Anti-Osp C antibodies are capable of killing Borrelia, while anti-Osp A antibodies can only prevent transmission of infection to mammals. Vaccine protection against Borrelia burgdorferi Outer surface protein A (Osp A) All current vaccines induce antibodies against outer surface protein A (OspA). OspA expression is required for Borrelia to infect ticks and is found in Borrelia that are located in the

Back to Table of Contents 140 midgut of the tick. OspA expression is reduced soon after tick attachment to mammals and OspA immunity appears to be effective only during a narrow window at the beginning of a blood meal, but it helps prevent further transmission of B. burgdorferi from ticks feeding on vaccinated dogs. A recently published controlled clinical trial demonstrated that an OspA-only vaccine was unable to provide complete protection against infection when a challenge infection with Borrelia burgdorferi was administered. In that study, 2 of 15 dogs in the vaccinated group became infected after challenge, and 1 of those 2 dogs showed evidence of joint inflammation on histopathology at the end of the 6-month study period (Grosenbaugh et al., 2016). Outer surface protein C (Osp C) OspC expression is required for Borrelia to infect mammals. This is the main immunogenic protein of B. burgdorferi and is located in the tick salivary glands and in the dog’s body during natural infection. There are approximately 15 OspC types in the USA and 30 OspC types have been identified worldwide. Until recently, it was thought that a single ‘universal’ OspC type could induce antibodies that would cross-protect against the other OspC types. This has recently been disproven (Oliver et al., 2016), emphasizing the importance of inducing antibodies against a number of different OspC types to help provide optimal protection from Borrelia infection in mammals. Broader protection is provided if both antibodies against both OspA and OspC are induced. Vaccination can induce a clinically insignificant rise in Lyme disease specific circulating immune complexes. However, studies have not linked canine Lyme-nephritis with vaccination against Lyme disease.  Transmission time estimates – o Since Anaplasma lives in the tick salivary glands it is transmitted very soon after feeding starts (<24 hours). o E. canis is transmitted in <24 hours (Fourie et al., 2013. Transmission of Ehrlichia canis by Rhipicephalus sanguineus ticks feeding on dogs and on artificial membranes. Veterinary Parasitology 197(3-4):595-603). o Very few Borrelia burgdorferi are transmitted within 24-48 hours of attachment and feeding, but if feeding is longer, very efficient transmission occurs.  Time frame for successful acaricide intervention varies among tick-borne infections depending on transmission times

3. How long after infection can I expect a blue dot, and how long will seropositivity persist? (Little, 2009) -  Borrelia burgdorferi - 4-6 weeks  A. phagocytophilum - 2-3 weeks  E. canis - 3-4 weeks  Clinical signs can precede seropositive status for Anaplasma and Ehrlichia infection, so re-test a suspect clinical, seronegative case 1-2 weeks later to see if it has seroconverted.  Seropositive status for Anaplasma and Ehrlichia can last for years after exposure; in some areas >50% dogs test positive for Anaplasma and up to 15% dogs test positive for Ehrlichia  Doxycycline administration has no impact on the production of antibodies or timing of seroconversion (Sainz, 2015)  Serologic cross-reactions – While no important cross reaction exists between Ehrlichia and Anaplasma, potential cross-reactions could occur if titers against one pathogen is very high; there can be cross-reactions between species within each genus

4. Which clinical signs/lab results should I expect? (Sainz, 2015; Little, 2010)  A. phagocytophilum - Incubation period is usually 1-2 weeks; acute stage with fever, anorexia, lethargy, polyarthropathy, bleeding diatheses, epistaxis, vomiting, diarrhea, thrombocytopenia,

141 lymphopenia, elevated liver enzymes. Most infected dogs either present in the acute stage or remain healthy.  A. platys – Infected dogs can become clinically ill with febrile disease associated with cyclic (every 1-2 weeks) thrombocytopenia. However, in general A. platys infection creates a milder course of disease than other Ehrlichia/Anaplasma agents, although disease may be more severe in dogs that are co-infected with A. platys and other rickettsial pathogens.  E. canis - Incubation period is usually 1-3 weeks; 2-4 week acute phase with fever, anorexia, lethargy, bleeding disorders, polyarthropathy, lameness, lymphadenomegaly, neurological signs. Many dogs have subclinical infections, sometimes with mild thrombocytopenia. The chronic infection stage has a grave prognosis and can develop months to years after initial infection. Typical signs include fever, anorexia, weight loss, myalgia, anterior uveitis, severe pancytopenia, and bleeding tendencies. German shepherds are predisposed to the development of chronic ehrlichiosis.

5. What should I do when there’s a blue dot in a clinically healthy dog? Anaplasma and Ehrlichia (Little, 2010)  Revisit tick control with dog owner  Decision to treat is made when there are clinical signs of disease, not based solely on positive serologic status, which could indicate either past or current infection  Seropositive asymptomatic dog - Perform CBC and if in reference range may choose to not treat, or to treat with a single course of antimicrobials to avoid potential disease progression Borrelia burgdorferi (Little, 2009) -  Revisit tick control with dog owner  Vaccinated dogs will not be positive on SNAP4Dx or C6Quant; will be positive on IFA and whole cell ELISA; Western blot is a DIVA test  Always follow positive serology with UA; can also consider Quant C6  Treat symptomatic seropositive dogs, but the decision to treat asymptomatic dogs is controversial; balance between lack of evidence-based information on the prevalence of clinical infections and the pathology caused; renal failure is progressive and terminal; arthropathy is a painful condition and clinical signs might not always be noticed/reported by dog owners  Anaplasma and Borrelia burgdorferi co-infections are relatively common since they have the same Ixodes tick vector; clinical signs are more severe with co-infections and diagnosis might be more difficult since more clinical signs generate a longer DDx list

6. What about antigen detection methods? Blood smears and PCR panels (Sainz, 2015) Blood smears  E. canis – Morulae only found in 4-6% clinical cases; increased sensitivity if examine monocytes in buffy coat, and if specialist cytologists examine lymph node aspirates using multiple oil immersion fields (50%)  A. phagocytophilum – Morulae in neutrophils in up to 60% cases PCR  PCR testing is more sensitive than direct microscopic evaluation; use EDTA blood and/or splenic aspirates  Enables speciation and can provide estimation of bacterial load; tick-borne PCR panels can detect co-infections to facilitate successful management  False negative results can occur, especially once doxycycline treatment has commenced or at certain stages of infection due to reduced copy numbers – negative test means ‘no pathogen detected’  False positive results can occur in microfilaremic D. immitis-infected dogs because of cross- reactions with 16S primers by Wolbachia spp. (Little, 2010)

142 7. How do I treat clinically infected dogs and what response should I expect from successful treatment? (Little, 2010)  Anaplasma, Ehrlichia – o Acute phase shows marked clinical response to doxycycline within 24-48 hours o Platelet count should return to normal in 14 days (up to 2-4 weeks) after successful treatment; don’t repeat serologic testing because it just proves exposure  B. burgdorferi - Marked clinical response to antimicrobial treatment within 24-48 hours  E. canis and B. burgdorferi infection might persist subclinically even after successful treatment  Immunity stimulated by natural infection with E. canis or B. burgdorferi does not prevent re- infection

8. How do I prevent infection?  Annual screening to monitor effectiveness of tick prevention methods such as vaccination against Lyme disease and acaricides, as a guide to local prevalence; as a marker for tick exposure (follow up with dog owner if positive); and as a marker for local Borrelia risk to humans.  B. burgdorferi – Annual vaccination after initial primary series. Broad spectrum Osp C plus Osp A protection is essential.  Landscaping, avoidance of tick habitats  Acaricides - What should I be looking for? o Need for speed because transmission times relatively short for Anaplasma and Ehrlichia o Must remain effective for the full dosing interval. Dryden et al. (2006) demonstrated reversable neurotoxicity rather than tick killing with topical imidacloprid-permethrin treated dogs by Day 21 post-treatment. This resulted in ticks not being killed for the last week of the 1-month dosing interval for the product and being active in the environment of the treated dogs. o Year-round protection essential since many ticks are resistant to cold temperatures and R. sanguineus prefers to live indoors o Safety – Data based on field conditions with very large numbers of dogs

REFERENCES  Dryden et al., 2006. Veterinary Therapeutics 7 (3):173-186.  Grosenbaugh et al., 2016. Veterinary Immunology and Immunopathology 180:29-33.  Kidd & Breitschwerdt, 2003. Compendium 25 (10):742-751.  Little, S. 2009. https://idexxlearningcenter.idexx.com/idexx/resources/library/media_edu/archived_webina rs/faqs/Anaplasmosis_and_Ehrlichiosis_Webinar_FAQs.pdf (accessed 1/12/17)  Little, S. 2010. Veterinary Clinics of North America Small Animal Practice 40: 1121–1140.  Oliver LD Jr., et al. 2016. The Veterinary Journal 218:27-33.  Sainz et al. Parasites & Vectors (2015) 8:75.

143 Tick-borne Disease Timeline1, 2

TRANSMISSION TIME BLUE DOT

B. burgdorferi B. burgdorferi

Anaplasma & Ehrlichia Anaplasma & Ehrlichia A E

0 24 48 72 1 2 3 4 5 6 7 8 9 10 11 Hours Post-attachment Weeks Post-attachment

Anaplasma & Ehrlichia B. burgdorferi

CLINICAL SIGNS

1. Kidd & Breitschwerdt, 2003. Compendium 25 (10):742-751. 144 2. Little, S. 2009. https://idexxlearningcenter.idexx.com/idexx/resources/library/media_edu/archived_ webinars/faqs/Anaplasmosis_and_Ehrlichiosis_Webinar_FAQs.pdf (accessed 1/12/17) Reading a Biopsy Report

An approachable team of specialists providing advanced, collaborative, and compassionate care.

Rebecca Regan Back to Table of Contents 145

This document is intended for confidential use by the SAGE organization and/or its affiliates. Any review, dissemination, distribution, or copying of this document is strictly prohibited. About me…

146 My BFF

147 148 About me…

149 About me…

150 Outline

▪ Is it cancer?

▪ What type of cancer? ▪ Special stains (IHC)

▪ Other important pieces ▪ Mitotic index, margins

▪ When do I order ancillary tests?

151 Is it cancer?

▪ First rule…use your best judgment

-If it seems like cancer, it certainly could be even if FNA is inconclusive

▪ Dixie, 11 yo FS Lab mix

1528 153 Is it cancer?

• Shiloh, 9 yo MN Golden

– Enlarged lymph nodes – No clinical signs

154 155 Is it cancer?

• Flow cytometry confirms CD45- T zone lymphoma

156 T-zone lymphoma • 60% of indolent LSAs

• 45% are Goldens

• 10% have demodex

• Can be diagnosed via biopsy or with flow – Due to unique expression pattern

157 What sort of cancer?

• Only matters if firmer diagnosis changes the treatment – Round cell tumor • Need to know – Mesenchymal tumor • Histiocytic sarcoma • Hemangiosarcoma • Melanoma – Epithelial

158 What sort of cancer?

• Maya, 6 yo FS Pit Bull – Large SQ mass removed from shoulder

159 160 161 162 What sort of cancer?

• Velvet, 14 yo FS Lab X – Well demarcated, smooth, caudal tongue tumor

163 Meh 164 What sort of cancer?

• Ginger, 10 yo FS beagle – Pink tongue mass

165 166 What sort of cancer?

• Most melanomas pigmented – A minority are amelanotic

• Melan A, PNL2

• Melanoma vaccine

167 What sort of cancer?

• Kona, 9 yo MN lab – Large SQ mass on hip removed

168 169 170 CD204

(Kato 2013)

171 Mitotic index

• Number of diving cells per 10 HPF

• Provides prognostic information for some tumor types – Mast cell tumors – Soft tissue sarcomas – Melanomas

172 Mitotic index

• Mast cell tumors

– >5 – Kiupel 2 tier scheme >7

173 Patnaik vs. Two-tiered grading • Patnaik: grade 1-3 (best to worst) • Kiupel: high vs low

(Kiupel 2011) 174 Mitotic index

• Moose, 8 yo MN chow x – Mast cell tumor removed from flank fold

175 176 Back to Maya…

177 Mitotic index

• Remember to watch the units

178 Mitotic index

• Soft tissue sarcomas

– Kuntz grading scheme

– 0-9, 10-19, >20

179 Mitotic Index

• Melanoma

– Oral • Subgroup with MI = 0 may have a better prognosis

180 Mitotic Index

• Melanoma

– Cutaneous • MI > 3 = malignant

181 Margins

• Make sure they are mentioned

• Watch out for the units!

182 Margins

• Neo, 12 yo FS cattle dog X – Large mass on R thigh

183 184 Additional testing?

• Mast cell tumor prognostic panel

– Ki-67 – AGNOR – Kit mutation status

185 KIT • All MCTs express

• Expression pattern prognostic

(Webster 2006) 186 Additional testing? • Immunophenotyping – Gold standard: IHC

– Flow cytometry • Need live cells

– PARR • PCR for antigen receptor rearrangement • Can be done on stained slides • Only test for clonality

– Immunocytochemistry

187 Immunophenotyping

• PARR has a lower sensitivity than flow – up to 25% false negatives – Specificity is the same (you can believe a positive)

• 94% of flow samples agree with IHC

• 70% of PARR samples agree with IHC

188 Questions? *References available upon request*

189 Incomplete Margins: Now What?

An approachable team of specialists providing advanced, collaborative, and compassionate care.

Wendi Velando Rankin, DVM, MS, DACVIM Back to Table of Contents (Oncology) 190 This document is intended for confidential use by the SAGE organization and/or its affiliates. SAGE Dublin Any review, dissemination, distribution, or copying of this document is strictly prohibited. Objectives

• What are “incomplete” margins? • Importance of margins – Canine mast cell tumors – Canine soft tissue sarcomas – Canine squamous cell carcinoma – Canine oral melanoma – Feline injection site sarcoma

191 Objectives

• Treatment options after margins – Recut – Radiation – Electrochemotherapy – Intralesional chemotherapy – Standard chemotherapy – Metronomic chemotherapy

192 Margins: Not as black and white as you’d think • Consensus statement (Kamstock 2011, Milanovec 2017) – Margins • Histologic free tumor margin (HTFM) • Gross surgical margins – Quantitative (e.g. 4 mm) – Qualitative (e.g. normal adipose tissue) – Avoid subjective terms • Clean – Clean but close • Dirty • Close • Narrow

193 Margins: Limitations • Immediate post-excision period – 15%-32% shrinkage • Tissue fixation • Trimming – Breadloafing vs radial Milanovec 2017

Kamstock 2011

194 Margins: Limitations • Histologic processing (post fixation) – 20% reduction in length – Felines: >100% increase in thickness • Slide evaluation – Need 1000s of sections examined in a small tissue – Can have false negative margins Bray 2016 – Pseudocapsule

195 Margins: Prognosis – Canine MCT • Variable results • Complete margins  improved outcome (Schultheiss 2011) – 114 MCTs – No recurrence >10 mm lateral margins

• Complete margins: 36% recurrence (Donnelly 2015)

• Incomplete margins grade II (Seguin 2006) – Recurrence rate 23%

196 Margins: Prognosis – Canine STS

• Incomplete margins (Kuntz 1997) – 10.5x more likely for regrowth – 17% recurrence overall, including “clean but close” (Stefanello 2008) • Grade is predictive

– Low-grade (McSporran 2009, Stefanello 2008, Chase 2009, Bray 2014) • 7-20% recurrence – Grade 2 and MI >9 (McSporran 2009, Bostock 1980) • >60%, up to 75% recurrence

197 Margins: Prognosis – Canine SCC • Nasal planum (Lascelles 2000) – Complete margins: recurrence 1 of 5 – Incomplete: recurrence 8 of 8 • Digital SCC (Marino 1995) – Incomplete/marginal excision higher recurrence • Oral SCC (Schwarz 1991) – Incomplete excision: • 2.4-3.6x more likely to die of disease from regrowth • 57% recurrence – Complete: • 17% recurrence

198 Margins: Prognosis – Canine Oral Malignant Melanoma

• Incomplete excision (Tuohy 2014) – 1.5 yrs progression free • Complete (Tuohy 2014) – 6 yrs progression free – (Not statistically significant) • Removal of bone with wide resection did improve outcome (Hahn 1994)

199 Margins: Prognosis – Feline Injection Site Sarcoma

“Complete” “Incomplete” Margins Margins

DFI 11-21 month 2-6 months (Davidson 1997, (Davidson 1997, Cronin Muller 2017) 1998, Hershey 2000)

Regrowth 19-38% 58-69% (Giudice 2010, Poirier (Giudice 2010, Poirier 2002, Muller 2017) 2002)

200 Margins: Prognosis – Feline Injection Site Sarcoma

3 cm margins 5 cm lateral (Muller 2017) margins and 2 fascial planes deep (Phelps 2011)

DFI 21 months 49 months

Regrowth 38% 14%

• Referral institution versus not (Hershey 2000) – DFI 9 months versus 3 months

201 Margins: What should we use? • Multiple factors – Clinical impressions • Exam findings • Gross margins in surgery • CT scan – HTFM • Quantitative • Qualitative – Tumor characteristics • Grade • MI • Tumor type

202 Treatment options after incomplete margins: Recut • Location – Limbs – probably won’t benefit • Incision size – Large incisions – may not benefit • Difficult to assess margins • Tumor type – Feline ISS – recuts can be difficult • Recurrence versus new tumors: – 55% recurrence versus 33% for new tumors (Muller 2017) – MCT • MST >6 yrs (Kry 2014) • 13% recurrence 203 Treatment options after incomplete margins: Radiation therapy - Canine – Technical details • 16-19 anesthetic episodes • SAGE Campbell PetCure Oncology – Multiple studies known – Good outcome – Standard of care

204 Treatment options after incomplete margins: Radiation therapy - Canine – Standard of care • Soft tissue Sarcomas (Forrest 2000, McKnight 2000, Graves 1988) – >80% disease free at 1-2 years after diagnosis – Survival times >80% alive at 3-5 years – One of the few tumors we MAY be able to use the word “cure” • MCT – 6.7%-8% recurrence (Poirier 2006, Kry 2014) » 38% recurrence no treatment (Kry 2014) – MST 5-6 yrs (Kry 2014, Lejeune 2015) • Melanoma – Variable reports » MST 3 mo-2 yrs post-op (Kawabe 2015, Proulx 2003) 205 Treatment options after incomplete margins: Radiation therapy – Feline Injection site Sarcomas • Standard of care – Even with 3 cm clean margins for injection-site sarcomas • Outcomes (Cronin 1998, Bregazzi 2001, Eckstein 2009, Cohen 2005, 2001) – 28-45% will have regrowth within 1-2 years – Survival times can still be >1.5 years – Average time to recurrence 12 mo-2 years • Technical details – 19-21 anesthetic episodes – SAGE Campbell PetCure Oncology • Multiple studies known (but many retrospective) • Standard of care

206 Treatment options after incomplete margins: Electrochemotherapy  Many of the papers out of Italy  Lack of access to radiation therapy  First came to California 3 yrs ago  Now several sites in California are using  Other uses in humans:  Botox

207 Treatment options after incomplete margins: Electrochemotherapy - Rationale

 Standard IV chemotherapy challenges  Needs to be distributed in blood vessels into the tumor  Needs to get to the solid tumor and into the cell  Cell membrane serves as a barrier  Interstitial space around the tumor can be a barrier  Thus, only small doses of chemotherapy may get to the actual solid tumor  Must use a max. tolerated dose

208 Treatment options after incomplete margins: Electrochemotherapy - Rationale  Get larger doses to the tumor site and minimize systemic toxicity  ECT increases bleomycin concentration 1000x compared to IV (Maglietti 2016)  Combines local or systemic chemotherapy (or both)  Electropulsation and Electroporation

209 Treatment options after incomplete margins: Electrochemotherapy - Technical  Sedation/premedication  Chemotherapy  IV chemotherapy (bleomycin, carboplatin, gemcitabine)  For bulky tumors, ulcerated  Intralesional chemotherapy (cisplatin, bleomycin)  For superficial tumors or incision sites  Can give in cats – low dose and taken up by cells  Combination of both  For bulky tumors to penetrate deep and superficial tumor  Improved responses for variety of tumors (Maglietti 2016)

210 Treatment options after incomplete margins: Electrochemotherapy - Technical

 Propofol anesthesia  Or dexdomitor/butorphanol  Electric pulses applied  Recover patient  For microscopic disease  2-3 treatments  2 treatments for low-grade sarcomas  3 treatments for higher-grade tumors

211 Treatment options after incomplete margins: Electrochemotherapy – Canine STS • Spugnini 2007 – 22 dogs – Surgery then ECT: time to recurrence >2 years • 50% of these patients no recurrence at all • The 3 with largest tumors had dehiscence – May have been due to sx or combination of sx and electrochemotherapy – Other studies have shown no increased risk of complications with ECT peri-operatively (Lowe 2017)

212 Treatment options after incomplete margins: Electrochemotherapy – Feline Injection Site Sarcoma

• Spugnini 2007 – Surgery alone (14)– recurrence at 4 months – Surgery+ intra-op ECT (19) - recurrence 12 months – Surgery + post-op ECT (39)– recurrence 19 months

213 Treatment options after incomplete margins: Electrochemotherapy – Canine Oral Melanoma • Spugnini 2006 – 10 dogs – 7/10 complete remission, 1 partial remission • 80% response rate overall • 3 stable disease – 4/10 >16 month survival time • These dogs developed vitiligo

214 Treatment options after incomplete margins: Electrochemotherapy – Canine Oral Melanoma

215 Treatment options after incomplete margins: Electrochemotherapy – Canine MCT

• Mast cell tumors (Kodre 2009, Spugnini 2006, 2011, Tozon 2016, Lowe 2017) – (77-100% response rate for gross disease) – 78% had no growth >6 years (Spugnini) – Time to recurrence >3-4 years in multiple papers • For surgery then ECT

216 Treatment options after incomplete margins: Electrochemotherapy – Side effects

• Systemic? – Not typical unless related to anesthesia – Possibly large, aggressive tumors potentiating pulmonary thromboembolism • Local side effects – Inflammation/scabbing – Discomfort (24-72 hours) – Heat – Mast cell degranulation – Pruritis – Radiation recall – in patients with previous irradiation 217 Treatment options after incomplete margins: Electrochemotherapy – Management of side effects • Early local reactions – 1-3 days – NSAIDs or steroids – Pain medications – Ice pack – +/- E-collar • Later local reactions (scabbing, necrosis, dehiscence) – TIME – Sometimes Antibiotics, sometimes sx • Rare: Systemic (PTE) – Aspirin, +/- heparin at the time of treatment

218 Treatment options after incomplete margins: Electrochemotherapy – Side effects

219 Treatment options after incomplete margins: Electrochemotherapy – Advantages • Good to great overall response rates – Gross disease (some) and as adjuvant therapy • Low systemic side effects – Even the local reactions very manageable – Not limited by maximum toxicity (like radiation therapy) • Can re-treat (radiation have to wait a certain amount of time) • Outpatient procedure

220 Treatment options after incomplete margins: Electrochemotherapy – Advantages • When another surgery not a great option – Cost concerns – Tumors that are in locations that are difficult for another surgery (large perianal masses, nasal planum, periorbital tumors, digits, foodpads)

• When radiation therapy not a great option – Client can’t travel – Increased risk of many anesthesias

221 Treatment options after incomplete margins: Intralesional chemotherapy • 5-fluorouracil (STS) – Limited data (Marconato 2007) • 6 dogs – pilot study • 4 of 6 no disease at > 18 months • 2 died of disease (9 months and 13 months) • Treat every week for 6 treatments

222 Treatment options after incomplete margins: Intralesional chemotherapy – Technical details • Injected into the incision • 1-2 weeks after surgery • Not to be used in cats (fatal neurotoxicity) – Side effects • Hyperpigmentation • Inflammation of skin

Courtesy of Dr. Crawford- Jakubiak 223 Treatment options after incomplete margins: Intralesional chemotherapy • Advantages: – Low cost relative to radiation therapy – No systemic side effects – Relatively low local side effects (hyperpigmentation, inflammation, ulceration) – Seems to have good tumor control in the 6 dogs published – +/- Sedation • Disadvantages: – Unknowns: Published in 6 dogs – +/- Sedation – Frequency of visits – Can get necrosis – Cats? Maybe use carboplatin?

224 Treatment options after incomplete margins: Chemotherapy: Canine STS

• Surgery, then doxorubicin for high-grade STS (Selting 2005) – No benefit for recurrence, metastasis, or overall survival time

225 Treatment options after incomplete margins: Chemotherapy: Canine MCTs

• Surgery, +/-radiation, then chemotherapy (Lejeune 2015, Thamm 2006) – MST 3-4 yrs – Prednisone, vinblastine, CCNU

• Surgery, then vinblastine/prednisone (Thamm 1999) – MST ~1-2 years

• Surgery then Palladia???

226 Treatment options after incomplete margins: Chemotherapy: Feline ISS

• Surgery, radiation therapy, doxorubicin (Poirier 2002) – DFI 13 months – (3 months for surgery alone historical controls)

227 Treatment options after incomplete margins: Metronomic chemotherapy  Goals:  Low daily dosing  Inhibit angiogenesis  Maintain remission or growth

228 Treatment options after incomplete margins: Metronomic chemotherapy – Canine STS

 STS Retrospective in dogs (Elmslie 2008) – Drugs • Cyclophosphamide 10 mg/m2 PO SID • Piroxicam 0.3 mg/kg PO SID – 30 treated dogs versus 55 controls not treated – Disease-free interval • Not treated: 7 months • Treated: not reached – Side effects – 40% • 10% dogs developed cystitis (one euthanized)

229 Treatment options after incomplete margins: Metronomic chemotherapy – Canine MCT • Unknown for microscopic disease – Gross disease (Taylor 2009) – Chlorambucil 5 mg/m2 EOD and prednisolone • Prospective, 21 dogs • 13 intermediate grade, 6 high-grade • 38% response (CR and PR) • PFI for responders: 1.5 years • Overall MST: 5 months • Well tolerated, no toxicity

230 Treatment options after incomplete margins: Metronomic chemotherapy • Advantages – Visits are infrequent (every 4-12 weeks) – Clients can give at home – Minimal toxicity • Disadvantages – When do we stop? – Cats? – Systemic side effects – Some clients can’t medicate – Some clients don’t want exposure

231 Summary • Margins – Interpret carefully • Do not just go by “Clean”, “complete” • “Clean but close” or “narrow” clinically means incomplete – Clinical findings: location, size, surgeon assessment – Histologic findings: grade, mitotic index, tumor type • Treatment options – Recut if possible (remember limitations – location, large incisions, histopath limitations) – Radiation therapy is standard of care – Electrochemotherapy has many advantages – Intralesional 5FU is an option (limited information) – Chemotherapy for MCTs has reasonable outcomes

– Metronomic chemotherapy is least invasive 232 Summary Treatment after STS post-op MCT post-op Feline ISS post -op marginal excision None 17% to 75% recurrence 23-38% recurrence DFI 2-6 months DFI <1 yr? Most within 1 yr? Grade-dependent Recut ? 13% recurrence 55% recurrence (65% of them regrowing <10 mo) Radiation MST not reached (years) Not reached (5-6 years?) DFI 1.5-2 yrs DFI 80% >1-2 yrs 6-8% recurrence

Electrochemotherapy DFI >2 years DFI >3-4 years DFI 1.5 yrs

Intralesional DFI 1.5 yrs? ? ? chemotherapy Standard Chemotherapy No benefit for high-grade DFI 1-2 yrs DFI 13 mo (after sx DFI 3-4 yrs (MST) and radiation)

Metronomic DFI not reached in study ? (study was for gross dz) ? chemotherapy ~1.5 years?

233 Oncology Consultations Campbell • Campbell – Dr. Mike Kiselow Dr. Kiselow Dr. Shaw Dr. Regan – Dr. Steve Shaw San Mateo – Dr. Beki Regan • Redwood City – Dr. Naoko Sogame – Dr. Bryan Marker Dr. Sogame Dr. Marker • Concord – Dr. Martin Crawford-Jakubiak – Dr. Lori Cesario Concord • Dublin Dr. Jakubiak Dr. Cesario – Dr. Wendi Velando Rankin – Dr. Chantal Tu

Dublin

Dr. Rankin Dr. Tu 234 Questions?

Thank you to our sponsors

235 Electrochemotherapy: Tumors

• Soft tissue sarcomas (post-surgery for incomplete margins and some with bulky disease) • Mast cell tumors (bulky disease and incomplete margins) • Oral tumors (melanoma, acanthomatous epulis, squamous cell carcinoma, fibrosarcomas) • Nasal planum tumors in cats • Melanomas (cutaneous/oral - incompletely resected or bulky disease) • Perianal, anal sac or rectal tumors (rectal tumors that can be accessed with the probe) • Cutaneous tumors around the eye • Skin carcinoma (carcinoma in situ, solar-induced carcinoma/dermal hemangiosarcoma)

236 Clinical Lung Trial Information Sheet: Stereotactic Radiosurgery (SRS) for the Treatment of Primary Lung Tumors in Dogs

Kelsey Pohlmann, DVM, MS, DACVR (RO)

Statement of Intent: PetCure Oncology™ is currently recruiting patients for a prospective study evaluating the effectiveness of stereotactic radiosurgery (SRS) for the treatment of primary lung tumors in canine patients.

How to Enroll: Information about the study, including both print and electronic application forms, can be found at www.PetCureOncology.com/ClinicalTrials. Any additional inquiries may be directed to the Clinical Trials Coordinator, Kelli Sloane, at [email protected].

Background and Rationale: Radiation therapy uses high‐energy radiation to shrink tumors and kill cancer cells. The radiation is intended to damage the DNA of the cancer cells beyond repair so that they stop dividing or die. Stereotactic radiosurgery (SRS) is an advanced form of radiation therapy that delivers high‐dose radiation with sub‐millimeter precision, enabling precise targeting of a tumor with minimal collateral damage to nearby healthy tissue.

SRS has been used to successfully treat both inoperable and surgically removable lung tumors in humans.1–7 Studies have revealed that SRS is well‐tolerated, results in minimal complications and toxicities, maintains or improves quality of life, and results in equivalent survival times when compared to surgery for patients with operable tumors.1–4,6 Additionally, the peri‐procedural morbidity and mortality rate is less for the SRS‐treated patients than for those treated surgically.

Hypothesis: Canine patients with primary lung tumors can be safely and effectively treated with image‐guided SRS.

Study Design: This is a single‐arm prospective study. Eligible patients will be treated with a metric‐driven protocol consistent with the quality assurance practices of PetCure Oncology and the PetCure Scientific Advisory Board. The protocol has been developed with the guidance of the Scientific Advisory Board.

8770 West Bryn Mawr, Suite 1370  Chicago, IL 60631  PetCureOncology.com  773.850.3400 237 Back to Table of Contents Eligibility Criteria: Any canine patient diagnosed with a primary lung tumor is potentially eligible for study entry provided they meet all of the following requirements:

1. Histologic or cytologic confirmation of malignancy is desired, but this requirement may be waived for patients with central/inaccessible tumor locations 2. Complete reference lab bloodwork must be available and less than two weeks old 3. Three‐view metastatic check or diagnostic CT scan of the thorax must be performed prior to patient enrollment. Evidence of metastatic disease is exclusionary for this study, but alternative treatment paths may be available. 4. Significant co‐morbidities that would impact the patient’s ability to tolerate/survive multiple anesthetic events is exclusionary 5. Caregivers must sign informed consent that they understand this is an ongoing clinical study to better define the role of SRS in the treatment of primary lung tumors in dogs 6. Caregivers must agree to follow the prescribed follow‐up procedure, including repeat CT scans at 3 and 12 months post‐treatment 7. Necropsy will be required for any patient that dies following enrollment in the study

Terms of the Study: PetCure Oncology is interested in better defining the role of SRS for the treatment of canine patients with primary lung tumors. While this form of therapy is already being used to treat veterinary patients with lung cancer, there are no controlled, prospective studies in the veterinary literature that are designed to truly define the risks and benefits of this kind of radiation therapy for tumors of the canine lung. In order to facilitate case accrual in an appropriate manner, PetCure Oncology will:

1. Provide an SRS video consult free of charge 2. Provide the treatment‐planning CT free of charge 3. Provide entire SRS treatment course at subsidized cost of $4,500 for up to 30 enrolled patients 4. Provide the two‐week checkup free of charge 5. Provide the 3‐ and 12‐month follow‐up CT free of charge 6. Absorb the cost of having a necropsy performed for patients that die after study enrollment

8770 West Bryn Mawr, Suite 1370  Chicago, IL 60631  PetCureOncology.com  773.850.3400 238

Contact Information: If you have questions about enrollment criteria or would like to refer a patient for evaluation/inclusion in the study, contact:

Kelli Sloane, R.T. (R)(T) Radiation Therapist Clinical Trials Coordinator, PetCure Oncology [email protected] 513.530.0911

If you have questions about the study design or the protocol for treatment, contact:

Dr. Neal Mauldin Dipl. ACVIM (Internal Medicine and Oncology) Dipl. ACVR (Radiation Oncology) Director, PetCure Scientific Advisory Board [email protected] 773.850.3400

References: 1. Ematsu MIU, Hioda AKS, Uda ATS, et al. COMPUTED TOMOGRAPHY‐GUIDED FRAMELESS STEREOTACTIC RADIOTHERAPY FOR STAGE I NON – SMALL‐CELL LUNG CANCER : A 5‐YEAR EXPERIENCE. 2001;51(3):666‐670. 2. Crabtree TD, Denlinger CE, Meyers BF, et al. Stereotactic body radiation therapy versus surgical resection for stage I non‐small cell lung cancer. J Thorac Cardiovasc Surg. 2010;140(2):377‐386. doi:10.1016/j.jtcvs.2009.12.054. 3. Collins BT, Vahdat S, Erickson K, et al. Radical cyberknife radiosurgery with tumor tracking: an effective treatment for inoperable small peripheral stage I non‐small cell lung cancer. J Hematol Oncol. 2009;2:1. doi:10.1186/1756‐8722‐2‐1. 4. Onishi H, Shirato H, Nagata Y, et al. Stereotactic body radiotherapy (SBRT) for operable Stage i non‐small‐cell lung cancer: Can SBRT be comparable to surgery? Int J Radiat Oncol Biol Phys. 2011;81(5):1352‐1358. doi:10.1016/j.ijrobp.2009.07.1751. 5. Muacevic a, Drexler C, Wowra B, et al. Technical description, phantom accuracy, and clinical feasibility for single‐session lung radiosurgery using robotic image‐guided real‐time respiratory tumor tracking. Technol Cancer Res Treat. 2007;6(4):321‐328. 6. Hof H, Herfarth KK, Münter M, et al. Stereotactic single‐dose radiotherapy of stage I non–small‐ cell lung cancer (NSCLC). Int J Radiat Oncol. 2003;56(2):335‐341. doi:10.1016/S0360‐ 3016(02)04504‐2. 7. Cancer CL. Image‐Guided Radiation Therapy for Non‐small. 2008;D(50):177‐186.

8770 West Bryn Mawr, Suite 1370  Chicago, IL 60631  PetCureOncology.com  773.850.3400 239 240 241 242 243 Track 4 FELINE HEARTWORM DISEASE UPDATE Dr. Annette Litster BVSc, PhD, FACVSc (Feline Medicine), MMedSci (Clinical Epidemiology) Annette L. Litster BVSc, FANZCVSc (Feline Medicine), PhD, MMedSci (Clinical Epidemiology) Zoetis, Veterinary Specialty Operations Chicago, IL

INTRODUCTION Heartworm (Dirofilaria immitis) infection is an increasingly diagnosed entity in feline practice due to heightened awareness of the disease in cats and improved diagnostic methods. Clinically affected cats may present at veterinary clinics with a wide range of clinical signs, such as chronic coughing, laboured breathing and vomiting and some infected cats die suddenly without any premonitory signs. However, many cats are subclinically infected and infection tends to be self-limiting. Feline heartworm disease is clinically challenging on a number of different levels. Diagnostic confirmation usually requires a combination of tests and treatment is most often limited to symptomatic therapy since curative medical and surgical treatments place the feline patient at significant risk. Safe and effective prophylactic drugs which kill a number of life-cycle stages are readily available. The following clinical review will present what is currently known of the life-cycle, prevalence, pathophysiology, clinical signs, the acute death syndrome, diagnosis, treatment, necropsy findings and prophylaxis for feline heartworm disease.

LIFE-CYCLE OF DIROFILARIA IMMITIS Dogs are the usual definitive hosts for D. immitis but the life cycle may also be completed in cats. Mosquitoes act as the intermediate host in both canine and feline infections. Cats are less easily infected with heartworms than dogs; there are fewer filariae in feline infections (usually six or less filariae); and the lifespan of the filariae is only about half the length of that in dogs (2-3 years compared with 5-7 years). Microfilarial counts in experimentally infected and naturally infected cats are usually very low and transient, seldom lasting more than one to two months, probably due to the immune response of the host. The cat does not serve well as a definitive host because of the low and erratic microfilaremias detected. The average prepatent period is seven to eight months, one to two months longer than that in dogs. Aberrant migration of fourth-stage larvae (L4) occurs more frequently in cats than in dogs and ectopic heartworms have been found in the body cavities and central nervous systems of infected cats.

PREVALENCE D. immitis infections in cats have been reported in many areas of the world – from Brazil, Venezuela, Italy, Japan, Australia, The Philippines, Malaysia, Tahiti, Papua New Guinea, China, Sierra Leone, Armenia, Canada and from at least 29 of the 50 states in the USA. Evidence from both published reports and personal communications suggest that in the United States over the past 10 years, the number of infected cats being diagnosed has increased. This apparent increase may reflect an increase in both veterinary and owner awareness and surveillance of cats. The distribution of feline D. immitis infection parallels that in dogs with an overall prevalence in cats of between 5% and 10% of that in dogs in any given area. It has been suggested that the lack of a consistent ratio between the prevalence of heartworm infection in

Back to Table of Contents 244 dogs and cats in the same area reflects the willingness of the local species of mosquitoes in the area to feed on both dogs and cats. The true prevalence of heartworm infection in cats may be understated due to their greater tendency to either spontaneously eliminate the parasite or die from the infection.

PATHOPHYSIOLOGY OF FELINE HEARTWORM DISEASE Feline infection can occur at any age and immunosuppression is not a prerequisite for infection. Indoor and outdoor cats are equally represented. Male cats were thought to have a higher prevalence of infection than female cats, but a relatively large retrospective study disputes this point. Acute lung injury is a major contributing factor to the initiation of clinical signs. It is hypothesised that the arrival of fifth stage larvae in the lungs and the death of the adult are the most likely stages of the life cycle to be associated with clinical signs. After an initial host response, the signs may abate and become subclinical. In chronic cases, perivascular reaction and evidence of thrombus formation with recanalisation are noted. D. immitis has evolved an array of specific molecular strategies to evade host immune attack. Marked differences in the surface properties of the third and fourth larval stages may delay potentially destructive immune responses to these stages in the host. Clinical and laboratory investigation have suggested that the acellular nature of the D. immitis cuticle and its thrombo-resistant surface properties allow the parasite to circumvent the host’s immune response and improve long-term survival. There is evidence that Wolbachia, an endosymbiontic bacteria present in D. immitis, may a play a role in the immunopathogenesis of heartworm disease. Heartworm-infected cats can be exposed to Wolbachia when larvae, or adult worms, are killed; when Wolbachia are released with microfilariae from the uterus of the females; and possibly through the excretory system of both male and female worms. One recent study demonstrated a strong IgG response against the surface protein of Wolbachia in heartworm-infected cats, leading to the suggestion that bacteria could play an important role also in the inflammatory reactions which characterize the heartworm infection in cats.

CLINICAL SIGNS Clinical presentations of feline heartworm disease vary widely in severity and include acute death, chronic coughing or intermittent dyspnea, and asymptomatic infections. In one study of 50 cases, asymptomatic infections were diagnosed incidentally in 28% of cats. Cats infected with immature worms, or as few as one adult worm may show clinical signs. At presentation, clinical signs are most commonly related to the respiratory tract, with dyspnea and coughing most often observed. Vomiting is a relatively common finding, reported in about a quarter to a third of cases, but the pathogenesis of this is unknown. Neurological signs, including syncope, collapse, blindness and vestibular signs, may also occur, probably in association with aberrant larval migration through the brain. The initial host response of diffuse pulmonary infiltrate and resultant clinical signs occurs most frequently about four to seven months after infection and is usually followed by a subclinical stage. However, the subsequent death of adult heartworms may cause additional severe signs, such as acute collapse and death.

245 THE ACUTE DEATH SYNDROME IN FELINE HEARTWORM DISEASE Acute death has been widely reported in asymptomatic cats infected with heartworms but the pathogenesis of the syndrome has yet to be elucidated. Acute collapse may occur with or without previous clinical signs and may be caused by only one worm. This is a much more common clinical presentation in feline heartworm disease than in canine heartworm disease. In one Australian report, 21 of 45 heartworm-infected cats (47%) exhibited acute death either at home or upon arrival at the veterinary clinic. This may overestimate the percentage of heartworm-infected cats that present with the acute death syndrome, since acute death is more readily diagnosed and recalled than other presentations of feline heartworm disease. Acute death in heartworm-infected cats has been attributed to circulatory collapse and respiratory failure from acute pulmonary arterial infarction, specifically acute pulmonary thromboembolism as a result of spontaneous death of adult heartworms. However, in the acute death syndrome, filariae are not always found embolising the main pulmonary arteries and radioisotope studies have demonstrated that lung lobes are rarely ischaemic. It has been suggested that pulmonary hypertension may also play a role, but it is rarely present in affected cats, at least based on secondary signs such as right-sided heart failure and congestive heart failure. Extraction procedures performed in cats, complicated by the accidental dissection of worms, have resulted in an acute shock-like reaction and death. It is hypothesised that the damage to the heartworm cuticle causes the sudden release of large amounts of heartworm antigen resulting in acute systemic anaphylaxis. Interestingly, in an experimental model of acute systemic anaphylaxis using D. immitis-sensitized cats challenged with intravenous heartworm antigen, a similar acute shock-like reaction was reported, and was characterized by dyspnea, hypoxaemia and systemic hypotension and haemoconcentration. The same model demonstrated that the amount of exposed internal filarial antigen may influence the severity of the response to challenge.

DIAGNOSIS A thorough diagnostic approach using a combination of tests is necessary in the diagnosis of feline heartworm disease because of the low worm burdens and light antigen load. Serology available for the diagnosis of feline heartworm infection includes serum antigen (Ag) and serum antibody (Ab) tests. In the serum Ag test, an enzyme-linked immunosorbent assay (ELISA) detects a protein found primarily in the reproductive tract of the female worm. This test may lack sensitivity due to low worm numbers and the possibility of infection solely with male worms and so it is not recommended as a screening test for feline heartworm infections. However, two recent studies (Little et al., 2014; Gruntmeir et al., 2016) reported increased sensitivity with antigen testing in feline serum after heat treatment for 10 minutes at 103 °C was used to break up antigen-antibody complexes that could interfere with antigen detection. Since the rate of false-positive results with Ag serology is low, so that a positive result generally indicates a current infection. ELISA Ab tests are available commercially as screening tests for cats when there is an index of suspicion for heartworm infection. The specificity of Ab tests may be compromised because they detect exposure to migrating heartworm larvae and will also be positive in cats with previous heartworm infections. False-negative antibody (Ab) test results were previously considered rare, but in two independently conducted studies, 14% of infected cats had negative Ab test results. Another

246 more recent study reported that more than 20% of antigen-positive heartworm-infected cats were antibody-negative. Combining the results of serum antigen and antibody tests achieves higher sensitivity and specificity than by using either test alone. Sensitivities of up to 100% and specificities of up to 99.4% were reported in one study when antigen and antibody tests were used in combination, compared to a maximum sensitivity of 89.5% and specificity of 92.9% when serum antigen or antibody tests were used alone. Thoracic radiography is a valuable tool for diagnosis and case monitoring in feline heartworm disease. Radiographic changes associated with feline heartworm disease include enlargement, blunting and tortuosity of the peripheral pulmonary arteries, especially on the right side in the DV or VD view; cardiomegaly and right ventricular enlargement; and patchy focal or diffuse pulmonary parenchymal changes. A mean ratio of greater than 1.6 for the width of the right pulmonary artery (at the caudal border with rib 9) to the width of rib 9 in the DV or VD view has been reported in association with feline heartworm disease. Objective measurement of radiographic heart size in heartworm-infected cats showed that mean heart size on lateral radiographs was significantly larger than the reference value for vertebral heart score. There was also a significant positive correlation between mean diameter of the caudal vena cava and heart size on lateral radiographs of infected cats. Alterations to structures visible on thoracic radiographs may occur less consistently in feline heartworm disease than in canine heartworm disease and the absence of radiographic abnormalities does not exclude a diagnosis of heartworm disease in cats. Echocardiography is a useful adjunctive test in cats in which there is a suspicion of heartworm disease but antigen test results are negative. One retrospective study of heartworm-infected cats reported that heartworms were detectable by use of echocardiography in 17 of 43 cats, most often in the pulmonary arteries, but also in the right ventricle, right atrium, and caudal vena cava. Heartworm infection was diagnosed exclusively by use of echocardiography in five cats in which the antigen test result was negative. The sensitivity of echocardiography for the detection of heartworm infections in cats is highly operator dependent and some experienced investigators have reported up to 100% sensitivity. It is possible to obtain false positive results when assessing cats at-risk for heartworm using echocardiography, due to the occasional presence of linear densities that mimic filariae. These densities are found where the main pulmonary artery branches and their cause is unknown, but they are presumed to be sonic reflections from the pulmonary artery wall. Necropsy confirmation of heartworm infection has been used as the standard for determining heartworm status in dogs, but routine necropsies may miss ectopic infections, which are more common in cats. Precardiac infections may also cause clinical signs in cats, but are difficult to confirm on necropsy. However, necropsy is still the method against which the performance of other tests are judged.

TREATMENT Medical Treatment Adulticidal treatment of cats with heartworm infection is associated with significant risk. In addition to the toxicity and reported lack of efficacy of heartworm adulticidal agents, adulticide treatment of heartworm-infected cats results in nearly universal and often fatal pulmonary thromboembolism with necrosis. Thiacetarsemide is believed to be a less effective adulticide in cats than dogs (reported efficacy <70%) and cats are more likely to manifest adverse reactions to this arsenical agent. The safety and efficacy of melarsomine in

247 heartworm-infected cats is being investigated, but preliminary data indicate its efficacy is only about 36% against adult heartworms in cats. For these reasons and because heartworm infection in cats is often self-limiting, infected cats are frequently managed only with supportive treatment (glucocorticoids, bronchodilators, antiemetics). Prednisone in diminishing doses is often effective for infected cats with radiographic evidence of lung disease, or infected cats that display clinical signs. An empirical oral regimen is 2 mg/kg body weight/day, declining gradually to 0.5 mg/kg every other day by two weeks and then discontinued after an additional two weeks. At that time the effects of treatment should be reassessed based on the clinical response and/or thoracic radiography. This treatment may be repeated in cats with recurrent clinical signs. However, conservative management is not without risk, as the acute death syndrome may occur without premonitory signs and in the presence of only one filaria. Surgical Treatment Surgical removal of heartworms is feasible and effective in symptomatic cats with echocardiographically visible filariae in the right heart and main pulmonary arteries. Transjugular catheterisation and removal of heartworms using rigid or flexible alligator forceps, horsehair brushes, endoscopy grasping forceps or basket-type retrieval catheters has been well described in the literature. Other more invasive surgical techniques including right auricular entry into the heart and main pulmonary arteriotomy have also been developed. Heartworm extraction often results in rapid and dramatic clinical improvement. However, accidental damage to the heartworms during the extraction procedure can result in shock-like signs and death.

NECROPSY FINDINGS While a primary aim of necropsy is to locate adult filariae in the heart or pulmonary outflow tract in clinically affected cats where there is an index of suspicion for heartworm disease, most pathological findings in heartworm-infected cats involve the lungs. Affected cats develop villous endarteritis and muscular hypertrophy of the pulmonary arteries and arterioles. One study of pulmonary artery changes in 11 heartworm-infected cats described intimal thickening in the main pulmonary arteries, with the formation of elevated ridges projecting above the surface. Lobar and medium-sized pulmonary arteries were similarly affected, with villous-like structures that protruded into the lumen and partially obliterated affected vessels. Multiple areas of infiltration of eosinophils, lymphocytes, macrophages and plasma cells were observed in the intima and mild multifocal accumulation of macrophages was present in the alveoli of most cats. Medial hypertrophy of the pulmonary arteries is a commonly reported finding, but cats infected with Toxocara cati or Aleurostrongylus abstrusus may develop similar pulmonary arterial pathology to cats infected with heartworms. In one study, pulmonary arterial hypertrophy and hyperplasia were demonstrated for two years after infection with A. abstrusus and it was suggested that these changes may persist for the entire life of the cat. Confusingly, pulmonary artery medial hypertrophy and hyperplasia has also been reported in specific pathogen free cats, with one study reporting the same frequency in both specific pathogen free and conventional cats, indicating that pulmonary parasitic infection is not a prerequisite for the condition. Increased muscular thickness of the medial layer of the pulmonary arteries must also be differentiated from vasoconstriction, since both can appear similar microscopically. This is achieved by calculating the area of the media on cross-section in a number of large and small arteries in a section of lung. The resultant figures are compared with reference ranges for normotensive pulmonary arteries and those with moderate and severe pulmonary

248 hypertension. In summary, necropsy findings in heartworm-infected cats are almost entirely pulmonary and they vary widely in type and severity. Their interpretation must be approached with caution, especially if conclusions are drawn concerning causation.

PROPHYLAXIS There are currently four macrocytic lactone drugs registered for feline heartworm prophylaxis – moxidectin (topical), ivermectin (oral), and selamectin (topical). These products are a safe and convenient option for cats living in areas where canine heartworm disease is considered endemic and exposure to infective mosquitoes is possible. Additionally, depending on the active ingredient, these products protect cats from a variety of common endo- and ecto- parasitic infections. Indoor-only housing status is not a reliable method for prevention of infection, since the home environment may not provide an effective barrier to the entry of mosquitoes. One retrospective study reported that 27% of infected cats were kept exclusively indoors. Efficacy of 95% or more requires dosing for 9–30 months, and older worms are difficult to kill. Of the various macrocytic lactones, ivermectin has the most potent combination of clinical prophylaxis, reachback activity (ability to kill developing larval stages) and adulticidal activity; milbemycin oxime has the least; and selamectin and moxidectin injectable lie somewhere in between. The unique effects of ivermectin are related to the age of the heartworms at the initiation of treatment. The earlier treatment is started, the more stunted and smaller the worms are and the shorter their survival time.

CONCLUSIONS Feline heartworm disease remains a significant entity in many areas of the world, and warrants inclusion on the differential diagnosis list for any cat from heartworm-endemic areas presenting with acute or chronic respiratory signs, perhaps accompanied by a history of chronic vomiting, or cats that die acutely without premonitory signs. Exclusively indoor housing status is not necessarily protective and the diagnosis requires commitment from both the cat owner and the attending veterinarian, since a range of tests are required. While heartworm infection can be fatal, most cases are self-limiting and many are asymptomatic. Client education about feline heartworm disease allows cat owners to make informed choices regarding heartworm prophylaxis.

References: American Heartworm Society. Summary of the current feline guidelines for the prevention, diagnosis and management of heartworm (Dirofilaria immitis) infection in cats. https://www.heartwormsociety.org/images/pdf/Feline-Guidelines-Summary.pdf

Gruntmeir JM, Adolph CB, Thomas JE, Reichard MV, Blagburn BL, Little SE. Increased detection of Dirofilaria immitis antigen in cats after heat pretreatment of samples. J Feline Med Surg. 2016 Sep 30. pii: 1098612X16670562.

Litster AL, Atwell RB. Feline heartworm disease: a clinical review. J Feline Med Surg. 2008 Apr;10(2):137-44.

249 Little SE, Raymond MR, Thomas JE, Gruntmeir J, Hostetler JA, Meinkoth JH, Blagburn BL. Heat treatment prior to testing allows detection of antigen of Dirofilaria immitis in feline serum. Parasit Vectors. 2014 Jan 13;7:1.

250 From The Window To The Wall: Set-Up and Care of An Isolation Patient

Nancy “Kim” Adams, RVT Clinical Trainer SAGE Veterinary Centers for Specialty and Emergency Care [email protected]

Common Feline Vaccines and Contagious Illnesses:

FVRCP-C: Feline Viral Rhinotracheitis, Calicivirus, Panleukopenia, and Chlamydiae

FVR: Feline Viral Rhinotracheitis RESPIRATORY • Viral infection • Transmitted via aerosolized droplets and fomites • Incubation period is 2-6 days post exposure • Symptoms can include lethargy, hyporexia or anorexia, fever, frequent sneezing, conjunctivitis, rhinitis, and often salivation. Periods of excitement can induce episodes of sneezing • Severely affected cats can develop ulcerative stomatitis or keratitis • Signs can persist for 5-10 days in healthy adult cats and up to 6 weeks in kittens, geriatric cats, or immunocompromised cats. • Prognosis is typically favorable unless underlying diseases or conditions are present, or if they are kittens or geriatric cats • Treatment is symptomatic and supportive, generally paired with antibiotics to treat/prevent secondary bacterial infections. . In more severe cases, patients can present dyspneic and require continuous oxygen therapy, nebulization, 24-hour care and monitoring, intravenous fluids to correct dehydration, and force-feeding is usually necessary (cats won’t eat what they can’t smell and congestion prevents them from smelling their food). • Vaccination is the most effective prevention.

Back to Table of Contents 251 C: Calicivirus RESPIRATORY • Viral infection • Transmitted via aerosolized droplets and fomites. . There is some new research showing it is also present in the urine and feces of infected cats, but not in quantities deemed high enough to be considered contagious. • Incubation period is 2-6 days post exposure • Symptoms can include hyporexia or anorexia, lethargy, fever, blepharospasm, and ulcers on the tongue, hard palate, gums, lips or nose. Due to the presence of ulcers, cats with Calicivirus can also present with ptyalism. . Two strains of Calicivirus may produce a transient “Limping Syndrome” without signs of oral ulceration or pneumonia. These strains can produce a waxing/waning fever, alternating leg lameness, and pain on palpation of affected joints. Signs occur most often in kittens and usually resolves without treatment. • In more severe cases, it can also cause pneumonia. • If the infection is uncomplicated, it will typically last for 14-21 days depending on the particular disease agent. During this entire time, the cat will potentially be infectious to other cats. . In approximately 10% of cases, cats become “carrier cats” and shed the virus for life even if they are asymptomatic. • Prognosis is typically favorable unless underlying diseases or conditions are present. • Treatment is symptomatic and supportive, generally paired with antibiotics to treat/prevent secondary bacterial infections. Anti-inflammatory medication may be prescribed to relieve symptoms of lameness. Cats that have persistent ulcers may benefit from treatments that modulate or support the immune system, in addition to medications like Sucralfate to help coat mouth/esophageal ulcers. . In more severe cases, patients can present dyspneic and require continuous oxygen therapy, nebulization, 24-hour care and monitoring, intravenous fluids to correct dehydration, and force-feeding is usually necessary (cats won’t eat what they can’t smell and congestion prevents them from smelling their food). . Vaccination is the most effective prevention.

252 P: Panleukopenia (aka Feline Parvovirus) RESPIRATORY • Viral infection • According to the AVMA, FPV is everywhere in the environment and virtually all kittens and cats are exposed to the virus at some point in their lives. • Transmitted in all secretions and excretions (nasal discharge, vomitus, urine, feces, etc.) as well as fomites • Can persist for up to 1 year in an environment at room temperature • Incubation period is 2-7 days post exposure • Cats that become ill are usually less than 1 year old. Peracute cases may die suddenly with little or no warning (aka “Fading Kittens”). • Acute cases can present with lethargy, fever, hyporexia or anorexia, vomiting (typically bilious and not correlated to eating), +/- diarrhea, cerebellar hypoplasia, ataxia, tremors, and rapidly developing dehydration, and occasional retinal lesions. . There are numerous reported cases of Panleukopenia positive cats (discovered at time of necropsy) sitting at their water bowls for hours without drinking • Terminal cases are hypothermic and can develop septic shock as well as DIC. • Duration is rarely greater than 5-7 days in surviving cats. • Mortality is highest in kittens less than 5 months old. • Prognosis in infected kittens and cats is very poor. Adult cats have a better chance of survival but only with aggressive supportive care. Without care, mortality is approximately 90%. • Aggressive treatment is required including but not limited to: intravenous fluids, nutritional support via E-Tube, multiple supplements to correct electrolyte derangements and provide internal organ and immune support, plasma and/or blood transfusions, environmental control (heat, humidity, etc.), pain control, etc. • Panleukopenia is thankfully no longer frequently diagnosed as a consequence of widespread vaccine use. • Vaccination is the most effective prevention.

253 -C: Chlamydiae Zoonotic Risk RESPIRATORY • Bacterial infection • Transmission occurs as a result of direct, close contact between cats because the organism survives poorly in the environment. Infected cats also shed chlamydiae from their rectum and vagina. • Cats between 8 weeks to 1 year old are most susceptible. . The cases of kittens contracting Chlamydia earlier than 8 weeks is rare presumably because of the presence of maternal antibodies. • Incubation period is 3-10 days post exposure • Symptoms can include sneezing, unilateral or bilateral conjunctival hyperemia, chemosis, ocular discharge, nasal discharge, sneezing, and serous to mucopurulent conjunctivitis. • Severe cases can include the presence of keratitis and secondary infections • Signs are most severe 9-13 days after onset, then become milder over a 2-3 week period, although some cats can have clinical signs for much longer. Recurrent infections are common, and some cats may harbor the organism for months after the infection if untreated. • Prognosis is favorable as long as it’s not in concurrence with other infections. • All Chlamidiae isolates are susceptible to Tetracyclines. • On rare occasions, C felis and C caviae have been isolated from people living with infected cats and guinea pigs. Their presenting complaint was conjunctivitis (aka Pink Eye). • As with most other bacterial vaccines, feline chlamydial vaccines do not provide complete protection from infection but may reduce disease severity and infection rates.

254 FIP: Feline Infectious Peritonitis (aka Feline Coronavirus) ENTERIC • Viral infection • Transmission is fecal-oral, or inhalation (although this is significantly less likely) • Incubation period is not well-known because it depends on the immune response of the individual cat. • FIP happens when the Coronavirus mutates in the individual cat and becomes Infectious Peritonitis (approximately 10% of exposed cats suffer this mutation). • There are technically 3 types of FIP, although the forms can transform into each other. The 3 types are: 1. An effusive, exudative “wet form” 2. A noneffusive, nonexudative “dry form” 3. A mixed form. • Symptoms can include mild-to-severe diarrhea and/or vomiting, stunted growth or upper respiratory tract signs, weight loss, organ failure, FUO resistant to antibiotics, and lethargy. • In more severe cases, symptoms can include ocular lesions, retinal hemorrhage (with occasional detachment), CNS changes including ataxia, nystagmus, seizures, incoordination, hyperesthesia, behavioral changes, loss of menace, paresis, Skin Fragility Syndrome, tremors, and hydrocephalus (discovered on CT or necropsy). • Prognosis is grave. When the Coronavirus mutates into FIP in the kitten or cat, it is fatal. • There is no cure for FIP, and attempts at treatment can be very frustrating. If moving forward with treatment is chosen, options can include aggressive supportive therapy with IV fluids and medications, pain control, anti-virals, 24-hour hospitalization, diagnostics including advanced imagining, and medications to correct electrolyte derangements. • There is a vaccine for FIP, and it has been shown to protect up to 75% of vaccinated cats, but it’s not effective in cats previously exposed to the Feline Coronavirus, and will cause false positive results on any future testing. . Research also shows that kittens get infected before they are old enough to respond to the vaccine.

255 FIV: Feline Immunodeficiency Virus AUTOIMMUNE • Viral infection • Transmitted through deep bites from another infected cat, or more rarely, from queen to kitten. • Incubation can take years, but once symptoms develop, they usually continually progress. • Symptoms can include enlarged lymph nodes, fever, anemia, weight loss, poor appetite, vomiting/diarrhea, conjunctivitis, stomatitis, gingivitis, dental disease, unhealing wounds, stranguria, skin and coat changes, nasal and ocular discharge, and behavioral changes. • Prognosis depends on how healthy the cat is at the time of presentation, but typically an otherwise healthy cat can live out a long life with FIV as long as there is timely and aggressive management of secondary infections, and owners pay close attention to seemingly subtle changes in their pet. • Treatment includes management of secondary infections that arise from a compromised immune system, ensuring the cat is kept exclusively indoors, and making sure the cat is spayed/neutered. • There is an FIV vaccine available, but it’s not 100% effective, and will cause false positive results on future testing. The best prevention is keeping the cat exclusively indoors to prevent fighting/initial infection.

256 FeLV: Feline Leukemia Virus

AUTOIMMUNE

• Viral infection • Transmitted through direct contact with a multitude of bodily fluids including saliva, nasal secretions, feces, urine, and blood. • Incubation period is approximately 8 weeks post exposure • Infected cats can be completely asymptomatic. • In more severe cases, cats can exhibit lethargy, weight loss, hyporexia or anorexia, pale or inflames gums, coat changes, abscesses, fever, URI’s, vomiting, diarrhea, behavior changes, vision changes, and seizures. • Prognosis is variable. Studies show only approximately 20% of cats showing clinical signs survive past 3 years. • Treatment includes management of presenting signs and any secondary infections that may arise due to compromised immunity. • There is a FeLV vaccine, but it’s not 100% effective. The best prevention is keeping the cat indoors and eliminating exposure to infected cats.

257 Canine and Feline

RV: Rabies Virus Zoonotic Risk NEUROLOGIC VIRUS • Viral infection • Transmitted through saliva via the bite of an infected animal. • Incubation period is 2-8 weeks post exposure, but can be as little as 9 days depending on the species. • Felines are the most susceptible species in the USA, but canines are the most numerous species effected by Rabies worldwide. • According to the California Department of Public Health, there have been 144 confirmed cases of Rabies in the state of California in 2017 alone. The majority were bats and skunks, but that total number also includes dogs and cats. • There are 3 main phases of Rabies: 1. Prodromal Phase, aka “Loving Phase” . 1-2 days . Mild and nonspecific symptoms including general malaise, chills, fever, headache, photophobia, anorexia, nausea, vomiting, diarrhea, cough, and general discomfort/non-specific pain. . Animals can become overly loving and affectionate during this phase, making them extremely dangerous because of their approachability. 2. Acute Neurologic/Excitable Phase, aka “Furious Phase” . 2-7 days . Think “Cujo” . Nervous system dysfunction, agitation and hyperactivity, extreme aggression, dysphagia, hypersalivation, and delirium 3. Paralytic Phase, aka “Dumb Phase” . Up to 30 days post exposure . Paralysis caused by damage to motor neurons . Excessive drooling due to difficulty swallowing caused by paralysis of the facial and throat muscles . Leads to respiratory and/or cardiac failure and death • Prognosis is grave.

• If we in the veterinary community see a patient we suspect has Rabies, or a patient that has bitten anyone within the last 10 days of its death (regardless of whether it was an unassisted or assisted death), we are federally obligated to report it and submit the head for testing.

258 • All mammals including humans are susceptible to Rabies infection, and it is almost always 100% fatal. • There are treatment options for humans who have potentially been exposed to Rabies. Treatment should begin IMMEDIATELY- before the submitted testing yields results- because of the likelihood of fatality should a human contract the disease. • Rabies is one of the only pathogens domestic animals carry that has a high fatality rate among humans if left untreated. • Vaccination is the most effective prevention.

259 NEW CANINE INFLUENZA STRAIN (H3N2) RESPIRATORY • Viral • Transmission is inhalation (airborne) or through contact with virus-contaminated fomites. • There have been studies that show transmission from feline to canine patients with this strain of influenza. • Incubation period is 1 – 5 days • Symptoms can include lethargy, anorexia, sneezing, fever, nasal discharge, ocular discharge, and a persistent soft, moist cough or dry that lasts for 10-21 days despite cough suppressants or antibiotics. • More severe symptoms can include high grade fevers, dyspnea and pneumonia, and lung lobe consolidation. • Persisting signs can last up to 21 days unless pneumonia develops, in which case it may take longer to resolve based on severity, but dogs that are positive for the H3N2 Influenza should be kept isolated at home for a full 4 weeks. • Prognosis is generally very good depending on the presence of any underlying infections or conditions (a recent study shows an 80% full recovery rate). • Treatment is usually symptomatic and supportive, including a cough suppressant and an antibiotic for secondary infections. NSAIDs may be used to help reduce fever and inflammation. In more severe cases, hospitalization with IV fluids and oxygen therapy may be warranted. • Diligent disinfecting and hand-washing seems to be the best preventative, as well as keeping coughing dogs isolated. The H3N2 Influenza virus is easily killed by most disinfectants, but can survive in the environment for up to 48 hours and on clothing for up to 24 hours. • There is also a vaccine available for the H3N2 strain that will need to be boostered initially. It may not prevent an infection altogether, but it may reduce the severity and duration of clinical illness.

260 Common Canine Vaccines and Contagious Illnesses

DA2PP: Distemper, Adenovirus, Parainfluenza, and Parvovirus

D: Distemper RESPIRATORY AND ENTERIC • Viral infection • Transmission is inhalation (airborne) or through contact with virus-contaminated fomites. It is also passed from mother to puppies • Puppies less than 16 weeks are most susceptible • Incubation period is 1-2 weeks post exposure, but can be as long as 4-5 weeks • Symptoms can include ocular discharge, fever, nasal discharge, coughing, sneezing, lethargy, hyporexia, neutropenia, vomiting, and diarrhea • In more severe cases, pets can exhibit a head tilt, circling, tremors, seizures, partial and complete paralysis, encephalitis, urinary and fecal incontinence, tooth enamel malformations (aka Distemper Teeth), and severe hyperkeratosis of the footpads (aka Hard Pad Disease). This hardening can also affect the nose. • Signs can persist anywhere from 10 days to several months depending on the amount of CNS involvement • Prognosis depends on the strain of Distemper and the patient’s immune response. 2 weeks to 3 months after the initial infection, mortality rate is still >50% due to CNS complications. • Treatment is symptomatic and supportive, generally paired with antibiotics to treat/prevent secondary bacterial infections, unfortunately treatment is generally unsuccessful if the patient progresses to or presents at the neurologic stage of the infection. • Vaccination is the most effective prevention

261 A: Adenovirus (aka Contagious Hepatitis, sometimes listed as “H” instead of “A” in the vaccine abbreviation, i.e.: DHPP) RESPIRATORY • Viral infection • Transmitted through ingestion of urine, feces, or saliva of infected dogs, or through contact with virus-contaminated fomites. • Recovered dogs can shed the virus in their urine for up to 6 months. • Incubation period is 4-14 days post exposure • Symptoms can include fever, neutropenia, hyporexia, conjunctivitis, ocular and nasal discharge, abdominal pain, vomiting, diarrhea, and edema. • More severe symptoms can include delayed clotting times and DIC, petichiae, convulsions, and tracheobronchitis depending on the strain of the virus, acute hepatocellular injury including elevated ALT and AST, and proteinuria, and corneal opacities. • Despite Adenovirus being damaging to the liver, icterus or elevated bilirubin levels are rarely seen. • Duration of disease is typically 10-14 days, but can be shed in the urine for 6-9 months after treatment. • Prognosis is variable. Type 1 of the Adenovirus can cause liver failure, making prognosis poor. Type 2 can cause as little as minor respiratory signs, making prognosis very good. • Treatment is symptomatic and supportive, generally paired with antibiotics to treat/prevent secondary bacterial infections • Vaccination is the most effective prevention.

262 P: Parainfluenza RESPIRATORY • Viral infection • Transmission is inhalation (airborne) or through contact with virus-contaminated fomites. It is also passed from mother to puppies • Incubation period is 1-5 days post exposure • Symptoms can include nasal and ocular discharge, coughing, sneezing, hyporexia, rhinitis, tracheitis, and bronchitis. • In more severe cases, symptoms can include pneumonia, high grade fevers, dyspnea, and lung consolidation on x-ray • Prognosis is good- most dogs recover without incident. • Duration of disease can be up to 21 days. • Treatment is symptomatic and supportive, generally paired with antibiotics to treat/prevent secondary bacterial infections • Vaccination is the most effective prevention.

263 P: Parvovirus RESPIRATORY AND ENTERIC • Viral infection • Transmitted through direct oral or nasal contact with infected fecal material or indirectly through virus-contaminated fomites. • Incubation is 3-5 days post exposure • Puppies <6 months are most susceptible . Studies have suggested that certain breeds are more susceptible than others including: • Rottweilers • Dobermans • Pit Bulls • English Springer Spaniels • German Shepherds • Symptoms can include lethargy, fever, hyporexia, vomiting, diarrhea that can progress to hemorrhagic diarrhea, GI protein loss (ALB and TS), dehydration, moderate neutropenia, and dilated/fluid filled intestinal loops. • More severe cases can include collapse, prolonged CRTs, severe neutropenia, tachycardia, hypothermia, hypoglycemia, electrolyte derangements, sepsis, intussusception, thrombosis, ARDS, and sudden death. • Treatment is symptomatic and supportive, generally paired with antibiotics to treat/prevent secondary bacterial infections, and can range from out-patient to full hospitalization depending on the severity of symptoms. • Prognosis ranges widely with a variety of determining factors such as age, stage of illness when treatment began, and the health of the patient prior to infection. Most puppies that survive the first 3-4 days of illness make a full recovery, usually within 1 week with appropriate supportive care. • Vaccination is the most effective prevention.

264 Kennel Cough: Infectious Tracheobronchitis POSSIBLE Zoonotic Risk RESPIRATORY • Can be bacterial or viral depending on the originating infection • General term to include a variety of highly contagious upper respiratory diseases, both bacterial and viral (including Bordetella Bronchiseptica, which is a bacteria) • Transmission is inhalation (airborne) or through contact with contaminated fomites. • Incubation period is generally 1-3 days post exposure depending on the cause of infection • Symptoms can include coughing spasms and slight fever • In more extreme cases, symptoms can include high fevers, purulent nasal discharge, lethargy, and hyporexia. If left untreated in this stage, it can also progress to chronic bronchitis or fatal bronchopneumonia (especially in puppies, geriatric pets, or immunocompromised pets). • Symptoms generally diminish within about 5 days, but signs can last for up to 10-20 days depending on the cause and severity of infection • Treatment is usually symptomatic and supportive, including a cough suppressant and an antibiotic. In more severe cases, hospitalization with IV fluids and oxygen therapy may be warranted. • Prognosis is generally favorable • The Bordetella vaccine isn’t 100% effective because of 2 major factors: 1. Bordetella Bronchiseptica is a bacteria, making vaccination efficacy very challenging (vs a viral vaccine) 2. There is a wide range of highly contagious upper respiratory infections that the vaccine doesn’t cover • Bordetella Bronchiseptica has been found in humans (mainly children) that are both immunocompromised and have underlying respiratory infections (i.e. cystic fibrosis). Researchers suspect infection from household pets (cats can carry Bordetella as well).

265 Leptospirosis (the L in DHLPP) Zoonotic Risk SPIROCHETE BACTERIA • Bacterial infection • Transmitted via direct mucous membrane contact (or any open wound) with infected urine, urine-contaminated surfaces or fomites (including soil), through the bite of an infected animal, by ingesting infected tissues or carcasses, from mother to puppies, and breeding (though this is rare). • Incubation period is usually 4-12 days post exposure • Symptoms can include fever, shivering, muscle tenderness, lethargy, PU/PD, vomiting, diarrhea, hyporexia, jaundice, and uveitis. • In more severe cases, symptoms can include kidney failure, liver failure, dyspnea, severe lung disease, coagulopathies causing hematemesis, hematuria, hematochezia, epistaxis, petichiae, edema, effusion, ascites, and death • Persisting signs can take 2-4 weeks to completely resolve • Prognosis is generally good when caught early and treatment is administered, but there is still a risk of permanent kidney and/or liver damage • Treatment is usually symptomatic and supportive, including antibiotics, IV fluid therapy, and frequent bloodwork to monitor kidney and liver changes. • There are leptospirosis vaccines available, and it is recommended that at-risk pets receive appropriate vaccination, but as with other bacterial infections, the vaccine isn’t 100% effective • Humans can become infected with Leptospirosis in the same manner as pets (see above). The effects of infection are similar (liver and kidney damage).

266 MRSA: Methicillin-Resistant Staphylococcus Aureus High Zoonotic Risk MRSP: Methicillin-Resistant Staphylococcus Pseudointermedius Low Zoonotic Risk MRSS: Methicillin-Resistant Staphylococcus Schleifiri Low Zoonotic Risk COCCIDIA BACTERIA • Bacterial infection • Transmitted through direct contact including contact with contaminated surfaces or fomites • MRSP is the most prevalent of the 3 strains in companion animals • Incubation period is 1-10 days • Symptoms include papules, pustules, epidermal collarettes, scaling, erythema, alopecia, and lack of response to empirical antibiotics • More severe symptoms can include pain, odor, exudation of blood and pus, swelling, nodules, bullae, hemorrhagic crusts, and ulcerated areas. • Persisting signs can last 21-30 days in mild-moderate infections, and 8-12 weeks in more severe infections • Prognosis is generally very good with treatment as long as the pet doesn’t have secondary conditions or infections • Treatment includes appropriate antibiotics according to the resistance, clipping/cleaning, bathing with appropriate shampoos or solutions, topical antibiotics as appropriate, and possible pain control • Prevention is tricky. Hygiene seems to be the biggest factor, however MRSA, MRSP, and MRSS are everywhere in our environment. Early detection and appropriate management are key to successfully treating these infections. • MRSA seems to prefer people, while MRSP seems to prefer companion animals. These infections can be passed back and forth, however. Children, geriatric people, immunocompromised people, and pregnant women tend to be the most susceptible. Hospitalization and aggressive wound management are typically the human treatments if infection is present. Avoiding contact with affected areas, appropriate hygiene, and hand-washing are the best preventatives.

267 Ringworm: Microsporum Canis Zoonotic Risk FUNGAL • Dermatophytosis: Fungal infection • Transmitted through direct contact including contact with contaminated surfaces or fomites • Incubation period is 7-14 days post exposure • Symptoms can include dandruff, scales on the skin, erythema, hyperpigmentation, pruritis, alopecia, and red, raised rashy areas that take on a circular shape • More severe symptoms can include granulomatous lesions, kerions, and paronchyia. • Infection timeline can range from 2 weeks to 2 months and even become chronic depending on whether or not it’s treated • Prognosis is generally very good depending on whether or not the pet has underlying disease • Treatment can include oral and topical antifungal medications and baths, with occasional antibiotic therapy for any underlying infection • Regularly cleaning the area where the animal spends a lot of time and avoiding direct contact with contaminated animals or surfaces is the best preventative • Humans can contract Miscrosporum Canis, too. Treatment options are the same- topical and sometimes oral medications to control infection.

268 Isolation Must-Haves

• LABELS- Take great care to label everything as necessary to ensure anyone nearing the area is aware that they are entering an isolation area. This includes labeling the trash bin or bag, and the laundry bin or bag. The label should include the diagnosis and required equipment:

PARVO GLOVES, GOWN, SHOE COVERS

• Dedicated space- whether that be a room, a crate, or a cage where you can easily isolate the patient from other pets and still monitor them. • Dedicated equipment that will not be used throughout the rest of the hospital: . Trash bin and bags . Laundry bin and bags . Isolation gowns . Gloves . Masks . Shoe covers, +/- foot bath . Thermometer and probe covers . Lube . Stethoscope . Bedding, towels, and pee pads . Litter box and litter . Dishes . Food . A bottle of appropriate disinfectant for surfaces (i.e. Bleach, Snyper, etc.) . Pens, Sharpie’s, highlighters as needed . Paper/post-its/scrap paper for notes . E-collar if needed, whether on the patient or on standby . Clippers . Isopropyl alcohol . Syringes, needles, butterfly catheters, flush, and IV catheter supplies . Blood tubes +/- glucometer as needed . Porous tape . Bandaging supplies as needed . Gauze . Scrub for catheter sites as needed (i.e. chlorhexidine solution and scrub) . IV pump 269 . +/- Syringe pump . Required medications and equipment to deliver them, including monitoring equipment (i.e. IV fluids, pulse ox, a nebulizer, oral medications, topical medications, injectable medications, etc.) . If able, try to have an “Isolation Only” stock of dishes, litter boxes, and laundry so it doesn’t get washed and circulated throughout the hospital upon discharge of the patient. These items should be stored separate from other hospital items. You can keep a large Rubbermaid bin of “Isolation Items” for future use. You can also use this same bin to soak items for cleaning.

*If the hospital is not stocked with enough equipment to spare to dedicate items solely to the isolation patient, make sure you thoroughly soak the equipment used according to the contact times determined by the manufacturer of your disinfectant.*

Tips: • PEE PADS ARE YOUR FRIENDS. They are cheap and a very effective way to ensure you are minimizing cross contamination via bedding and towels throughout the hospital. • Place a pee pad (or several) down on surfaces you need to place the isolation patient on outside of its enclosure (i.e. treatment tables, x-ray table, etc.) • If able, keep a gurney or roll-away cart near the patient’s enclosure and place pee pads on it. You can use this surface for exams, TPRs, treatments, etc. without contaminating other treatment surfaces • Place several layers of pee pads under the patient in the enclosure (don’t be stingy), especially if the patient is vomiting, having diarrhea, or excreting contaminated urine (Lepto). You can pull the top one out and have several underneath so you don’t have to replace the bedding constantly, and it’s better to throw away contaminated items vs. washing reusable items like towels and blankets. • Isolation laundry should be washed twice and dried once, then returned to the Isolation area vs. being distributed throughout the hospital. Tape a piece of paper to the front of the washer with “ISOLATION LAUNDRY” and draw check boxes for the 2 times it needs to be washed. Be sure to use bleach (or equivalent) along with the laundry detergent both times. • Wear an isolation gown under a lead apron, then the apron, then another isolation gown on the outside of the x-ray gown, should you need to take radiographs • If the patient isn’t easily viewable, you can purchase a fairly inexpensive baby monitor with a camera to use during times where treatments aren’t due to minimize staff exposure and traffic in and out of the isolation area.

270 • If able, select one (or two) people to handle the isolation patient exclusively, and take care to ensure they don’t handle other patients within the hospital that could be more susceptible to the contagion over others (i.e. if managing a Parvo puppy, the staff member(s) overseeing the case would only handle cats and fully vaccinated adult dogs). If this isn’t possible, wear gloves with every patient handled even outside of isolation. • DON’T FORGET YOUR FEET! Use shoe covers over a foot bath- even if it’s trash bags tied over your shoes. Foot baths are like surgical scrub- it’s not how hard you push (or stomp), it’s CONTACT TIME. If you aren’t standing in the foot bath for at least the minimum amount of time required per the solution you’re using (usually about 10 minutes on average), foot baths are ineffective. You can be a fomite for contagions and are putting pets at risk otherwise (including your own when you get home). • Charge accordingly. Put an isolation fee in place to cover the cost of managing a contagious patient.

Develop an Isolation Protocol for your hospital. Below are 2 examples- the first one being a protocol used at one of our facilities (with information omitted that wouldn’t apply to other hospitals outside of SAGE). The second protocol was written by the National Association of State Public Health Veterinarians (NASPHV) and the Veterinary Infection Control Committee (VICC).

Sample SAGE Protocol:

Triage:

• Suspected infectious patients like Parvo, severe URI with sneezing, kennel cough, should be roomed immediately and triaged in a designated “contagious” or “contaminated” exam room. • “Pack it in, pack it out” - That is, if you care for that patient, you are responsible for cleaning up after it. This includes the exam room, isolation, sink areas, and table tops. • Please remember that this is shared space. Use a labeling system to remind yourself or others that this room needs special cleaning-even if it’s porous tape across the door with “Parvo- needs cleaning”. • Try to limit traffic through the rooms. This may mean keeping all family members in the room, along with the patient, while tests are being done. • Please restock after using this room. Pay special attention to the cleaning supplies, thermometer covers, gloves and garbage.

271 Tests:

• Perform exam, blood draws, and outpatient care in the Triage room. • If x-rays are needed, please be sure to cover clothes with an Isolation gown, then the lead gown, then ANOTHER isolation gown. This reduces contamination of the lead gowns which are shared items. • Place samples taken for Isolation patients into a clean glove for transport to the lab area.

Housing in Isolation:

• Patients in Isolation stay there until released home. The exception is radiology. • Isolation is stocked with most of the needed things, but every shift is responsible for stocking commonly used items like pee pads, thermometer covers, food, bowls and fresh bedding. • Laundry and trash should be double bagged before leaving the Isolation area.

Owner visits:

• Owners may visit only in the Isolation ward and only as the veterinarian/hospital deems appropriate. • Visitors must wear shoe covers, gowns and gloves. No exceptions. • After visiting, please help the family remove and properly dispose of these materials, then wash hands.

Isolation Protocols:

Isolation is intended to protect the general patient population from infectious diseases. It also helps protect staff from zoonosis.

Who belongs in Isolation:

Any patient with confirmed or suspected serious infectious disease.

This might include:

• Parvo • Upper respiratory infections 272 • Distemper • Severe or resistant skin disease (i.e. MRSA, MRSP) • Leptospirosis

Triage for these cases

• Ideally use a designated “contaminated” or “contagious” room • As within Isolation itself, gloves, gowns and shoe covers are required for staff. • Wash hands after leaving the room

Visits in Isolation

• Owners may visit as deemed appropriate by your hospital, but the use of gloves, gowns and shoe covers are required. • Ask owners to try to limit visits to 15 minutes so that we are able to focus on patient care which is often complex and/or takes more time because we are trying to provide good biosecurity. • With this in mind, a DVM or technicians should be with the owners during the visit. • Discourage owners from bringing in items from home. We do not want to lose or ruin their property. • After an Isolation visit, owners should wash hands

Cleaning and Stocking

• Ideally, Isolation is a self-contained area with most of the tools needed for patient care. • This is a shared space so everyone who uses the unit is expected to pitch in • If something is missing, please stock it. At the end of a shift, look around for items that might be needed by the next shift and pass this along if you have not had time to stock. • Clean as you go AND after you discharge a patient

• Clean surfaces and cages. Be sure to look for a “splash zone”- contamination of other cages near the patient. • Use squirt bottles, not sprayers. This helps limit aerosolization of feces and other infectious waste, plus reduces the risk of inhaling or getting cleaning agent in your eyes. • The floors can be cleaned with a mop dedicated to Isolation if available • Cage doors should be power washed once a month or as needed. 273 Trash and Laundry

• Double bag all trash and take it directly outside as needed • Double bag all laundry. Run it through 2 full wash cycles and bleach the washer after use. • Please leave a note or marker to identify this as isolation laundry to avoid mix-ups

The Grey Zone

• We have some patients, especially puppies with hypoglycemia, vomiting and/or diarrhea, who are suspicious for infectious disease. • They may test Parvo negative or even have a reliable vaccination history, but we should be careful about infection control. • Please use gloves, gowns, show covers, and isolated laundry/trash.

Sample protocol written by the National Association of State Public Health Veterinarians (NASPHV) and the Veterinary Infection Control Committee (VICC):

Model Infection Control Plan for Veterinary Practices, 2015

National Association of State Public Health Veterinarians (NASPHV) Veterinary Infection Control Committee (VICC)

This plan should be adapted to your practice in keeping with local, state, and federal regulations. A modifiable electronic version is available on the NASPHV Website (www.nasphv.org). Please refer to the full Compendium of Veterinary Standard Precautions for complete information and guidance (also available at www.nasphv.org).

274 Clinic: ______

Date of Plan Adoption: ______

Date of Next Review: ______

Infection Control Officer: ______

This plan will be followed as part of our practice’s routine procedures. The plan will be reviewed at least annually and as part of new employee training.

PERSONAL PROTECTIVE ACTIONS AND EQUIPMENT

Hand hygiene: Perform hand hygiene between examinations of individual animals or animal groups (e.g. litters of puppies or kittens, groups of cattle) and after contact with feces, body fluids, vomitus, exudates, and articles contaminated by these substances. Perform hand hygiene before eating, drinking, or smoking; after using the toilet; after cleaning animal cages; after contact with environmental surfaces in animal areas; after handling laboratory specimens; after removing gloves; and whenever hands are visibly soiled. Keep fingernails short. Do not wear artificial nails or hand jewelry when handling animals. Keep hand-hygiene supplies stocked at all times. Staff responsible: ______

Correct handwashing procedure: Wet hands with running water Place soap in palms Rub hands together to make a lather Scrub hands thoroughly for 20 seconds Rinse soap off hands Dry hands with disposable towel 275 Turn off faucet using the disposable towel to avoid hand contact Correct use of hand rubs: Place alcohol-based hand rub in palms Apply to all surfaces of hands Rub hands together until dry

Gloves: Gloves are not necessary when examining or handling healthy animals. Wear gloves when touching feces, body fluids, vomitus, exudates, and non-intact skin. Wear gloves for dentistry, resuscitations, necropsies, and obstetrical procedures; when cleaning cages, litter boxes, and environmental surfaces and equipment in animal areas; when handling dirty laundry; when handling diagnostic specimens (eg, urine, feces, aspirates, or swabs); and when handling an animal with a suspected infectious disease. Wear gloves if you have wounds or compromised skin integrity of the hands. Change gloves between examination of individual animals or animal groups (eg, a litter of puppies), between dirty and clean procedures performed on the same patient, and when torn. Gloves should be removed promptly and disposed of after use. Disposable gloves should not be washed and reused. Hands should be washed immediately after glove removal.

Facial protection: Use a face shield, or goggles worn with a surgical mask whenever splashes or sprays are likely to occur. Wear facial protection for the following procedures: lancing abscesses, flushing wounds, dentistry, nebulization, suctioning, lavage, obstetrical procedures, and necropsies.

Respiratory tract protection: Use a molded particulate respirator (N95, N99) when exposure to airborne pathogens is likely. Use respiratory protection under the supervision of a veterinarian and following OSHA regulations. Training and fit testing are required for their use.

Protective outerwear: Wear a protective outer garment such as a laboratory coat, smock, non-sterile gown, or coveralls when attending animals and when conducting cleaning chores in animal areas. Protective outerwear should be changed after handling an animal with a known or suspected infectious disease, after working in an isolation room, after performing a necropsy or other high-risk procedure, and whenever soiled. Impermeable outwear should be worn during obstetric procedures and necropsies, and whenever substantial splashes or large

276 quantities of body fluids may be encountered. Shoes or boots should have thick soles and closed toes and be impermeable to water and easily cleaned. Disposable shoe covers or washable boots should be worn when heavy quantities of infectious materials are expected. Garments should be changed and laundered daily, and whenever they become visibly soiled or contaminated. Coveralls should be changed and boots cleaned between farm premises/facilities/locations/herds. Protective outerwear should not be worn outside of the work environment. Keep clean outer garments available at all times. Staff responsible: ______

PROTECTIVE ACTIONS DURING VETERINARY PROCEDURES

Patient Intake: Place animals that have neurologic signs, diarrhea, respiratory signs, fever, infected wounds, chronic infections, or a known exposure to an infectious agent directly into a designated exam or isolation room. Bring them in a side entrance if possible.

Animal handling and injury prevention: Take precautions to prevent bites and other animal- related injuries. Identify aggressive animals and alert clinic staff. Use physical restraints, muzzles, bite-resistant gloves, and sedation or anesthesia as necessary in accordance with practice policies. Plan an escape route when handling large animals. Do not rely on owners or untrained staff for animal restraint. If there is concern for personal safety, notify: ______When injuries occur, wash wounds with soap and water, then immediately report incident to: ______(infection control officer) If medical attention is needed contact: ______(health-care provider) Bite incidents will be reported to: ______(public health agency) as required by law. Telephone number:______

Examination of animals: Wear protective outerwear and perform hand hygiene before and after examination of individual animals or animal groups (eg, a litter of puppies). Use gloves and other protective equipment as appropriate to examine potentially infectious animals. Keep potentially infectious animals in a designated examination room until diagnostic procedures and treatments have been performed.

277 Injections, venipuncture, and aspiration procedures: Wear gloves when performing soft tissue or body fluid aspirations and while performing venipuncture on animals suspected of having an infectious disease. Trained personnel should restrain animals to minimize needlestick injuries due to animal movement. Do not bend needles, pass an uncapped needle to another person, or walk around with uncapped needles. Do not remove an uncapped needle from the syringe by hand or place a needle cap in the mouth. Do not recap needles unless the one-handed scoop method is used.

One-handed scoop method for recapping needles: Place the cap on a horizontal surface Hold the syringe with attached needle in 1 hand Use the needle to scoop up the cap without use of the other hand Secure the cap by pushing it against a hard surface

Dispose of all sharps in designated containers. After injection of live vaccines, or performing soft tissue or body fluid aspirations, dispose of the used syringe with needle attached in a sharps container. Otherwise, you may remove the needle with a forceps and throw the syringe away in the trash. Do not transfer sharps from one container to another. Replace sharps containers before they are completely full. Staff responsible: ______

Dental procedures: Wear protective outerwear, headcover, gloves, and facial protection when performing dental procedures or when in range of splashes or sprays (such as when monitoring anesthesia).

Resuscitation: Wear gloves and facial protection. Use a manual resuscitator, anesthesia machine, or ventilator to resuscitate animals. Do not blow directly into the mouth, nose, or endotracheal tube of the animal.

Obstetrics: Wear gloves or shoulder-length sleeves, facial protection, and impermeable outerwear. Do not blow directly into the nose or mouth of a non-respiring neonate.

278 Necropsy: Wear cut-resistant gloves, facial protection, and impermeable outerwear. Also wear eye protection and a respirator when using a band saw or other power equipment. Only necessary personnel are allowed in the vicinity of the procedure. If an animal is suspected of having a notifiable infectious or a foreign animal disease, consult with the State Veterinarian before proceeding with a necropsy. Contact information for State Veterinarian’s office:______

Diagnostic specimen handling: Wear protective outerwear and gloves. Handle feces, urine, vomitus, aspirates, and swabs as if they were infectious. Discard gloves and perform hand hygiene before touching clean items (eg, medical records, keyboard, telephone). Eating and drinking are not allowed in the laboratory.

Wound care and abscesses: Wear protective outerwear and gloves for debridement, treatment, and bandaging of wounds. Facial protection should also be used when lancing abscesses or lavaging wounds. Discard used bandages. Handle used scissors, clipper blades and other equipment as if contaminated. Autoclave or gas sterilize left-over bandaging material before putting it away. Perform hand hygiene after removing gloves.

ENVIRONMENTAL INFECTION CONTROL

Cleaning and disinfection of equipment and environmental surfaces: Wear gloves when cleaning and disinfecting cages and other surfaces in animal areas. Perform hand hygiene afterwards. Clean surfaces and equipment to remove organic matter, and then disinfectant according to manufacturer’s instructions. Clean and disinfect animal cages, toys, and food and water bowls between uses and whenever visibly soiled. Clean litter boxes at least once daily. Keep clean items separate from dirty items.

Isolation of infectious animals: Put animals with an infectious disease in isolation as soon as possible. Clearly mark the room or cage to indicate the patient’s status and describe additional precautions. Limit access to the isolation room. Keep a sign-in log of all people (including owners or other non-employees) having contact with an animal in isolation. Keep only the equipment needed for the care and treatment of the patient in the isolation room, including dedicated cleaning supplies. PPE should be donned immediately prior to care of the animal in isolation and removed just prior to leaving isolation. Discard gloves after use. Leave reusable

279 personal protective equipment (eg, gown, mask) in the isolation room. Clean and disinfect or discard protective equipment between patients and whenever contaminated by body fluids. Disassemble and thoroughly clean and disinfect any equipment that has been used in the isolation room. Place potentially contaminated materials in a bag before removal from the isolation room. Staff responsible: ______

Handling laundry: Wear gloves and protective outerwear when handling soiled laundry. Check for sharps before items are laundered. Wash animal bedding and other laundry in the facility with standard laundry detergent, and completely machine dry at the highest temperature suitable for the material. Use separate storage and transport bins for clean and dirty laundry. Outerwear to be laundered at home should be transported in a plastic bag, kept separate from household items, washed separately and then thoroughly machine dried.

Spill Response and decontamination: Immediately contain spills and splashes of potentially infective substances with absorbent material (eg, paper towels, sawdust, or cat litter). Use PPE to protect against the potentially infective agent and the cleaning/disinfectant to be used. Consult and follow the label recommendations. Pick up the material, seal it in a leak-proof plastic bag, and clean and disinfect the area. Keep clients, patients, and employees away from the spill area until disinfection is completed.

Veterinary medical waste: Insert here your local and state ordinances regulating disposal of animal waste, pathology waste, animal carcasses, bedding, sharps, and biologics. Refer to the US Environmental Protection Agency website (http://www.epa.gov/epawaste/nonhaz/industrial/medical/programs.htm) and the American Veterinary Medical Association website (https://www.avma.org/PracticeManagement/Administration/Pages/AVMA-Policies-Relevant- to-Waste-Disposal.aspx) for guidance.

Rodent and vector control: Seal entry portals, eliminate clutter and sources of standing water, keep animal food in closed metal or thick plastic covered containers, and dispose of food waste properly to keep the facility free of rodents, mosquitoes, and other arthropods. Check and treat animals entering the veterinary facility for vector parasites.

280 Other environmental controls: Use the employee break room or designated area for eating, drinking, smoking, application of make-up, and similar activities. These activities should not occur in animal-care areas or in the laboratory. Do not keep food or drink for human consumption in the same refrigerator as food for animals, biologics, or laboratory specimens. Dishes for human use should be washed and stored away from animal-care and animal food preparation areas.

OCCUPATIONAL HEALTH Infection control and employee health management: The following personnel are responsible for development and maintenance of the practice’s infection control policies, record keeping, and management of workplace exposure and injury incidents. Staff responsible: ______

Record keeping: Current emergency contact information will be maintained for each employee. Records will be maintained on vaccinations, rabies virus antibody titers, and exposure and injury incidents. Changes in health status (eg, pregnancy) that may affect work duties should be reported to and recorded by the office manager so that accommodations may be made.

Pre-exposure rabies vaccination: All staff with animal contact must be vaccinated against rabies, followed by periodic titer checks and rabies vaccine boosters, in accordance with the recommendations of the Advisory Committee on Immunization Practices (CDC, 2008).

Tetanus vaccination: Tetanus immunizations must be up-to-date. Report and record puncture wounds, animal bites, and other animal-related trauma. Consult a health-care provider regarding the need for a tetanus booster.

Influenza vaccination: Veterinary personnel are encouraged to receive the current seasonal influenza vaccine. The CDC website and healthcare consultation will be used for guidance (www.cdc.gov).

Documenting and reporting exposure incidents: Report incidents that result in injury or potential exposure to an infectious agent to: ______281 Information will be collected for each exposure incident using OSHA forms 301, 300, 300A. Incident reporting includes documenting date, time, location, person(s) injured or exposed, vaccination status of injured person(s), other persons present, description of the incident, whether health-care providers and public health authorities were consulted, the status of any animals involved (eg, vaccination history, clinical condition, and diagnostic information), first aid provided, and plans for follow-up.

Staff training and education: Infection control and hazard awareness training and education will be documented in the employee health record.

Pregnant and immunocompromised personnel: Pregnant and immunocompromised employees are at increased risk from zoonotic diseases. If you are concerned that your work responsibilities may put you at increased risk, inform: ______so that preventive measures may be taken (such as increased use of PPE) and other accommodations may be made. Consultation between the supervising veterinarian and a health-care provider may be needed.

The following information is attached to the Infection Control Plan: • Emergency services telephone numbers—fire, police, sheriff, animal control, poison control, etc • Reportable or notifiable veterinary diseases and where to report • State Department of Agriculture or Board of Animal Health contact information and regulations • State and local public health contacts for consultation on zoonotic diseases • Public Health Laboratory services and contact information • Environmental Protection Agency (EPA)-registered disinfectants • Occupational Safety and Health Administration (OSHA) regulations • Animal waste disposal and biohazard regulations • Rabies regulations • Animal control and exotic animal regulations and contacts • Other useful resources

282 And Finally….

Two important takeaways: 1. Ultimately, remember that not only is the patient contagious, but you can be the fomite. Appropriate disinfection, PPE, and hygiene are the best preventatives when concerned with spreading the infection through your clinic. 2. WEAR SHOE COVERS. Foot baths are not effective unless you stand in them for at least 10 minutes!

Notes References: Jessica Beymer, DVM, DACVECC Kacie Regan Marsee, RVT www.avma.org www.aaha.org www.cdc.gov www.merckvetmanual.com www.usda.gov www.animalsheltering.org www.aspca.org www.vetmed.oregonstate.edu www.vet.cornell.edu www.vetmed.ucdavis.edu www.nasphv.org

283 Specimen Preparation: How to Get the Most Accurate Results

Monie Yee, DVM

IDEXX Learning Center https://idexxlearningcenter.idexx.com Tutorials -> Scientific Medical Blood sample collection (20 minutes) https://idexxlearningcenter.idexx.com/idexx/user_activity_info.aspx?id=957 Getting the most out of your biopsy pathology submissions (9 minutes) https://idexxlearningcenter.idexx.com/idexx/user_courses.aspx?track=Tutorials Getting the most out of your cytology pathology submissions (11 minutes) https://idexxlearningcenter.idexx.com/idexx/user_courses.aspx?track=Tutorials Guidelines for submitting specimens to IDEXX Reference laboratories (12 minutes) https://idexxlearningcenter.idexx.com/idexx/user_activity_info.aspx?id=5895 Urine sample collection, handling and preparation (20 minutes) https://idexxlearningcenter.idexx.com/idexx/user_courses.aspx?track=Tutorials

Snippets Butterfly catheter blood draw (2 minutes) https://idexxlearningcenter.idexx.com/idexx/user_activity_info.aspx Canine jugular venipuncture (3 minutes) https://idexxlearningcenter.idexx.com/idexx/user_activity_info.aspx

On-line courses->Companion animal general diagnostics Dot Plot case studies for the ProCyte Dx hematology analyzer https://idexxlearningcenter.idexx.com/idexx/user_courses.aspx?track=Online+Courses

On-line courses-> archived Common diagnostic issues in pathology: submitting samples and getting to know your pathologist https://idexxlearningcenter.idexx.com/idexx/user_courses.aspx?track=Archived+Webina rs

Back to Table of Contents 284 SAGE Symposium 2018 Anemia: What does the blood show us? Jo Woodison, RVT

Introduction

Anemia is a low red blood cell (RBC) mass as evidenced by decreased RBC count, hemoglobin (Hgb) concentration, or packed cell volume (PCV). Anemia is a relatively common blood abnormality with almost 10% of patients presenting to veterinary clinics being affected. Anemia can be acute or chronic, mild to severe, regenerative or non-regenerative.

Identifying the Anemic Patient

Clinical signs of anemia vary considerably depending on the severity, the duration, and the underlying cause. Severe acute anemia can result in shock and death if more than one third of the patient’s blood volume is lost quickly and not replaced. In addition to pale mucous membranes, acutely anemic patients will likely present with tachycardia, bounding or weak peripheral pulses, and hypotension. Blood loss can be obvious, as in the case of hit-by-car or other traumatic event, or

Back to Table of Contents 285 hidden as in the case of a ruptured splenic mass, coagulopathy or parasitic infection. Animals with chronic anemia have may not show obvious signs of blood loss because their bodies have had time to adjust and compensate. They may be lethargic, weak, and inappetent. Mild anemias may not be detected until blood work is performed.

Characterizing Anemia

The steps for characterizing anemia are first, to recognize it. As mentioned, this may be blatantly evident or undetectable on physical examination, only identified once further diagnostics are performed. Once recognized, focus is placed on severity and characterising it as regenerative or not.

Severity

Determining the severity of anemia is key to arriving at a prognosis and determining whether a blood transfusion is necessary. Veterinary hematology textbooks have guidelines on grading the severity of anemia, but these a can be somewhat arbitrary. The following are taken from the Cornell University School of Veterinary Medicine eClinPath web site:

Grade of Anemia Dog (PCV %) Cat (PCV %)

None 41-58 31-48

Mild 30-40 25-30

Moderate 20-30 15-25

Severe <20 <15

As always, it is the patient, not the numbers who should be treated. Pulse quality, heart and respiration rate, mentation and strength should be considered. Hydration status is an important factor in this evaluation: an over-hydrated patient may have a relative anemia, and a dehydrated patient may have an anemia masked by their hydration status. Do not forget that anesthetic agents and sedatives act as splenic relaxants and can cause the spleen to sequester up to 30% of the available RBCs resulting in a low peripheral PCV and apparent anemia.

286 Regenerative or Nonregenerative?

Another important characteristic to assess in the anemic patient is whether it is regenerative or nonregenerative. Establishing this helps direct the diagnostic plan, and gives insight into the cause: whether it is occurring through blood loss, a hemolytic process, a chronic disease or bone marrow dysfunction. A regenerative anemia is one where the patient’s bone marrow is responding appropriately to an increased peripheral demand. A nonregenerative anemia is one where there is inadequate bone marrow response to increased peripheral demand. In acute cases, do not condemn a patient, or their bone marrow, too quickly. It can take several days to see evidence of the bone marrow response - there will be a delay between the need and the response. This time period is sometimes referred to as the pre-regenerative phase.

The best method for characterizing whether an anemia is regenerative or not, amongst other important characteristics, is evaluation of a blood smear. That is not to say our automated blood analyzers, regardless of brand or methodology, do not provide valuable information.

Packed Cell Volume

PCV is the percentage of RBCs in a blood sample. It is often used interchangeably with hematocrit (Hct), the latter being determined (by calculation) by our automated hematology analyzers. Hct will often be a few percent lower than PCV.

287 The typical calculation used to obtain Hct is:

MCV ×RBC 10 = Hct (%)

While the PCV does not give insight into the etiology or definitive characterization of anemia, it is a quick, cheap, and reliable measurement of RBC mass. In addition, the buffy coat can sometimes give a clue as to the type of anemia. If there are a significant number of immature erythrocytes (reticulocytes) in circulation, they may appear at the intersection of RBCs and buffy coat, or within the buffy coat itself, due to their lower density, and give the buffy coat a slight pink tinge.

Mean Corpuscular Volume

Mean corpuscular volume (MCV) is the average size of the RBC population. Modern hematology analyzers can measure this. When calculated, the following formula is typically used:

PCV × 10 RBC count (mil) = MCV (femtoliters)

It can be a good indicator of regenerative anemia, but this is a mean, or average, value that may not fall outside the reference range unless there are a large number of reticulocytes in circulation. In cases of light demand, such as with a mild anemia, the MCV may also remain within the reference range because not many additional cells are required and there has been little overall impact to the mean. Also worth noting is that agglutination can falsely elevate MCV. A normal MCV is referred to as normocytic, an increased MCV is macrocytic, and a decreased MCV is microcytic.

Factors leading to an elevated MCV include: reticulocytosis, Poodle breeds, FeLV positive cats, and B12 and folate deficiencies. Decreased MCV may result from: underfilled EDTA tube, iron deficiency, portosystemic shunt, or some Japanese breed dogs.

Mean Corpuscular Hemoglobin Concentration

Mean corpuscular hemoglobin concentration (MCHC) is the average amount of Hgb in the RBCs. Hgb can also be measured by many of today’s hematology analyzers. A common calculation used to determine MCHC is:

Hgb Hct × 1 00 = MCHC (g/dL)

Decreases in MCHC are commonly seen in regenerative anemia because the new, immature erythrocytes (reticulocytes) do not have as much hemoglobin as more mature cells. A normal MCHC

288 leads to normochromic RBCs, a decreased MCHC means the cells are hypochromic, and a increased MCHC would be referred to as hyperchromic, which is physiologically not possible. An increased MCHC does not correspond to a true increase in hemoglobin concentration, but indicates in vitro or in vivo hemolysis. That is, the hemoglobin value is falsely elevated or the number of RBCs is decreased. Lipemia can also impact the hemoglobin measurement in some hematology analyzers. The MCHC may be decreased with reticulocytosis, iron deficiency, or chronic blood loss.

RBC Distribution Width

Red blood cell distribution width (RDW) indicates the size variation of the RBC population. It measures the deviation of the RBC width, not the actual width or size of individual cells. It is a common parameter on most hematology analyzers, typically calculated by:

1 standard deviation mean cell volume × 1 00 = RDW

A low width suggests that the RBCs are uniform in size, and a larger value indicates there is more variation in size, or anisocytosis. An increased RDW can be indicative of regeneration because there will be a mixture of larger immature RBCs amongst the normal, or even pathologic, cells. There are other conditions that can also cause this increase so an elevated RDW by itself is not definitive for regeneration.

Reticulocyte Count

Reticulocytes are young RBCs without a nucleus, but still containing more RNA than mature RBCs. An elevated reticulocyte count shows that the bone marrow is successfully responding to an increased demand. This then rules out a production issue (bone marrow disease) as the cause of the anemia; it is due to an acute loss (hemorrhage) or destruction of the RBCs (hemolysis). Modern analyzers can give both an absolute reticulocyte count and a percentage. If, however, you only have a percentage, the simplest way to calculate the absolute count is:

Retic % × RBC count (mil/µL) = Absolute retics (/µL)

The reticulocyte percentage alone does not consider the severity of anemia; the absolute count and reticulocyte production index (RPI) are more useful values.

289 Degree of Canine Retics Feline Aggregate Retics Regeneration (/µL) (/µL)

Inadequate/None < 95,000 < 60,000

Mild 95,000-150,000 60,000-100,000

Moderate 150,000-300,000 100,000-200,000

Marked > 300,000 > 200,000

Dog and cat reticulocytes are counted differently. Cat reticulocytes are separated into two types: aggregate, which last about 12-24 hours in circulation, and punctate, which last 7-10 days before maturing into typical erythrocytes. Due to the longevity of punctate reticulocytes in feline circulation, aggregate reticulocytes are used to evaluate the more recent bone marrow response.

The corrected reticulocyte percentage (CRP) considers the current anemia, but makes assumptions about normal Hct (dog: 45%, cat: 35%), but as we know, this varies by hydration status and breed.

patient Hct Retic % × normal Hct = CRP %

Normal CRP for a dog is considered to be < 1 %, and for a cat is < 0.4 %.

RPI allows for both the anemia and the maturation rate of the cells. It uses CRP, so once again, there is the built-in assumption for a normal hematocrit. Additionally, the lifespan of reticulocytes is borrowed from data on humans, and may not be apply to our species of interest.

CRP retic lifespan (days) = RPI

Hct Retic Lifespan (days) 45 1.0 35 1.5 25 2.0 15 2.5

An RPI of 1.0 indicates normal red cell production; greater than 1.0 indicates an increased rate of production in response to blood loss anemia, or an early or mild hemolytic process; an RPI greater than 3.0 suggests a hemolytic process.

290 Reticulocytes can be identified on the ever-important blood smear with common staining techniques. Romanowsky-based stains (e.g. Wright’s, DiffQuik) will stain the RNA blue and the hemoglobin red. Identifying the reticulocytes on these slides will be dependent on how much RNA is in the cells. They can be better visualised after incubating some blood sample with new methylene blue stain.

Nucleated Red Blood Cells

As the name suggests, nucleated red blood cells (nRBC) are erythrocytes that still have a nucleus. These are not typically seen in healthy mammals. When they are, it is usually in low numbers, and they are orthochromic metarubricytes: cells with a small pyknotic nucleus and red cytoplasm. When these, in large numbers, or other even earlier forms of RBC (polychromatophilic metarubricytes, basophilic rubricytes) are present they indicate a strongly regenerative process. NRBCs are counted as lymphocytes by most hematology analyzers, and can be confused with lymphocytes on peripheral blood smears, too.

Blood Smear

The blood smear is arguably the most important diagnostic to evaluate. Automatic blood analyzers still have a long way to develop before they can accurately evaluate morphology and the presence of parasites. The predominant sign that regeneration is occurring is polychromasia; this is seen more commonly than nRBCs. Polychromasia describes the color variation among the RBCs. It occurs because the younger, larger than normal RBCs stain slightly pale blue due to the presence of residual RNA in the cytoplasm. They represent reticulocytes. Reticulocytes may be evident with the presence of basophilic-stained fragments within. Other morphological differentiators are anisocytosis, macrocytes, basophilic stippling, leptocytes (target cells), Howell-Jolly Bodies, nRBCs. These findings may be seen under other conditions and are not definitive for regeneration; they are supportive of it in the presence of significant polychromasia.

291 Complete Blood Count Indices Summary

RBC Measure of red blood cell mass - show severity of Hct anemia Hgb

MCV

MCH Describe the characteristics of red blood cell population

MCHC

RDW Measure of variation on RBC size

Retic % Measure of regeneration Retic #

Hemorrhage or Hemolysis

Once it has been established that an anemia is present and that it is regenerative, focus can turn to finding the cause for the anemia, if not already obvious.

Blood loss through hemorrhage can occur externally through the skin, gastrointestinal (GI) tract, respiratory or urinary tracts, or it can be lost internally into a body cavity as in the case of a hemoabdomen. Hemorrhage can be acute or chronic, and may be accompanied by low total protein, especially if the blood loss is external. Total protein may not be decreased with internal blood loss because the protein remains within the body. External blood loss can result in iron deficiency, consequently reducing the regenerative response.

Hemolysis indicates premature destruction of RBCs. Extravascular hemolysis occurs when RBCs are removed from the circulation by macrophages, phagocytizing them before their lifespan is complete. This destruction typically takes place in the spleen, but can occur in the liver and bone marrow. This occurs with all hemolytic disorders; some patients may have concurrent intravascular hemolysis where RBCs rupture or burst within the blood vessels. Hemolytic anemia can result in icterus due to an increase in total bilirubin (from the breakdown of the heme pigment in the RBCs). Iron may increase and help spur the regenerative process.

292 Hemolytic anemias are typically more highly regenerative. There will be a higher number of reticulocytes in circulation. Iron from the destroyed RBCs remain in the body and is available for hemoglobin production, whereas with a blood loss anemia, it is lost to the body and must be mobilized from elsewhere, slowing the bone marrow response. In addition to bone marrow response time, many hemolytic anemias show specific RBC morphologic changes that provide insight into the process of destruction.

Spherocytes

Spherocytes are small red blood cells with little to no central pallor. Their presence and the absence of poikilocytosis suggests an extra-vascular immune-mediated hemolytic process.

Acanthocytes

Acanthocytes are irregularly shaped RBCs with blunt, finger-like projections resulting primarily from an abnormality in the cholesterol:phospholipid ratio. Liver abnormalities, underlying splenic or metabolic disease are differentials when acanthocytosis is observed.

Leptocytes

Leptocytes, sometimes known as target cells, are cells with a bump of hemoglobinized cytoplasm in the middle instead of the usual central pallor. They are thought to have increased surface:volume ratio. Similar to acanthocytes, conditions to consider include liver, splenic and metabolic disorders.

293 Schistocytes

Schistocytes are RBC fragments. They are thought to occur due physical injury. Disseminated intravascular coagulopathy (DIC), where fibrin strands gather in small blood vessels, are high on the list of possible causes. Glomerulonephritis, high adult heartworm burden, cardiac valvular disease, and other illnesses where mechanical injury to RBCs can occur are differentials.

Heinz Bodies

Heinz Bodies indicate significant oxidative injury to Hgb. They appear like short, blunt projections for the cell surface, where oxidized hemoglobin collects. New methylene blue staining can be helpful in visualizing Heinz bodies. In dogs, onion toxicity is a rule out, and in cats, onions, garlic, and acetaminophen should be considered.

Nonregenerative Anemia

Nonregenerative anemia occurs when the bone marrow has decreased, is ineffective, or has no ability to produce RBCs. Recall that in cases of acute hemorrhage and hemolysis, there will be a delay of three to five days before a regenerative response is seen. Diagnosis of patients with confirmed nonregenerative anemia can be quite involved and sometimes the etiology is never established. In the early phases of evaluation, routine testing, including serial CBCs, is important to

294 confirm that the anemia is not regenerative. Nonregenerative anemia is typically normocytic, normochromic and there may be no RBC morphological changes to aid in identifying the underlying mechanism. Often, nonregenerative anemia is secondary to another disease process and a complete diagnostic evaluation should always be performed.

Characterization Summary

Classic regenerative anemia will typically show increased MCV, decreased MCHC, increased RDW and an elevated absolute reticulocyte count. The blood smear will show polychromasia, anisocytosis, and possibly nRBCs and target cells. Non-regeneration will show little or none of these characteristics.

Bibliography

DeNicola, DB, Matthews, JA, Fernandes, PJ. Comparison of reticulocyte counts to mean corpuscular volume and mean corpuscular hemoglobin concentration in anemic dogs. Paper presented at: XIIth Congress of the International Society of Animal Clinical Biochemistry; 2006; Istanbul, Turkey.

Goodfellow, M., Papasouliotis, K., Cue, S., Crawford, E. and Hall, E. (2008). Effect of storage on microcytosis observed in dogs with portosystemic vascular anomalies. Research in Veterinary Science, 84(3), pp.490-493.

L Gookin, J & E Bunch, S & Rush, Laura & Grindem, Carol. (1998). Evaluation of microcytosis in 18 Shibas. Journal of the American Veterinary Medical Association. 212. 1258-9.

Grimes, C. and Fry, M. (2014). Nonregenerative Anemia. Veterinary Pathology, 52(2), pp.298-311.

“Hematology.” EClinpath, www.eclinpath.com/hematology/

Thrall, M. (2012). Veterinary hematology and clinical chemistry. Ames, Iowa: Lippincott Williams & Wilkins.

Steinberg, J. and Olver, C. (2005). Hematologic and biochemical abnormalities indicating iron deficiency are associated with decreased reticulocyte hemoglobin content (CHr) and reticulocyte volume (rMCV) in dogs. Veterinary Clinical Pathology, 34(1), pp.23-27.

295 SAGE Symposium 2018 Point-of-Care Diagnostics in the ER Jo Woodison, RVT

Introduction

Point-of-care (POC) diagnostics are those run at or near the location of the patient. By performing sample collection and analysis at the same location, transportation and processing delays are avoided, allowing decisions to be quickly and more efficiently made regarding treatment protocols and the efficacy of ongoing treatment. In addition to the obvious time savings in obtaining test results, POC testing may also save money by virtue of treating patients in a more timely, appropriate and efficient manner, and enabling ongoing monitoring and assessment, potentially leading to patients being discharged from hospital sooner. All of this adds up to better patient care. Not just a benefit for hospitalized patients, POC diagnostics can also inform when it is safe to treat as an outpatient, avoiding unnecessary hospital stays and potentially unnecessary treatments or further interim workups.

Back to Table of Contents 296 With continual advances in molecular biology and technology, diagnostic tests, testing devices and analyzers are becoming more advanced, smaller, cheaper, and more readily available than ever before . Diagnostic tests are becoming more accurate, quicker and easier to use. That said, time, money and confidence are important; what diagnostics are the most useful and valuable for use in a veterinary emergency room?

Common Tests

These tests are already commonly performed in many veterinary clinic settings.

Lactate

Lactic acid results from the anaerobic breakdown of glucose in the tissues. It exits the cells, travels to the liver and is oxidized back to pyruvate and is ultimately converted back to glucose. This is termed the Cori cycle. Lactate occurs in two optical isometric forms: D-lactate and L-lactate. D-lactate is a byproduct of bacterial metabolism and may be increased in patients with short-bowel syndrome or severe gastrointestinal (GI) disease. L-lactate is the isomer measured by our POC tests. It occurs as a result of anaerobic metabolism, and when elevated, represents increased anaerobic metabolism due to hypoperfusion. Put another way, an elevated L-lactate (henceforth referred to as lactate) signals inadequate oxygen delivery to the tissues. Lactate concentration is commonly used in the emergency setting for rapid assessment of perfusion status and for guiding resuscitation efforts. A lactate of less than 2.5 mmol/L is considered normal.

Hyperlactatemia is classified by cause: the manner in which it developed. Type A occurs due to systemic or local hypoperfusion, reduced hemoglobin oxygen carrying capacity (dishemoglobinemia), severe euvolemic anemia, severe hypoxemia, or increased oxygen demand due to exercise, seizure activity, muscle tremors, trembling, etc. Type B hyperlactatemia can be broken down into several categories, but essentially they all stem from altered metabolism of lactate. This can happen due to drugs, toxins, or neoplasia.

Lactate concentration in blood samples has proven useful as a biomarker for severity of disease, as well as for measuring response to treatment for both dogs and cats. Diseases causing an elevation of lactate include shock, infectious diseases, immune mediated hemolytic anemia (IMHA), gastric dilatation and volvulus (GDV), and intracranial disease. There is also evidence suggesting that the lactate of cavitary effusions offers additional diagnostic information.

297 As stated, lactate concentration is elevated in cases of hypoperfusion. It is a routine test in emergency rooms to identify and assess perfusion status, and to initiate fluid resuscitation. Patients presenting with hyperlactatemia typically benefit from early and aggressive intravenous (IV) fluid therapy: bolus 20ml/kg and reevaluate heart rate, mentation, capillary refresh time, and pulse. Also useful are further lactate measurements. Lactate is cleared from the body relatively quickly in response to fluids and will often decrease by half within an hour of initiating appropriate fluid therapy. If the lactate concentration does not decrease with aggressive fluid therapy, it may suggest a type B lactic acidosis.

There have been studies performed on the prognostic value of lactate concentration values in both humans and animals. In dogs with GDV, reduced lactate clearance may be a negative prognostic indicator, but certainly not always. Lactate may be elevated in dogs and cats with anemia due to hypoxemia and, in conjunction with a PCV, could determine to initiate a blood transfusion.

Cavitary fluids such as abdominal effusion can be tested for lactate. Studies suggest that if the lactate of the effusion is greater than that of the peripheral blood, a septic process is underway. More work needs to be done in this area.

Lactate testing is easy and relatively economical to perform at the POC on both handheld lactometers (e.g. Nova Biomedical® Lactate Plus) and more extensive analyzers, such as the i-Stat®. Samples must be tested soon after obtaining as studies in healthy dogs suggest that blood lactate increases with time.

Packed Cell Volume

Packed cell volume (PCV) is the percentage of blood volume filled by erythrocytes (red blood cells). They are a measure of the oxygen carrying capacity of blood. A normal PCV for cats and dogs is about 35-45%, depending on species and breed. An elevated PCV is most often a sign of dehydration, however there is a disease state called polycythemia where the RBC count is elevated. A decreased PCV is a sign of anemia, which could be through blood loss due to trauma, neoplasia or coagulopathy, or insufficient production of RBCs by the bone marrow, or premature destruction of RBCs. Total protein (TP) synonymous with total solids (TS) is typically read at the same time as a PCV and the values are useful together to identify how concentrated or dilute the plasma portion of the blood is. Normal values range from 6.5 g/dL to 8 g/dL. An elevated TS is most often a sign of dehydration, but can also indicate chronic inflammation, neoplasia, or an infectious disease. A decreased TS may indicate hemorrhage, malabsorption, liver disease, GI disease, or kidney disease. When running a PCV/TS, the colour of the plasma should be noted. Excess bilirubin will cause the

298 plasma to take on a yellow hue; red indicates the sample is hemolyzed, perhaps due traumatic venipuncture or due to disease, a milky appearance signifies lipemia.

Complete Blood Count

A complete blood count (CBC) provides a good overall picture of blood levels. This automated count typically includes:

Red blood cells (RBC) Informs of anemia.

Percentage of RBCs in blood, akin to PCV, but calculated by an Hematocrit (Hct) analyzer. Can inform of hydration status. Decreased value indicates anemia.

Describes the oxygen carrying capacity of the RBCs. Used in Hemoglobin (Hgb) calculation of MCH and MCHC.

Average volume of RBCs. Increased with reticulocytes/regenerative Mean corpuscular volume anemia. Decreased with iron-deficiency anemia. MCV should always (MCV) be interpreted in conjunction with other clinical data.

Average amount of hemoglobin in RBCs. An increase is most Mean corpuscular commonly the result of hemolysis. A decrease suggests hemoglobin (MCH) hypochromasia, common in iron deficiency anemia, and reticulocytosis.

Average concentration of hemoglobin in RBCs; ratio of hemoglobin Mean corpuscular mass to volume of RBC. With anemia, normal MCHC (with normal hemoglobin concentration MCV) is consistent with non-regenerative anemia due to chronic (MCHC) disease. A decreased MCHC signals hypochromasia, consistent with reticulocytosis.

Measure of the range of RBC volume. Elevated RDW equals Red cell distribution width anisocytosis. With anemia, an increased RDW with an associated (RDW) increase in MCV can indicate reticulocytosis.

Helps identify infection, immune system dysfunction or stimulation, and some cancers. WBC count is usually then broken down into the White blood cells (WBC) different types of each WBC: neutrophils, lymphocytes, monocytes, eosinophils and basophils.

Elevated with inflammation, neoplasia, stress or exercise. Decreased Neutrophils with infection or bone marrow depression

Elevated with chronic inflammation, acute infection/recovery, lymphocytic leukemia, hypoadrenocorticism. Decreased with Lymphocytes acute/severe disease, viral disease, endotoxemia, hyperadrenocorticism, or stress-related corticosteroid response.

Elevated with inflammation; necrotic, malignant, hemorrhagic, or Monocytes immune mediated diseases. There is no known significance to a decreased presence of monocytes.

299 Elevated with parasitic infection, allergic reaction, or Eosinophils hypoadrenocorticism. Decreased with stress, hyperadrenocorticism or ACTH therapy.

Elevated with allergic reaction, parasitic infection, neoplasia. There is Basophils no known significance to a decreased presence of basophils.

Informs of possible coagulopathy. An increase may occur with excess bleeding, iron deficiency anemia or myeloproliferative syndromes. Platelets (Plt) Decreased value can indicate disseminated intravascular coagulation, bone marrow depression, immune-mediated hemolytic anemia, severe hemorrhage, liver disease, parasites.

Large platelets may be indirect evidence of increased (bone marrow) Platelet volume megakaryocyte response.

Blood Chemistry and Electrolytes

Plasma or serum chemistry tests are performed to evaluate overall organ function and attempt to identify organ and tissue damage or injury. Electrolytes are minerals found in tissues and blood that help move nutrients into, and waste products out of, cells. Electrolytes maintain a healthy water balance and help stabilize a body’s acid-base balance. Potassium is found mainly inside the body's cells. Small amounts are also found in blood plasma. It has an important role in regulating the heart's rhythm and ability to contract. Sodium is primarily found outside the cells where it helps to regulate the amount of water in the body.

A summary of parameters that may be looked at:

Organ / System Substance Measured

Kidney function Blood urea nitrate (BUN) Creatinine

Liver function Alanine aminotransferase (ALT) Alkaline phosphatase (ALP) Aspartate transaminase (AST) Bilirubin Albumin Total protein

Other Glucose

Electrolytes Potassium Sodium Chloride Bicarbonate Phosphorus Calcium

300 Blood Gases and Acid-Base

Blood gas analysis provides information about respiratory function and acid-base status. The test results are used to determine and monitor treatment of patients with primary or secondary respiratory illness and metabolic disorders. Blood gases can be run on arterial and venous blood samples; oxygenation evaluation can only be performed on arterial blood samples, but both arterial and venous blood gases can be used to evaluate acid-base disturbances. Acid-base is regulated by the respiratory system and kidneys, and some intra- and extracellular buffers. Disruptions of acid-base balance lead to acidosis or alkalosis which can be life-threatening.

Acid-base status is described by pH, which refers to hydrogen ion concentration. pH regulation is performed by the lungs which regulate carbon dioxide (CO2) and the kidneys, which regulate bicarbonate (HCO3). Compromised lung function may cause respiratory acidosis or alkalosis, and disturbances of kidney function may result in metabolic acidosis or alkalosis. These two systems work together to maintain balance and when a dysfunction occurs, or when one system is compromised, the other will attempt to compensate for it.

Carbon dioxide is sometimes thought of as acidic, and bicarbonate is basic.

● Respiratory acidosis is caused by an increase in CO2.

● Respiratory alkalosis is caused by a decrease in CO2.

● Metabolic acidosis is due to a loss of HCO3.

● Metabolic alkalosis is due to retention or resorption of HCO3.

Normal values for cats and dogs are:

Dog Cat

Arterial Venous Arterial Venous

pH 7.35-7.45 7.35-7.45 7.34 ± 0.1 7.30 ± 0.08

pCO2 (mmHG) 35-45 40-50 33.6 ± 11 41.8 ± 9

pO2 (mmHG) 90-100 30-42 102.9 ± 15 38.6 ± 11

HCO3 (mEq/L) 20-24 20-24 17.5 ± 3 19.4 ± 4

Base Excess (BE) (mEq/L) -4-+4 -4-+4 -6.4 ± 5 -5.7 ± 5

There are entire books and many articles written on blood gas and acid-base, but to summarise their interpretation very briefly:

301 1. If concerned, and arterial sample is drawn, evaluate PaO2 to determine if patient is hypoxemic and needs oxygen support.

2. Evaluate pH to determine whether patient is normal, acidotic or alkalotic.

3. Evaluate pCO2 to determine whether it supports the pH. If it does, the condition is primarily respiratory in origin; if it does not, then the condition is not respiratory.

4. Evaluate HCO3 to determine whether it supports the pH result. If it does, then the condition is primarily metabolic in origin; if it does not then the condition is not primarily metabolic.

5. Evaluate the parameter that is not responsible for the abnormality to determine whether there is a compensatory component.

A-B Disorder p Compensation Primary Change H

Respiratory Acidosis ↓ pCO2 ↑ HCO3 ↑

Respiratory Alkalosis ↑ pCO2 ↓ HCO3 ↓

Metabolic Acidosis ↓ HCO3 ↓ pCO2 ↓

Metabolic Alkalosis ↑ HCO3 ↑ pCO2 ↑

Respiratory Acidosis

Causes for respiratory acidosis include: hypoventilation, large and small airway obstruction, lack of thoracic wall integrity (e.g. open pneumothorax, flail chest, diaphragm compression), late pulmonary parenchymal disease, inappropriate ventilator settings, and administration of bicarbonate.

Respiratory Alkalosis

Respiratory alkalosis can occur as a result of: fever, sepsis, excitement, pain, pulmonary thromboembolism, early pulmonary parenchymal disease, cytokine release in systemic inflammatory response syndrome (SIRS), inappropriate ventilator settings.

Metabolic Acidosis

Possible causes for metabolic acidosis include: loss of HCO3 from the GI tract (e.g vomiting, diarrhea), loss of HCO3 from the kidneys, renal hydrogen retention, and parenteral nutrition.

302 Metabolic Alkalosis

Metabolic Alkalosis can occur as a result of: furosemide administration, pyloric outflow obstruction, hypochloremia, and hypokalemia.

Infectious Disease Tests

Canine Parvovirus

Canine parvovirus is a highly infectious, single-stranded DNA virus that causes severe gastrointestinal upset, and typically presents in younger, unvaccinated dogs. The virus is extremely stable in the environment, which makes dog-to-dog transmission easy and decontamination difficult. Vaccines and a proper immune response are extremely effective at preventing disease, and parvovirus infections are mostly diagnosed in dogs less than a year old that are unvaccinated or inadequately vaccinated. There are several rapid POC screening tests for this infectious disease with similar accuracy claims. Testing immediately on suspicion of the disease allows for appropriate isolation and sanitation protocols to be implemented and followed, in addition to commencing the most appropriate treatment and any further diagnostics. A negative result on these screening tests does not definitively rule out canine parvovirus infection, and patient presentation and CBC should be considered. Both false negatives and false positives are possible, and a recent study at University of California Davis showed that all POC fecal canine parvovirus tests on the market have been shown to produce false positive and false negative results.

Leptospirosis

Leptospirosis is currently the fastest growing zoonotic disease, and can be found worldwide in soil and water. There are at least 20 serovars of leptospira. Leptospira are found in both domesticated and wild animals, and the main carriers of the bacteria are rats, pigs, raccoons, cattle, fox, skunks, and opossums. Signs of leptospirosis can include fever, shivering, muscle soreness, increased thirst, changes in the frequency or amount of urination, dehydration, vomiting, diarrhea, loss of appetite, lethargy, jaundice, or uveitis. The disease can cause kidney failure with or without liver failure.

Given the potential severity of the disease and its zoonotic potential, it is desirable to have a reliable screening test to allow identification of the contamination risk and so that precautions can be taken. Several diagnostic test providers have released tests relatively recently. These tests detect canine antibodies produced in response to acute leptospirosis. These antibodies develop within a week of onset of disease and are produced in response to a wide range of leptospira serogroups. Utility of the tests have yet to be proven.

303 Drug Testing

Urine drug tests for dogs presenting to the emergency clinic can be useful in determining ingestion of benzodiazepines, barbiturates, amphetamines, and opiates. These economical, easy to use tests are designed for human drug testing and are quite effective at identifying the commonly used drugs listed. Unfortunately, they are not very reliable for marijuana toxicity. Dogs metabolize marijuana differently to humans and those metabolites may not be detected, or may cause interference with the test. False negatives can also occur if the patient is tested too soon after ingestion. Gas chromatography and mass spectrometry would be better methods for THC detection but can take several days and are not practical for initiation of therapy. False positives of other drugs can also occur in pets receiving prescribed medications such as tramadol and diphenhydramine, among others. Despite the limitations, these tests can be helpful in guiding the treatment plan and in presenting that to the client.

Ethylene Glycol Testing

Ethylene glycol is a sweet-tasting, odorless liquid that is the active ingredient in most automotive antifreeze products. It can also be found, in lower concentrations in some windshield de-icing agents, hydraulic brake fluid, motor oils, solvents, paints, film processing solutions, wood stains, inks, etc. Dogs and cats seem to be tempted by the sweet taste, and there are cases where malevolent people have left antifreeze laced meat out in populated areas for animals to consume.

Ethylene glycol has a narrow margin of safety and a small amount can result in a fatal poisoning, and it happens very quickly. Due to the rapid onset of damage, early detection of toxicity and prompt treatment with 4-Methylpyrazole (4-MP, fomepizole) is highly desirable. Current test kits measure ethylene glycol rather than its metabolites and the peak levels are reached within 1 to 4 hours of ingestion. Testing can be performed up to 12 hours after ingestion, but after any longer, the test will be negative because all the ethylene glycol has been transformed into its metabolites. False positives on the test can occur if the pet has ingested solutions containing propylene glycol, pentobarbital and diazepam.

304 Coming Soon?

ProBNP

NT-proBNP is a neurohormone secreted from the atria and ventricles of the heart in response to volume expansion or pressure overload. It is a functional cardiac biomarker that is increased with stress, stretch, or strain on cardiomyocytes due to occult or overt heart disease.

A test for NT-proBNP is available at reference laboratories. An NT-proBNP POC screening test, the IDEXX SNAP® Feline ProBNP test, is available for cats and can help distinguish heart disease from respiratory disease, making it a very useful tool in the emergency hospital. The test is validated for use on whole blood and serum, but some studies are investigating using pleural effusion for the test. Some cats may receive emergency thoracentesis but not be stable enough for venipuncture. To date, it seems the SNAP proBNP test has been useful for ruling out cardiac disease when used in this manner, but a positive test did not necessarily confirm heart disease.

C-Reactive Protein

C-Reactive Protein (CRP) is an acute phase protein produced by the liver in response to inflammation. CRP levels rise within hours of the onset of inflammation, and return to normal one to two weeks after the condition subsides. It has been found to be elevated in infectious diseases, immune mediated diseases, and neoplasia. A CRP test as a marker of inflammation could be useful in the diagnosis and monitoring of inflammatory diseases, however CRP may be elevated for other reasons also. The utility of a patient-side test for CRP test in the veterinary emergency environment is currently unclear, but there are more studies underway. It could prove useful for management of chronic inflammatory conditions.

Conclusion

Properly utilized POC diagnostic testing has shown to yield measurable improvements in patient care, workflow efficiency, and provide significant financial benefits. Designers and developers of these tools need to ensure reliable quality standards are continually met, Veterinary practitioners must ensure they have an appropriate organizational structure to utilize these tests, process the results, and communicate treatment plan changes and progress to staff and clients. As always, the patient should be assessed completely, and no single diagnostic value should be utilized in isolation.

305 Bibliography

DiBartola, S. (2000). Fluid therapy in small animal practice. 2nd ed. Philadelphia, Pa.: W.B. Saunders Company.

Ettinger, Stephen J. et al. Textbook of Veterinary Internal Medicine, 8th Edition. 991-996.

Fitzgerald, K., Bronstein, A. and Newquist, K. (2013). Marijuana Poisoning. Topics in Companion Animal Medicine, 28(1), pp.8-12.

Gebhardt, C., Hirschberger, J., Rau, S., et al. (2009), Use of C-reactive protein to predict outcome in dogs with systemic inflammatory response syndrome or sepsis. Journal of Veterinary Emergency and Critical Care, 19: 450–458. doi:10.1111/j.1476-4431.2009.00462.x

Hassdenteufel, E., Henrich, E., Hildebrandt, et al. (2013). Assessment of circulating N-terminal pro B-type natriuretic peptide concentration to differentiate between cardiac from noncardiac causes of pleural effusion in cats. Journal of Veterinary Emergency and Critical Care, 23(4), pp.416-422.

Hezzell, M., Rush, J., Humm, et al. (2016). Differentiation of Cardiac from Noncardiac Pleural Effusions in Cats using Second-Generation Quantitative and Point-of-Care NT-proBNP Measurements. Journal of Veterinary Internal Medicine, 30(2), pp.536-542. http://www.sheltermedicine.com/library/resources/canine-parvovirus-cpv#Recognition

Kreü, S., Jazrawi, A., Miller, J., Baigi, A. and Chew, M. (2017). Alkalosis in Critically Ill Patients with Severe Sepsis and Septic Shock. PLOS ONE, 12(1), p.e0168563.

Larsson, A., Greig-Pylypczuk, R. and Huisman, A. (2015). The state of point-of-care testing: a european perspective. Upsala Journal of Medical Sciences, 120(1), pp.1-10.

Teitler, J. (2009). Evaluation of a Human On-site Urine Multidrug Test for Emergency Use With Dogs. Journal of the American Animal Hospital Association, 45(2), pp.59-66.

306 CLANDESTINE ORAL PATHOLOGY MISSED ON EXAMINATION BUT CAPTURED WITH INTRAORAL DENTAL RADIOGRAPHY

Sage Symposium 2018 Kevin S. Stepaniuk, B.Sc., DVM, FAVD Diplomate, American Veterinary Dental College

Veterinary Dental Education Consulting Services, LLC www.veterinarydentisryeducation.com [email protected] Columbia River Veterinary Specialists

Introduction It is impossible to describe all the dental and oral pathology and pathophysiology in a single set of notes. Instead, the lecture and notes will focus on a visual tour of common dental and oral pathology and the subtle visual and examination clues indicating hidden subgingival disease.

Conscious Exam The oral examination begins in the exam room. A complete medical and oral history, general physical exam, and conscious oral examination are necessary. A complete history and evaluation of the chief complaint is investigated. Questions such as, but not limited to, onset, duration, environment, chew toys, oral health care, current medications, diet, past illness, past anesthetic episodes, behavioral changes, etc. are explored. Many patients with oral disease do not have obvious clinical signs. When the diseases become unbearable for the patient and acute on chronic conditions manifest they may exhibit ptyalism, face rubbing, halitosis, partial anorexia, sneezing, nasal discharge, pawing at the mouth, ocular discharge, disproportionate deposits of plaque and calculus, or nothing at all (suffer quietly in silence).

Temperature, pulse, respiration, body weight, and the organ systems are evaluated. Particular attention to the cardiopulmonary system is made. The maxillofacial skeletal is palpated and the eyes retropulsed. The three basic skull types are brachycephalic (e.g., Pugs, Bulldogs, Persian Cats), mesocephalic (e.g., Labrador, DSH), and dolichocephalic (e.g., Sight hounds, Collies). The regional lymph nodes and salivary glands are palpated. Facial symmetry and occlusion are noted. The range of motion of the temporomandibular joints should be palpated and the patient observed for pain and/or difficulty in opening and closing the mouth. The lips and mucocutaneous junctions should be observed for ulcerations that might indicate regional pyoderma or an autoimmune disease. Finally, the dentition is evaluated and the teeth counted to determine if all teeth are present. Discolored teeth, persistent deciduous teeth, root and furcation exposure, oral mucosal lesions, sinus tracts, tongue, oral masses, plaque and calculus are noted. Note the symmetry of the maxillofacial skeleton.

The occlusion should be evaluated in the non-anesthetized patient so that the relationships of the teeth and bones can be determined before an endotracheal tube is placed. The normal canine mesocephalic skull has anisognathic mandibles. With orthocclusion, the mandibular incisors occlude on the cingulums of the maxillary incisors, the mandibular canines interdigitate, without touching, between the maxillary third incisors and canine teeth. The tips of the mandibular 4th premolars will point directly upward between the maxillary 3rd and 4th premolars. The mandibular and maxillary premolars interdigitate, and the tips of the upper and lower second premolars are at the same horizontal level.

Appropriate pre-anesthetic blood testing is obtained based on patient signalment and history. No patient is anesthetized without minimal blood work (packed cell volume, BUN, glucose, and total protein).

Back to Table of Contents 307 However, most dentistry patients are older and more extensive bloodwork such CBC / Chemistry Panel / Urinalysis are necessary and recommended for anesthetic planning.

Anesthesia and The Oral Examination It is impossible to completely examine the oral cavity in a conscious patient. At best, we can estimate the extent of periodontal disease, identify fractured teeth, and see obvious large oral masses. Anesthesia is required (www.avdc.org for AVDC position statement) to accurately assess periodontal disease, fractured teeth, and other oral pathology.

MISCELLANEOUS DENTAL AND ORAL PATHOLOGY

Hidden palatal maxillary canine oronasal fistula An oronasal fistula (ONF) is a communication between the oral and nasal cavity. The epithelial surfaces of the nasal and oral cavity communicate via the fistula. A loss of the maxillary canine tooth and remaining defect results in a clinically obvious oronasal fistula. However, deep intrabony palatal pockets are missed during clinical examination and due to summation of opaque radiographic structures, is often missed with intraoral dental radiographs. Bacteria and the associated inflammatory response only require microscopic communications between the oral and nasal cavities to create a hidden chronic oronasal fistula resulting in upper respiratory clinical signs. Clinical signs may include chronic nasal discharge (serous, mucopurulent, and/or epistaxis). Sneezing may or may not be present. Oronasal fistulas may be obvious upon clinical examination or may be a pinpoint lesion that requires anesthesia and a thorough oral exam to identify. The teeth may, or may not, be mobile and it is not uncommon to have normal or slightly increased to moderate buccal periodontal probing measurements with very large probing depths palatally. Occasionally, a trickle of blood may be seen exiting from the ipsilateral nares when the probing depths are measured palatally, confirming an ONF. Occasionally, the periodontal probe is inhibited from reaching true probing depths by large accumulations of subgingival calculus and inflammatory tissue.

Diagnosis of maxillary canine tooth palatal oronasal fistulas can be missed on intraoral radiographs due to summation of anatomical structures. Assessment with radiographs and clinical examination probing is necessary. Surgical extraction and appropriate tension free closure with mucoperiosteal flaps is necessary to correctly treat the oronasal fistula during the surgical procedure.

Parulis A parulis is a raised nodule at the opening of a draining sinus tract. If the parulis is located apical to the mucogingival junction it is often associated with endodontic disease. If the parulis is located at/or coronal to the mucogingival junction, it is often associated with periodontal disease. Intraoral dental radiographs and extraction or endodontic treatment, as indicated, is required.

Maxillary 1st and 2nd molars Hidden Periodontal Disease The maxillary 1st and 2nd molars in dogs may have minimal clinical probing depths but may be mobile during clinical examination. The intraoral radiographs may identify a very wide or absent periodontal ligament space/large palatal root periapical lucency. Likewise, the superimposed buccal roots may have 50-100% bone loss (Periodontal Disease Stage 4) and without careful evaluation of the intraoral radiograph the bone loss is easily missed. These clinical and radiographic findings are consistent with severe periodontal disease and surgical extraction and closure of the extraction site is required.

Hidden probing depths - dog mandibular 1st molars and mesial roots maxillary 4th premolars

308 Large periodontal probing depths may be identified mesial or distal to the mandibular 1st molars in dogs with minimally associated gingival inflammation. Intraoral radiographs will identify large intrabony pockets. Treatment may include extraction of the adjacent non-strategic 4th premolar or 2nd molar. If these teeth are associated with the intrabony pocket of the 1st molar, then open root planning and bone augmentation or guided tissue regeneration are often necessary. If the mandibular molar cannot be saved, then surgical extraction or hemi-section with root canal treatment is recommended.

When probing the teeth always probe between them mesial buccal and mesial palatal roots of the maxillary 4th premolars. This is a common place for a hidden intrabony pocket that is not easily identified with intraoral radiographs due to summation and superimposition of radiopaque dental structures and bone. Deep intrabony pockets will require guided tissue regeneration or the tooth will require surgical extraction.

Feline mandibular 1st molar periodontal disease Many domestic cats have a tight occlusion and with little translation movement of the temporomandibular joint the resulting maxillary 4th premolar cusp can traumatize the buccal aspect of the mandibular first molar. Likewise, brachycephalic cats often have a scissors or level occlusion of the incisors. However, the mandibles have bowed laterally during growth. As a result, the central cusp of the maxillary 4th premolar contacts the mesial/buccal tooth and periodontium of the mandibular 1st molars resulting in periodontal dehiscence and disease.

Likewise, the veterinarian may extract the mandibular 1st molar and identify the surgical site is not healing and/or identify a mass pre- or post-extraction that has a histological description such as pyogenic granuloma, lymphoplasmacytic gingivitis, etc. secondary to the trauma created by the maxillary 4th premolars.

Surgical extraction of a periodontally expired mandibular 1st molar is necessary. The maxillary 4th premolar requires surgical extraction or appropriate crown reduction/odontoplasty and endodontic and/or restorative treatment to remove the offending cusp(s).

Ocular discharge and the nasolacrimal canal The nasolacrimal canal is located millimeters from the apical aspect of the maxillary canine tooth, particularly in cats. Chronic endodontic disease or even severe periodontal disease with the associated periapical infection and inflammation can occlude and damage the nasolacrimal canal resulting in impaired drainage and epiphora.

Assessment, intraoral radiographs, and surgical extraction or endodontic treatment, if not periodontal disease, of the maxillary canine tooth is necessary. However, permanent damage may preclude complete resolution of the epiphora.

Drug related gingival enlargement/hyperplasia The use of cyclosporine for atopic dermatitis has greatly increased the prevalence of drug induced gingival enlargement in dogs. A combination of the plaque, drug dosage, and individual susceptibility results in the creation of pseudopockets that lead to true periodontal pockets with chronic infection, pain, and tooth loss. Finding the lowest possible dose to maintain control of the dermatological condition but minimize the gingival enlargement is recommended. Annual to semi-annual dental cleanings and daily home care with brushing to control the plaque is recommended. Intraoral radiographs and extractions are necessary for teeth that have progressed to late stages of irreversible periodontal disease.

Feline sublingual squamous cell carcinoma

309 Cats will present late in the disease course for partial or complete anorexia, ptyalism, and oral pain. Biopsy and histopathology are necessary for diagnosis because differentials that may appear clinically similar include treatable lesions such as eosinophilic granuloma or a granuloma/infection associated with a sublingual foreign body (e.g., needle, string, plant material). Pyogranulomatous inflammation can appear clinically similar to squamous cell carcinoma. Always biopsy!

Maxillofacial swellings and draining tracts Maxillary draining tracts should be investigated for odontogenic infections such as periodontal disease or endodontic disease prior to extensive dermatological or neoplastic work ups including advanced imaging and biopsy. Teeth should be the primary differential for the maxillofacial swellings and draining tracts. The pathology is easily diagnosed with an appropriate anesthetized examination and intraoral radiographs, if the veterinarian knows the knowledge of the pathophysiology. If an odontogenic infection is not the cause, then evaluation for neoplasia, etc. can be pursued.

Periocular Swellings The dentition is closely related to maxillofacial structures and the orbit/eyes. Periorbital swelling, chemosis, swelling closed of the palpebral fissure can all occur secondary to odontogenic infection. Hence, not only is an ocular examination warranted but close evaluation of the oral cavity is necessary. Many patients end up being treated and/or referred to ophthalmologists only to then be referred for odontogenic infection.

Deciduous tooth fractures Deciduous tooth fractures can lead to endodontic disease, damage to developing tooth buds, and maxillofacial swellings. Complicated crown fractures (exposed pulp) require extraction and a “wait for them to exfoliate with adult tooth eruption” is incorrect and potential malpractice.

Uncomplicated crown fractures Dentin contains 45 000 – 70 000 tubules/mm2 allowing oral bacteria to translocate into the endodontic system and result in pulpitis and death of the tooth. The clinical point is that exposed pulp (complicated crown fracture) always leads to endodontic disease but ALSO uncomplicated crown fractures and enamel fractures exposing dentin tubules can lead to endodontic disease.

Non-healing extraction sites All extraction sites, except some deciduous tooth extractions, should be sutured closed. If correct surgical closure was performed (e.g., no tension on mucoperiosteal flaps, suture lines over bone) and the surgical site does not heal, the differential diagnosis immediately include neoplasia or retained tooth root. Ideally, intraoral radiographs post-extraction would have confirmed the entire tooth was extracted. However, if they were not obtained, then anesthesia and intraoral radiographs, with removal a tooth root, if present is necessary. If no tooth root is present, obtain representative biopsy of the site followed by a large mucoperiosteal flap for closure.

Dentigerous Cysts Unerupted teeth (embedded or impacted) can lead to dentigerous cysts formation and destruction of the bone and adjacent teeth. This condition is preventable so all regions of missing teeth should be evaluated with intraoral radiographs. Unerupted teeth should be extracted. Dentigerous cysts need to be surgically debrided and the cystic lining removed with the offending tooth.

Complicated Crown Fractures

310 Intraoral dental radiographs for assessment and treatment are required. All fractured teeth with pulp exposure (acute or chronic) require endodontic treatment or extraction. Many teeth with uncomplicated crown fractures and enamel fractures may also have endodontic disease requiring treatment that can only be found via intraoral radiographs.

Non-vital Teeth Localized intrinsic staining is consistent with a non-vital tooth. Total or partial pulp necrosis was found in 92.2% of intrinsically stained teeth. Radiographic signs consistent with endodontic disease were absent in 42.9% of the teeth. The intrinsic stain is the result of pulpitis and pulp hemorrhage resulting in hemoglobin and the subsequent breakdown products in the dentin tubules.

Often the patient suffers quietly in silence with only subtle clinical signs of chronic pain being noticed by an astute owner. Clients often remark the improved change in behavior following treatment of a non-vital tooth.

Likewise, many examples of full mouth intraoral radiographs during a periodontal cleaning have documented and published identification of hidden non-vital teeth without any color or morphological changes in the teeth.

Apoquel (Oclacitinib) Please read the package insert! Please read the label and approved usages. It has a good approved usage in veterinary medicine. But do not let it be a honey moon drug. Please read the contraindications and when not to use it. Please understand it is not to be used in face of infections, cancer, and pre-cancerous conditions. It ideally is not to be used long-term and not studied long-term with other immunosuppressant such as cyclosporine, another immunosuppressant at this time. Understand that periodontal and endodontic disease are chronic infections and inflammatory conditions in constant battle with the immune system. Understand it may be possible to unmask and cause acute on chronic exacerbations and acute on chronic infections in geriatric patients, in particular, when using off label (e.g. for “rhinitis”), long-term, and/or concurrently with other immunosuppressant medications. Understand the relationship between the tooth and nose relationship. First do no harm! Regardless, it is not to be used in precancerous conditions so another reason not to use it without a diagnosis. I have never prescribed the medication it but many of my patients have presented on it urgently through referrals and the emergency department for acute maxillofacial infections.

I only have anecdotal observations in several patients and cannot draw any causal relationship or an association but keep an open mind in your own patients and think twice about the geriatric patient with severe periodontal disease or the Labrador with the chronically fractured maxillary 4th premolar before you reach for the prescription pad as you are about to prescribe a drug where the manufacture warns you not to use in the face of infection.

311 Anesthetic Drugs: How do they work? Liza Morales, RVT Judy Kpa, RVT

I. Opioids: Although they work on several different receptors, all opioids provide analgesia and some degree of sedation a. Agonists: bind and stimulate receptors, most profound analgesia b. Antagonist: bind and block or inhibit activity c. Partial agonists: bind and stimulate d. Mixed agonist/antagonists: stimulating some receptors while blocking others i. There are 4 opioid receptors: mu, kappa, delta, and zeta (for this presentation we will focus on just mu and kappa) 1. Mu receptors = profound analgesia; causes euphoria, respiratory depression, physical dependence and bradycardia. 2. Kappa receptors = lesser analgesic response, may cause miosis, sedation, and dysphoria. e. Reversal i. Agonists can be reversed with an opioid agonist/antagonist (Butorphanol) or fully reversed with an opioid antagonist (Naloxone). ii. Pure mu agonists 1. Fentanyl Citrate a. Momentary analgesia, respiratory depression, decreased cardiac output especially at high doses and with neonatal or geriatric patients, panting, no histamine release b. Usage: MAC reducer, profound analgesia as a CRI, provides c. Onset and duration: i. Single dose/bolus: 2 minute onset and 30-45 minute duration ii. CRI: 15 to 30 minute onset and duration is about 5 minutes beyond the end of the CRI. iii. Patches: 8 to 12 hour onset after application, expedited by exposure to heat with a duration of 72 to 96 hours d. Doses: i. Premed as a single dose: 5mcg/kg IV ii. Bolus: 2 to 4mcg/kg IV iii. CRI: 2 to 30mcg/kg/hr IV iv. Patch: 1mcg/lb 2. Hydromorphone a. Profound analgesic, sedative effect, b. General premed choice for surgical cases c. No histamine release if given IV d. Bradycardia, panting (hypothalamus) e. Dose: i. Premed: 0.05 to 0.1mg/kg ii. Analgesia: 0.1mg/kg

Back to Table of Contents 312 f. Duration: 4 to 6 hours g. Onset: i. IV: 1 to 2 minutes ii. IM: 15 to 20 minutes 3. Methadone a. Possible NMDA receptor antagonist in addition to pure mu b. Duration: 4 to 6 hours c. General premed i. Least likely to cause nausea/emesis d. Higher doses can cause bradycardia and respiratory depression e. Dose: i. Dog: 0.5 to 1mg/kg SC, IM or IV ii. Cat: 0.25 to 0.5mg/kg SC, IM or IV slow 4. Morphine Sulphate a. Transient hypotension b. Histamine release c. Duration 4 to 6 hours d. Higher doses = bradycardia and respiratory depression e. Often causes vomiting and defecation IM or SC- less likely if given slowly f. Histamine release IV-caution g. Cats are sensitive so use with caution; low doses okay (i.e. epidurals), better with a tranquilizer or sedative h. Dose: i. Dog: 0.5mg to 1mg/kg IV, SC, IM ii. Cat: 0.25 to 0.5mg/kg SC, IM, IV iii. CRIs iv. Epidural iii. Partial mu agonist 1. Buprenorphine: Partial mu agonist of extremely high affinity to the mu receptor, provides minimal sedation as a Kappa antagonist, a. Class III drug b. Good for mild to moderate pain c. Minimal sedative effect d. Delayed onset: i. 30 minutes to peak effect IV ii. 45 to 60 minutes to peak effect IM e. Difficult to reverse i. Antagonizes other pure mu agonists like morphine, hydromorphone, fentanyl, and oxymorphone f. Dose: i. Dogs: 0.01 to 0.04mg/kg IM or IV ii. Cats: 0.01 to 0.04mg/kg IM, IV, or TM 2. Simbadol a. Post-operative pain in cats b. 24 hour duration for one injection post-op; can do up to 3 injections post-op for 72 hour relief c. 1.8mg/mL

313 d. Dose: 0.24mg/kg iv. Mixed 1. Butorphanol a. Mixed w/ primary agonistic activity at the kappa receptor; generally antagonistic at the mu receptor b. Good for very mild pain-good for visceral pain c. Short duration of effect i. Dogs: 30 minutes to 1 hour ii. Cats: 1 to 3 hours d. Dose: 0.2 to 0.4mg/kg IV, SC II. Benzodiazepines a. Diazepam i. Hypnotic sedative, muscle relaxer and anticonvulsant ii. Cats: good sedative for cats; induces hunger iii. Dogs: extremely short duration makes it suitable for sedation as a sole agent for dog iv. Propylen glycol base = painful IM injection and less predictably absorbed than Midazolam 1. Can cause hemolysis and vasodilation if given in sufficient quantity a. Rapid IV administration can lead to short term arrhythmia 2. Dose: a. 0.2mg to 0.4mg/kg IV b. Midazolam i. Hypnotic sedative, muscle relaxer and anticonvulsant ii. Overall similar to Diazepam w/out Propelyne Glycol iii. Given alone can cause dysphoria, agitation, and difficult restraint—mostly in younger animals and cats iv. Dose: 0.2 to 0.4mg/kg IV or IM III. Alpha-2 Agonist a. Dexmedetomidine i. Potent sedative with analgesia ii. Decreases insulin production iii. Initial peripheral vasoconstriction, then profound peripheral vasodilation after administration iv. Best reserved for young healthy patients v. Significant MAC reducer vi. Caution: do not use: 1. As a sole agent at box label doses 2. Debilitated or cardiovascular unstable patients 3. Extremely stressed patients may not respond well-catecholamine’s!!! 4. Non-insulin dependent diabetics vii. Dramatic bradycardia 1. Do not give anticholinergic unless it has been at least one hour post administration of Dexdomitor---- bradycardia not mediated by vagus nerve*** 2. Dose: a. 0.0005 to 0.015mg/kg IV, IM, SC alone**** b. 0.001 to 0.01******

314 c. CRI* 3. Reverse with b. Xylazine: alpha-1 agonist i. IV. Chyclohexamines a. Ketamine i. Dissociative anesthetic ii. Usually combined with a benzodiazepine for induction iii. Reasonable choice for stable valvular heart patients iv. Can be given orally to fractious cats (5mg/#) v. Avoid in: 1. History of seizures 2. Intracranial disease suspected 3. Significant renal disease especially in cats; metabolized in liver in dogs 4. Corneal desiccation can occur so protection is required** 5. Initially causes myocardial depression generally followed by indirect sympathetic stimulation 6. Increase heart rate can be detrimental for: a. Hypertrophic cardiomyopathy b. Hyperthyroid patients c. Pheochromocytomas vi. Dose: 1. Induction: 5 to 10mg/kg 2. CRI: 2 to 10mg/kg/min; loading dose 0.25 to 0.5mg/kg IV V. Induction Drugs a. Propofol 1. Injections should be given over a period of 20-60 seconds until desired anesthetic depth is reached 2. Dose: 4-6 mg/kg IV 3. Can be delivered as a CRI at 0.2-0.4mg/kg/min via a syringe pump for continuous administration 4. Avoid in: a. Patients with hypotension, shock, blood loss or dehydration

315 Track 5 Assessment of the Critically Ill Patient: Nursing Basics Kristin Freitas BS, RVT, VTS(ECC)

A. A critically ill patient is a patient so seriously ill or injured as to be in danger of dying.

B. Main goal of treatment is to optimize tissue perfusion and oxygen delivery.

C. Assessment and monitoring of a critically ill patient should consider findings from serial physical exam, as well as the results of any tests performed or technologically derived data. We need to treat the whole patient not a number.

D. The monitoring plan for a critically ill patient should allow for early detection of changes in patient status while minimizing the risks for iatrogenesis, unnecessary cost to the client, and inappropriate use of intensive care unit resources.

E. Not only should action to correct values outside of normal parameters be taken, but attention should be paid to trends, so actions can be taken early to avoid crisis situations.

Vitals to Monitor:

A. Airway and Breathing 1. Respiratory Rate: Normal i. 18-30 bpm (dog) ii. 20-30 bpm (cat)

Abnormal i. Tachypnea: respiratory rate greater than normal. ii. Bradypnea: respiratory rate less than normal.

2. Respiratory Effort: Normal i. Eupnea: quiet, unlabored breathing. Abnormal i. Dyspnea: difficult or labored breathing. ii. Obstructive breathing pattern: Patients will breath slowly and deeply 1. Respiratory effort on inspiration suggests upper airway or extrathoracic obstructions. 2. Respiratory effort on expiration suggests obstruction or collapse of the intrathoracic small airways. iii. Restrictive breathing pattern: rapid shallow breathing 1. Pleural Space Disease 2. Atelectasis

Back to Table of Contents 316 3. Pulmonary Fibrosis B. Circulation 1. Heart rate: Normal i Dog: 60-140 bpm 90-120 bpm (small dog) 70-110 bpm (medium dog) 60-90 bpm (large dog) ii. Cat: 150-240 bpm

Abnormal ii. Bradycardia: abnormally slow heart action. a. Results in decreased cardiac output and subsequent poor perfusion. b. This can be associated with imminent cardiac arrest. iii. Tachycardia: a heart rate that exceeds the normal resting rate. a. Can result in compromised diastolic filling and decreased stroke volume.

2. Mucous membrane color: Normal i. Pink: indicative of normal perfusion and oxygenation.

Abnormal i. Pale or white mucous membranes: indicative of anemia or shock. ii. Red mucous membranes: suggest vasodilation as seen in systemic inflammatory states and hyperthermia iii. Cyanotic gums: indicate a normal packed cell volume but severe hypoxemia. iv. Yellow hue: indicates increased serum bilirubin v. Brown color: can be seen with methemoglobinemia. vi. Note any petechiae or bleeding

3. Capillary refill time: CRT can help assess a patient's blood volume and peripheral perfusion Normal i. A normal CRT is 1 to 2 seconds and is consistent with normal blood volume and perfusion.

Abnormal i. A CRT longer than 2 seconds can be a sign of poor perfusion or peripheral vasoconstriction. ii. A CRT less than 1 second is indicative of a hyperdynamic state, which can be seen in cases of systemic inflammation, heat stroke or hyperthermia, distributive shock, and vasodilation.

317 4. Pulse Quality: The pulse should be palpated while listening to the heart or palpating heart motion at the apex of the chest. Normal i. A strong pulse that is synchronous with each heartbeat is normal and consistent with adequate blood volume and cardiac output.

Abnormal i. An irregular pulse or one that is asynchronous with cardiac auscultation is a sign of a significant cardiac arrhythmia. ii. Weak pulse can be due to decreased cardiac output (either low stroke volume or decreased contractility), peripheral vasoconstriction, or decreased pulse pressure.

5. Blood Pressure Normal i. Systolic a. Dog 110-160 mm Hg b. Cat 120-160 mm Hg ii. Diastolic a. Dog 55-110 mm Hg b. Cat 70-120 mm Hg iii. Mean Arterial Pressure (MAP) a. Dog 80-130 mm Hg b. Cat 60- 130 mm Hg

Abnormal i. Hypotension: a. Defined as a MAP less than 60 mm Hg or Systolic < 90 mm Hg b. With a MAP< 60mm Hg blood perfusion to the brain and kidneys is compromised ii. Hypertension: a. Defined as a Systolic >160 mm Hg b. With a systolic blood pressure > 180 mm Hg the risk of end organ damage is considered severe. 1. The eyes and the brain are the organs most affected by hypertension in veterinary patients. 2. If the risk of end-organ damage leading to significant permanent abnormalities from a hypertensive crisis is high emergency therapy to lower the patient’s blood pressure is indicated.

C. Level of Consciousness: Normal i. The animal has a normal demeanor and interaction with its environment.

Abnormal

318 i. Lethargy: reflecting decreased level of consciousness with listlessness and drowsiness. ii. Obtunded: A state of decreased responsiveness or alertness and is graded as mild, moderate, or severe. iii. Semicomatose or Stuporous: The patient responds only to vigorous or painful stimuli. iv. Comatose: The patient does not respond consciously to any stimuli

D. Eyes: 1. Pupil Size and Reactivity: Normal i. Both pupils contract on exposure to light to the same degree and at the same speed. ii. Pupils are equal in size and are an appropriate size for given light conditions.

Abnormal i. Anisocoria: one pupil is larger than the other. a. Unilateral mydriatic, unresponsive pupil: Loss of parasympathetic innervation to the eye. 1. often associated with increased intracranial pressure and unilateral cerebral herniation. 2. Rule out unilateral topical ophthalmic atropine or tropicamide. ii.Miosis: excessive constrictions of the pupils a. Can be seen with metabolic encephalopathies or diffuse midbrain compression with increased intracranial pressure, and may precede mydriatic, unresponsive pupils. iii. Bilateral, mydriatic, unresponsive pupils: Fixed and dilated pupils. a. Severe, bilateral compression or destruction of the midbrain or cranial nerve III, typically from bilateral cerebral herniation. Grave prognosis.

2. Motion and Positioning Normal i. Eyes are aligned with each other and all motion seems controlled.

Abnormal i. Nystagmus: Eyes make repetitive uncontrolled movement ii. Strabismus: Eyes do not properly align with each other.

5. Temperature: Normal i. Dog: 99.5°F (37.5°C) to 102.5°F (39.2°C) ii. Cat: 99.5°F (37.5°C) to 102.5°F (39.2°C)

319 Abnormal i. Hypothermia is a condition in which the core body temperature is below the normal physiologic parameters for an individual species a. Hypothermia causes severe cardiovascular, respiratory, electrolyte, nervous system, acid-base, and coagulation abnormalities ii. Hyperthermia is any elevation in body temperature above accepted normal values a. True fever is a normal response of the body to invasion or injury and is part of the “acute phase response.” b. A fever may be beneficial to the host by decreasing bacterial growth and inhibiting viral replication. c. Most fevers are not a threat to life unless body temperature exceeds 107°F (41.6°C).

The Vitals Have Changed: Now What? A. Be concerned when vials are outside of normal parameters. B. Not only should action to correct values outside of the normal parameters for the vitals being monitored be taken, but attention should be paid to trends so actions can be taken to avoid crisis situations. C. Actions taken will depend on what value or values are abnormal. D. Important to make sure the patients basic needs are taken care of prior to medical interventions being taken. For example: An increase in heart rate may be due to the need urinate. E. Take all observations into consideration prior to acting.

Medical Actions: Goal: optimize tissue perfusion and oxygen delivery.

A. Respiratory Compromise Vitals to Monitor 1. Respiratory Rate 2. Respiratory Effort 3. Mucous Membrane 4. Capillary Refill Time 5. Level of Consciousness 6. Pupillary Response and Eye Position

Potential Actions 1. Assess Pain Control i. Uncontrolled pain is detrimental to cardiovascular function ii. Easier to prevent than treat iii. Signs of Pain a. Tachycardia b. Tachypnea c. Hypertension

320 d. Restlessness e. Mental depression f. Poor attitude 2. Oxygen supplementation: Not all dyspneic patients will respond to oxygen . 3. Thoracentesis 4. Tracheostomy

B. Circulatory Compromise Vitals to Monitor 1. Heart Rate 2. Mucous Membrane 3. Capillary Refill Time 4. Pulse Quality 5. Blood Pressure 6. Temperature 7. Level of Consciousness 8. Pupillary Response and Eye Position

Potential Actions 1. Assess Pain Control 2. Fluid Bolus i. Multiple smaller fluid challenges (10 -20ml/kg given over 15- 20min) ii. Assess response to fluid bolus before repeating. 3. Consider a pressor if no response to fluid bolus i. dopamine ii. dobutamine iii. norepinephrine iv. vasopressin 4. Assess Body Temperature i. If normal no action ii. If low consider warming patient. a. Can interfere with ability to get accurate blood pressure. iii. If high consider active cooling.

C. Neurologically Abnormal Vitals to Monitor 1. Level of Consciousness 2. Pupillary Response and Eye Position 3. Heart Rate 4. Blood Pressure 5. Temperature 6. Respiratory Rate and Effort

Potential Actions

321 1. Check blood glucose. 2. Treat as for respiratory or circulatory compromise

Special Considerations: A. Recumbent patients B. Head Trauma C. Heart Disease D. Pediatric patients E. Geriatric patients

322 Lecture: Evans Syndrome: A Technician’s Role Yvonne Brandenburg, RVT, VTS Internal Medicine - Small Animal RVT at SAGE Centers for Veterinary Emergency and Specialty Care Dublin, California, USA

Introduction As technicians, either in specialty practice or on the front lines in general practice, knowing how to recognize patients with hematologic disorders is important in preventing complications and improving long-term survivability of patients. Evans Syndrome is a rare autoimmune hematologic disorder that affects both red blood cells and platelets.

The goals of the lecture are to review: 1) define Evans Syndrome; 2) review basic hematologic cytology so able to recognize specific markers for Evans; 3) review patient care and client education; 4) discuss treatment options available; and 5) discuss the long term management and risk reduction for patients.

Review of Evans Syndrome Evans Syndrome is a rare autoimmune disease where both primary immune mediated hemolytic anemia (IMHA) and immune mediated thrombocytopenia (IMTP) are present. The disease was originally described by Robert Evans in 1951 when he monitored 24 human patients with IMHA and IMTP and how they reacted similarly to treatments including splenectomy (Norton & Roberts, 2005). Primary IMHA is defined by the antibody-mediated destruction of red blood cells and is characterized by a moderate to marked regenerative anemia, spherocytes, and auto-agglutination (Mitchell & Kruth, 2010). Typically, patients present with severe anemia (PCV’s of 13%-21%) that is most often regenerative, although this may not always be the case. Antibodies stick to the surface of the red blood cell and label the cells as ‘foreign intruders’ which activates the immune system to target and destroy them. This can be done either as extravascular hemolysis (more common) with macrophages breaking down the cells primarily in the spleen; or as intravascular hemolysis (less common) which happens when the red blood cells are broken down in the blood stream. Patients typically present pale, lethargic, depressed, weak, and anorexic. Primary IMTP is described as an autoimmune disorder with production of antibodies directed against normal platelet antigens (Brooks & Catalfamo, 2010). This can happen either at the level of the bone marrow with inadequate production or as platelet destruction once they are in circulation. Thrombocytopenia is described as platelet counts less than 200,000/mcL. Once a patient is < 50,000/mcL, abnormal hemostasis may occur and once <20,000/mcL spontaneous bleeding is common which can be seen in the oral cavity, nose, or urinary tract. It has been reported that 25%-75% of IMHA patients have concurrent thrombocytopenia at the time of diagnosis and are thought to have Evans (Mitchell & Kruth, 2010). Patients typically present with multiple petechiae and spontaneous bleeding such as epistaxsis.

April 2017 Back to Table of Contents 323 Evans Syndrome: A Technician’s Role Yvonne Brandenburg, RVT, VTS (SAIM)

It is important when diagnosing Evans to rule out underlying diseases. The typical diagnostic work up consists of: a full chemistry, CBC, vector-borne disease testing, thoracic radiographs, and an abdominal ultrasound. Performing a PT, PTT and D-Dimer (or TEG) is warranted in case DIC is also present or a cause of the anemia and thrombocytopenia. DIC should not have a positive Coombs anemia, spherocytes or platelet antibodies. A bone marrow biopsy and cytology can help with ruling out leukemia, multiple myeloma, lymphoma or other myeloproliferative disorders that can cause anemia and thrombocytopenia. Severe thrombocytopenia is not a contraindication for performing a bone marrow biopsy (Neel, Birkenheuer, & Grindem, 2014). Ensuring that the patient is stable for the procedure is indicated and a blood transfusion may be warranted if clinical signs associated with hypoxia are present. Published reports of prognosis of IMHA alone are 50%-88% that will survive to release from the clinical setting (Mitchell & Kruth, 2010). Of those patients that are released from the hospital, death or euthanasia from ongoing or complications typically occurs by 2 months (Mitchell & Kruth, 2010). Variables that have been seen to increase mortality include hyperbilirubinemia, auto-agglutination, increased band neutrophil counts, thrombocytopenia, and hypoalbuminemia (Mitchell & Kruth, 2010). At this time, there are no specific studies about the prognosis with Evans, but it is inferred that Evans has a 50%-70% survival to release, with similar variables for mortality. The most common complication and cause of death for IMHA and Evans is confirmed or suspected thromboembolic disease, including pulmonary thromboembolism (PTE) and disseminated intravascular coagulation (DIC) (Mitchell & Kruth, 2010). The systemic inflammatory response in the body from this disease promotes a hypercoagulable state and is the cause of significant morbidity and mortality (Mitchell & Kruth, 2010).

Review of Hematologic Cytology The CBC should be reviewed microscopically by a clinical pathologist. However, this is not readily available for most and a turnaround time of 12 to 24 hours is expected. Because of this, technicians should have the training and be able to review a blood smear slide to look for classic cytological changes. For IMHA, spherocytes are suggestive of red blood cell damage and destruction. Spherocytes are round in shape, smaller in diameter, and have decreased central pallor. They are formed when partial phagocytosis occurs of the cellular membrane and the red blood cell reseals itself and reenters circulation. Another important cell characteristic to look for is whether the anemia is regenerative or non-regenerative. Regeneration is suggested on the hemogram (cell volume, hemoglobin concentration) but cytologically anisocytosis (different RBC cell sizes), polychromasia (multiple colors), and increased nucleated red blood cells may be seen. Reticulocytes are released early from the bone marrow when stimulated by decreased oxygenation and can be identified by staining with new methylene blue (Mitchell & Kruth, 2010). Reticulocytes are more sensitive and specific indicators of regeneration. A nonregenerative anemia occurs when the bone marrow does not respond to stimulation and does not

March 2018 324 Evans Syndrome: A Technician’s Role Yvonne Brandenburg, RVT, VTS (SAIM)

produce or release young RBC’s to replenish the supply in the blood stream. It is also possible that the red cell destruction occurs within the bone marrow so no young red cells (reticulocytes) are produced and a non-regenerative anemia is seen. A saline agglutination test should also be performed to evaluate the presence of RBC auto-agglutination. One drop of whole EDTA blood and 1 drop of 0.9% saline is placed on a microscope slide. Once the sample is prepared it is important to review the slide both macroscopically and microscopically. If there is persistent agglutination, it is suggestive of antibody-mediated clumping of the cells. It is important to review microscopically to ensure that it is auto-agglutination and not rouleaux formation (Mitchell & Kruth, 2010). Cytological characteristics of IMTP are severe thrombocytopenia (< 50,000/mcL), normal to increased megakaryopoiesis, and microthrombocytosis. Performing manual platelet counts are important to monitor for response to immunotherapy. Typically, a blood smear is done and viewed under high power magnification in oil immersion. The platelet count can be estimated by counting platelets in 10 high power fields, adding together and dividing by 10, and then multiplying by 15,000-20,000. It is important to scan the feathered edge and the slide to look for platelet clumping as this will alter the actual platelet count. It is common for megakaryocytes to be present early once the body starts producing and releasing platelets, as these are young immature cells (Brooks & Catalfamo, 2010). Daily monitoring of PCV and cytology is common during treatment to evaluate response to treatment. This includes fresh blood smears looking at morphology of RBC’s and platelets. In the photo below an Evans patient’s blood smear was reviewed on day 5 after initial presentation (Brandenburg Y. R., 2016). Notice that spherocytes are still present. There is also moderate-severe anisocytosis, polychromasia and megakaryocytes present, all indicating that the bone marrow is responding appropriately and immunosuppressive therapy is starting to work, although not completely resolved.

March 2018 325 Evans Syndrome: A Technician’s Role Yvonne Brandenburg, RVT, VTS (SAIM)

Review Technician’s Role in Clinical Setting Initial triage can prevent serious complications with these patients. Recognition of pettechia or other suggestions of hemorrhage is critical to prevent obtaining blood samples from inappropriate vessels such as the jugular vein. If a technician suspects a bleeding disorder it is vital to minimize the amount of venipuncture performed on a patient and take samples form sites that are easier to apply pressure to minimize hemorrhage. Initial blood samples can be acquired through placing intravenous catheters to minimize the number of times a blood vessel is breached. Typically, the technicians are involved in performing the initial work-up for Evans patients. The technicians ensure that the patient is admitted into the patient care ward and completes the treatments recommended by the veterinarian of record. Once the veterinarian has given the preliminary diagnosis it is vital that a senior technician performs the patient care for these patients as there are significant risks associated with the disease. These patients are typically severely anemic when they arrive and the first 3-5 days in the hospital is when blood transfusions typically occur. There may be multiple transfusions needed as it can take up to 5 days for the immune system to be suppressed enough to allow for red blood cells (RBC’s) and platelets to be formed and not attacked. Increased platelets typically occur 2-5 days after starting immunosuppressive therapy (Brooks & Catalfamo, 2010). For RBC’s, once the bone marrow has been stimulated it takes 2-5 days for reticulocytes to be identified in circulation. Peak numbers occur 4-7 days after stimulation (Mitchell & Kruth, 2010). Blood transfusion are indicated for patients with PCV’s of <15% as oxygen transport is severely impaired at that point and can lead to hypoxia to the body’s tissues. Blood typing and cross matching the patient to the donor prior to starting a transfusion is often performed by technicians. Blood typing is often done with cards or kits but cross matching is often performed manually with repeated cell washes. Alternatively, kits are available. Once a compatible blood product is found, technicians administer the blood product, typically packed red blood cells, and monitor closely for any potential transfusion reactions. These reactions can be broken down into four categories: immunologic or non-immunologic; and acute or delayed (Garcia & South- Bodiford, 2012). While the patient is hospitalized it is important to ensure that the patient is comfortable and stable. Supportive care with fluid therapy is recommended to maximize tissue perfusion and minimize kidney damage associated with hemoglobin excretion and systemic inflammation (Garcia & South-Bodiford, 2012). Jugular venipuncture, central catheters, cystocentesis are all contraindicated in these patients due to the inability to clot. Gentle handling and wet food is also indicated. Careful venipuncture of a peripheral vein with small gauge needles is recommended with low platelet counts. Applying a pressure wrap is recommended for 30-60 minutes with careful monitoring of the site once the wrap is removed to ensure the patient does not continue to bleed from the venipuncture site. These patients are immune compromised and should be handled with gloves to prevent the acquisition of a nosocomial infection. A dedicated patient care technician should be assigned

March 2018 326 Evans Syndrome: A Technician’s Role Yvonne Brandenburg, RVT, VTS (SAIM) to these patients, and these technicians should not handle any potentially infectious patients to help minimize the risk. Close monitoring for pulmonary thromboembolism (PTE) is important both in the hospital and once the patient is released. Due to the severe inflammatory response associated with the disease as well as the hypercoagulable state associated with glucocorticoids, microembolism is common complication and a cause of death in these patients (Mitchell & Kruth, 2010). Close monitoring of respiratory effort and function is crucial to early recognition of PTE. Collecting blood for a D-Dimer or TEG tracing can help support the diagnosis of a thrombus as it represents the breakdown of a clot (Nakamura, Tompkins, & Bianco, 2012).

Treatment Options Available to Patients During the acute phase, transfusion therapy is warranted depending on the severity of the anemia. As red blood cells carry oxygen, low red blood cell count will result in decreased oxygen delivery to the tissues, or hypoxemia. Oxygen therapy does not address the primary problem as the red blood cells are already saturated with oxygen. To treat hypoxemia associated with anemia, packed red blood cells are given to increase the number of red blood cells available to carry oxygen. Arterial blood gas analysis (paO2) is preferred to determine hypoxemia rather than SpO2 monitors. paO2 measures oxygen delivery to the tissues whereas SpO2 measures red blood cell oxygen saturation. Clinical signs of hypoxemia include increased heart rate, increased respiratory rate, lethargy and pale or muddy mucous membranes. Prior to any transfusion, blood typing and a cross match is recommended to minimize transfusion reactions. Auto-agglutination can make interpretation of cross matches difficult. Immunosuppressive therapy is the cornerstone of treatment for Evans (Mitchell & Kruth, 2010). The first line of drug therapy is the use of glucocorticoids such as or prednisone orally or dexamethasone SP injections if the patient is not tolerating oral medications. Glucocorticoids at immunosuppressive doses are the foundation of treatment therapy for Evans patients (Mitchell & Kruth, 2010). The standard starting dose of prednisone is 1 to 2 mg/kg q12h in dogs, with some internists limiting the dose for larger dogs to decrease the amount of side effects seen (Johnson & Dow, 2014). Monitoring PCV and platelet counts determines when it is appropriate to taper the prednisone. This is typically done slowly to prevent a relapse as long as the patient is tolerating the glucocorticoids. Human intravenous immunoglobulin (IVIg) and plasmapheresis can also be used in these patients. Human IVIg has been shown to decrease the platelet recovery time therefore decreasing the amount of time spent in hospital (Nakamura, Tompkins, & Bianco, 2012). IVIg has not been shown to be beneficial in cases of IMHA alone (Nakamura, Tompkins, & Bianco, 2012). IVIg can be cost prohibitive for some clients. Plasmapheresis has been shown to help with IMHA but not necessarily in IMTP (Nakamura, Tompkins, & Bianco, 2012). Vincristine has been shown to stimulate thrombopoiesis in healthy dogs (Nakamura, Tompkins, & Bianco, 2012). There have been some concerns raised about the function of these

March 2018 327 Evans Syndrome: A Technician’s Role Yvonne Brandenburg, RVT, VTS (SAIM)

early released platelets. There are contradictory studies regarding platelet function. However, it was speculated that platelet function in patients with IMTP that had >40,000 platelets per mcL did not show signs of active hemorrhage, indicating that vincristine may help (Nakamura, Tompkins, & Bianco, 2012). Secondary immunosuppressive drugs are recommended for patients with Evans to help facilitate the tapering of the glucocorticoids. Azathioprine was the standard for treating IMHA, IMTP and Evans for years. The initial dose recommended is 2 mg/kg PO q24h. Azathioprine has fallen out of favor due to its bone marrow suppression effects as well as the potential for acute liver toxicity (Mitchell & Kruth, 2010). Careful monitoring of liver chemistries is recommended in addition to CBC’s. Per Plumb (Plumb, 2011) the starting dose is 2 mg/kg PO q 24h; with long term therapy being 0.5-1 mg/kg PO every other day. A common drug to use is cyclosporine modified. Cyclosporine is a ‘potent immunosuppressive drug indicated for the treatment of inflammatory and immune-mediated diseases, and for organ transplantation’ (Mackin, 2016). The dose is 5-10 mg/kg PO q12h-q24h. Variability in absorption has been reported between formulations and using the brand Neoral™ (human formula) or Atopica™ (veterinary formula) verses generic forms have been shown to have better bioavailability and control of disease (Mackin, 2016). Monitoring drug trough plasma concentrations at 2-4 weeks to maintain the concentrations between 100-300 mg/mL is recommended (Mitchell & Kruth, 2010). More recently, assays of lymphocyte activity are available for cyclosporine and thought to be a better biologic indicator of disease control than blood levels. The test is now available at Mississippi State University (Pharmacology Laboratory, 2014). Mycophenolate mofetil has been used in humans for patients receiving organ transplants. This is an option for treating veterinary patients, but there is very limited data regarding efficacy. Reports suggest that the dose required may be toxic to the gastrointestinal system and caution should be used with this drug (Pharmacology Laboratory, 2014). The current recommended dose of mycophenolate is 12-17mg/kg PO per day; once or divided in two doses (Plumb, 2011). Prophylactic anticoagulant therapy to prevent PTE is typically done by platelet inhibitory drugs such as low-dose aspirin at 5 mg/kg PO q24h, or clopidogrel at 10 mg/kg loading dose, with 2 mg/kg PO q24h afterwards (Johnson & Dow, 2014). A limited case series was done with melatonin used in association with IMTP (Nakamura, Tompkins, & Bianco, 2012). It is thought to ‘stimulate platelet generation, probably by promoting megakayocyte fragmentation’ (Nakamura, Tompkins, & Bianco, 2012). The dose per Plumb (Plumb, 2011) for dogs under 20 kg is 3 mg PO BID, and >20 kg dogs at 6 mg PO BID. Some reports have a dose up to 20 mg PO daily (Nakamura, Tompkins, & Bianco, 2012). Splenectomy can also be a treatment option for these patients. This is indicated when the first-line therapy has failed and is thought to be due to removing the primary organ response for destruction of anti-body sensitized platelets and red blood cells (Nakamura, Tompkins, & Bianco, 2012).

March 2018 328 Evans Syndrome: A Technician’s Role Yvonne Brandenburg, RVT, VTS (SAIM)

Review of Technician’s Role in Client Education One of the biggest responsibilities of the technician is to work with the client to ensure that they fully understand medication dosing instructions, as well as side effects they should be aware of. Compliance with following medication recommendations is crucial to minimize relapse and potentially life-threatening conditions. Explaining what they should expect from their pets as they transition from the hospital to home can help alleviate unnecessary frustrations. Patients typically are released with immunosuppressive doses of glucocorticoids and other immunosuppressants that are associated with side effects, so setting up realistic expectations regarding adverse reactions is important. Explaining to clients the significant clinical changes such as polyuric (PU), polydypsic (PD), and polyphagic (PD) that are common with glucocorticoids and that they can be quite extreme. Warning clients that the pet will typically need to urinate every 1-2 hours even overnight is indicated. Clients should also be aware of potential behavioral changes associated with steroids including aggression, food scavenging, and begging. Ensuring that food items are out of reach of pets is important, including garbage cans to prevent food related gastrointestinal upset. Muscle wasting is also something that clients should be made aware of. This can be very dramatic especially on the temporalis muscle and the spine. Explaining that this is temporary until glucocorticoid doses are reduced can also alleviate client concerns. Larger dogs can have more pronounced muscle wasting and can have issues with lameness due to muscle loss. These muscle wasting side effects, increased susceptibility to infection, susceptibility to clot formation and insulin resistance are reasons why glucocorticoid therapy is minimized and alternative immunosuppressants used. Clients should be informed that wet food is recommended during the initial phase until platelet numbers are above 80-100 k/mcL. It is also recommended that the pet not be allowed to chew on toys, bones or other objects that can exacerbate gingival bleeding. Patients should also have restrictions of no running, or strenuous activity to help prevent undue pettechia and/or hemorrhage. These patients need close CBC monitoring every 1-2 weeks to ensure that they are not relapsing during the tapering of drug therapy to the lowest effective dose (Mitchell & Kruth, 2010). After release from the clinical setting, chemistries are monitored a minimum of every 6 months, or more frequently if the patient had abnormalities while in hospital. The goal is to wean patients off of the steroids as safely and quickly as possible to minimize the adverse side effects. Evans Syndrome patients have a higher risk of relapse and are more likely to require lifelong immunosuppressive drugs so multimodal drug therapy is typically done. Educating clients on how to recognize a thromboembolic event specifically PTE is key to catching an event early and potentially treating if possible. Anticoagulant therapy can be initiated once platelet numbers are significant enough to not cause spontaneous bleeding. See treatment options for more information. The doctor and technicians should also explain that a pet’s immune system is suppressed and they are more susceptible to infectious diseases. Clients and dogs should avoid dog parks,

March 2018 329 Evans Syndrome: A Technician’s Role Yvonne Brandenburg, RVT, VTS (SAIM)

grooming centers, and other places with high animal traffic. Limiting other dogs from contacting their pet is appropriate too, especially young animals whose vaccine status is unknown. The final aspect to discuss is the financial implications of this disease. With weekly rechecks, lab work, and the drug therapies associated with maintaining these patients the financial commitment can be a limiting factor for clients. Pet insurance is helping to bridge the financial gap for owners fortunate to have insurance prior to diagnosis, but once a pet is diagnosed insurance will not cover this disease. Help clients to know that they are not alone. The emotional roller-coaster that clients feel is understandable and normal. Being an advocate for both the pet and the client can build a lasting partnership for the patient’s health. There are few resources for clients specifically about Evans but owners can try Facebook or other support pages. (Immune Medicated Hemolytic Anemia in Dogs (IMHA), 2017) (Immune-Mediated Thrombocytopenia (IMT)~Canine Immune Disorders~Blood Clots, 2017)

Technician’s Role in Long Term Case Management and Risk Reduction Client communication and follow up is crucial to long term survivability of patient with Evans syndrome. Facilitating follow up appointments and checking in with clients to ensure that they do not have questions can reduce the chance of non-compliance. Answering client’s questions as they come up and letting them know that they should feel comfortable asking these questions, can prevent a major relapse, or worse, other potential life-threatening complications. Reminder calls for rechecks and recommended lab work, can be beneficial for clients struggling with compliance. Maintenance of these patients involves slow, gradual tapering of immunosuppressive therapy, with minimal exposure to unnecessary drugs, vaccination, or stress conditions to avoid relapse (Brooks & Catalfamo, 2010). Clients should always check with their veterinarian before changing medications or adding over the counter medications as some of these can interact with prescribed medications. Flea and tick prevention is warranted to prevent infectious agents as these patients are immune suppressed. Vaccinations are not recommended because of the inability of the animal to mount an effective response to the vaccine.

Conclusion Evans Syndrome is a combination of both immune-mediated hemolytic anemia and immune-mediated thrombocytopenia. Veterinary technicians play a crucial role in performing diagnostics including basic hematologic cytology, patient treatment, and performing client education which facilitates successful outcomes of this life-threatening disease.

March 2018 330 Evans Syndrome: A Technician’s Role Yvonne Brandenburg, RVT, VTS (SAIM)

References Bistner, S. I., Ford, R. B., & Raffe, M. R. (2000). Kirk and Bistner's Handbook of Veterinary Procedures and Emergency Treatment (7th ed.). Philidelphia, Pennsylvania: W. B. Saunders Company.

Brandenburg, Y. (2017). Evans Syndrome: A Technician's Role. ACVIM. National Harbor: American College of Veterinary Internal Medicine.

Brandenburg, Y. R. (2016). Microscope View of Spherocytes. Livermore, California.

Brooks, M. B., & Catalfamo, J. L. (2010). Chapter 189 Immune-Mediated Thrombocytopenia, von Willebrand Disease, and Platelet Disorders. In S. J. Ettinger, Textbook of Veterinary Internal Medicine Disease of the Dog and the Cat (7th ed., Vol. 1, pp. 772-783). St. Louis, Missouri: Sounders Elsevier.

Garcia, J., & South-Bodiford, R. (2012). Chapter 7 Hematology. In L. Merrill, Small Animal Internal Medicne for Veterinary Technicians and Nurses (pp. 161-192). Danvers, Massechusetts: Blackwell Publishing.

Immune Mediated Hemolytic Anemia in Dogs IMHA. (2017). Retrieved February 14, 2017, from Facebook: https://www.facebook.com/groups/6228146980/

Immune Medicated Hemolytic Anemia in Dogs (IMHA). (2017, 12 6). Retrieved from Facebook: https://www.facebook.com/groups/6228146980

Immune-Mediated Thrombocytopenia (IMT)~Canine Immune Disorders~Blood Clots. (2017, 12 6). Retrieved from Facebook: https://www.facebook.com/groups/ImmMediatedThrombocytopeniaCanineImmuneDisorders/

Johnson, V., & Dow, S. (2014). Chapter 60 Management of Immune-Mediated Hemolytic Anemia in Dogs. In J. D. Bongura, & D. C. Twedt, Kirk's Currenty Veterinary Therapy (XV ed., pp. 275-279). St. Louis, Missouri: Elsevier.

Mackin, A. (2016). Immunosuppressie Therapy in Dogs and Cats: Recent Drug Development. 2016 ACVIM Forum (pp. 1113-1117). Denver: American College of Veterinary Internal Medicine.

Mitchell, K., & Kruth, S. (2010). Chapter 188 Immune-Mediated Hemolytic Anemia and Other Regenerative Anemias. In S. J. Ettinger, Textbook of Veteirnary Internal Medicine Diseases of the Dog and the Ca (7th ed., Vol. 1, pp. 761-772). St. Louis, Missouri: Saunders Elsevier.

Nakamura, R. K., Tompkins, E., & Bianco, D. (2012, January 25). Therapeutic Options For Immune- Mediated Thrombocytopenia. Journal of Veterinary Emergency and Critical Care, 22(1), 59-72. doi:10.1111/j.1476-4431.2011.00705.x

Neel, J. A., Birkenheuer, A. J., & Grindem, C. B. (2014). Chapter 61 Thrombocytopenia. In J. D. Bonagura, & D. C. Twedt, Kirk's Current Veterinary Therapy (Vol. XV, pp. 280-286). St. Louis, Missouri: Elsevier.

March 2018 331 Evans Syndrome: A Technician’s Role Yvonne Brandenburg, RVT, VTS (SAIM)

Norton, A., & Roberts, I. (2005). Management of Evans Syndrome. British Journal of Haematology, 125- 137. doi:10.1111/j.1365-2141.2005.05809.x

Pharmacology Laboratory. (2014). Retrieved from Mississippi State University College of Veterinary Medicine: http://www.cvm.msstate.edu/animal-health-center/pharmacodynamic-laboratory

Plumb, D. (2011). Plumb's Veterinary Drug Handbook (7th ed.). Stockholm, Wisconsin: Wiley-Blackwell.

Thomason, J. D., & Calvert, C. A. (2012). Chapter 5 Thrombotic Disorders in Small Animal Medicine. In L. Merrill, Small Animal Internal Medicne for Veterinary Technicians and Nurses (pp. 127-135). Danvers, Massechusetts: Blackwell Publishing.

West, L. D., & Hart, J. R. (2014). Treatment of Idiopathic Immune-Mediated Hemolytic Anemia with Mycophenolate Mofetil in Five Dogs. Journal of Veterinary Emergency and Critical Care, 24(2), 226-231. doi:10.1111/vec.12121

Speaker Information

Yvonne Brandenburg, RVT, VTS Internal Medicine Small Animal

[email protected]

SAGE Centers for Veterinary Specialty and Emergency Care, Dublin, California, USA

This article was previously published in the ACVIM 2017 proceedings under the title “Evans Syndrome: A Technician’s Role” (Brandenburg Y. , 2017).

March 2018 332 Managing canine inappetence and an introduction to Entyce (capromorelin)

Liz Hughston, RVT, VTS Stephen Cital RVT, VTS

• Inappetance affects upwards of 10 million dogs a year, about 4 million are treated • There are MANY reasons why an animal may be inappetant, some examples include: o Chronic reasons: CKD, CHF, cancer, IBD, aging, etc . CKD: Inappetance has been found to be predictive of CKD in dogs and noted in about 40% of dogs after diagnosis . CHF: survival is significantly associated with body weight changes in canine CHF o Acute reasons: infectious disease, vestibular syndrome, change to Rx diet, boarding, etc • All medicines that have been historically used as appetite stimulants have 2 things in common: o They are being used off-label o They weren’t designed to be used as appetite stimulants o Examples . Cerenia: anti-emetic . Mirtazapine: anti-depressant . Cyproheptadine: antihistamine • Appetite is driven in large part by the hormone ghrelin o Produced by the cells in the stomach in a fasted state o Stimulates appetite via orexigenic neurons in the hypothalamus o Stimulates growth hormone (GH) release from the pituitary gland which subsequently leads to insulin-like growth factor 1 (IGF-1) release from the liver. IGF-1 negatively feeds back to prevent uncontrolled GH release . Downstream effects of GH and IGF-1 release include increased muscle mass and overall body weight o Ghrelin is a prokinetic in the GI tract • Entyce is the first FDA approved appetite stimulant in veterinary medicine currently labelled for use in canines o The active compound, capromorelin, is a ghrelin receptor agonist o It is on-label to use Entyce in any condition that leads to inappetence o There is no restriction on duration of use. It may be used acutely or indefinitely depending on the disease state o There is no minimum weight or age (i.e. parvoviral enteritis) o It has not been evaluated in pregnant or lactating dogs • 4 studies summarize the safety and efficacy of Entyce in dogs o 12 month safety study: a single daily dose was administered to dogs up to 17.5x the eventual label dose for an entire year. Emesis, loose stool and hypersalivation were the most common side effects noted among all groups. Overall: capromorelin was well- tolerated in all groups . Note: capromorelin did not accumulate in any of the dogs despite the extra- label dosing o 7 day laboratory study: determined that 3mg/kg PO SID was determined to be the lowest effective dose. . GH levels were found to be lower on day 7 of dosing compared to day 1. This is because with consecutive daily dosing of Entyce, IGF-1 levels steadily rose

Back to Table of Contents 333 increasing the negative inhibition on GH release from the pituitary gland. This intact negative feedback loop prevents uncontrolled GH release o 4-day laboratory effectiveness study: demonstrated that dogs fed Entyce in a laboratory setting ate an average of 61% more food over the study period compared to placebo o Clinical field study: 244 client owned dogs with various conditions (acute & chronic) treated for 4 days @ 3mg/kg PO SID. . By owner assessment, 68.6% of dogs had an improved appetite after 4 days of treatment . Owners also noted statistically significant improvement in behaviors associated with mealtime such as willingness to eat, anticipating mealtime, hunger/begging behavior, etc . Capromorelin treated dogs also had an increase in body weight at the end of the study period . Dogs with CKD were included in this study and were found to have stable renal values after treatment while receiving the label dose of 3mg/kg PO SID (they did not receive a dose reduction) • Label explanations o Although the efficacy study was performed over 4 days, because of the safety work demonstrating tolerance to extra-label doses for a year, the Entyce label is open for duration of treatment. It is NOT a 4-day restriction o Like any drug that is metabolized by the liver and at least partially eliminated by the kidneys, the label for Entyce says use with caution in hepatic and renal insufficiency. It is not a contraindication to use Entyce in animals with those conditions where it could be very helpdul. For example, Mirtazapine has identical precautionary label language

References: Slupe, J.L., Freeman, L.M., Rush, J.E. Association of body weight and body condition with survival in dogs with heart failure. J Vet Intern Med 2008; 22:561-565

O'Neill, D.G., Elliott, J., Church, D.B., McGreevy, P.D., Thomson, P.C. and Brodbelt, D.C. (2013), Chronic Kidney Disease in Dogs in UK Veterinary Practices: Prevalence, Risk Factors, and Survival. J Vet Intern Med, 27: 814–821. doi:10.1111/jvim.12090

P . C. Bartlett, J. W. Van Buren, M. Neterer, and C. Zhou, “Disease surveillance and referral bias in the veterinary medical database,” Preventive Veterinary Medicine, vol. 94, no. 3-4, pp. 264–271, 2010

Zollers, B., Huebner, M., Armintrout, G., Rausch-Derra, L. C., Rhodes, L. Evaluation of the safety in dogs of long-term, daily oral administration of capromorelin (ENTYCE®), a novel drug for stimulation of appetite. J Vet Pharmacol Ther. 2016 Sep 25. doi: 10.1111/jvp.12358.

Zollers B, Rhodes L, Smith RG. Capromorelin increases food consumption, body weight, growth hormone and sustained insulin-like growth factor 1 concentrations when administered to healthy adult Beagle dogs. J Vet Pharmacol Ther. 2016 Sep 5. doi: 10.1111/jvp.12344

Zollers B, Rhodes L, Heinen E. Capromorelin oral solution (ENTYCE®) increases food consumption and body weight when administered for 4 consecutive days to healthy adult Beagle dogs in a randomized,

334 masked, placebo controlled study. BMC Veterinary Research. 2017 13:10 doi 10.1186/s12917-016-0925- z

335 336 Special Note Regarding Forward-Looking Statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this presentation that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements with respect to our ability to bring innovative products to the market; study, development and commercialization of NOCITA or our other approved therapeutics or therapeutic candidates, including potential expansion of the label for existing therapeutics; and statements regarding the Company's plans and opportunities, including, without limitation, offering innovative therapeutics that help manage pet’s medical needs safely and effectively and that result in longer and improved quality of life for pets.

These forward-looking statements are based on management's current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: our history of operating losses and our expectation that we will continue to incur losses for the foreseeable future; failure to obtain sufficient capital to fund our operations; risks relating to the impairment of intangible assets, including BLONTRESS, TACTRESS, AT-007 and AT-011; risks pertaining to stockholder class action lawsuits; unstable market and economic conditions; restrictions on our financial flexibility due to the terms of our credit facility; our substantial dependence upon the commercial success of our therapeutics; development of our biologic therapeutic candidates is dependent upon relatively novel technologies and uncertain regulatory pathways, and biologics may not be commercially viable; denial or delay of regulatory approval for our existing or future therapeutic candidates; failure of our therapeutic candidates that receive regulatory approval to obtain market approval or achieve commercial success; product liability lawsuits that could cause us to incur substantial liabilities and limit commercialization of current and future therapeutics; failure to realize anticipated benefits of our acquisitions and difficulties associated with integrating the acquired businesses; development of pet therapeutics is a lengthy and expensive process with an uncertain outcome; competition in the pet therapeutics market, including from generic alternatives to our therapeutic candidates, and failure to compete effectively; failure to identify, license or acquire, develop and commercialize additional therapeutic candidates; failure to attract and retain senior management and key scientific personnel; our reliance on third-party manufacturers, suppliers and partners; regulatory restrictions on the marketing of our therapeutic candidates; our small commercial sales organization, and any failure to create a sales force or collaborate with third-parties to commercialize our therapeutic candidates; difficulties in managing the growth of our company; significant costs of being a public company; risks related to the restatement of our financial statements for the year ended December 31, 2013, and the identification of a material weakness in our internal control over financial reporting; changes in distribution channels for pet therapeutics; consolidation of our veterinarian customers; limitations on our ability to use our net operating loss carryforwards; impacts of generic products; safety or efficacy concerns with respect to our therapeutic candidates; effects of system failures or security breaches; delay or termination of the development of grapiprant therapeutic candidates and commercialization of grapiprant products that may arise from termination of or failure to perform under the collaboration agreement and/or the co-promotion agreement with Elanco; failure to obtain ownership of issued patents covering our therapeutic candidates or failure to prosecute or enforce licensed patents; failure to comply with our obligations under our license agreements; effects of patent or other intellectual property lawsuits; failure to protect our intellectual property; changing patent laws and regulations; non-compliance with any legal or regulatory requirements; litigation resulting from the misuse of our confidential information; the uncertainty of the regulatory approval process and the costs associated with government regulation of our therapeutic candidates; failure to obtain regulatory approvals in foreign jurisdictions; effects of legislative or regulatory reform with respect to pet therapeutics; the volatility of the price of our common stock; our status as an emerging growth company, which could make our common stock less attractive to investors; dilution of our common stock as a result of future financings; the influence of certain significant stockholders over our business; and provisions in our charter documents and under Delaware law could delay or prevent a change in control. These and other important factors discussed under the caption "Risk Factors" in the Company's Annual Report on Form 10-K filed with the Securities and Exchange Commission, or SEC, on March 14, 2017, along with our other reports filed with the SEC could cause actual results to differ materially from those indicated by the forward-looking statements made in this presentation. Any such forward-looking statements represent management's estimates as of the date of this presentation. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change, except as required under applicable law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this presentation.

Created June 19, 2017 as part of an oral presentation and the speaker and/or Aratana disclaims any duty to update.

337 A New Beginning in CCL Post-Operative Pain NOCITA® (bupivacaine liposome injectable suspension) Stephen Cital RVT, SRA, RLAT, VTS-LAM

338 Disclosures

Paid consultant • Aratana Therapeutics, Inc

Created June 19, 2017 as part of an oral presentation and the speaker and/or Aratana disclaims any duty to update.

339 The Perception of Pain

Pg 11 &16 Created June 19, 2017 as part of an oral presentation and the speaker and/or Aratana disclaims any duty to update.

340 Types of Pain

• Acute pain • Chronic pain • Neuropathic pain • Neuroplasticity

1Epstein ME, Rodanm I, Griffenhagen G, et al. 2015 AAHA/AAFP pain management guidelines for dogs and cats. J Feline Med Surg. 2015;17(3):251-272. Created June 19, 2017 as part of an oral presentation and the speaker and/or Aratana disclaims any duty to update.

341 Post-Operative Pain

• All surgical procedures result in some degree of tissue trauma and associated pain1 • There are 3 main reasons to minimize acute, post-surgical pain: • Ethical obligation to minimize pain and suffering • Pain delays healing and return to function • Unmanaged, acute pain can lead to chronic, maladaptive pain • Most patients are discharged from the hospital within 24-48 hours after surgery

342 Local Anesthetics

• Local anesthetics (LAs) are one of the most effective means of preventing transduction and transmission of pain signals

Created June 19, 2017 as part of an oral presentation and the speaker and/or Aratana disclaims any duty to update.

343 Why are local anesthetics underused?

• Time to administer • Fears about effects on wounds • Lack of technical descriptions • Relatively short duration of action

Created June 19, 2017 as part of an oral presentation and the speaker and/or Aratana disclaims any duty to update.

344 A New Beginning in Post-Operative Pain

A long-acting local anesthetic formulation of bupivacaine for single-dose infiltration into the surgical site to provide local postoperative analgesia for cranial cruciate ligament surgery in dogs. • Bupivacaine in a liposome injectable suspension that releases over time • Long-acting analgesia lasts up to 72 hours post-surgery • Single dose administered by infiltration injection into the tissues of a CCL surgical site during closure

Created June 19, 2017 as part of an oral presentation and the speaker and/or Aratana disclaims any duty to update.

345 Bupivacaine Liposome Injectable Suspension

• Sterile, non-pyrogenic, preservative-free aqueous suspension of multivesicular liposomes containing bupivacaine • Bupivacaine is released over time

Created June 19, 2017 as part of an oral presentation and the speaker and/or Aratana disclaims any duty to update.

346 Infiltration Injection Technique

Created June 19, 2017 as part of an oral presentation and the speaker and/or Aratana disclaims any duty to update.

347 NOCITA (bupivacaine liposome injectable suspension)

• Labeled for use in CCL surgery in dogs • 5.3 mg/kg administered by infiltration injection at surgical closure - Moving needle technique • Duration of action up to 72 hours

Created June 19, 2017 as part of an oral presentation and the speaker and/or Aratana disclaims any duty to update.

348 Case Examples

Left Image Date: 2/2017 Location: United Veterinary Specialty and Emergency

Right Image Date: 3/2017 Location: United Veterinary Specialty and Emergency

Created June 19, 2017 as part of an oral presentation and the speaker and/or Aratana disclaims any duty to update.

349 Case Examples

Date: 3/2017 Location: United Veterinary Specialty and Emergency

Created June 19, 2017 as part of an oral presentation and the speaker and/or Aratana disclaims any duty to update.

350 Case Examples

Date: 1/2017 Location: United Veterinary Specialty and Emergency

Created June 19, 2017 as part of an oral presentation and the speaker and/or Aratana disclaims any duty to update.

351 But what about how my practice prices NOCITA?

Created June 19, 2017 as part of an oral presentation and the speaker and/or Aratana disclaims any duty to update.

352 But what about how my practice prices NOCITA?

Created June 19, 2017 as part of an oral presentation and the speaker and/or Aratana disclaims any duty to update.

353 Questions? Gracias!

354 355 356 Dermatology Tools: Joining forces with the Microscope

Stacey N. Holz, DVM

Dermatology

SAGE Centers - Dublin

Dermatology Diagnostics

Virtually all patients presenting with dermatological problems such as pruritus, skin lesions, and/or ear issues should have a dermatology minimum data base with a good history, dermatological exam, as well as cytology and usually skin scrapings. The following outlines the tools and methods needed for this data base.

History taking tips for technicians

The key to a good history is knowing the right questions to ask. For example: If asking a pet owner about flea control for their dog, do not simply ask “Do you use flea control?” and end with a yes or no answer. Instead ask more detailed and more insightful questions such as “What flea control product do you use ? When did you last use this for your pet? How often do you usually use this? Do the other pets in the household receive flea control?” Using a more detailed and insightful approach will help reveal key information to aid the patient.

The Microscope

The Microscope is the most important piece of diagnostic equipment we use in dermatology. Using the microscope regularly will help you raise your level of medicine to a higher standard. Become well acquainted with your microscope. Make sure it is clean, in working order, and has a dust cover on it when not in use (a plastic bag or pillow case will do in a pinch).

To look at skin and ear cytologies: Turn the light up - “brighter is better”- (this is usually on the right hand side) Open the aperture (this is below the stage) Look at by focusing on lower powers and then on 100x with immersion oil Do not drag the 40 through the oil Always clean the oil off of the objective after use with lens paper and lens cleaner To look at skin scrapings: Turn the light down (this is usually on the right hand side of the scope) Close the aperture (this is below the stage) Look at on 10x (possibly 4x if you have “special eyes”). Always use a cover slip on the slide over the messy mineral oil. This not only gives you a “frame of reference” but is cleaner.

Ba ck to Table of Contents 357 Stains A clean set of glass staining jars (3 jars) and 3 stains including the #1 fixative, #2 red, and #3 purple Dif Quik are essential. Most stains needs to be changed weekly in a busy practice and the jars cleaned. These steps improve staining and the sample that you ultimately look at.

Diagnostic Methods

Cytology is used most commonly to look for bacteria, Malassezia, or study the inflammatory cell components of affected skin.

• Skin Cytology using Sticky Tape - clear sticky tape is used to press the skin and thus obtain a cytology sample of the superficial skin. Simply press the tape sticky side on to the area you wish to obtain a sample from. This can work quite well in “hard to reach places” such as nail beds, around eyes, in between the toes of a biting Chihuahua! This is then stained in the #2 (red) and #3 (purple) stain of the Dif Quik stains and placed on a microscope slide sticky side down on the slide. This does not need to be fixed in step #1 as the stickiness has already fixed the sample and placing in step #1 will make tape cloudy.

• Skin Cytology via Impression with Slide - a glass microscope slide is used to obtain a cytology sample by holding the slide edges between you thumb and middle finger with your index finger on the back of the slide behind the area you wish to obtain a sample from (you can wear gloves of course) and applying the same amount of pressure you would to obtain a “finger print”. This works very well for obtaining a clear direct impression of skin lesions. The sample/slide can be lightly heat fixed using a lighter. Some clinicians do not heat fix at all. The slide is stained in the 3 step Diff Quik stains for an adequate amount of time in each step (at least 30 seconds to 1 minute).

• Ear Cytology - gently obtain a swab sample from the external ear canal and roll (or write/ roll “L” and “R” or a box onto the microscope slide.

Skin scrapings and Trichograms Deep skin scrapings are often used to look for the hair follicle mites Demodex and Superficial skin scrapings are often used to look for non hair follicle mites such as Sarcoptes, etc. Try to free the area of hair as much as possible, i.e. ask the owners to clip the area if performing a deep skin scraping. For the superficial skin scrapings removing the hair is often not warranted.

• Deep "Skin Scraping" Tape method: the area of affected skin is “squeezed” with the index finger and thumb of one hand and then the tape is pressed onto the area with the other hand. The piece of tape/sample is then placed on a microscope slide that has mineral oil on it. Now it has a “cover slip” and you can look at this on lower power (i.e usually 10x). Some previous studies have shown this to procure as many and sometimes more demodex mites than the scalpel method.

• Deep Skin Scraping Scalpel method: a new 10 blade is used (the blade can easily be “dulled” by scraping in on the inside of the blade wrapper it came in with the wrapper on the table away from your other hand or by scraping on a piece of sand paper briefly). Squeeze the skin with your non-dominant hand, apply some mineral oil, and with the other hand use the new but dull blade to gently scrape the skin in a sweeping motion to collect the sample as

358 you scrape. Be careful not to scrape too hard or go in the wrong direction. Place the sample on a slide with mineral oil and place a cover slip over the sample to examine on lower power (usually 10x).

• Deep Skin Scraping Spatula method: A medical stainless steel spatula is used with mineral oil to scrape the affected skin and collect sample. This is often used for smaller animals such as rabbits, guinea pigs, and other pocket pets or pets with thinner skin. Don’t forget to squeeze the skin.

• Superficial scrapings to look for superficial mites such as Sarcoptes or Cheyletiella can be performed a variety of ways. Spatula or scalpel blade: can be used and scrape gently and very superficially almost like combing. You can also use the clear tape to collect superficial samples or a flea comb to collect fine scale or dander. These samples are looked at on lower power (i.e. usually 10x)

• Trichograms can be used to look for demodex mites, observe hair stage such as Telogen (spear) versus Anagen (club), or examine hair for abnormalities such as Melanin clumping. The hair is plucked using a mosquito forceps and placed in the mineral oil that has been placed on a microscope slide and looked at on lower power (10x).

359 CLANDESTINE ORAL PATHOLOGY MISSED ON EXAMINATION BUT CAPTURED WITH INTRAORAL DENTAL RADIOGRAPHY

Sage Symposium 2018 Kevin S. Stepaniuk, B.Sc., DVM, FAVD Diplomate, American Veterinary Dental College

Veterinary Dental Education Consulting Services, LLC www.veterinarydentisryeducation.com [email protected] Columbia River Veterinary Specialists

Back to Table of Contents 360 However, most dentistry patients are older and more extensive bloodwork such CBC / Chemistry Panel / Urinalysis are necessary and recommended for anesthetic planning.

MISCELLANEOUS DENTAL AND ORAL PATHOLOGY

Hidden probing depths - dog mandibular 1st molars and mesial roots maxillary 4th premolars

361 Large periodontal probing depths may be identified mesial or distal to the mandibular 1st molars in dogs with minimally associated gingival inflammation. Intraoral radiographs will identify large intrabony pockets. Treatment may include extraction of the adjacent non-strategic 4th premolar or 2nd molar. If these teeth are associated with the intrabony pocket of the 1st molar, then open root planning and bone augmentation or guided tissue regeneration are often necessary. If the mandibular molar cannot be saved, then surgical extraction or hemi-section with root canal treatment is recommended.

Feline sublingual squamous cell carcinoma

362 Cats will present late in the disease course for partial or complete anorexia, ptyalism, and oral pain. Biopsy and histopathology are necessary for diagnosis because differentials that may appear clinically similar include treatable lesions such as eosinophilic granuloma or a granuloma/infection associated with a sublingual foreign body (e.g., needle, string, plant material). Pyogranulomatous inflammation can appear clinically similar to squamous cell carcinoma. Always biopsy!

Complicated Crown Fractures

363 Intraoral dental radiographs for assessment and treatment are required. All fractured teeth with pulp exposure (acute or chronic) require endodontic treatment or extraction. Many teeth with uncomplicated crown fractures and enamel fractures may also have endodontic disease requiring treatment that can only be found via intraoral radiographs.

364 SAGE Symposium 2018 Managing Respiratory Cases Jo Woodison, RVT

Overview

Difficulty breathing is a common presenting complaint to veterinary emergency clinics. Immediate supportive measures should be implemented, while assessing the patient, forming a differential diagnoses list, and obtaining brief and relevant history. There are many possible causes of respiratory distress, each treated differently. Common causes of dyspnea include: airway obstruction (from foreign body or congenital malformations), asthma, pneumonia, edema, contusions, diaphragmatic hernia, pneumothorax, pyothorax, pleural effusion, pericardial effusion, heart disease, or even pain, stress or metabolic disturbances. The first and easiest supportive therapy is oxygen supplementation, which may be in the form of the marginally effective flow-by, oxygen cages, “old-man” nasal cannulas, nasal catheters, intubation +/- positive pressure ventilation, or even tracheostomy tube placement. The signalment of the patient, history and physical examination can help enormously in prioritizing therapy and diagnostics. Extra care should be taken to reduce stress to respiratory patients, and efforts should be made to prioritize diagnostics and therapy while keeping the patient stable and comfortable. We will discuss common respiratory emergencies, and suggested approach to prioritization of diagnostics including radiology, pulse oximetry, blood gas measurement, and therapy whether administering diuretics, placing an intravenous catheter, performing thoracentesis, a tracheotomy or preparing for emergency thoracotomy.

Full conference proceedings available at www.fuzzyears.com/sage18 .

Back to Table of Contents 365 SAGE Symposium 2018 Polytrauma: Where to Start Jo Woodison, RVT

Introduction

A patient suffering from polytrauma is one suffering from multiple multi-system injuries. These injuries are life-threatening, or may quickly become so, and can often lead to sequential systemic reactions resulting in further organ dysfunction or failure of vital systems, even when those may not have been directly injured. These traumatic injuries are often blunt force or penetrating in nature, caused by automobile accidents, falls, gunshots, etc. The polytrauma patient poses a variety of issues and nursing concerns. On presentation, the patient must be assessed and stabilized. A team-based approach is optimal for any multi-trauma patient.

The objectives of this team are to:

❏ Identify and correct any life threatening injuries. ❏ Resuscitate the patient and stabilize vital signs, blood flow and ensure adequate delivery of oxygen. ❏ Determine the extent of other immediate but non-life threatening injuries, and categorise and prioritise them.

Back to Table of Contents 366 ❏ Provide support, operative repair and other care as needed. ❏ Provide continued post-operative care and monitoring.

A team-based approach remains helpful to provide the best care, even days after the trauma occurred.

The Trauma Team

With multiple multi-system injuries, often confounding and compounding one another, polytrauma patients pose major therapeutic challenges to the veterinary team. The size and composition of our veterinary trauma team may vary, but teamwork, leadership and clear ongoing communication are integral to their success and increasing the probability of patient survival. Team members should be trained to perform their duties, and know where necessary equipment and medications are stored. The team leader is typically the emergency clinician or the admitting veterinarian. They are responsible for supervising the initial assessment, coordinating resuscitation and treatment, and pursuing early consultations and referrals to veterinary specialists which may include any or all of: criticalist, orthopedic surgeon, soft-tissue surgeon, neurosurgeon, ophthalmologist, anesthesiologist, etc. Time is of the essence and rapid, appropriate assessment during the first hours post-injury is essential to increase survival. Early involvement of the appropriate specialty services in assessing the patient and agreeing upon a care plan improves patient outcome.

Ideally, the admitting veterinarian and at least one member of the nursing team will follow a patient from admission to discharge ensuring continuity of care and reducing opportunities for communication breakdowns. However, with multiple specialties involved over multiple days, or even weeks, of hospitalized care, rotation of staff is unavoidable. It is imperative that there is a smooth and seamless transfer of the patient between the specialty teams, and that they work together as a larger, cohesive patient care team to maintain continuity for the best patient outcome.

Rapid Assessment/Response Leadership Communication

367 Primary Survey

Patients should be assessed immediately, and treatment priorities should be established based on their injuries. During the initial triage, the team must identify any major life-threatening injuries. Patient assessment is conducted first in what is referred to as a primary survey. Immediate life-threats should be addressed on detection before continuing with the remainder of the survey. An obstructed airway should be cleared prior to identifying a chest wound, for example. Once again, it is critical that the team is trained and confident at performing their duties, and that team members communicate clearly and frequently to other team members. Frequent patient reassessment at all phases of trauma care is critical: injuries that were previously unrecognized or seemingly insignificant may manifest or progress and become life-threatening.

Assessment

During the primary survey, airway, breathing and circulation, and immediate life-threatening problems must be identified and addressed. This should take no longer than a few minutes. The mnemonic ABCDE is easy to remember and stands for: airway, breathing, circulation, disability and exposure/environment control. The primary survey must be repeated any time the patient’s status changes, whether that be mental status, vital signs, or administration of medications and treatments. While airway and breathing are listed first, in the case of massive hemorrhage, efforts should be directed at stopping the blood flow to maintain circulation. At the same time the primary survey is being performed, another team member may be securing intravenous (IV) access.

Airway

An obstructed airway is one of the most immediate and deadliest threats to life. The goals are to confirm, or provide, a patent airway, and to protect the airway from future obstruction by blood, edema, vomitus, or other possible causes of blockage.

Breathing

Look, listen and feel for any immediate life-threatening obstacles to breathing: impaled objects, pneumothorax, flail chest, hemothorax. These must be addressed immediately. Impaled objects should be secured; open chest wounds sealed; tension pneumothorax decompressed. Administer supplemental oxygen, with mechanical ventilation if needed. The patient is undoubtedly in shock,

368 which means they are suffering reduced oxygen delivery to their organs and tissues and will benefit from supplemental oxygen even if they are breathing without assistance.

Circulation

The patient should be evaluated for signs of hemorrhage. Any life threatening external hemorrhage should be controlled with direct pressure and a pressure wrap. Suspected internal hemorrhage should be evaluated with focused assessment with sonography in triage, tracking and trauma (FAST3). Assess perfusion status by assessing heart rate, mucous membrane color, capillary refill time, femoral pulse rate and quality, extremity temperature. Establish IV access and bolus fluids to address hypoperfusion.

Disability

Disability, in this case, is a brief neurologic examination. Assess the patient’s level of consciousness (LOC); ensure their pupils are equal, round, and reactive to light (PERRL); and assess for suspicion of spinal cord injury which could lead to respiratory compromise or neurogenic shock. Take appropriate precautions to stabilize spinal cord when moving and manipulating the patient.

Exposure/Environment

Hypothermia is a frequent complication of trauma, due to the trauma itself and peripheral vasoconstriction through the body’s own mechanisms to react and protect the internal organs. Keeping the patient warm should not be neglected. Place the patient on dry, insulated bedding and cover with a blanket and supplementary warming aids as needed.

Pain Control

Each case will be a little different as to when is most appropriate to administer analgesia depending on the types and severity of injuries and patient status. Do not, however, overlook giving the patient analgesics. Pain relief should always be considered early in the evaluation and treatment process and, especially, prior to manipulation of any fractured bones, dislocated joints, burns or wounds.

Adjuncts

Adjunctive diagnostics may be performed at this time. They may include: ● Blood work: a PCV, lactate, complete blood count (CBC), biochemistry profile, electrolytes, blood gas, coagulation tests, urinalysis.

369 ● Radiographs: thoracic and abdominal films may prove useful in identifying injuries in the chest or to the abdominal organs (e.g. hemorrhage, bladder rupture).

● Blood typing and crossmatching may be warranted in cases of acute blood loss.

● Blood pressure, electrocardiography (ECG), oxygen saturation, temperature may warrant initiation of monitoring.

Transfer?

At the end of the primary survey, enough should be known about the patient’s status and needs, to determine whether they can be dealt with at the current facility, or should be transferred to another to provide a higher level of care, or specialized care. If a transfer is in the patient’s best interest and agreed to by the client, the patient should be stabilized and prepared for transport. The receiving facility should be notified, and records of all findings and treatments performed should be gathered for sending with the client, or directly to the receiving hospital while the pet and client are en route.

Shock

Shock is the condition where organs and tissues of the body are not receiving sufficient flow of blood. This results in the organs and tissues not receiving enough oxygen to function properly, and an accumulation of waste products that are not being removed. This can cause damage to the organs, and if left untreated, death.

Hypovolemic Shock

Shock in trauma patients is most commonly due to hemorrhage. Hypovolemic shock due to hemorrhage is treated initially with (warmed) isotonic crystalloid fluids, and blood products if indicated. Surgical control of bleeding may need to be part of the resuscitation effort and should not be delayed. Treatment for hemorrhagic shock is targeted towards re-establishing normal pulse, blood pressure, lactate concentration, blood pH, and urine output.

Distributive Shock

Neurogenic shock is a term used more in human medicine than veterinary. It is a type of distributive shock that occurs due to spinal cord injury disrupting the sympathetic outflow to the heart and blood vessels. Clinical signs might include slow pulse, warm extremities and hypotension,

370 particularly if they show signs of paraplegia. Resuscitation will include isotonic crystalloids, and possibly vasopressors. A neurology consult is indicated.

Secondary Survey

A secondary survey is performed after the primary survey has been completed and the most urgent, life-threatening injuries have been addressed. The secondary survey is a nose-to-tail examination to identify any injuries that did not require immediate treatment or may have been missed. The secondary survey should include:

➢ Patient history: while not required to commence stabilisation and treatment, a patient history should be obtained from the client or pet guardian. ➢ Vital signs: the patient’s vital signs should be reassessed and monitored periodically. These include: heart rate, femoral pulse rate and quality, capillary refill time, mucous membrane color, respiration rate, respiration effort and pattern, and core temperature. ➢ Full body scan: a systematic nose-to-tail scan should be performed. Identify any injuries or conditions that might have been missed previously, or may be developing as time elapses since the trauma occurred. Inspect, auscultate, or palpate each region of the body for DCAP-BTLS: ○ Deformities and discolorations ○ Crepitus and contusions ○ Abrasions and avulsions ○ Penetrations and punctures ○ Burns ○ Tenderness ○ Lacerations ○ Swelling and symmetry Treat injuries as they are identified, and prioritize those that pose the greatest threat to life and recovery.

➢ Clean and comfortable: keep the patient clean and comfortable. ➢ Musculoskeletal: treat any secondary injuries and wounds as appropriate. All joints and long bones should be assessed, along with pulses. Test for sensation and motor strength. Radiographs of extremities may now be indicated to identify fractures or dislocations. Broken bones may need to be splinted (above and below the joint); open wounds should be cleaned, flushed and covered until the patient is stable enough to address them surgically.

371 ➢ Reassess: repeat the secondary evaluation at regular intervals for the duration of the patient’s hospital stay, and treat accordingly.

Prioritization

The primary goal of management of any trauma patient is to prevent death. It is estimated that 10% to 20% of deaths occuring as a result of trauma might be prevented with immediate resuscitation. Time is of the essence. As injuries are identified during primary and secondary surveys, the trauma team must establish priorities for patient care and management. Obviously, a patient’s obstructed airway must take precedence over their open femur fracture. Additionally, there are priorities of the associated treatments. Fluid replacement typically takes high precedence, but there is no “one protocol fits all” strategy. A patient with uncontrollable, inaccessible hemorrhage will likely have a different fluid plan than one suffering from traumatic brain injury. In the former, the patient may tolerate permissive hypotension until the blood loss is curtailed, whereas with the latter, maintaining normal blood pressure to preserve cerebral perfusion will take precedence.

Tertiary Survey

In the human medical field, it has been found that a percentage of injuries remain unidentified, even after primary and secondary surveys. A tertiary survey is a further reassessment of the patient to identify any missed injuries or conditions that were not apparent previously. It is typically performed 24 hours after the polytrauma patient has been admitted to the intensive or critical care unit. It should include a detailed history and physical examination, and a review of written radiology reports and other diagnostic test results. The patient should be evaluated for potential compartment syndrome due to bowel and mesentery swelling which can cause high intra-abdominal pressure; pneumothorax, intracavitary bleeding, falling blood pressure, or other decompensations.

Summary

Seriously injured patients with trauma affecting multiple body areas and organs pose a unique variety of issues and nursing concerns. On presentation, the patient must be assessed and stabilized. A multidisciplinary team-based approach is optimal for any multi-trauma patient. The team should be skilled, knowledgeable and confident, with good leadership and clear communication. No two trauma cases will be the same, and as always, the patient should be assessed and treated in consideration of all vital signs and diagnostic test results. When in doubt, communicate observations and findings to the veterinarian managing the patient care team.

372 Bibliography

Advanced trauma life support (ATLS®). (2013). Journal of Trauma and Acute Care Surgery, 74(5), pp.1363-1366.

Biffl, W., Harrington, D. and Cioffi, W. (2003). Implementation of a Tertiary Trauma Survey Decreases Missed Injuries. The Journal of Trauma: Injury, Infection, and Critical Care, 54(1), pp.38-44.

Crowe, D. and Devey, J. (1994). Assessment and Management of the Hemorrhaging Patient. Veterinary Clinics of North America: Small Animal Practice, 24(6), pp.1095-1122.

Crowe, D. T. (2006), Assessment and management of the severely polytraumatized small animal patient. Journal of Veterinary Emergency and Critical Care, 16: 264–275.

Palmer, L. and Martin, L. (2013). Traumatic coagulopathy-Part 1: Pathophysiology and diagnosis. Journal of Veterinary Emergency and Critical Care, 24(1), pp.63-74.

Palmer, L. and Martin, L. (2014). Traumatic coagulopathy-Part 2: Resuscitative strategies. Journal of Veterinary Emergency and Critical Care, 24(1), pp.75-92.

373 Track 6 What if We Applied the Ritz Carlton Model in our Practices? Robin Brogdon, MA Owner/President – BluePrints Veterinary Marketing Group, Inc.

Objective: To identify companies that are known for superior service and examine exactly what they do to deliver so well time and time again. Using the Ritz Carlton as a prime example, we’ll break down the strategies and tactics they use in addition to a dozen other companies and show veterinarians how to apply these methods to their own veterinary practice.

The most common strategies employed by these successful businesses include: 1. Connect with clients – they understand and are relatable 2. Engage with clients – good communication requires an exchange 3. Stay true to core values – consistency to a set of principles is paramount 4. Empowerment – autonomy is essential for job satisfaction 5. Respect – everyone deserves to feel special 6. Listen – most importantly, listen and learn what your clients want and need

What are Your Clients Turning to Dr. Google For and How Can You Help Them See You as a More Valuable Resource?

Objective: To show veterinarians that there is a trust gap with their clients and how to close it so that when information is needed, they turn to the medical professionals instead of unverified, unscientific, personal opinion online.

We will look at some of the most common questions pet owners pose to other pet owners online: 1. What should I feed my pet? 2. When should I spay/neuter my pet, at what age? 3. How do I help my pet with arthritis/age related conditions? (supplements/meds, etc.). What works for your pet? 4. Teeth – What is the best way to clean my pet’s teeth? (chews, non-anesthetic dentals) 5. Vaccinations – To Do or not To Do, how much, how often, what’s necessary? 6. Flea and tick treatments and remedies – What to use? Where to buy? 7. What can they chew on – antlers, bully sticks?

We’ll pose questions such as: why aren’t they asking the veterinarian, these questions? And/or why are they not listening to your recommendations? We’ll discuss the primary

151 Kalmus Dr. B200. Costa Mesa, CA 92626 Ph 949-756-8071 Fx 949-756-8473 374 Back to Table of Contents concerns of pet owners that they may not be addressing adequately and how to build greater trust with each client.

151 Kalmus Dr. B200. Costa Mesa, CA 92626 Ph 949-756-8071 Fx 949-756-8473 375 Pet Nutrition & Profitability; Evolve & Grow Jeff Wineke, National Account Manager Royal Canin USA

Introduction: Many clinics have a love/hate relationship when it comes to nutrition as a category. Our goal is to learn why pet nutrition is a powerful tool that will increase profitability, improve relationship, and support best medicine practices. Consumer purchasing behaviors are rapidly changing, effecting everything hospitals sell including pet food. The objective of this session is to help develop a game plan to earn revenue with online nutrition sales and provide practical advice to equip your clinic to reach every generation of pet parent in clinic and online.

Pet & Vet Industry Facts: It’s estimated there are over 1 billion cats and dog in the world. The United States has over 177 million cats and dogs, making it a highly indexed country when compared to its human population. The United States is a financially developed market, and it has nearly double the senior pet population at 31.5% compared to the collected world data by 44 other markets. One reason the higher senior population percentage exists in the US is likely related to pet owners being financially able to provide better care for their pets through nutrition, veterinary care, and overall pet support available.

When looking at survey data of how much people spend on pets, pet owners report they spend more money combined on pet food and treats, than on routine veterinary care annually. These survey results make sense when over $30 billion a year is spent on pet food making it the largest sub category with over 40% of all purchases within the pet care category. At this time, only 5% of pets a clinic sees receives it’s nutrition from a veterinary clinic, making it a missed opportunity for revenue growth.

There are approximately 33,000 registered veterinary businesses in the United States. The average veterinary clinic generates between $400-700K per FTE. The average clinic will have over 3FTE’s and generate approximately $1.2 – 2.1 million dollars in revenue annually. Clinics generate revenue through services, diagnostics, and product sales. Lab diagnostics and product sales generate around 50% of a clinics revenue. Pet food represents 4% of the total revenue generated in a clinic.

Why Sell Pet Food? Many veterinarians struggle with promoting nutrition and talking about its importance to pet owners. The top obstacles faced by the veterinarians in discussing nutrition include misinformation from multiple sources like television/internet advertising, cost concerns, challenges in convincing clients to change diet or feeding habits, and needing a better understanding of the diet options in general when speaking to clients. These obstacles can be overcome through pet nutrition education, and improving communication skills during the client and veterinarian interaction. To start overcoming these obstacles a clinic must first commit to focusing on improving pet food revenue.

By focusing on increasing pet food revenue, the clinic provides an opportunity to provide better overall health care, increase client relationships, and grow the overall business revenue through the increase of financially opportunistic interactions connected with the clinic visit.

Compliance is one of the top challenges veterinarians having when managing a sick pet. Administering oral medications, for example, can be very difficult for a cat owner. In many cases the proper nutrition may reduce or remove the need for medical or surgical intervention. Nine of the top ten pet insurance claims made for cats and dogs involve a medical condition that nutrition can play a key role in managing. Healthy pets represent an even larger opportunity because many “healthy” pets are overweight, have periodontal disease, or are seniors that would benefit from targeted nutrition to improve their quality of life.

Nutrition can act as a vehicle to connect an owner more closely with a hospital. Over 90% of pet owners expect a nutritional recommendation from their veterinarian, yet only 11% get one. Over 50% of pet owners will follow the recommendation given by their veterinarian. When pet owners purchase food from their veterinarians, the number of clinic/pet owner interactions can increase by over 10x during the life of the pet.

Back to Table of Contents 376 Pet owners who purchase nutrition from the veterinarian clinic often become better clients. Each interaction that occurs when picking up a pet diet becomes a potential business opportunity. These interactions support additional avenues to sell in other services that provide higher margin or additional revenue, and ultimately, better care for the pet. Pet food should be leveraged as an anchor category to serve the greater business.

Some veterinary businesses do not believe they make enough money on pet nutrition compared to other categories. From a single sale perspective that can be true. From a retail perspective of “turns equals earns” that is a myth. See example below:

Product A Product B Retail $30 $30 Cost $20 $15 Gross Margin 33% 50% Markup 50% 100% Gross Profit $10 $15 Sales Per Year 12 2 Annual Profit $120 $30

In this case product “A” is 4 times more profitable than product “B”. Product “A” in this example represents a monthly purchase of pet food and product “B” represents a twice a year purchase of different category product.

Evolving Marketplace: As critical as it is for veterinary clinics to generate revenue in clinic on pet nutrition, the buying habits of consumers are rapidly changing to prefer to shop in an online marketplace. As of 2016, more consumers are purchasing more products overall online than in store. Of the nearly $30 billion dollar pet food category $1 billion dollars of pet food purchases are made online. Looking at the newest consumer audience, 42% of millennials have purchased vet products online and 67% reported that they are likely to in the near future.

With the evolution of commerce, multiple online pharmacy retailers have emerged. Some of these online pharmacies are built with a revenue share model, creating a relationship that incentivizes veterinarians to utilize the online pharmacy as place for the pet owner to purchase the product, in exchange for a percentage of the revenue without having to stock product.

Two key benefits these revenue share online pharmacies provide is they excel at marketing to people online and creating a very efficient interaction. The revenue share online pharmacies put a great deal of energy into creating back end reporting and prescription management tools. This enables the clinic to interact well with the online service and the pet owner. Most online pharmacies promote auto shipment of products on a reoccurring cycle that turns typical in-clinic compliance of nutrition of 2.5 purchases to nearly 9.5 for a given patient. With a higher rate of compliance on auto shipment, a veterinary clinic may make more profit per patient online than in clinic, even with a different percentage of profit per transaction.

One misconception with online pharmacies is that they remove in-clinic sales. When looking at the potential customer base of pet food buyers currently, many clinics are not engaging the consumers who prefer to shop online. Through online pharmacy utilization and optimization, a hospital can increase client compliance as well as engage those clients not purchasing nutrition in-clinic thus increasing the revenue derived from the nutritional category. Online pharmacies add incremental revenue to the overall business model and diversifies the revenue streams for a veterinary business.

Conclusion: Pet nutrition is a widely untapped category that can drive revenue, improve relationships, and support overall pet health. As the way consumers purchase evolves, we must embrace a business strategy that improves the current model and fosters the new models. Below is a chart of some strategies to improve both in-clinic and online nutrition sales.

377 In Clinic Online Pharmacy Benchmark clinic sales to industry standards Identify online revenue share partners and utilize Review current recommendation model and adjust Create strategy to reach target audience Make nutrition education a regular topic- use vendors Educate staff on how to sell through service Create incentive models for staff with nutrition sales Implement a test plan and review monthly Create a healthy pet selling strategy…consider online After testing, review, modify and expand Improve in-clinic merchandising of nutrition Expand nutrition presence on website and social media

References:

• Mars Petcare. (2016). Pet Population 2016. • Euromonitor. (2015). Human Population. • U.S. Department of Commerce; Sundale Research. • Glassman,G. (2017). Burzenski & Company, PC; 100 South Shore Drive, Suite 100, East Haven, CT 06512. • APPA. (2017). National Pet Owners Survey 2017-2018 • Ipsos. (2016). Veterinarian AAU Study – Wave 3 • Nationwide,(2016, June 31). Nation’s largest Pet Insurer Unveils Top Pet Ailments that Prompt Veterinary Visits. • Stevens, L. (2016, June 8) The Wall Street Journal Online. • Vets First Choice. (2016, June) Compliance Impact Study, 2016 and specific analysis of 30 corporate clinic group

378 Compassion Fatigue: It’s Real Julie Squires, CCFS

Compassion Fatigue Compassion fatigue is often coined “the cost of caring” (Figley). It is the physical,emotional, psy- chological and spiritual depletion or exhaustion that can result when we are repeatedly exposed to another’s pain and suffering. In veterinary medicine this pain and suffering can refer to that of both the patient and the client.

According to Merriam-Webster Dictionary empathy is defined as:

1.the imaginative projection of a subjective state into an object so that the object appears to be infused with it 2. the action of understanding, being aware of, being sensitive to, and vicariously experiencing the feelings, thoughts, and experience of another of either the past or present without having the feelings, thoughts, and experience fully communicated in an objectively explicit manner; also : the capacity for this

Charles Figley PhD, a pioneer in the field of compassion fatigue states in “Compassion Fatigue in the Animal Care Community” that empathy is a response and a process.

Compassion according to Merriam-Webster Dictionary is:

sympathetic consciousness of others' distress together with a desire to alleviate it

Figley points out that compassion while related to empathy is really “a focused empathy, one that is action oriented”. This is an important distinction to make as many thought leaders in the area of compassion fatigue are suggesting we should really call compassion fatigue, empathy fatigue because as with compassion, our desire to alleviate another’s pain and suffering may actually be somewhat protective.

Professional Quality of Life

Dr. Beth Hudnall-Stamm and Dr. Charles Figley developed a self-test called the ProQol (Profes- sional Quality of Life) that can be accessed from www.proqol.org. This test assesses one’s own levels of secondary trauma, burnout and compassion fatigue.

Burnout

Back to Table of Contents 379 Compassion Fatigue: It’s Real Julie Squires, CCFS We must now define burnout and how it differs from compassion fatigue. Burnout is physical or emotional collapse caused by overwork or stress. It is a work-related issue whereby compassion fatigue is a personal issue. Said another way, it is when the work exceeds the resources. The work we all understand (patient load, appointments, surgeries, etc) but the resources can be anything from time, money, staff, appointment slots, etc.

Burnout results from the work environment itself. If we were to leave that environment and did not go to another with the same lack of resources, we would not be burned out. In contrast, if we are suffering from compassion fatigue and leave a practice to go to another, we will still be suffering from compassion fatigue because it is about who we are, the emotions we are absorbing and how we are perceiving the work and it’s effects.

Secondary Trauma

When we become traumatized by witnessing or hearing about another’s trauma is called secondary trauma.

Secondary trauma is also called vicarious trauma and refers to the cumulative transformative effect of working with traumatized individuals. Our view of the world changes. Take animal shelter workers for example. The nature of their work exposes them to some of the worst in human- ity as they witness the results of neglect, abuse and disposal of animals. They start to develop a strong disdain for humans and a general hatred toward people. This is the result of vicarious trauma.

Signs and Symptoms

Regardless of what terms are used to describe compassion fatigue, the signs and symptoms are very real. While the symptoms can vary among individuals, many include:depression • hopelessness • increases in mistakes • physical and emotional exhaus- • anxiety tion • problems in personal relation- • diminished sense of career en- ships joyment • isolation • bottled-up emotions • physical ailments • irritability • suicide • substance abuse

Occupational Hazard

Compassion fatigue is an occupational hazard inherent in veterinary medicine. While it may not be avoidable, it certainly can be managed. We want to provide authentic caring and compassion for our patients and clients but we don’t want to lose ourselves in the process.

How healthy is your practice? Only as healthy as it’s doctors and staff. If they are struggling with compassion fatigue, the organization can suffer in the following ways: • substandard level of care • team conflict • absenteeism • low morale • high turnover • increased cynicism, complaining • lack of teamwork • erosion of customer loyalty

380 Compassion Fatigue: It’s Real Julie Squires, CCFS • reduced customer satisfaction • poor quality control • reputation at risk • deterioration of the org’s mission These are costly issues to any organization but especially to veterinary practices. How can can we expect our clients to have an exceptional experience at our practice when everyone they interacted with would give their job satisfaction a 2 out of a scale of 10 (10 being the highest)?

Moral Stress

Moral distress or simply moral stress is when our own beliefs and morals conflict with what we are asked to do. For instance the euthanasia due to lack of finances, or the reluctance from a client to continue treatment when the you believe it is what is best for the patient or the euthanasia despite a treatable condition. When we fundamentally disagree with what is being asked of us, yet policies and routines dictate.

According to Dr. Elizabeth Strand, Founding Director of Veterinary Social Work at the Univer- sity of Tennessee College of Veterinary Medicine, moral distress is the biggest contributor to compassion fatigue among veterinarians. For example when one believes the best course of treatment is the one prescribed and yet the client can not afford the treatment or chooses not to do it, moral stress ensues.

Contributing Factors

What contributes to compassion fatigue is both plentiful and individual and may include some of the following:

-lack of awareness -lack of training -inexperience -non-compliant clients -stress of practice -not being able to forgive oneself for mistakes -debt -perfectionistic personality -lack of healthy coping mechanisms/stress management techniques -unreasonable expectations by others and of ourselves

Who is Vulnerable

Anyone whose work or caregiving puts them in an environment that is emotionally taxing is susceptible to compassion fatigue. When we foster empathy, we are at risk. In addition to veterinary medicine, healthcare workers, mental health providers, eldercare workers, child care advocates, lawyers, jurors, hospice workers and teachers are all vulnerable.

381 How To Feel Better in Veterinary Medicine Part 1 Julie Squires, CCFS

Compassion Fatigue Strategies: Mind Management

Our thinking can create a lot of self-induced suffering. Veterinarians have been identified as em- bodying perfectionistic tendencies and being very hard on themselves, especially in regard to mistakes. While no one intends to make a mistake, it is inevitable as we are human beings after all and not perfect.

How easily can we forgive ourselves? Do we beat ourselves up when things don’t go the way we want them to? Can we let ultimately let go of the unrealistic expectations we have for ourselves? Can we let go of the sadness and pain when the outcome is not what we desire?

Managing our minds is a skill that provides us freedom from suffering. Our emotions can become overwhelming, damaging and breed rumination.

The Self-Coaching Model

This self-coaching model can offer relief. Based on cognitive psychology and the work of Master Life Coach Brooke Castillo, this model gives us the ability to identify thoughts that are creating negative emotions and then, and only then, we can change those thoughts to ones that make us feel better.

Circumstances: Things that happen in the world that we cannot control.

Thoughts: Things that happen in your mind. This is where you self coach.

Feelings: Vibrations that happen in your body— caused by thoughts, not circumstances.

Actions: Behavior—what we do in the world. Caused by feelings, determined by thought.

Results: What we see in the world (our lives) as an effect of our actions. The result will always be evidence for the original thought.

Page 1 of 4 Back to Table of Contents 382 How To Feel Better in Veterinary Medicine Part 1 Julie Squires, CCFS This model is based on the following truths: • We cannot control the world • Nothing outside of us has the power to make us feel good or bad • It is not the circumstances, but our thoughts about the circumstances that create our experience • We attract what we think about • Emotions are vibrations that lead to action • We can’t permanently change our results without changing our thoughts • We don’t have to get anything to feel better; we can feel better right now

Being conscious and choosing our thoughts are the most important components to feeling better.

Here are reasons to use this model: • To feel better • To create results • To become conscious • To think more deliberately • To create/manifest what you want in your life • To remove negative thinking and emotions • To create positive thinking and emotions • Putting the Model to Use to Solve Any Problem

1. Identify the problem. Even those things that seem petty, if it is bothering you it’s worthy of your attention.

My client won’t do what I ask.

I have no work/life balance.

I’m overwhelmed with the stress of the practice.

My student debt is bearing down on me.

I made a mistake and my patient is now very sick and fighting to live.

2. Plug it into the model in the appropriate category.

Circumstance

Thought I made a mistake and my patient is now very sick and fighting to live.

Feeling

Action

Result

383 How To Feel Better in Veterinary Medicine Part 1 Julie Squires, CCFS 3. Fill in the rest of the model based on the problem.

Circumstance My patient

Thought I made a mistake and my patient is now very sick and fighting to live.

Feeling Guilt

Action I ruminate on what I did and what I should’ve done.

Result I’m less available to my other patients and clients

Use this template to see a problem in your life and how it is manifesting. At first most models start with the Circumstance or Thought but you can start anywhere and work backwards.

Circumstance ______

Thought ______

Feeling ______

Action ______

Result ______

4. Since THOUGHTS create our FEELINGS we have to find an alternate thought but it must be one we believe otherwise this won’t work. The thought “I’m not a good vet” is creating doubt and that doubt is then causing one to shut down and ultimately lose confidence.

In order to feel better we have to find a THOUGHT that we can believe and that makes us FEEL better when we think it. How else could we think about this situation?

Circumstance My patient

Thought It was an unfortunate oversight that I will try to never let hap pen again.

Feeling Acceptance, forgiveness

Action I treat myself with compassion

Result I let it go.

You must remember that it is not the circumstance or situation that is causing your feelings but your thought(s) about the situation.

384 How To Feel Better in Veterinary Medicine Part 1 Julie Squires, CCFS Following the steps outlined above, use this template to find relief from the problem or issue that you did a model for above. This is where you will change the THOUGHT to one you can believe and that feels better when you think it.

Circumstance ______

Thought ______

Feeling ______

Action ______

Result ______

You can plug something into the model at any point. For instance you can start with the Feeling or the Action or even the Result. In this example I start with the Result and work backwards.

Circumstance Life

Thought I can’t do it all.

Feeling Inadequate

Action I overeat and overdrink.

Result Compassion fatigue

You have to acknowledge your first model before you can re-work it, before you can change the thought.

Source: Self-Coaching 101:Use Your Mind-Don’t Let It Use You! by Brooke Castillo(2009) www.brookecastillo.com

385 How To Feel Better in Veterinary Medicine: Part 2 Julie Squires, CCFS

The Self-Coaching Model

This self-coaching model can offer relief. Based on the work of Master Life Coach Brooke Cas- tillo, this model gives us the ability to identify thoughts that are creating negative emotions and then, and only then, we can change those thoughts to ones that make us feel better.

This model is based on the following truths: • We cannot control the world • Nothing outside of us has the power to make us feel good or bad • It is not the circumstances, but our thoughts about the circumstances that create our experience • We attract what we think about • Emotions are vibrations that lead to action • We can’t permanently change our results without changing our thoughts • We don’t have to get anything to feel better; we can feel better right now

Being conscious and choosing our thoughts are the most important components to feeling better.

Here are reasons to use this model: • To feel better • To create results • To become conscious • To think more deliberately • To create/manifest what you want in your life

Circumstances: Things that happen in the world that we cannot control.

Thoughts: Things that happen in your mind. This is where you self coach.

Feelings: Vibrations that happen in your body— caused by thoughts, not circumstances.

Actions: Behavior—what we do in the world. Caused by feelings, determined by thought.

Results: What we see in the world (our lives) as an effect of our actions. The result will always be evidence for the original thought.

Page 1 of 4 Back to Table of Contents 386 How To Feel Better in Veterinary Medicine: Part 2 Julie Squires, CCFS • To remove negative thinking and emotions • To create positive thinking and emotions

In the first session we learned how to use this model to self-coach ourselves through difficult situations. Because it is our thinking that creates our emotional state and therefore our experience in the world, it is also here that we coach ourselves. We can shift our thinking. You have to tell your brain what to think, otherwise left to it’s own devices it will think negative, critical and judgmental thoughts.

Using the Model to Understand Others

While we never know exactly why others behave the way they do we can try to understand why they might act a certain way and that may offer some understanding for us.

So a way in which we can use the model for this is to create a model of someone else. Let’s take a client for example. Say you have a client who comes in with a stack of information printed off the internet, off of pet centric websites. Not credible info but info nonetheless.

It can bring up all sorts of thoughts and emotions for you such as anger, defensiveness, exhaustion, resentment, etc. And if you created a model for yourself it may look something like this.

C - Client presents with stack of information

T- They don’t trust my opinion.

F - Anger

A - Act defensive

R - We don’t connect and patient suffers.

If we were to create, to the best of our ability (and yes we are surmising) what your client’s model would like like, it may be something like.

C - Bring in my research to vet

T - I’m scared of what might be wrong with my dog

F- Fear

A- Short/curt with vet

R- We don’t connect

Think now to a person whom you are having a difficult time with and see if you can try creating a model for them.

C ______

T______

387 How To Feel Better in Veterinary Medicine: Part 2 Julie Squires, CCFS F______

A______

R______

How Do You Want To Feel?

Everything you want in your life is possible. Compassion fatigue results from how we are thinking about our experiences. We cannot change what happens but we can absolutely change how we react, respond and think about it. This is the key!

1.Take a look at the list above and identify 2-3 feelings you want to feel about your work. Of course you can use this for your personal life too.

3 Desired Positive Feelings

Example

a. Confident

POSITIVE FEELINGS proud excited purposeful amazing fabulous relaxed appreciated friendly satisfied awesome fulfilled thankful balance generous thrilled calm grateful touched capable happy valued cheerful healthy wonderful comfortable hopeful confident impassioned connected inspired considerate invigorated content joyful creative kind curious open-hearted delighted open-minded determined optimistic devoted passionate empowered peaceful energized positive enthusiastic 388 How To Feel Better in Veterinary Medicine: Part 2 Julie Squires, CCFS b. Kind

c. Energized

2. With the understanding that your thoughts create your feelings, what would you have to THINK in order to FEEL that way?

a. Confident - “I have the best interest of my patients and clients at heart.”

b. Kind -“I believe we are all doing the best we can in any given moment.”

c. Energized - “Veterinary medicine fuels me.”

3. Create a phrase/sentence for each of your desired feelings that makes you FEEL that feeling when you THINK it.

This may take a few times until you get it right, be ok with that. But once you get it:

-write the thought down where you will see if often

-set your alarm on your phone to go off at a certain time everyday and think that thought

-think that thought the moment your feet hit the floor in the a.m.

-practice it over and over and over until it becomes a belief. Beliefs are just thoughts we’ve thought over and over.

Source: Self-Coaching 101:Use Your Mind-Don’t Let It Use You! by Brooke Castillo(2009) www.brookecastillo.com

389 Boundaries: The Missing Ingredient in Veterinary Medicine Julie Squires, CCFS

Boundaries are the ultimate act of self-love and without them we become ineffective at caring for others. Self-love and self-care are one and the same and without boundaries we can’t effectively take care of ourselves so how can we expect to effectively care for others? Boundaries are a way of not only respecting ourselves but protecting ourselves.

From a physical standpoint our skin is a boundary. Without it our insides would spill all over and we couldn’t function. The same applies to non-physical boundaries. If you know what I will accept and what I won’t accept it changes our entire relationship for the better and improves it’s functionality.

Why We Lack Boundaries

We are people pleasers -We want everyone to like us and we don’t want to “hurt anyone’s feelings”. Please know that no one has the power to make us feel a certain way. Our feelings come from our thoughts and not the circumstance. -Ask yourself how is this working being a people pleaser? My bet is that it is not working for you because you end up feeling angry and resentful and asking why no one is thinking about you since you are thinking about everyone else and their needs. Again, it’s your job to meet your own needs, no one else’s.

We lack an understanding of boundaries -Typically we learn about boundaries from our parents. What did you learn from your mother about boundaries? How about from Dad? When we don’t have an understanding of their importance, we don’t know why we need them. -You will also find that those that have very poor boundaries will constantly infringe on ours and test ours.

Worthiness -Many of us come with a “not enough” or “not worthy” tape playing on continuous. Some version of not being good enough or not worthy of having our needs met. We think “who am I to ask people to not text me from work unless it’s a true emergency?”. Who are you NOT to? -Others of us don’t feel comfortable standing up for ourselves but if we don’t others will see how far they can infiltrate our space. Boundaries prevent this. Self-esteem and confidence - Enforcing boundaries is not easy and requires patience, diligence and practice but consider the possibility that it’s these exact boundaries that will help build both your self-esteem and confidence.

Where Do We Begin?

Boundaries are about US, not the other person. What’s ok with you and what’s not ok with you. Boundaries are not about trying to manipulate other people and getting them to do or not do certain things.

Instead a boundary is, if you do THIS, then I will do THAT.

“If you yell at me, I will leave the room.” “If you ask for my cell phone number, I will not give it to you.” “If you text me pictures of your dog, I will not respond.”

Back to Table of Contents 390 Boundaries: The Missing Ingredient in Veterinary Medicine Julie Squires, CCFS “If you show up at my house unannounced, I will not open the door.”

1. Start small -Find little things to start with such as telling friends you turn your phone on do-not-dis- turb at 9pm and that you won’t be answering texts after that time. Sure you will likely have to remind them, that’s what it means to enforce boundaries. Once you get good at setting and enforcing small boundaries, then you can move to larger ones like setting boundaries with co- workers, clients and family, etc.

2. Usa a mantra -Brené Brown, a research professor at University of Houston Graduate College of Social Work and author of the two #1 New York Times bestselling books The Gifts of Imperfection and Daring Greatly, uses the mantra “Choose discomfort over resentment” to remind herself to not be pulled into saying Yes when she really wants to say No.

3. Practice, practice, practice -Start saying aloud (alone or to others) what it is you want to say. The more you become comfortable setting and enforcing your boundaries, the easier it will be.

“That sounds interesting but I cannot make it” “No I’m not available.” “I wish I could go but I can’t. Thanks for asking though.” “No, my plate is already full.” “Thanks for the invite. My weekend plans are to be with my family so I won’t be able to attend.” “No I cannot work on that day, I already made plans.”

I highly recommend you check out Brené Brown’s video “Boundaries, Empathy & Compassion” www.theworkofthepeople.com/boundaries.

A key takeaway from the video is when she states, “Empathy minus boundaries is not empathy. Compassion minus boundaries is not genuine…” . She goes against the current belief that empathy can lead to burnout. Instead she feels that “empathy is not about feeling for someone but feeling with someone”. And in this way empathy actually can give back, tenfold.

Compassion fatigue has also been called empathy fatigue but I believe it is when we get lost in feeling for others (rather than with them) combined with not having clear boundaries that we make ourselves vulnerable and drastically increase our chances for compassion fatigue.

The most compassionate people are also the most boundaried.

Look for where in your life you are feeling angry, resentful, overwhelmed and/or frustrated. Chances are those are the areas you need to create and enforce some boundaries.

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